Indian Patents
Title of Invention

PROCESS FOR THE PREPARATION OF OPIOID MODULATORS
Abstract The present invention is directed to novel processes for the preparation of opioid modulators (agonists and antagonists) and intermediates in their synthesis. The opioid modulators are useful for the treatment and prevention of as pain and gastrointestinal disorders.
Full Text WO 2006/099060 PCT/US2006/008450
PROCESS FOR THE PREPARATION OF OPIOID MODULATORS
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U. S. Provisional Application
60/661,784, filed on March 14, 2005, which is incorporated by reference herein
in its entirety.
FIELD OF THE INVENTION
The present invention is directed to a novel process for the preparation
of opioid modulators (agonists and antagonists), and intermediates in their
synthesis. The opioid modulators are useful in the treatment and prevention of
such disorders as pain, visceral pain including post-operative pain,
gastrointestinal disorders including diarrheic syndromes, motility disorders
including post-operative ileus, constipation, irritable bowel syndrome and
inflammatory bowel disorders.
BACKGROUND OF THE INVENTION
The present invention is directed to the preparation of novel opioid
receptor modulators and intermediates in their synthesis. More specifically, the
present invention is directed to novel processes for the preparation of
compounds of formula (II)

wherein all variables are as hereinafter defined, disclosed in United
States Patent Application No. 11/079,647, filed March 15, 2004, and published
as US Patent Publication US-2005-0203143-A1, September 15, 2005, which is
hereby incorporated by reference in its entirety.
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Known methods for the preparation of the compounds of formula (II) and
compounds of formula (I), as herein defined, require the use of dimethyl-
tyrosine, which is expensive and thus not suitable for large scale synthesis.
Thus there remains a need for a process for the preparation of compounds of
formula (I) and compounds of formula (II) which is suitable for large scale
production.
SUMMARY OF THE INVENTION
The present invention is directed to a process for the preparation of
compounds of formula (I.)

wherein
is C6-10aryl or a heteroaryl selected from the group consisting of
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl,
benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl,
isoquinolinyl and quinazolinyl;
each R41P is independently selected from C1-6alkyl, C1-6alkoxy or fluoro;
RJ and RK are each independently selected from hydrogen or C1-4alkyl;
alternatively, RJ and RK are taken together with the nitrogen atom to which they
are bound to form a five to seven membered heterocyclyl;
Pg1 is a nitrogen protecting group;
comprising
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reacting a compound of formula (X), wherein XP is selected from OH,
CN, -CO2H, -C(O)-CI or-C(O)-OC1-4alkyl and wherein YP is selected from Br,
CI or I, to yield the corresponding compound of formula (XII);

reacting the compound of formula (XII) with a suitably substituted
compound of formula (XVIII); in the presence of palladium catalyst; in the
presence of an organic or inorganic base; in an organic solvent; at a
temperature greater than about room temperature; to yield the corresponding
compound of formula (XIX);

reacting the compound of formula (XIX) with hydrogen or a source of
hydrogen; in the presence of a catalyst; in a solvent; at a temperature greater
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than about room temperature; to yield the corresponding compound of formula
(XX);

reacting the compound of formula (XX) with an aqueous base; in an
organic solvent; to yield the corresponding compound of formula (I).
The present invention is further directed to a process for the preparation
of a compound of formula (I)

wherein
is C1-10aryl or a heteroaryl selected from the group consisting of
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl,
benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl,
isoquinolinyl and quinazolinyl;
each R41P is independently selected from C1-6alkyl, C1-6alkoxy or fluoro;
RJ and RK are each independently selected from hydrogen or C1-4alkyl;
alternatively, RJ and RK are taken together with the nitrogen atom to which they
are bound to form a five to seven membered heterocyclyl;
Pg1 is a nitrogen protecting group;
comprising
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reacting the compound of formula (XIX) with hydrogen or a source of
hydrogen; in the presence of a catalyst; in a solvent; at a temperature greater
than about room temperature; to yield the corresponding compound of formula
(XX);

reacting the compound of formula (XX) with an aqueous base; in an
organic solvent; to yield the corresponding compound of formula (I).
The present invention is further directed to a process for the preparation
of a compound of formula (la) (also known as, 4-(aminocarbonyl)-N-[(1,1-
dimethylethoxy)carbonyl]-2,6-dimethyl-L-phenylalanine)

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reacting a compound of formula (Xa), wherein XP is selected from OH,
CN, -CO2H, -C(O)-CI or -C(O)-OC1-4alkyl and wherein YP is selected from Br,
Cl or I, to yield the corresponding compound of formula (Xlla);

reacting the compound of formula (Xlla) with a suitably substituted
compound of formula (XVIIIa); in the presence of palladium catalyst; in the
presence of an organic or inorganic base; in an organic solvent; at a
temperature greater than about room temperature; to yield the corresponding
compound of formula (XIXa);

reacting compound of formula (XlXa) with hydrogen gas, at a pressure
sufficient to hydrogenate; in the presence of a suitable chiral catalyst; at a
temperature greater than about room temperature; in an organic solvent; to
yield the corresponding compound of formula (XXa);

reacting the compound of formula (XXa) with an aqueous base; in an
organic solvent; to yield the corresponding compound of formula (la).
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The present invention is further directed to a process for the preparation
of the compound of formula (la)

reacting compound of formula (XlXa) with hydrogen gas, at a pressure
sufficient to hydrogenate; in the presence of a suitable chiral catalyst; at a
temperature greater than about room temperature; in an organic solvent; to
yield the corresponding compound of formula (XXa);

reacting the compound of formula (XXa) with an aqueous base; in an
organic solvent; to yield the corresponding compound of formula (la).
The present invention is further directed to processes for the preparation
of compounds of formula (XIX)
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The present invention is further directed to processes for the preparation
of the compound of formula (XlXb)



The present invention is further directed to a process for the preparation
of compounds of formula (II)

is C1-10aryl or a heteroaryl selected from the group consisting of
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl,
benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl,
isoquinolinyl and quinazolinyl;
each R41P is independently selected from C1-6alkyl, C1-6alkoxy or fluoro;
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RJ and RK are each independently selected from hydrogen or C1-4alkyl;
alternatively, RJ and RK are taken together with the nitrogen atom to which they
are bound to form a five to seven membered heterocyclyl;
R1 is selected from the group consisting of hydrogen, C1-6alkyl,
cycloalkyl, heterocyclyl, aryl(C1-6)alkyl, and heteroaryl(C1-6)alkyl;
wherein when R1 is phenyl(C1-6)alkyl, phenyl is optionally fused to a
heterocyclyl or cycloalkyl;
wherein when R1 is C1-2alkyl, said C1-2alkyl is optionally substituted with
one to two substituents independently selected from the group
consisting of C1-6alkoxy, aryl, cycloalkyl, heterocyclyl, hydroxy, cyano,
amino, C1-6alkylamino, (C1-6alkyl)2amino, trifluoromethyl, and carboxy;
and further, wherein when R1 is C3-6alkyl, said C3-6alkyl is optionally
substituted with one to three substituents independently selected from
the group consisting of C1-6alkoxy, aryl, cycloalkyl, heterocyclyl, hydroxy,
cyano, amino, C1-6aikylamino, (C1-6alkyl)2amino, trifluoromethyl, and
carboxy;
wherein the cycloalkyl and heterocyclyl of C1-2alkyl and C3-6alkyl are
optionally substituted with one to two substituents independently
selected from the group consisting of C1-6alkyl, hydroxy(C1-6)alkyl, C-1-
6alkoxy, hydroxy, cyano, amino, C1-6alkylamino, (C1-6alkyl)2amino,
trifluoromethyl, carboxy, aryl(C1-6)alkoxycarbonyl, C1-6alkoxycarbonyl,
aminocarbonyl, C1-6alkylaminocarbonyl, (C1.6alkyl)2aminocarbonyl, and
aminosulfonyl;
furthermore, wherein the cycloalkyl and heterocyclyl of R1 are optionally
substituted with one to two substituents independently selected from the
group consisting of C1-6alkyl, hydroxy(C1-6)alkyl, C1-6alkoxy, hydroxy,
cyano, amino, C1-6alkylamino, (C1-6alkyl)2amino, trifluoromethyl, carboxy,
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aryl(C1-6)alkoxycarbonyl, C1-6alkoxycarbonyl, aminocarbonyl, C1-
6alkylaminocarbonyl, (C1-6alkyl)2aminocarbonyl, and aminosulfonyl;
furthermore, wherein the aryl and heteroaryl portion of the R1
substituents aryl(C1-6)alkyl and heteroaryl(C1-6)alkyl, are optionally
substituted with one to three R11 substituents independently selected
from the group consisting of C1-6alkyl; hydroxy(C1-6)alkyl; C1-6alkoxy; C6-
10aryl(C1-6)alkyl; C1-6oaryl(C1-6)alkoxy; C1-10aryl; heteroaryl optionally
substituted with one to two substituents independently selected from the
group consisting of C1-4alkyl, C1-4alkoxy, and carboxy; cycloalkyl;
heterocyclyl; C6-10oaryloxy; heteroaryloxy; cycloalkyloxy; heterocyclyloxy;
amino; C1-6alkylamino; (C1-6alkyl)2amino; C3-6cycloalkylaminocarbonyl;
hydroxy(C1-6)alkylaminocarbonyl; C1-10arylaminocarbonyl wherein C6-
10aryl is optionally substituted with carboxy or C1-4alkoxycarbonyl;
heterocyclylcarbonyl; carboxy; C1-6alkylcarbonyloxy; C1-6alkoxycarbonyl;
C1-6alkylcarbonyl; C1-6alkylcarbonylamino; aminocarbonyl; C1-
6alkylaminocarbonyl; (C1-6alkyl)2aminocarbonyl; cyanoaaaaa; halogen;
trifluoromethyl; trifluoromethoxy; and hydroxy;
provided that no more than one R11 substituent is selected from the
group consisting of C6-10aryl(C1-6)alkyl; C1-10aryl(C1-6)alkoxy; C6-10aryl;
heteroaryl optionally substituted with one to two substituents
independently selected from the group consisting of C1-4alkyl, C1-4alkoxy,
and carboxy; cycloalkyl; heterocyclyl; C6-10aryloxy; heteroaryloxy;
cycloalkyloxy; C6-10oarylaminocarbonyl, heterocyclylcarbonyl; and
heterocyclyloxy;
R2 is hydrogen, C1-8alkyl, hydroxy(C1-8)alkyl, C6-10aryl(C1-6)alkoxy(C1--
6)alkyl, orC6-10aryl(C1-8)alkyl;
wherein the C6-10aryl group in the C6-10aryl-containing substituents of R2
is optionally substituted with one to two substituents independently
selected from the group consisting of C1-6alkyl, C1-6alkoxy, hydroxy,
amino, C1-6alkylamino, (C1-6alkyl)2amino, aminocarbonyl, C1-
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6alkylaminocarbonyl, (C1-6alkyl)2aminocarbonyl, cyano, fluoro, chloro,
bromo, trifluoromethyl, and trifluoromethoxy; and, wherein the C1-6alkyl
and C1-6alkoxy substituents of aryl are optionally substituted with
hydroxy, amino, C1.6alkylamino, (C1-6alkyl)2amino, orC6-10aryl;
A is selected from the group consisting of aryl, ring system a-1, a-2, a-3,
and a-4, optionally substituted with R3and R5;

wherein A-B is selected from the group consisting of N-C, C-N, N-N and
C-C; wherein D-E is selected from the group consisting of O-C, S-C, and
O-N; and wherein F-G is selected from the group consisting of N-0 and
C-O;
R3 is one to two substituents independently selected from the group
consisting of C1-6alkyl, aryl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl,
heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl(C21-6)alkenyl, heteroaryl(C2-6)alkynyl,
amino, C1-6alkylamino, (C1-6alkyl)2amino, arylamino, heteroarylamino, aryloxy,
heteroaryloxy, trifluoromethyl, and halogen;
wherein the aryl, heteroaryl, and the aryl and heteroaryl of aryl(C1-6)alkyl,
aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, heteroaryl(C1-6)alkyl, heteroaryl(C2.
6)alkenyl, heteroaryl(C2-6)alkynyl, arylamino, heteroarylamino, aryloxy,
and heteroaryloxy, are optionally substituted with one to five fluoro
substituents or one to three substituents independently selected from the
group consisting of C1-6alkyl, hydroxy(C1-6)alkyl, C1-6alkoxy, C1-6oaryl(C1-
6)alkyl, C6-1oaryl(C1-6)alkoxy, C6.10aryl, C6-10aryloxy, heteroaryl(C1-6)alkyl,
heteroaryl(C1-6)alkoxy, heteroaryl, heteroaryloxy, C6-10arylamino,
heteroarylamino, amino, C1-6alkylamino, (C1-6alkyl)2amino, carboxy(C1-
6)alkylamino, carboxy, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-
6alkylcarbonylamino, aminocarbonyl, C1-6alkylaminocarbonyl, (C1-
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6alkyl)2aminocarbonyl, carboxy(C1-6)alkylaminocarbonyl, cyano, halogen,
trifluoromethyl, trifluoromethoxy, hydroxy, C1-6alkylsulfonyl, and C-1-
6alkylsulfonylamino; provided that not more than one such substituent on
aryl and heteroaryl portion of R3 is selected from the group consisting of
C6-10,aryl, heteroaryl, C6-10aryl(C1-6)alkyl. C6-10 aryl(C6-10)alkoxy,
aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, heteroaryl, heteroary(C6-10)alkyl,
heteroaryl(C2-6)alkoxy, C6-10arylamino, heteroarylamino, C6-10aryloxy,
and heteroaryloxy;
and wherein C1-6alkyl, and C1-6alkyl of aryl(C1-6)alkyl and heteroaryl(C1-
6)alkyl, are optionally substituted with a substituent selected from the
group consisting of hydroxy, carboxy, d1-4alkoxycarbonyl, amino, C1-
6alkylamino, (C1-6alkyl)2amino, aminocarbonyl, (C1-4)alkylaminocarbonyl,
di(C1-4)alkylaminocarbonyl, aryl, heteroaryl, arylamino, heteroarylamino,
aryloxy, heteroaryloxy, aryl(C1-4)alkoxy, and heteroaryl(C1-4)alkoxy;
R5 is a substituent on a nitrogen atom of ring A selected from the group
consisting of hydrogen and C1-4alkyl;
Ra and Rb are independently selected from the group consisting of
hydrogen, C1-6alkyl, and C1-6alkoxycarbonyl; alternatively, when Raand Rbare
each other than hydrogen, Ra and Rb are optionally taken together with the
nitrogen atom to which they are both attached to form a five to eight membered
monocyclic ring;
and pharmaceutically acceptable enantiomers, diastereomers,
racemates, and salts thereof;
comprising

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reacting a compound of formula (X), wherein Xp is selected from OH,
CN, -CO2H, -C(O)-CI or-C(O)-OC1-4alkyl and wherein Yp is selected from Br,
Cl or I, to yield the corresponding compound of formula (XII);

reacting the compound of formula (XII) with a suitably substituted
compound of formula (XVIII) wherein Pg1 is a nitrogen protecting group; in the
presence of palladium catalyst; in the presence of an organic or inorganic base;
in an organic solvent; at a temperature greater than about room temperature; to
yield the corresponding compound of formula (XIX);

reacting the compound of formula (XIX) with hydrogen or a source of
hydrogen; in the presence of a catalyst; in a solvent; at a temperature greater
than about room temperature; to yield the corresponding compound of formula
(XX);
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reacting the compound of formula (XX) with an aqueous base; in an
organic solvent; to yield the corresponding compound of formula (I);

reacting the compound of formula (I), to yield the corresponding
compound of formula (II).
In an embodiment, the present invention is directed to processes for the
preparation of the compound of formula (IV)
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also known as, 5-({[2-amino-3-(4-carbamoyl-2,5-dimethyl-phenyl)-
propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-
benzoic acid.
In an embodiment, the present invention is directed to processes for the
preparation of the compound of formula (V)

also known as, 5-[([2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-
propionyl]-{1-[4-(4-iodo-phenyl)-1H-imidazol-2-yl]-ethyl}-amino)-methyl]-2-
methoxy-benzoic acid.
The present invention is further directed to a product prepared according
to any of the processes described herein.
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Illustrative of the invention is a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and at a product prepared according to the
process described herein. An illustration of the invention is a pharmaceutical
composition made by mixing a product prepared according to the process
described herein and a pharmaceutically acceptable carrier. Illustrating the
invention is a process for making a pharmaceutical composition comprising
mixing a product prepared according to the process described herein and a
pharmaceutically acceptable carrier.
Exemplifying the invention are methods of treating or preventing a
disorder mediated by at least one opioid receptor, preferably the δ or μ opioid
receptor selected from the group consisting of pain and gastrointestinal
disorders, in a subject in need thereof comprising administering to the subject a
therapeutically effective amount of any of the compounds or pharmaceutical
compositions prepared as described above.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to processes for the preparation of
compounds of formula (I)
wherein Pg1, RJ, RK and R41P are as herein defined. The
compounds of formula (I) are useful in the preparation of opioid receptor
modulators - compounds of formula (II) as defined herein. The present
invention is further directed to processes for the preparation of the compound
of formula (la) as herein defined, useful as intermediates in the synthesis of
opioid receptor modulators.
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In an embodiment, the present invention is directed to processes for the
preparation of compounds wherein the ring is unsubstituted. In an
embodiment of the present invention, the ring is substituted with one
R41P group, which is bound at the 2- or 6-position. In another embodiment, the
present invention is directed to processes for the preparation of compounds
wherein the ring is substituted with two R41P groups, which are bound
at the 2- and 6-positions. For example, processes wherein is phenyl,
the compound of formula (I) is of the following structure:

In an embodiment, the present invention is directed to processes for the
preparation of compounds of formula (Ic)

wherein R41Q is selected from methyl, ethyl, methoxy, ethoxy or fluoro
and wherein RJ, RK and Pg1 are as herein defined.
In another embodiment, the present invention is directed to processes
for the preparation of the compound of formula (Ib)
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(i.e. a compound of formula (I) wherein is phenyl; RJ and RK are
each hydrogen; the phenyl ring is further substituted with two R41P groups,
which are each methyl and Pg1 is Boc), also known as 2-tert-
butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid.
In another embodiment, the present invention is directed to processes
for the preparation of the compound of formula (la)

The present invention is further directed to processes for the preparation
of compounds of formula (XIX)

In an embodiment, the present invention is directed to processes for the
preparation of the compound of formula (XlXb),
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Preferably, the present invention is directed to processes for the
preparation of the compound of formula (XlXa)

The compounds of formula (XIX) are useful as intermediates in the
synthesis of compounds of formula (II).
The present invention is further directed to processes for the preparation
of compound of formula (II)

wherein , RJ, RK, R41P, Ra, Rb, R1, R2, R3, R5, and areas
herein defined. The compounds of the present invention are opioid receptor
modulators, useful in the treatment of disorders mediated by at least one opioid
receptor (preferably δ or μ opioid receptor), including, but not limited to pain
and gastrointestinal disorders.
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Embodiments of the present invention include processes for the
preparation of compounds wherein R1 is selected from the group consisting of
hydrogen, C1-6alkyl, aryl(C1-4)alkyl, and heteroaryl(C1-4)alkyl; wherein the aryl
and heteroaryl portion of aryl(C1-4)alkyl and heteroaryl(C1-4)alkyl are optionally
substituted with one to three R11 substituents independently selected from the
group consisting of C1-6alkoxy; heteroaryl optionally substituted with one to two
substituents independently selected from the group consisting of C1-4alkyl, C1-
4alkoxy, and carboxy; carboxy; C1-4alkoxycarbonyl; C1-4alkoxycarbonyloxy;
aminocarbonyl; C1-4alkylaminocarbonyl; C3-6cycloalkylaminocarbonyl;
hydroxy(C1.6)alkylaminocarbonyl; C6-10arylaminocarbonyl wherein C6-10aryl is
optionally substituted with carboxy or C1-4alkoxycarbonyl; heterocyclylcarbonyl;
cyano; halogen; trifluoromethoxy; and hydroxy; provided that no more than one
R11 is heteroaryl (optionally substituted with one to two C1-4alkyl substituents);
C6-10arylaminocarbonyl wherein C6-10aryl is optionally substituted with carboxy
or C1-4alkoxycarbonyl; or heterocyclylcarbonyl.
Embodiments of the present invention further include processes for the
preparation of compounds wherein R1 is selected from the group consisting of
C6-10aryl(C1-4)alkyl, pyridinyl(C1-4)alkyl, and furanyl(C1-4)alkyl; wherein C6-10aryl,
pyridinyl, and furanyl are optionally substituted with one to three R11
substituents independently selected from the group consisting of C1-3alkoxy;
tetrazolyl; carboxy; C1-4alkoxycarbonyl; aminocarbonyl; C1-4alkylaminocarbonyl;
C3-6Cycloalkylaminocarbonyl; hydroxy(C1-4)alkylaminocarbonyl; C6-
10arylaminocarbonyl wherein C6-10aryl is optionally substituted with carboxy or
C1-4alkoxycarbonyl; morpholin-4-ylcarbonyl; cyano; halogen; and
trifluoromethoxy; provided that that no more than one R11 is C6-
10arylaminocarbonyl.
Embodiments of the present invention further include processes for the
preparation of compounds wherein R1 is selected from the group consisting of
phenyl(C1-3)alkyl, pyridinyKC1-3alkyl, and furanyl(C1-3)alkyl; wherein phenyl,
pyridinyl, and furanyl are optionally substituted with one to three R11
substituents independently selected from the group consisting of C1-3alkoxy;
tetrazolyl, C3.6cycloalkylaminocarbonyl; hydroxy(C1-4)alkylaminocarbonyl; C6-
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10arylaminocarbonyl wherein C6-10aryl is optionally substituted with carboxy or
C1.4alkoxycarbonyl; morpholin-4-ylcarbonyl; chloro; fluoro; trifluoromethoxy; C1-
4alkoxycarbonyl; and carboxy; provided that that no more than one R11is C6-
10arylaminocarbonyl.
Embodiments of the present invention further include processes for the
preparation of compounds wherein R1 is phenylmethyl, pyridinylmethyl, or
furanylmethyl; wherein phenyl, pyridinyl, and furanyl are optionally substituted
with one to three R11 substituents independently selected from the group
consisting of methoxy; tetrazolyl; cyclopropylaminocarbonyl; (2-hydroxyeth-1-
yl)aminocarbonyl; methoxycarbonyl; phenylaminocarbonyl wherein phenyl is
optionally substituted with carboxy; morpholin-4-ylcarbonyl; and carboxy;
provided that that no more than one R11 is phenylaminocarbonyl.
Embodiments of the present invention include processes for the
preparation of compounds wherein R2 is a substituent selected from the group
consisting of hydrogen, C1-4alkyl, hydroxy(C1.4)alkyl, and phenyl(C1-6)alkoxy(C1.
4)alkyl; wherein said phenyl is optionally substituted with one to two
substituents independently selected from the group consisting of C1-3alkyl, C1-
3alkoxy, hydroxy, cyano, fluoro, chloro, bromo, trifluoromethyl, and
trifluoromethoxy.
Embodiments of the present invention further include processes for the
preparation of compounds wherein R2 is selected from the group consisting of
hydrogen and C-1-4alkyl. Embodiments of the present invention further include
processes for the preparation of those compounds wherein R2 is hydrogen or
methyl.
Embodiments of the present invention include processes for the
preparation of compounds wherein ring A is a-1. Embodiments of the present
invention further include processes for the preparation of compounds wherein
A-B of ring a-1 is N-C.
Embodiments of the present invention include processes for the
preparation of compounds wherein R3 is one to two substituents independently
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selected from the group consisting of C1-6alkyl, halogen, and aryl; wherein aryl
is optionally substituted with one to three substituents independently selected
from the group consisting of halogen, carboxy, aminocarbonyl, C1-
3alkylsulfonylamino, cyano, hydroxy, amino, C1.3alkylamino, and (C1-
3alkyl)2amino.
Embodiments of the present invention further include processes for the
preparation of compounds wherein R3 is one to two substituents independently
selected from the group consisting of C1-3alkyl, bromo, and phenyl; wherein
phenyl is optionally substituted with one to three substituents independently
selected from the group consisting of chloro, fluoro, carboxy, aminocarbonyl,
and cyano.
Embodiments of the present invention further include processes for the
preparation of compounds wherein R3 is one to two substituents independently
selected from the group consisting of methyl and phenyl; wherein phenyl is
optionally substituted with one to three substituents independently selected
from the group consisting of chloro and carboxy.
Embodiments of the present invention further include processes for the
preparation of compounds wherein at least one R3 substituent is phenyl.
Embodiments of the present invention further include processes for the
preparation of compounds wherein R3 is a substituent selected from the group
consisting of methyl and phenyl; wherein phenyl is optionally substituted with
one to two substituents independently selected from the group consisting of
chloro and carboxy.
Embodiments of the present invention include processes for the
I
preparation of compounds wherein is C6.-ioaryl. Embodiments of the
present invention further include processes for the preparation of compounds
wherein is phenyl.
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Embodiments of the present invention include processes for the
preparation of compounds wherein R41P is selected from C1-3alkyl, C1-6alkoxy or
fluoro. Embodiments of the present invention further include processes for the
preparation of compounds wherein R41P is selected from C1-3alkyl or C1-3alkoxy.
Embodiments of the present invention further include processes for the
preparation of compounds wherein R41P is selected from methyl, ethyl,
methoxy, ethoxy or fluoro. Embodiments of the present invention further
include processes for the preparation of compounds wherein R41P is selected
from methyl or methoxy.
Embodiments of the present invention include processes for the
preparation of compounds wherein R5 is hydrogen or methyl. Embodiments of
the present invention further include processes for the preparation of
compounds wherein R5 is hydrogen.
Embodiments of the present invention include processes for the
preparation of compounds wherein Raand Rb are independently selected from
the group consisting of hydrogen and C1-3alkyl; or, when Raand Rbare each
other than hydrogen, Ra and Rb are optionally taken together with the nitrogen
atom to which they are both attached to form a five to seven membered
monocyclic ring. Embodiments of the present invention further include
processes for the preparation of compounds wherein Ra and Rb are
independently hydrogen or methyl. Embodiments of the present invention
further include processes for the preparation of compounds wherein Ra and Rb
are each hydrogen.
Embodiments of the present invention include processes for the
preparation of compounds of formula (I) wherein the stereo-center denoted with
a "*"as shown below,
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WO 2006/099060 PCT/US2006/008450

is in the S-configuration. In another embodiment are processes for the
preparation of compounds of formula (I) wherein the stereo-center denoted with
a "*" on the compound of formula (I) is in the R-configuration.
Embodiments of the present invention include processes for the
preparation of compounds of formula (II) that are present in their RR, SS, RS,
or SR configuration. Embodiments of the present invention further include
processes for the preparation of compounds of formula (II) that are present in
their S,S configuration.
Embodiments of the present invention include processes for the
preparation of compounds of formula (lie)

wherein:
R1 is selected from the group consisting of hydrogen, C1-6alkyl, aryl(C1-
4)alkyl, and heteroaryl(C1-4)alkyl;
wherein the aryl and heteroaryl portion of aryl(C1-4)alkyl and
heteroaryl(C1-4)alkyl are optionally substituted with one to three R11
substituents independently selected from the group consisting of C1-
6alkoxy; heteroaryl optionally substituted with one to two substituents
independently selected from the group consisting of C1-4alkyl, C1-4alkoxy,
and carboxy; carboxy; C1-4alkoxycarbonyloxy; C1-4alkoxycarbonyl;
24

WO 2006/099060 PCT/US2006/008450
aminocarbonyl; C1-4alkylaminocarbonyl; C3.6cycloalkylaminocarbonyl;
hydroxy(C1-6)alkylaminocarbonyl; C6-10arylaminocarbonyl wherein C6.
10aryl is optionally substituted with carboxy or C1-4alkoxycarbony[;
heterocyclylcarbonyl; cyano; halogen; trifluoromethoxy; and hydroxy;
provided that no more than one R11 is heteroaryl (optionally substituted
with one to two C1-4alkyI substituents); C6-ioarylaminocarbonyl wherein
C6-10aryl is optionally substituted with carboxy or C1-4alkoxycarbonyl; or
heterocyclylcarbonyl;
R2 is selected from the group consisting of hydrogen, C1-4alkyl,
hydroxy(C1-4)alkyl, and phenyl(C1-6)alkoxy(C1.4)alkyl;
wherein said phenyl is optionally substituted with one to two substituents
independently selected from the group consisting of C1-3alkyl, C1-3alkoxy,
hydroxy, cyano, fluorine, chlorine, bromine, trifluoromethyl, and
trifluoromethoxy;
R3 is one to two substituents independently selected from the group
consisting of Chalkyl, halogen, and aryl; wherein aryl is optionally substituted
with one to three substituents independently selected from the group consisting
of halogen, carboxy, aminocarbonyl, C1.3alkylsulfonylamino, cyano, hydroxy,
amino, C1-3alkylamino, and (C1-3alkyl)2amino;
R5 is hydrogen or methyl;
Raand Rb are independently hydrogen or C1-3alkyl; or, when Raand Rb
are each other than hydrogen, Raand Rb are optionally taken together with the
nitrogen atom to which they are both attached to form a five to seven
membered monocyclic ring;
is C6-10aryl;
R41P is selected from C1-3alkyl, C1-6alkoxy or fluoro;
RJ and RK are each independently selected from hydrogen or C1-4alkyl;
alternatively, RJ and RK are taken together with the nitrogen atom to which they
are bound to form a five to seven membered heterocyclyl;
25

WO 2006/099060 PCT/US2006/008450
and pharmaceutically acceptable enantiomers, diastereomers,
racemates, and salts thereof.
Embodiments of the present invention further include processes for the
preparation of compounds of formula (Me) wherein
R1 is selected from the group consisting of C6-10aryl(C1-4)alkyl,
pyridinyl(C1-4)alkyl, and furanyl(C1-4)alkyl; wherein C6-10aryl, pyridinyl, and
furanyl are optionally substituted with one to three R11 substituents
independently selected from the group consisting of C1-3alkoxy; tetrazolyl;
carboxy; C1-3alkoxycarbonyl; aminocarbonyl; C1-4alkylaminocarbonyl; C1-
3alkylaminocarbonyl; C3-6cycloalkylaminocarbonyl; hydroxy(C1-
4)alkylaminocarbonyl; C6-10arylaminocarbonyl wherein C6-10aryl is optionally
substituted with carboxy or C1-4alkoxycarbonyl; morpholin-4-ylcarbonyl; cyano;
halogen; and trifluoromethoxy; provided that no more than one R11 is C6.
10arylaminocarbonyl;
R2 is hydrogen or C1.4alkyl;
R3 is one to two substituents independently selected from the group
consisting of C1-3alkyl, bromo, and phenyl; wherein phenyl is optionally
substituted with one to three substituents independently selected from the
group consisting of chloro, fluoro, carboxy, aminocarbonyl, and cyano;
R5 is hydrogen;
Ra and Rb are independently hydrogen or methyl;
is C6-10aryl;
R41P is selected from C1-3alkyl or C1-6alkoxy;
RJ and RK are each independently selected from hydrogen or C1-4alkyl;
and pharmaceutically acceptable enantiomers, diastereomers,
racemates, and salts thereof.
Embodiments of the present invention further include processes for the
preparation of compounds of formula (lie) wherein
R1 is selected from the group consisting of phenyl(C1-4)alkyl, pyridinyl(C1-
3)alkyl, and furanyl(C1-3)alkyl; wherein phenyl, pyridinyl, and furanyl are
26

WO 2006/099060 PCT/US2006/008450
optionally substituted with one to three R11 substituents independently selected
from the group consisting of C1-3alkoxy; tetrazolyl, C3.6cycloalkylaminocarbonyl;
hydroxy(C1-4)alkylaminocarbonyl; C6-10arylaminocarbonyl wherein C6-10aryl is
optionally substituted with carboxy or C1-4alkoxycarbonyl; morpholin-4-
ylcarbonyl; chloro; fluoro; trifluoromethoxy; and carboxy;
R2 is hydrogen or methyl;
R3 is one to two substituents independently selected from the group
consisting of methyl and phenyl; wherein phenyl is optionally substituted with
one to three substituents independently selected from the group consisting of
chloro and carboxy;
R5 is hydrogen;
Raand Rb are each hydrogen;
is phenyl;
R41P is selected from methyl, ethyl, methoxy, ethoxy or fluoro.
RJ and RK are each independently selected from hydrogen or C1-3alkyl;
and pharmaceutically acceptable enantiomers, diastereomers,
racemates, and salts thereof.
Additional embodiments of the present invention, include processes for
the preparation of compounds wherein the substituents for one or more of the
variables defined herein (i.e. , RJ, RK, R41P, Pg\ etc.) are independently
selected to be any individual substituent or any subset of substituents selected
from the complete list as defined herein.
As used herein, unless otherwise noted, "alkyl" whether used alone or
as part of a substituent group refers to straight and branched carbon chains
having 1 to 8 carbon atoms or any number within this range. The term
"alkoxy" refers to an -Oalkyl substituent group, wherein alkyl is as defined
supra. Similarly, the terms "alkenyl" and "alkynyl" refer to straight and
27

WO 2006/099060 PCT/US2006/008450
branched carbon chains having 2 to 8 carbon atoms or any number within this
range, wherein an alkenyl chain has at least one double bond in the chain and
an alkynyl chain has at least one triple bond in the chain. An alkyl and alkoxy
chain may be substituted on a carbon atom. In substituent groups with multiple
alkyl groups such as (C1-6alkyl)2amino- the C1-6alkyl groups of the dialkylamino
may be the same or different.
The term "cycloalkyl" refers to saturated or partially unsaturated,
moncyclic or polycyclic hydrocarbon rings of from 3 to 14 carbon atom members.
Examples of such rings include, and are not limited to cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and adamantyl. Alternatively, the cycloalkyl
ring may be fused to a benzene ring (benzo fused cycloalkyl), a 5 or 6 membered
heteroaryl ring (containing one of O, S or N and, optionally, one additional
nitrogen) to form a heteroaryl fused cycloalkyl.
The term "heterocyclyl" refers to a nonaromatic cyclic ring of 5 to 7
members in which 1 to 2 members are nitrogen, or a nonaromatic cyclic ring of 5
to 7 members in which zero, one or two members are nitrogen and up to two
members are oxygen or sulfur; wherein, optionally, the ring contains zero to one
unsaturated bonds, and, optionally, when the ring is of 6 or 7 members, it
contains up to two unsaturated bonds. The term heterocyclyl includes 5 to 7
membered monocycle wherein the heterocyclyl may be fused to a benzene ring
(benzo fused heterocyclyl), a 5 or 6 membered heteroaryl ring (containing one of
O, S or N and, optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl
or cycloalkenyl ring, a 5 to 7 membered heterocyclyl ring (of the same definition
as above but absent the option of a further fused ring) or fused with the carbon of
attachment of a cycloalkyl, cycloalkenyl or heterocyclyl ring to form a spiro moiety.
For instant compounds of the invention, the carbon atom ring members that form
the heterocyclyl ring are fully saturated. Other compounds of the invention may
have a partially saturated heterocyclyl ring. The term heterocyclyl include a 5 to 7
membered moncyclic ring bridged to form bicyclic rings. Such compounds are
not considered to be fully aromatic and are not referred to as heteroaryl
compounds. Examples of heterocyclyl groups include, and are not limited to,
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WO 2006/099060 PCT/US2006/008450
pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl,
2-imidazolinyI, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl and piperazinyl.
The term "aryl" refers to an unsaturated, aromatic monocyclic ring of 6
carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14
carbon members. Examples of such aryl rings include, and are not limited to,
phenyl, naphthalenyl or anthracenyl. Preferred aryl groups for the practice of this
invention are phenyl and naphthalenyl.
The term "heteroaryl" refers to an aromatic ring of 5 or 6 members
wherein the ring consists of carbon atoms and has at least one heteroatom
member. Suitable heteroatoms include nitrogen, oxygen or sulfur. In the case
of 5 membered rings, the heteroaryl ring contains one member of nitrogen,
oxygen or sulfur and, in addition, may contain up to three additional nitrogens.
In the case of 6 membered rings, the heteroaryl ring may contain from one to
three nitrogen atoms. For the case wherein the 6 membered ring has three
nitrogens, at most two nitrogen atoms are adjacent. Optionally, the heteroaryl
ring is fused to a benzene ring (benzo fused heteroaryl), a 5 or 6 membered
heteroaryl ring (containing one of O, S or N and, optionally, one additional
nitrogen), a 5 to 7 membered cycloalkyl ring or a 5 to 7 membered heterocyclo
ring (as defined supra but absent the option of a further fused ring). Examples of
heteroaryl groups include, and are not limited to, furyl, thienyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl; fused heteroaryl groups
include indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl, indazolyl,
benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl,
benzotriazolyl, quinolizinyl, quinolinyl, isoquinolinyl or quinazolinyl.
The term "arylalkyl" means an alkyl group substituted with an aryl group
(e.g., benzyl, phenethyl). Similarly, the term "arylalkoxy" indicates an alkoxy
group substituted with an aryl group (e.g., benzyloxy).
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WO 2006/099060 PCT/US2006/008450
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
Substituents that are substituted with multiple halogens are substituted in a
manner that provides compounds, which are stable.
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in
a name of a substituent (e.g., arylalkyl, alkylamino) it shall be interpreted as
including those limitations given above for "alkyl" and "aryl." Designated
numbers of carbon atoms (e.g., C1-C6) shall refer independently to the number
of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent
in which alkyl appears as its prefix root. For alkyl, and alkoxy substituents the
designated number of carbon atoms includes all of the independent members
included in the range specified individually and all the combination of ranges
within in the range specified. For example C1-6 alkyl would include methyl,
ethyl, propyl, butyl, pentyl and hexyl individually as well as sub-combinations
thereof (e.g. C1-2, C1-3, C1-4, C1-5, C2-6, C3-6, C4-6, C5-6, C2-5, etc.).
Where the compounds according to this invention have at least one
chiral center, they may accordingly exist as enantiomers. Where the
compounds possess two or more chiral centers, they may additionally exist as
diastereomers. It is to be understood that all such isomers and mixtures
thereof are encompassed within the scope of the present invention.
Furthermore, some of the crystalline forms for the compounds may exist as
polymorphs and as such are intended to be included in the present invention.
In addition, some of the compounds may form solvates with water (i.e.,
hydrates) or common organic solvents, and such solvates are also intended to
be encompassed within the scope of this invention.
An "independently" selected substituent refers to a group of
substituents, wherein the substituents may be different. Therefore, designated
numbers of carbon atoms (e.g. C1-8) shall refer independently to the number of
carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger
substituent in which alkyl appears as its prefix root.
30

WO 2006/099060 PCT/US2006/008450
Under standard nomenclature used throughout this disclosure, the terminal
portion of the designated side chain is described first, followed by the adjacent
functionality toward the point of attachment. Thus, for example, a "phenyl-(Cr
6alkyl)amino-carbonyl-(C1-6alkyl)" substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes and
Examples, are as follows:

Ac Acetyl group (-C(O)-CH3)
Ac2O = Acetic anhydride
Cbz or CBZ Benzyloxy-carbonyl-
Cpd Compound
DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene
DCM = Dichloromethane
DIPEAorDlEA = Diisopropylethylamine
DMF = N,N-Dirnethylformamide
DPPE = 1,2-Bis(diphenylphosphino)ethane
DPPF 1,1'-Bis(diphenylphosphino)ferrocene
DPPP = 1,3-Bis(diphenylphosphino)propane
EDCI or EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
Et2O Diethyl ether
EtOAc = Ethyl acetate
Fmoc 9-fluorenyl-methoxy-carbonyl-
HOAc = Acetic acid
HOBT = 1 -Hydroxybenzotriazole
Me Methyl
MeOH Methanol
MeO = Methoxy
MTBE Methyl-terf-butyl ether
31

WO 2006/099060 PC 17US2006/008450

NaBH(OAc)3 = Sodium triacetoxybrohydride
Pd-C = Palladium on Carbon Catalyst
Pd2(OAc)2 = Palladium(ll)acetate
Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(0)
Pd(PPh3)4 Tetrakis(triphenylphosphine)pa!ladium (0)
Ph Phenyl
P(Ph)3 Triphenylphosphine
PyBop Benzotriazol-1 -yloxy-
tris(pyrrolidino)phosphonium
hexafluorophosphate
PyBrop Bromotri(pyrrolidino)phsophonium
hexafluorophosphate
[Rh(cod)(R,R-
DIPAMP)]+BF4- (R,R)-(-)-Bis[(o-
methoxyphenyl)(phenyl)phosphino]ethane(1,5-
cyclo-octadiene)rhodium (I) tetrafluoroborate
rtorRT = Room temperature
t-BOC or Boc tert-Butoxycarbonyl
TEA Triethylamine
Tf Trifluoromethyl-sulfonyl- (-SO2-CF3)
TFA Trifluoroacetic acid
THF = Tetrahydrofuran
Tyr Tyrosine
As used herein, the term "pain" shall include centrally mediated pain,
peripherally mediated pain, structural or soft tissue injury related pain, pain
related to inflammation, progressive disease related pain, neuropathic pain,
acute pain and chronic pain. Further, the term "chronic pain" shall include
neuropathic pain conditions, diabetic peripheral neuropathy, post-herpetic
neuralgia, trigeminal neuralgia, post-stroke pain syndromes and cluster or
migraine headaches.
As used herein, the term "gastrointestinal disorder" shall include
diarrheic syndromes, motility disorders such as diarrhea-predominant,
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WO 2006/099060 PCT/US2006/008450
constipation-predominant, alternating irritable bowel syndrome, post-operative
ileus and constipation, and inflammatory bowel disease. Further, the term
"inflammatory bowel disease" shall include ulcerative colitis and Crohn's
disease.
The term "subject" as used herein, refers to an animal, preferably a
mammal, most preferably a human, who has been the object of treatment,
observation or experiment.
The term "therapeutically effective amount" as used herein, means that
amount of active compound or pharmaceutical agent that elicits the biological or
medicinal response in a tissue system, animal or human that is being sought by a
researcher, veterinarian, medical doctor or other clinician, which includes
alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified amounts, as well
as any product which results, directly or indirectly, from combinations of the
specified ingredients in the specified amounts.
To provide a more concise description, some of the quantitative
expressions given herein are not qualified with the term "about". It is
understood that whether the term "about" is used explicitly or not, every
quantity given herein is meant to refer to the actual given value, and it is also
meant to refer to the approximation to such given value that would reasonably
be inferred based on the ordinary skill in the art, including approximations due
to the experimental and/or measurement conditions for such given value.
As used herein, unless otherwise noted, the term "aprotic solvent" shall
mean any solvent that does not yield a proton. Suitable examples include, but
are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane,
dichloromethane, MTBE, toluene, and the like.
33

WO 2006/099060 PCT/US2006/008450
One skilled in the art will recognize that wherein a reaction step of the
present invention may be carried out in a variety of solvents or solvent systems,
said reaction step may also be carried out in a mixture of the suitable solvents
or solvent systems.
Where the processes for the preparation of the compounds according to
the invention give rise to mixture of stereoisomers, these isomers may be
separated by conventional techniques such as preparative chromatography.
The compounds may be prepared in racemic form, or individual enantiomers
may be prepared either by enantiospecific synthesis or by resolution. The
compounds may, for example, be resolved into their component enantiomers
by standard techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid
and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and
regeneration of the free base. The compounds may also be resolved by
formation of diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the compounds
may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the
present invention, it may be necessary and/or desirable to protect sensitive or
reactive groups on any of the molecules concerned. This may be achieved by
means of conventional protecting groups, such as those described in Protective
Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and
T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John
Wiley & Sons, 1991. The protecting groups may be removed at a convenient
subsequent stage using methods known from the art.
As used herein, unless otherwise noted, the term "nitrogen protecting
group" shall mean a group which may be attached to a nitrogen atom to
protect said nitrogen atom from participating in a reaction and which may be
readily removed following the reaction. Suitable nitrogen protecting groups
include, but are not limited to carbamates - groups of the formula -C(O)O-R
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WO 2006/099060 PCT/US2006/008450
wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH2=CH-
CH2-, and the like; amides - groups of the formula -C(O)-R' wherein R' is for
example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives -
groups of the formula -SO2-R" wherein R" is for example tolyl, phenyl,
trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-
methoxybenzene, and the like. Other suitable nitrogen protecting groups may
be found in texts such as T.W. Greene & P.G.M. Wuts, Protective Groups in
Organic Synthesis, John Wiley & Sons, 1991.
For use in medicine, the salts of the compounds of this invention refer to
nontoxic pharmaceutically acceptable salts.
The present invention is directed to processes for the preparation of
compounds of formula (I) as outlined in Scheme 1 below.
STEP 1: Preparation of Compounds of Formula (XII), wherein X is -OH and Y is
selected from Br or Cl
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WO 2006/099060 PCT/US2006/008450
A
or
STEP 1: Preparation of Compounds of Formula (XII), wherein X is -OC(O)-C1.
4alkyl and Y is selected from Br, Cl or I
36

WO 2006/099060 PCT/US2006/008450

or

37
STEP 1: Preparation of Compounds of Formula (XII), wherein X is -CN and Y is
selected from Br, Cl or I

WO 2006/099060 PCT/US2006/008450
STEP 2: Preparation of Compound of Formula (XIX)

STEP 3: Preparation of Compounds of Formula (XX)

STEP 4: Preparation of Compounds of Formula (I)

Scheme 1
STEP 1: Wherein X is OH and Y is selected from Br or Cl
Accordingly, a suitably substituted compound of formula (X), wherein Xp
is OH and wherein Yp is Br or Cl, preferably Yp is Br, a known compound or
compound prepared by known methods; is reacted with a triflating reagent such
as triflic anhydride, N-phenyltrifluoromethanesulfonimide, and the like; in the
presence of an organic or inorganic base such as pyridine, TEA, DIPEA,
K3PO4, K2CO3, and the like; optionally in an organic solvent such as DCM,
chloroform, THF, and the like; to yield the corresponding compound of formula
(XI).
38

WO 2006/099060 PCT/US2006/008450
The compound of formula (XI) is reacted with carbon monoxide or a
source of carbon monoxide such as Ac2O in combination with HCOONa (see
for example, S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett. (2003), 5(23),
pp4269-4272) and a suitably substituted amine, a compound of formula NRJRK
(a compound of formula (XIV)) or when RJ and RK are each hydrogen, with a
suitable source of ammonia such as HMDS, ammonia gas, and the like; in the
presence of a palladium catalyst such PdCI2, Pd2(OAc)2, and the like, in
combination with a suitable ligand, such DPPP, DPPF, P(Ph)3, and the like; or
in the presence of a palladiunrligand complex such as Pd(PPh3)4, and the like;
in an organic solvent such as DMF, THF, dioxane, and the like, preferably
DMF; at a temperature in the range of from about 50°C to about 160°C,
preferably at a temperature in the range of from about 60°C to about 120°C; to
yield the corresponding compound of formula (XII).
Alternatively, the compound of formula (XI) is reacted with carbon
monoxide or a source of carbon monoxide such as Ac2O in combination with
HCOONa (see for example, S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett.
(2003), 5(23), pp4269-4272); in the presence of an inorganic base such as
K2CO3, Na2CO3, and the like, in an organic solvent such as DMF, dioxane,
THF, and the like; at a temperature in the range of from about 50°C to about
160°C, preferably at a temperature in the range of from about 60°C to about
80°C; to yield the corresponding compound of formula (XIII).
The compound of formula (XIII) is reacted with a suitably substituted
compound of formula (XIV), a known compound or compound prepared by
known methods, or when RJ and RK are each hydrogen, with a suitable source
of ammonia such as HMDS, ammonia gas, and the like, preferably HMDS; in
the presence of a coupling agent such as EDCI, HOBT, PyBop, PyBrop, and
the like; preferably in the presence of an organic base such as TEA, DIPEA,
pyridine, the like, or an amount of the compound of formula (XIV) or source of
ammonia sufficient to act as the base, preferably greater than about 2
equivalents; in an organic solvent such as THF, dioxane, DMF, and the like; to
yield the corresponding compound of formula (XII).
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WO 2006/099060 PCT/US2006/008450
Alternatively, the compound of formula (XI) is reacted with carbon
monoxide or a source of carbon monoxide such as AC2O in combination with
HCOONa (see for example, S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett.
(2003), 5(23), pp4269-4272); in the presence of an inorganic base such as
K2CO3, Na2CO3, and the like, in an organic solvent such as DMF, dioxane,
THF, and the like; at a temperature in the range of from about 50°C to about
160°C, preferably at a temperature in the range of from about 60cC to about
80°C; to yield the corresponding compound of formula (XIII).
The compound of formula (XIII) is reacted with a suitably source of
chlorine such as thionyl chloride, PCI3, PCI5, oxalyl chloride, oxalyl chloride in
DMF, and the like; in an organic solvent such as DCM, chloroform, and the like,
preferably at a temperature greater than about room temperature, more
preferably at a temperature in the range of about 35°C to about 60°C; to yield
the corresponding compound of formula (XV).
The compound of formula (XV) is reacted with a suitably substituted
compound of formula (XIV), a known compound or compound prepared by
known methods, or when RJ and RK are each hydrogen, with a suitable source
of ammonia such as ammonium chloride, NH4OH, HMDS, ammonia gas, and
the like, preferably ammonium chloride; preferably in the presence of an
organic base such as TEA, DIPEA, pyridine, the like, or an amount of the
compound of formula (XIV) or source of ammonia sufficient to act as the base,
preferably greater than about 2 equivalents; in an organic solvent such as THF,
dioxane, DMF, and the like; to yield the corresponding compound of formula
(XII).
Alternatively, the compound of formula (XIII) is reacted with C1-4alkyl-
chloroformate, preferably, methylchloroformate; in the presence of a organic
base such as TEA, DIPEA, pyridine and the like; preferably at a temperature
less than about room temperature, more preferably at a temperature in the
range of from about 0°C; in an organic solvent such as DMF, DCM, chloroform,
THF, and the like; to yield the corresponding compound of formula (XVI)
wherein A1 is the corresponding C1-4alkyl, preferably methyl.
40

WO 2006/099060 PCT/US2006/008450
The compound of formula (XVI) is reacted with a suitably substituted
compound of formula (XIV) or when RJ and RK are each hydrogen, with a
suitable source of ammonia such as NH4OH, HMDS, ammonia gas, and the
like, preferably NH4OH; in the presence of a palladium catalyst such PdCI2,
Pd2(OAc)2, and the like, in combination with a suitable ligand, such DPPP,
DPPF, P(Ph)3, and the like; or in the presence of a palladium:ligand complex
such as Pd(PPh3)4, and the like; at a temperature in the range of from about
50°C to about 160°C, preferably at a temperature in the range of from about
60°C to about 80°C; to yield the corresponding compound of formula (XII).
One skilled in the art will further recognize that the compound of formula
(XI) may be reacted according to known methods, to yield the corresponding
compound of formula (X) wherein Xp is -C(O)-OC1-4alkyl or CN.
STEP 1: Wherein X is -C(0)-0C1-4alkyl and wherein Yp is Br, Cl or I
Alternatively, a suitably substituted compound of formula (X), wherein Xp
is -C(O)-OC1-4alkyl and wherein Yp is selected from Br, Cl or I, a known
compound or compound prepared by known methods, is reacted with a suitably
substituted compound of formula (XIV), a known compound or compound
prepared by known methods, or when RJ and RK are each hydrogen, with a
suitable source of ammonia such as NH4OH, HMDS, ammonia gas, and the
like; at a temperature greater than room temperature, preferably at about reflux
temperature; to yield the corresponding compound of formula (XII).
Alternatively, a suitably substituted compound of formula (X), wherein Xp
is -C(O)-OC1-4alkyl and wherein Yp is selected from Br, Cl or I, a known
compound or compound prepared by known methods, is reacted with a suitably
substituted compound of formula (XIV), a known compound or compound
prepared by known methods, or when RJ and RK are each hydrogen, with a
suitable source of ammonia such as NH4OH, HMDS, ammonia gas, and the
like; in the presence of an activating agent such as trimethylaluminum,
triisopropylaluminum, and the like; in an aprotic organic solvent such as THF,
dioxane, toluene, DCM, and the like; preferably at a temperature in the range of
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about 0°C to about reflux temperature; to yield the corresponding compound of
formula (XII).
Alternatively, a suitably substituted compound of formula (X), wherein Xp
is -C(O)-OC1-4alkyl and wherein Yp is selected from Br, Cl or I, a known
compound or compound prepared by known methods, is hydrolyzed according
to known methods, for example by reacting with a base such as NaOH, LiOH,
KOH, and the like, or by reacting with an acid such as HCI, H2SO4, and the like;
preferably, the compound of formula (X) is reacted with an acid at a
temperature greater than about room temperature, preferably at a temperature
in the range of from about 60° to about 120°C, more preferably at a
temperature of about 100°C; to yield the corresponding compound of formula
(XIII).
The compound of formula (XIII) is reacted with a suitably substituted
compound of formula (XIV), a known compound or compound prepared by
known methods, or when RJ and RK are each hydrogen, with a suitable source
of ammonia such as HMDS, ammonia gas, and the like, preferably HMDS; in
the presence of a coupling agent such as EDCI, HOBT, PyBop, PyBrop, and
the like; preferably in the presence of an organic base such as TEA, DIPEA,
pyridine, the like, or in the presence of an amount of the compound of formula
(XIV) or source of ammonia sufficient to act as the base, preferably greater
than about 2 equivalents; in an organic solvent such as THF, dioxane, DMF,
and the like, to yield the corresponding compound of formula (XII).
Alternatively, the compound of formula (X), wherein Xp is -C(O)-OC1.
4alkyl and wherein Yp is selected from Br, Cl or I, a known compound or
compound prepared by known methods, is reacted with carbon monoxide or a
source of carbon monoxide such as AC2O in combination with HCOONa (see
for example, S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett. (2003), 5(23),
pp4269-4272); in the presence of an inorganic base such as K2CO3, Na2CO3,
and the like, in an organic solvent such as DMF, dioxane, THF, and the like; at
a temperature in the range of from about 50°C to about 160°C, preferably at a
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temperature in the range of from about 60°C to about 80°C; to yield the
corresponding compound of formula (XIII).
The compound of formula (XIII) is reacted with a suitably source of
chlorine such as thionyl chloride, PCI3, PCI5, oxalyl chloride, oxalyl chloride in
DMF, and the like; in an organic solvent such as DCM, chloroform, and the like,
preferably at a temperature greater than about room temperature, more
preferably at a temperature in the range of about 35°C to about 60°C, to yield
the corresponding compound of formula (XV).
The compound of formula (XV) is reacted with a suitably substituted
compound of formula (XIV), a known compound or compound prepared by
known methods, or when RJ and RK are each hydrogen, with a suitable source
of ammonia such as ammonium chloride, NH4OH, HMDS, ammonia gas, and
the like, preferably ammonium chloride; preferably in the presence of an
organic base such as TEA, DIPEA, pyridine, the like, or in the presence of an
amount of the compound of formula (XIV) or source of ammonia sufficient to
act as the base, preferably greater than about 2 equivalents; in an organic
solvent such as THF, dioxane, DMF, and the like; to yield the corresponding
compound of formula (XII).
Alternatively, the compound of formula (X), wherein Xp is -C(O)-OC1-
4alkyl and wherein Yp is selected from Br, Cl or I, a known compound or
compound prepared by known methods, is reacted with carbon monoxide or a
source of carbon monoxide such as Ac2O in combination with HCOONa (see
for example, S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett. (2003), 5(23),
pp4269-4272); in the presence of an inorganic base such as K2CO3, Na2CO3,
and the like, in an organic solvent such as DMF, dioxane, THF, and the like; at
a temperature in the range of from about 50°C to about 160°C, preferably at a
temperature in the range of from about 60°C to about 80°C; to yield the
corresponding compound of formula (XIII).
Alternatively, the compound of formula (XIII) is reacted with Ci^alkyl-
chloroformate, preferably, methylchloroformate; in the presence of a organic
base such as TEA, DIPEA, pyridine and the like; preferably at a temperature
less than about room temperature, more preferably at a temperature of about
43

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0°C; in an organic solvent such as DMF, DCM, chloroform, THF, and the like;
to yield the corresponding compound of formula (XVI), wherein A1 is the
corresponding C1-4alkyl, preferably methyl.
The compound of formula (XVI) is reacted with a suitably substituted
compound of formula (XIV), a known compound or compound prepared by
known methods, or when RJ and RK are each hydrogen, with a suitable source
of ammonia such as NH4OH, HMDS, ammonia gas, and the like, preferably
NH4OH; in the presence of a palladium catalyst such PdCI2, Pd2(OAc)2, and the
like, in combination with a ligand, such DPPP, DPPF, P(Ph)3, and the like; or in
the presence of a palladium:ligand complex such as Pd(PPh3)4, and the like; at
a temperature in the range of from about 50°C to about 160°C, preferably at a
temperature in the range of from about 60°C to about 80°C; to yield the
corresponding compound of formula (XII).
STEP 1: Wherein X is -CN and wherein Yp is Br, Cl or I
Alternatively, a suitably substituted compound of formula (X), wherein Xp is CN
and wherein Yp is selected from Br, Cl or I, a known compound or compound
prepared by known methods, is reacted with a suitably substituted compound
of formula (XIV), a known compound or compound prepared by known
methods, according to known methods (for example as described in Parris,
CL, Org. Syn. Coll., (1973), 5, p73; Lin, S., Synthesis, (April 1978), p.330;
Murahashi, S., Takeshi Naota, T., and Eiichiro Saito, E., JACS, (1986),
108(24), p7846), to yield the corresponding compound of formula (XII).
Alternatively, a suitably substituted compound of formula (X), wherein Xp
is CN and wherein Yp is selected from Br, Cl or I, a known compound or
compound prepared by known methods, is reacted with an acid such as
concentrated sulfuric acid, and the like; at a temperature greater than about
room temperature, preferably at reflux temperature; to yield the corresponding
compound of formula (XVI).
Alternatively, a suitably substituted compound of formula (X), wherein Xp
is CN and wherein Yp is selected from Br, Cl or I, a known compound or
compound prepared by known methods, is reacted with an inorganic base such
44

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as NaOH, KOH, and the like; at a temperature greater than about room
temperature, preferably at about reflux temperature; to yield the corresponding
compound of formula (XVI).
The compound of formula (XVI) is reacted according to known methods,
for example, by alkylating in the presence of a base, to yield the corresponding
compound of formula (XII).
STEP 2:
The compound of formula (XII) is reacted with a suitably substituted
compound of formula (XVII), wherein Pg1 is a suitable nitrogen protecting group
such as Boc, Cbz, Fmoc, acetyl, and the like, preferably Pg1 is Boc, a known
compound or compound prepared by known methods; in the presence of
palladium catalyst such as Pd2(dba)3) Pd(OAc)2, PdCI2, and the like, preferably
Pd2(dba)3; and preferably in the presence of a phosphorous ligand such as P(o-
toluene)3, P(Ph)3, P(t-butyl)3, DPPE, and the like, preferably P(t-butyl)3 or P(o-
toluene)3; or in the presence of a palladium:ligand complex such as Pd(PPh3)4,
and the like; in the presence of an organic or inorganic base such as
dicyclohexylmethylamine, Na2CO3, K2CO3) TEA, DIPEA, pyridine, and the like,
preferably TEA; in an organic solvent such as DMF, dioxane, and the like; at a
temperature greater than about room temperature, preferably at a temperature
in the range of about 60°C to about 120°C; to yield the corresponding
compound of formula (XIX).
STEP 3:
The compound of formula (XIX) is hydrogenated according to known
methods; for example by reacting with hydrogen or a source of hydrogen (such
as cyclohexadiene, and the like); in the presence of a catalyst such as platinum
oxide, palladium on carbon, nickel, CIRh(PPh3)3, RuCI2, and the like, preferably
palladium on carbon; in an organic solvent such as methanol, ethanol, THF,
ethyl acetate, and the like, preferably methanol; at a temperature greater than
room temperature, preferably at a temperature in the range of about 60°C to
about 120°C, to yield the corresponding compound of formula (XX).
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One skilled in the art will recognize that the compound of formula (XIX)
may be optionally reacted in the presence of a chiral catalyst, to yield the
corresponding compound of formula (XX), wherein one stereo-isomer is
present in an enantiomeric excess.
STEP 4:
The compound of formula (XX) is reacted with an aqueous base such as
NaOH, LiOH, KOH, and the like; in an organic solvent such as methanol, THF,
ethanol, and the like; to yield the corresponding compound of formula (I).
In an embodiment, the present invention is directed to processes for the
preparation of compounds of formula (Ic).
In an embodiment, the present invention is directed to processes for the
preparation of a compound of formula (Ib), a compound of formula (I) wherein
is phenyl; RJ and RK are each hydrogen; the phenyl ring is further
substituted with two R41P groups, which are each methyl and Pg1 is Boc, also
known as 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-
propionic acid, as described in Scheme 1 above.
The present invention is further directed to processes for the preparation
of the compound of formula (la) as outlined in Scheme 2 below.
STEP 1a: Preparation of the Compound of Formula (Xlla), wherein X is -OH
and Y is selected from Br or Cl
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or
STEP 1a: Preparation of the Compound of Formula (Xlla), wherein X is -
OC(O)-C1-4alkyl and Y is selected from Br, Cl or I
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WO 2006/099060 PCT/US2006/008450

or
STEP 1a: Preparation of the Compound of Formula (Xlla), wherein X is -CN
and Y is selected from Br, Cl or I

48

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STEP 2a: Preparation of the Compound of Formula (XlXa)

STEP 3a: Preparation of the Compound of Formula (XXa)

STEP 4a: Preparation of the Compound of Formula (la)

Scheme 2
STEP1a: Wherein X is -OH and Y is selected from Br or Cl
Accordingly, a suitably substituted compound of formula (Xa), wherein
Xp is OH and wherein Yp is Br or Cl, preferably Yp is Br, a known compound or
compound prepared by known methods, is reacted with a triflating reagent such
as triflic anhydride, N-phenyltrifluoromethanesulfonimide, and the like; in the
presence of an organic or inorganic base such as pyridine, TEA, DIPEA,
K3PO4, K2CO3, and the like, preferably pyridine; optionally in an organic solvent
such as DCM, chloroform, THF, and the like, to yield the corresponding
compound of formula (Xla).
The compound of formula (Xla) is reacted with carbon monoxide or a
source of carbon monoxide such as Ac2O in combination with HCOONa (see
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for example, S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett. (2003), 5(23),
pp4269-4272) and a suitable source of ammonia such as HMDS, ammonia
gas, and the like; in the presence of a palladium catalyst such PdCI2,
Pd2(OAc)2, and the like, in combination with a ligand, such DPPP, DPPF,
P(Ph)3, and the like; or in the presence of a palladiunrligand complex such as
Pd(PPh3)4, and the like; in an organic solvent such as DMF, THF, dioxane, and
the like, preferably DMF; at a temperature in the range of from about 50°C to
about 160°C, preferably at a temperature in the range of from about 60°C to
about 120°C; to yield the corresponding compound of formula (Xlla).
Alternatively, the compound of formula (Xla) is reacted with carbon
monoxide or a source of carbon monoxide such as Ac2O in combination with
HCOONa (see for example, S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett.
(2003), 5(23), pp4269-4272); in the presence of an inorganic base such as
K2CO3, Na2CO3, and the like; in an organic solvent such as DMF, dioxane,
THF, and the like; at a temperature in the range of from about 50°C to about
160°C, preferably at a temperature in the range of from about 60°C to about
80°C; to yield the corresponding compound of formula (Xllla).
The compound of formula (Xllla) is reacted with a suitable source of
ammonia such as HMDS, ammonia gas, and the like, preferably HMDS; in the
presence of a coupling agent such as EDCI, HOBT, PyBop, PyBrop, and the
like; preferably in the presence of an organic base such as TEA, DIPEA,
pyridine, the like, or in the presence of an amount of the source of ammonia
sufficient to act as the base, preferably greater than about 2 equivalents; in an
organic solvent such as THF, dioxane, DMF, and the like, to yield the
corresponding compound of formula (Xlla).
Alternatively, the compound of formula (Xla) is reacted with carbon
monoxide or a source of carbon monoxide such as Ac2O in combination with
HCOONa (see for example, S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett.
(2003), 5(23), pp4269-4272); in the presence of an inorganic base such as
K2CO3, Na2CO3, and the like; in an organic solvent such as DMF, dioxane,
THF, and the like; at a temperature in the range of from about 50°C to about
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WO 2006/099060 PCT/US2006/008450
160°C, preferably at a temperature in the range of from about 60°C to about
80°C; to yield the corresponding compound of formula (Xllla).
The compound of formula (Xllla) is reacted with a suitable source of
chlorine such as thionyl chloride, PCI3, PCI5, oxalyl chloride, oxalyl chloride in
DMF, and the like; in an organic solvent such as DCM, chloroform, and the like;
preferably at a temperature greater than about room temperature, more
preferably at a temperature in the range of about 35°C to about 60°C; to yield
the corresponding compound of formula (XVa).
The compound of formula (XVa) is reacted with a suitable source of
ammonia such as ammonium chloride, NH4OH, HMDS, ammonia gas, and the
like, preferably ammonium chloride; preferably in the presence of an organic
base such as TEA, DIPEA, pyridine, the like, or in the presence of an amount
of the source of ammonia sufficient to act as the base, preferably greater than
about 2 equivalents; in an organic solvent such as THF, dioxane, DMF, and the
like; to yield the corresponding compound of formula (Xlla).
Alternatively, the compound of formula (Xla) is reacted with carbon
monoxide or a source of carbon monoxide such as AC2O in combination with
HCOONa (see for example, S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett.
(2003), 5(23), pp4269-4272); in the presence of an inorganic base such as
K2CO3, Na2CO3, and the like; in an organic solvent such as DMF, dioxane,
THF, and the like; at a temperature in the range of from about 50°C to about
160°C, preferably at a temperature in the range of from about 60°C to about
80°C; to yield the corresponding compound of formula (Xllla).
Alternatively, the compound of formula (Xllla) is reacted with C1-4alkyl-
chloroformate, preferably, methylchloroformate; in the presence of a organic
base such as TEA, DIPEA, pyridine and the like; preferably at a temperature
less than about room temperature, more preferably at a temperature of about
0°C; in an organic solvent such as DMF, DCM, chloroform, THF, and the like;
to yield the corresponding compound of formula (XVIa), wherein A1 is the
corresponding d-4alkyl, preferably methyl.
The compound of formula (XVIa) is reacted with a suitable source of
ammonia such as NH4OH, HMDS, ammonia gas, and the like, preferably
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NH4OH; in the presence of a palladium catalyst such PdCI2, Pd2(OAc)2, and the
like, in combination with a ligand, such DPPP, DPPF, P(Ph)3, and the like; or in
the presence of a palladiunrligand complex such as Pd(PPh3)4) and the like; at
a temperature in the range of from about 50°C to about 160°C, preferably at a
temperature in the range of from about 60°C to about 80°C; to yield the
corresponding compound of formula (Xlla).
One skilled in the art will further recognize that the compound of formula
(Xla) may be reacted according to known methods, to yield the corresponding
compound of formula (Xa) wherein Xp is -C(O)-OC1-4alkyl or CN.
STEP 1a: Wherein X is -C(O)-OC1-4alkvl and wherein Yp is Br, Cl or I
Alternatively, a suitably substituted compound of formula (Xa), wherein
Xp is -C(O)-OC1-4alkyl and wherein Yp is selected from Br, Cl or I, a known
compound or compound prepared by known methods, is reacted with a suitable
source of ammonia such as NH4OH, HMDS, ammonia gas, and the like; at a
temperature greater than room temperature, preferably at about reflux
temperature; to yield the corresponding compound of formula (Xlla).
Alternatively, a suitably substituted compound of formula (Xa), wherein
Xp is -C(O)-OC1-4alkyl and wherein Yp is selected from Br, Cl or I, a known
compound or compound prepared by known methods, is reacted with a suitable
source of ammonia such as NH4OH, HMDS, ammonia gas, and the like; in the
presence of a activating agent such as trimethylaluminum,
triisopropylaluminum, and the like; in an aprotic organic solvent such as THF,
dioxane, toluene, DCM, and the like; preferably, at a temperature in the range
of about 0°C to reflux temperature; to yield the corresponding compound of
formula (Xlla).
Alternatively, a suitably substituted compound of formula (Xa), wherein
Xp is -C(O)-OC1-4alkyl and wherein Yp is selected from Br, Cl or I, a known
compound or compound prepared by known methods, is hydrolyzed according
to known methods; for example by reacting with a base such as NaOH, LiOH,
KOH, and the like, or by reacting with an acid such as HCI, H2SO4, and the like;
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preferably, the compound of formula (Xa) is reacted with an acid at a
temperature greater than about room temperature, preferably at a temperature
in the range of from about 60° to about 120°C, preferably at a temperature of
about 100°C; to yield the corresponding compound of formula (Xllla).
The compound of formula (Xllla) is reacted with a suitable source of
ammonia such as HMDS, ammonia gas, and the like, preferably HMDS; in the
presence of a coupling agent such as EDCI, HOBT, PyBop, PyBrop, and the
like; preferably in the presence of an organic base such as TEA, DIPEA,
pyridine, the like, or in the presence of an amount of the source of ammonia
sufficient to act as the base, preferably greater than about 2 equivalents; in an
organic solvent such as THF, dioxane, DMF, and the like, to yield the
corresponding compound of formula (Xlla).
Alternatively, the compound of formula (Xa), wherein Xp is -C(O)-OC1-
4alkyl and wherein Yp is selected from Br, Cl or I, a known compound or
compound prepared by known methods, is reacted with carbon monoxide or a
source of carbon monoxide such as Ac2O in combination with HCOONa (see
for example, S, Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett. (2003), 5(23),
pp4269-4272); in the presence of an inorganic base such as K2CO3, Na2CO3,
and the like; in an organic solvent such as DMF, dioxane, THF, and the like; at
a temperature in the range of from about 50°C to about 160°C, preferably at a
temperature in the range of from about 60°C to about 80°C; to yield the
corresponding compound of formula (Xllla).
The compound of formula (Xllla) is reacted with a suitably source of
chlorine such as thionyl chloride, PCI3, PCI5, oxalyl chloride, oxalyl chloride in
DMF, and the like; in an organic solvent such as DCM, chloroform, and the like;
preferably at a temperature greater than about room temperature, more
preferably at a temperature in the range of about 35°C to about 60°C, to yield
the corresponding compound of formula (XVa).
The compound of formula (XVa) is reacted with a suitable source of
ammonia such as ammonium chloride, NH4OH, HMDS, ammonia gas, and the
like, preferably ammonium chloride; preferably in the presence of an organic
base such as TEA, DIPEA, pyridine, the like; or in the presence of an amount
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of the source of ammonia sufficient to act as the base, preferably greater than
about 2 equivalents; in an organic solvent such as THF, dioxane, DMF, and the
like; to yield the corresponding compound of formula (Xlla).
Alternatively, the compound of formula (Xa), wherein Xp is -C(O)-OC1-
4alkyl and wherein Yp is selected from Br, Cl or I, a known compound or
compound prepared by known methods, is reacted with carbon monoxide or a
source of carbon monoxide such as AC2O in combination with HCOONa (see
for example, S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett. (2003), 5(23),
pp4269-4272); in the presence of an inorganic base such as K2CO3, Na2CO3,
and the like; in an organic solvent such as DMF, dioxane, THF, and the like; at
a temperature in the range of from about 50°C to about 160°C, preferably at a
temperature in the range of from about 60°C to about 80°C; to yield the
corresponding compound of formula (Xllla).
Alternatively, the compound of formula (Xllla) is reacted with C1-4alkyl-
chloroformate, preferably, methylchloroformate; in the presence of a organic
base such as TEA, DIPEA, pyridine and the like; preferably at a temperature
less than about room temperature, more preferably at a temperature of about
0°C; in an organic solvent such as DMF, DCM, chloroform, THF, and the like;
to yield the corresponding compound of formula (XVIa), wherein A1 is the
corresponding C-|.4alkyl, preferably methyl.
The compound of formula (XVIa) is reacted with a suitable source of
ammonia such as NH4OH, HMDS, ammonia gas, and the like, preferably
NH4OH; in the presence of a palladium catalyst such PdCI2, Pd2(OAc)2, and the
like, in combination with a ligand, such DPPP, DPPF, P(Ph)3, and the like, or in
the presence of a palladium:ligand complex such as Pd(PPh3)4, and the like; at
a temperature in the range of from about 50°C to about 160°C, preferably at a
temperature in the range of from about 60°C to about 80°C; to yield the
corresponding compound of formula (Xlla).
STEP 1a: Wherein X is -CN and wherein Yp is Br, Cl or I
Alternatively, a suitably substituted compound of formula (Xa), wherein
Xp is CN and wherein Yp is selected from Br, Cl or I, a known compound or
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WO 2006/099060 PCT/US2006/008450
compound prepared by known methods, is reacted with an acid such as
concentrated sulfuric acid, and the like; at a temperature greater than about
room temperature, preferably at about reflux temperature; to yield the
corresponding compound of formula (XVIa).
Alternatively, a suitably substituted compound of formula (Xa), wherein
Xp is CN and wherein Yp is selected from Br, Cl or I, a known compound or
compound prepared by known methods, is reacted with an inorganic base such
as NaOH, KOH, and the like; at a temperature greater than about room
temperature, preferably at about reflux temperature; to yield the corresponding
compound of formula (XVIa).
Preferably, a suitably substituted compound of formula (Xa), a known
compound or compound prepared by known methods, is reacted with a
triflating reagent.such as triflic anhydride, N-phenyltrifluoromethanesulfonimide,
and the like, preferably triflic anhydride; in the presence of an organic or
inorganic base such as pyridine, TEA, DIPEA, K3PO4, K2CO3, and the like,
preferably pyridine; optionally in an organic solvent such as DCM, chloroform,
THF, and the like; to yield the corresponding compound of formula (Xla).
The compound of formula (Xla) is reacted with carbon monoxide or a
source of carbon monoxide such as Ac2O in combination with HCOONa (see
for example, S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Lett. (2003), 5(23),
pp4269-4272) and a suitable source of ammonia such as HMDS, ammonia
gas, and the like; preferably the compound of formula (Xla) is reacted with
carbon monoxide and HMDS; in the presence of a palladium catalyst such
PdCI2l Pd2(OAc)2, and the like, in combination with a suitable ligand, such
DPPP, DPPF, P(Ph)3, and the like; or in the presence of a palladium:ligand
complex such as Pd(PPh3)4, and the like; preferably, in the presence of PdCI2
in combination with DPPP; at a temperature in the range of from about 50°C to
about 160°C, preferably at a temperature in the range of from about 60°C to
about 120°C, more preferably, at a temperature of about 100°C; in an organic
solvent such as DMF, THF, dioxane, and the like, preferably, in DMF; to yield
the corresponding compound of formula (XII).
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STEP 2a:
The compound of formula (XIla) is reacted with a suitably substituted
compound of formula (XVIIIa), a known compound or compound prepared by
known methods, in the presence of palladium catalyst such as Pd2(dba)3,
Pd(OAc)2, PdCI2) and the like, preferably Pd2(dba)3; and preferably in the
presence of a phosphorous ligand such as P(o-toluene)3, P(Ph)3, P(t-butyl)3,
DPPE, and the like, preferably P(o-toluene)3; or in the presence of a
palladium:ligand complex such as Pd(PPh3)4, and the like; in the presence of
an organic or inorganic base such as dicyclohexylmethylamine, Na2CO3,
K2CO3, TEA, DIPEA, pyridine, and the like, preferably TEA; in an organic
solvent such as DMF, dioxane, and the like, preferably DMF; at a temperature
greater than about room temperature, preferably at a temperature in the range
of about 60°C to about 120°C, preferably at about 120°C; to yield the
corresponding compound of formula (XlXa).
STEP 3a:
The compound of formula (XlXa) is reacted with hydrogen gas, at a
pressure sufficient to hydrogenate, preferably at a pressure greater than about
500 psi, more preferably, at a pressure greater than about 800 psi, more
preferably still, at a pressure about 1000 psi; in the presence of a suitable chiral
catalyst such as [Rh(cod)(R,R-DIPAMP)]+BF4\ [Rh(cod)(R,R-
DIPAMP)]+SO2CF3', and the like; wherein the chiral catalyst is preferably
present in an amount greater than about 0.01 equivalents, more preferably, in
an amount of about 0.04 equivalents; at a temperature greater than about room
temperature, preferably at a temperature in the range of about 60°C to about
100°C, more preferably, at a temperature of about 60°C; in an organic solvent
such as methanol, ethanol, THF, ethyl acetate, and the like, preferably
methanol; preferably not under vacuum; to yield the corresponding compound
of formula (XXa), wherein the S-enantiomer is present in an enantiomeric
excess of greater than about 80%, preferably, in an enantiomeric excess of
greater than about 90%, more preferably, in an enantiomeric excess of greater
than about 95%, more preferably, in an enantiomeric excess of greater than
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about 98%, most preferably, in an enantiomeric excess of greater than about
99%.
One skilled in the art will recognize that if the chiral catalyst is oxygen
sensitive, then the hydrogenation reaction vessel is purged with an inert gas
such as argon, nitrogen, and the like, prior to charging the vessel with the
oxygen sensitive catalyst reagents and hydrogen gas.
One skilled in the art will recognize that the compound of formula (XlXa)
may be optionally reacted to yield the corresponding racemic compound of
formula (XXb), as outlined in the scheme below,

by hydrogenating the compound of formula (XlXa) according to known
methods, for example, by reacting with hydrogen or a source of hydrogen (such
as cyclohexadiene, and the like); in the presence of a catalyst such as platinum
oxide, palladium on carbon, nickel, CIRh(PPh3)3, RuCI2, and the like, preferably
palladium on carbon; in a solvent such as methanol, ethanol, THF, ethyl
acetate, and the like; in an organic solvent such as methanol, ethanol, THF,
ethyl acetate, and the like, preferably methanol; at a temperature greater than
room temperature, preferably at a temperature in the range of about 60°C to
about120°C.
Preferably, for the preparation of the compound of formula (Ib), the
compound of formula (XlXa) is reacted with hydrogen gas; at a pressure
sufficient to hydrogenate, preferably at a pressure greater than about 40 psi,
more preferably at a pressure of about 51 psi; in a solvent such as methanol,
ethanol, THF, and the like, preferably methanol; preferably, at about room
temperature; to yield the corresponding compound of formula (XXb).
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The compound of formula (XXb) is then reacted according to the
process described in Step 4a below, to yield the corresponding compound of
formula (Ib).
STEP 4a:
The compound of formula (XXa) is reacted with an aqueous base such
as NaOH, LiOH, KOH, and the like, preferably LiOH; in an organic solvent such
as methanol, THF, ethanol, and the like, preferably THF; to yield the
corresponding compound of formula (la).
The present invention is further directed to processes for the preparation
of compounds of formula (II).
The compounds of formula (I) may be further reacted according to
known processes, for example as disclosed in United States Patent Application
No. 11/079,647, filed March 14, 2005, and published as US Patent Publication
US-2005-0203143-A1, September 15, 2005, to yield the corresponding
compounds of formula (II). More specifically, the compounds of formula (II)
may be prepared according to the process outlined in Scheme 3 below.

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Accordingly, a suitably substituted compound of formula (I) is reacted
with a suitably substituted compound of formula (L), a known compound or
compound prepared by known methods, under standard peptide coupling
conditions (for example, with a coupling agent such as EDCI and an additive
such as HOBT), to yield the corresponding compound of formula (LI).
The compound of formula (LI) is then de-protected according to known
methods, and then further, optionally reacted according to know methods, to
yield the corresponding compound of formula (II) wherein Ra and Rb are each
other than hydrogen. For example, the compound of formula (LI) is de-
protected and the alkylated, according to known methods, to yield the
corresponding compound of formula (II) wherein one or both of Ra and Rb is
alkyl. Alternatively, for compounds of formula (II) wherein Ra and Rb are taken
together to form a ring, the compound of formula (LI) is de-protected and then
converted to the corresponding ring by reductive cyclization with a suitably
selected di-aldehyde.
The present invention is further directed to processes for the preparation
of compounds of formula (XIX). More specifically, in an embodiment, the
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present invention is directed to a process for the preparation of compounds of
formula (XIX) as outlined in Scheme 4.

Accordingly, a suitably substituted compound of formula (XIII), wherein
Yp is Br or Cl, is reacted with a formylating reagent such as a DMF, HC(O)-
N(CH3)(OCH3), and the like; in the presence of a base such as n-butyl lithium,
NaH, and the like; in an organic solvent such as THF, dioxane, and the like; at
a temperature less than about room temperature, preferably at a temperature in
the range of about -130°C to about CPC, more preferably, at about -100°C; to
yield the corresponding compound of formula (XXI).
The compound of formula (XXI) is reacted with a suitably substituted
compound of formula (XIV), a known compound or compound prepared by
known methods, or when RJ and RK are each hydrogen, with a suitable source
of ammonia such as HMDS, ammonia gas, and the like, preferably HMDS; in
the presence of a coupling agent such as EDCI, HOBT, PyBop, PyBrop, and
the like; preferably in the presence of an organic base such as TEA, DIPEA,
pyridine, the like, or an amount of the compound of formula (XIV) or source of
ammonia sufficient to act as the base, preferably greater than about 2
equivalents; in an organic solvent such as THF, dioxane, DMF, and the like; to
yield the corresponding compound of formula (XXII).
The compound of formula (XXII) is reacted with a suitably selected
compound of formula (XXIII), a known compound or compound prepared by
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known methods; in the presence of a base such as DBU, potassium t-butoxide,
NaH, and the like; in an organic solvent such as THF, dioxane, and the like;
preferably at about room temperature, to yield the corresponding compound of
formula (XIX).
In another embodiment, the present invention is directed to a process for
the preparation of compounds of formula (XIX) as outlined in Scheme 5.
h
R
Accordingly, a suitably substituted compound of formula (XXIV), a
known compound or compound prepared by known methods, is reacted with a
suitably substituted compound of formula (XIV), a known compound or
compound prepared by known methods, or when RJ and RK are each
hydrogen, with a suitable source of ammonia such as HMDS, ammonia gas,
and the like, preferably HMDS; in the presence of a coupling agent such as
EDCI, HOBT, PyBop, PyBrop, and the like; preferably in the presence of an
organic.base such as TEA, DIPEA, pyridine, the like, or an amount of the
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compound of formula (XIV) or source of ammonia sufficient to act as the base,
preferably greater than about 2 equivalents; in an organic solvent such as THF,
dioxane, DMF, and the like; to yield the corresponding compound of formula
(XXV).
The compound of formula (XXV) is reacted with triflating reagent such as
triflic anhydride, N-phenyltrifluoromethanesulfonimide, and the like; in the
presence of an organic or inorganic base such as pyridine, TEA, DIPEA,
K3PO4, K2CO3, and the like; optionally in an organic solvent such as DCM,
chloroform, THF, and the like; to yield the corresponding compound of formula
(XXVI).
The compound of formula (XXVI) is reacted with carbon monoxide; in
the presence of a palladium catalyst such PdCl2, Pd2(OAc)2, and the like, in
combination with a suitable ligand, such DPPP, DPPF, P(Ph)3, and the like; or
in the presence of a palladium:ligand complex such as Pd(PPh3)4, and the like;
in the presence of an organic base such as TEA, DIPEA, pyridine, and the like;
in the presence of (alkyl)3SiH; in an organic solvent such as DMF, THF,
dioxane, and the like; to yield the corresponding compound of formula (XXVII).
The compound of formula (XXVII) is reacted with a suitably selected
compound of formula (XXIII), a known compound or compound prepared by
known methods; in the presence of a base such as DBU, potassium t-butoxide,
NaH, and the like; in an organic solvent such as THF, dioxane, and the like;
preferably at about room temperature, to yield the corresponding compound of
formula (XIX).
In an embodiment, the present invention is directed to processes for the
preparation of the compound of formula (XIX). More specifically, in an
embodiment, the present invention is directed to a process for the preparation
of compounds of formula (XlXa) as outlined in Scheme 6.

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Accordingly, a suitably substituted compound of formula (Xllla), wherein
Yp is Br or Cl, is reacted with a formylating reagent such as a DMF, HC(O)-
N(CH3)(OCH3), and the like; in the presence of a base such as n-butyl lithium,
NaH, and the like; in an organic solvent such as THF, dioxane, and the like; at
a temperature less than about room temperature, preferably at a temperature in
the range of about -130°C to about 0°C, more preferably, at about -100°C; to
yield the corresponding compound of formula (XXIa).
The compound of formula (XXIa) is reacted with a suitable source of
ammonia such as HMDS, ammonia gas, and the like, preferably HMDS; in the
presence of a coupling agent such as EDCI, HOBT, PyBop, PyBrop, and the
like; preferably in the presence of an organic base such as TEA, DIPEA,
pyridine, the like, or an amount of the source of ammonia sufficient to act as the
base, preferably greater than about 2 equivalents; in an organic solvent such
as THF, dioxane, DMF, and the like; to yield the corresponding compound of
formula (XXIIa).
The compound of formula (XXIIa) is reacted with a suitably selected
compound of formula (XXIIIa), wherein Pg1 is a suitable nitrogen protecting
group such as Boc, Cbz, and the like, a known compound or compound
prepared by known methods; in the presence of a base such as DBU,
potassium t-butoxide, NaH, and the like; in an organic solvent such as THF,
dioxane, and the like; preferably at about room temperature, to yield the
corresponding compound of formula (XlXb).
In another embodiment, the present invention is directed a process for
the preparation of compounds of formula (XlXa) as outlined in Scheme 7.
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Accordingly, a suitably substituted compound of formula (XXIVa), a
known compound or compound prepared by known methods, is reacted with a
suitable source of ammonia such as HMDS, ammonia gas, and the like,
preferably HMDS; in the presence of a coupling agent such as EDCI, HOBT,
PyBop, PyBrop, and the like; preferably in the presence of an organic base
such as TEA, DIPEA, pyridine, the like, or in the presence of an amount of the
source of ammonia sufficient to act as the base, preferably greater than about 2
equivalents; in an organic solvent such as THF, dioxane, DMF, and the like; to
yield the corresponding compound of formula (XXVa).
The compound of formula (XXVa) is reacted with triflating reagent such
as triflic anhydride, N-phenyltrifluoromethanesulfonimide, and the like; in the
presence of an organic or inorganic base such as pyridine, TEA, DIPEA,
K3PO4, K2CO3, and the like; optionally in an organic solvent such as DCM,
chloroform, THF, and the like; to yield the corresponding compound of formula
(XXVIa).
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The compound of formula (XXVIa) is reacted with carbon monoxide; in
the presence of a palladium catalyst such PdCI2, Pd2(OAc)2, and the like, in
combination with a suitable ligand, such DPPP, DPPF, P(Ph)3, and the like; or
in the presence of a palladium:ligand complex such as Pd(PPh3)4, and the like;
in the presence of an organic base such as TEA, DIPEA, pyridine, and the like;
in the presence of (alkyl)3SiH; in an organic solvent such as DMF, THF,
dioxane, and the like; to yield the corresponding compound of formula (XXVIIa).
The compound of formula (XXVIIa) is reacted with a suitably selected
compound of formula (XXIIIa), wherein Pg1 is a suitable nitrogen protecting
group such as Boc, Cbz, abd the like, a known compound or compound
prepared by known methods; in the presence of a base such as DBU,
potassium t-butoxide, NaH, and the like; in an organic solvent such as THF,
dioxane, and the like; preferably at about room temperature, to yield the
corresponding compound of formula (XlXb).
The present invention further comprises pharmaceutical compositions
containing one or more compounds prepared according to any of the processes
described herein with a pharmaceutically acceptable carrier. Pharmaceutical
compositions containing one or more of the compounds of the invention
described herein as the active ingredient can be prepared by intimately mixing
the compound or compounds with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques. The carrier may take a
wide variety of forms depending upon the desired route of administration (e.g.,
oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs
and solutions, suitable carriers and additives include water, glycols, oils,
alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the
like; for solid oral preparations, such as powders, capsules and tablets, suitable
carriers and additives include starches, sugars, diluents, granulating agents,
lubricants, binders, disintegrating agents and the like. Solid oral preparations
may also be coated with substances such as sugars or be enteric-coated so as
to modulate major site of absorption. For parenteral administration, the carrier
will usually consist of sterile water and other ingredients may be added to
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increase solubility or preservation. Injectable suspensions or solutions may
also be prepared utilizing aqueous carriers along with appropriate additives.
Optimal dosages to be administered may be readily determined by those
skilled in the art, and will vary with the particular compound used, the mode of
administration, the strength of the preparation, the mode of administration, and
the advancement of the disease condition. In addition, factors associated with the
particular patient being treated, including patient age, weight, diet and time of
administration, will result in the need to adjust dosages.
The following Examples are set forth to aid in the understanding of the
invention, and are not intended and should not be construed to limit in any way
the invention set forth in the claims which follow thereafter.
In the Examples which follow, some synthesis products are listed as
having been isolated as a residue. It will be understood by one of ordinary skill
in the art that the term "residue" does not limit the physical state in which the
product was isolated and may include, for example, a solid, an oil, a foam, a
gum, a syrup, and the like.
Example 1
(S)-2-terf-Butoxvcarbonvlamino-3-(4-carbamovl-2,6-dimethyl-phenvl)-
propionic acid

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STEP A: Trifluoromethanesulfonic acid 4-bromo-3,5-dimethyl-phenyl
ester
To a cooled (0°C) solution of 4-bromo-3,5-dimethylpheno| (3.05 g, 15.2
mmol) in pyridine (8 ml_) was added trifluoromethanesulfonic anhydride (5.0 g,
17.7 mmol) dropwise. After completion of addition, the resulting mixture was
stirred at 0°C for 15 min, and then at room temperature overnight. The reaction
was quenched by addition of water, and then extracted with EtOAc. The
organic extracts were washed sequentially with water, 2N HCI (2x ), brine, and
then dried over MgSO4. Filtration and evaporation to dryness yielded
compound 1 b as a colorless oil.
1H NMR (300 MHz, CDCI3): 5 2.45 (6H, s), 7.00 (2H, s).
Step B: 4-Bromo-3,5-dimethylbenzoic acid
Into a solution of compound 1b (6.57 g, 19.7 mmol) in DMF (65 ml_)
were added K2CO3 (13.1 g, 94.7 mmol), Pd(OAc)2 (0.44 g, 1.97 mmol) and
1,1'-bis(diphenylphosphino)ferrocene (2.29 g, 4.14 mmol). The resulting
mixture was bubbled in gaseous CO for 10 min and was heated to 60°C for
7.5h with a CO(9) balloon. The cooled mixture was partitioned between
aqueous NaHCO3 and EtOAc, and filtered. The aqueous phase was
separated, acidified with aqueous 6N HCI, extracted with EtOAc, and then dried
over Na2SO4. Filtration and concentration of the filtrate yielded crude
compound 1c as a brown residue, which was used in the next step without
further purification.
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STEP C: Method A: 4-Bromo-3,5-dimethyl-benzamide
Into a suspension of compound 1c in DCM (40 mL) was added SOCI2
(3.1 mL, 42 mmol) and the mixture was heated at reflux for 2 h. Upon removal
of the solvent by evaporation, the residue was dissolved in DCM (40 mL) and
then ammonium hydroxide (28% NH3 in water, 2.8 mL) was added. The
reaction mixture was heated at 50°C for 2 h and concentrated. The residue
was diluted with H2O, extracted with EtOAc, and the organic portion was dried
over Na2SO4. After filtration and evaporation, the residue was purified by flash
column chramotagraphy (eluent: EtOAc) to yield compound 1d as an off-white
solid.
1H NMR (300 MHz, CD3CN): δ 2.45 (6H, s), 5.94 (1H, br s), 6.71 (1H, br
s), 7.57 (2H, s)
MS(ES+)(relative intensity): 228.0 (100%) (M+1).
Step C: Method B: 4-Bromo-3,5-dimethyl-benzamide
A mixture of compound 1b (3.33 g, 10 mmol), PdCI2 (0.053 g, 0.3 mmol),
hexamethyldisilazane (HMDS, 8.4 mL, 40 mmol), and DPPP (0.12 g, 0.3 mmol)
was bubbled with a gaseous CO for 5 min and then stirred in a CO balloon at
80°C for 4 h. To the reaction mixture was added MeOH (5 mL). The reaction
mixture was stirred for 10 min, diluted with 2N H2SO4 (200 mL), and then
extracted with EtOAc. The EtOAc extract was washed with saturated aqueous
NaHCO3, brine, and then dried over Na2SO4. Filtration and evaporation of the
resultant filtrate yielded a residue, which was purified by flash column
chromatography (eluent: EtOAc) to yield compound 1d as a white solid.
Step D: 2-terf-Butoxycarbonylaminoacrylic acid methyl ester
To a suspension of A/-Boc-serine methyl ester (Compound 1e, 2.19 g, 10
mmol) and EDCI (2.01 g, 10.5 mmol) in DCM (70 mL) was added CuCI (1.04 g,
10.5 mmol). The reaction mixture was stirred at room temperature for 72 h.
Upon removal of the solvent, the residue was diluted with EtOAc, washed
sequentially with water and brine and then dried over MgSO4. The crude
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product was purified by flash column chromatography (eluent: EtOAc:hexane
-1:4) to yield compound 1f as a colorless oil.
1H NMR (300 MHz, CDCI3): 5 1.49 (9H, s), 3.83 (3H, s), 5.73 (1H, d, J =
1.5 Hz), 6.16 (1H, s), 7.02(1 H, s).
STEP E: (2)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-
phenyl)acrylic acid methyl ester
A flask charged with compound 1d (0.46 g, 2.0 mmol), compound 1f
(0.80 g, 4.0 mmol), tri-o-tolylphosphine (0.098 g, 0.32 mmol) and DMF (8 mL)
was purged with N2(g) 3 times. After the addition of
tris(dibenzylideneacetone)dipalladium (0) (0.074 g, 0.08 mmol) and TEA (0.31
mL, 2.2 mol), the reaction mixture was heated at 110°C for 24 h. At that time,
the reaction was quenched by addition of water, and then extracted with
EtOAc. The organic phase was washed with 1N HCI, saturated aqueous
NaHCO3, brine, and dried over MgSO4. The mixture was concentrated to a
residue, which was purified by flash column chromatography (eluent:
EtOAc:hexane~1:1 to EtOAc only) to yield compound 1g as a white solid.
1H NMR (300 MHz, CD3OD): 5 1.36 (9H, s), 2.26 (6H, s), 3.83 (3H, s),
7.10 (1H,s), 7.56 (2H,s);
13C NMR (75 MHz, DMSO-d6): δ 17.6, 25.7, 50.2, 78.7, 124.9, 126.4,
128.3, 131.2, 135.2, 135.5, 152.8, 164.3, 169.6;
MS (ES+) (relative intensity): 349.1 (38%)(M+1).
STEP F: (S)-2-terf-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-
phenyl)propionic acid methyl ester
Into a reactor charged with a solution of compound 1g (0.56 g, 1.6
mmol) in degassed MeOH (80 mL) was added [Rh(cod)(R,R-DIPAMP)]+BF4-
under a stream of argon. The reactor was sealed and flushed with H2, stirred
at 60°C under 1000 psi of H2 for 14 days. The crude product was purified by
flash column chromatography (eluent: EtOAc:hexane -1:1) to yield compound
1 h as a white solid.
ee: >99%;
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1H NMR (300 MHz, CDCI3): δ 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J= 7.2
Hz), 3.65 (3H, s), 4.53-4.56 (1H, m), 5.12 (1H, d, J= 8.7 Hz), 5.65 (1H, br s),
6.09 (1H, brs), 7.46 (2H, s);
MS(ES+) (relative intensity): 250.9 (100) (M-Boc)+.
STEPG: (S)-2-fert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-
phenyl)propionic acid
Into an ice-cooled solution of compound 1h (0.22 g, 0.63 mmol) in THF
(3.5 ml_) was added an aqueous LiOH solution (1 N, 3.5 mL) and the reaction
mixture stirred at 0°C. Upon completion of the reaction, the reaction mixture
was concentrated and the aqueous phase was neutralized with cooled aqueous
1 N HCI at 0°C, and then extracted with EtOAc. The combined extracts were
dried over Na2SO4 overnight. Filtration and evaporation of the filtrate to
dryness yielded compound 1 j as a white solid.
1H NMR (300 MHz, DMSO-d6): 5 1.30 (9H, s), 2.32 (6H, s), 2.95(1 H, dd,
J= 8.8, 13.9 Hz), 3.10 (1H, dd, J= 6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23
(2H, m), 7.48 (2H,s), 7.80(1 H,s);
MS(ES+) (relative intensity): 236.9 (6) (M-Boc)+.
Example 2
Racemic 2-ferf-Butoxvcarbonvlamino-3-(4-carbamovl-2,6-dimethyl-
phenvp-propionic acid

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STEP A: Racemic 2-ferf-butoxycarbonylamino-3-(4-carbamoyl-2,6-
dimethyl-phenyl)propionic acid methyl ester
To a reactor charged with a solution of compound 1g (0.68 g, 1.95
mmol) in MeOH (80 mL) was added 10% Pd-C (0.5 g). The reactor was
connected to a hydrogenator and shaken under 51 psi of H2 overnight. The
mixture was filtered through a pad of Celite and the filtrate was concentrated to
dryness to yield compound 2a as a white solid.
The 1H NMR spectrum was identical to that of (S)-2-tert-
butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid
methyl ester, compound 1 h.
STEP B: Racemic 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-
dimethyl-phenyl)propionic acid
Following the procedure described for Example 1, STEP G (preparation
of (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-
phenyl)propionic acid), compound 2b - racemic 2-terf-butoxycarbonylamino-3-
(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid - was prepared.
Example 3
2-Amino-3-(4-hvdroxv-2,6-dimethvl-phenvl)-N-isopropvl-N-[1-(4-phenyl-
1H-imidazol-2-yl)-ethvn-propionamide

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STEP A. [1-(2-Oxo-2-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzyl
ester.
To a solution of commercially available N-cc-CBZ-L-alanine (2.11 g, 9.5
mmol) in dichloromethane (50 mL) was added 2-aminoacetophenone
hydrochloride (1.62g, 9.5 mmol). The resulting solution was cooled to 0°C and
N-methylmorpholine (1.15 g, 11 mmol), 1-hydroxybenzotriazole (2.55 g, 18.9
mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.35
g, 12.3 mmol), in that order, were added under an Argon atmosphere. The
reaction mixture was warmed to room temperature and stirred overnight. The
reaction was quenched by addition of saturated aqueous NaHCO3 solution; the
separated organic phase was washed with 2N citric acid, saturated NaHCO3
solution and brine, then dried over MgSO4 overnight. After filtration and
concentration, the residue was purified by column chromatography on silica gel
(eluent, EtOAc:hexane-1:1) to yield the title compound, [1-(2-oxo-2-phenyl-
ethylcarbamoyl)-ethyl]-carbamic acid benzyl ester.
1H NMR (300 MHz, CDCI3): 5 1.46 (3H, d), 4.39 (1H, m), 4.75 (2H, d),
5.13 (2H, d), 5.40 (1H, m), 7.03 (1H, m), 7.36 (5H, m), 7.50 (2H, m), 7.63 (1H,
m), 7.97(2H, m)
MS(ES+): 341.1 (100%).
step B. [1-(4-Phenyl-1H-imidazol-2-yl)-ethyl]-carbamic acid benzyl ester.
To a suspension of [1-(2-oxo-2-phenyl-ethylcarbamoyl)-ethyl]-carbamic
acid benzyl ester (2.60 g, 7.64 mmol) in xylene (60 ml_) was added NH4OAc
(10.3 g, 134 mmol) and HOAc (5 ml_). The resulting mixture was heated at
reflux for 7 h. After being cooled to room temperature, brine was added and
the mixture was separated. The aqueous phase was extracted with EtOAc,
and the combined organic phases were dried over Na2SO4 overnight. After
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filtration and concentration, the residue was purified by column chromatography
on silica gel (eluent, EtOAc:hexane-1:1) to yield the title compound.
1H NMR (300 MHz, CDCI3): 5 1.65 (3H, d), 5.06 (1H, m), 5.14 (2H, q),
5.94 (1H, d), 7.32 (10H, m), 7.59 (2H, d)
MS(ES+): 322.2 (100%).
Step C. 1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine
To a solution of [1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-carbamic acid
benzyl ester (1.5 g, 4.67 mmol) in methanol (25 mL) was added 10% palladium
on carbon (0.16 g). The mixture was shaken in a hydrogenation apparatus at rt
under a hydrogen atmosphere (10 psi) for 8 h. Filtration followed by
evaporation to dryness under reduced pressure yielded the crude product 1 -(4-
phenyl-1H-imidazol-2-yl)-ethylamine.
1H NMR (300 MHz, CDCI3): δ 1.53 (3H, d), 4.33 (1H, q), 7.23 (3H, m),
7.37 (2H, m), 7.67 (2H, m)
MS(ES+): 188.1 (38%).
STEP D. lsopropyl-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine
1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine (0.20 g, 1.07 mmol) and
acetone (0.062 g, 1.07 mmol) were mixed in 1,2-dichloroethane (4 mL),
followed by the addition of NaBH(OAc)3 (0.34 g, 1.61 mmol). The resulting
mixture was stirred at rt for 3 h. The reaction was quenched with saturated
NaHCO3 solution. The mixture was extracted with EtOAc and the combined
extracts were dried over Na2SO4. Filtration followed by evaporation to dryness
under reduced pressure yielded crude isopropyl-[1-(4-phenyl-1 H-imidazol-2-yl)-
ethyl]-amine, which was used for the next reaction without further purification.
1H NMR (300 MHz, CDCI3): 5 1.10 (3H, d), 1.18 (3H, d), 1.57 (3H, d),
2.86 (1H, m), 4.32 (1H, m), 7.24 (2H, m), 7.36 (2H, m), 7.69 (2H, m)
MS(ES+): 230.2 (100%).
STEP E. (2-(4-Hydroxy-2,6-dimethyl-phenyl)-1-{isopropyI-[1-(4-phenyl-1 H-
imidazol-2-yl)-ethyl]-carbamoyl}-ethyl)-carbamic acid ferf-butyl ester
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Into a solution of 2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-
phenyl)-propionic acid (0.18 g, 0.6 mmol) in DMF (7 ml_) was added isopropyl-
[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amine(0.11 g, 0.5 mmol), 1-
hydroxybenzotriazole (0.22 g, 1.6 mmol) and 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride (0.12 g, 0.6 mmol). The resulting mixture was
stirred under an Argon atmosphere at room temperature overnight. The
reaction mixture was extracted with EtOAc and the combined organic extracts
were washed sequentially with saturated aqueous NaHCO3 solution, 1N HCI,
saturated aqueous NaHCO3 solution, and brine. The organic phase was then
dried over MgSO4, filtered, and the filtrate was concentrated under reduced
pressure. The resulting residue was purified by flash column chromatography
(eluent: EtOAc) to yield the product (2-(4-hydroxy-2,6-dimethyl-phenyl)-1-
{isopropyl-[1 -(4-phenyl-1 H-imidazol-2-yl)-ethyl]-carbamoyl}-ethyl)-carbamic acid
tert-butyl ester.
MS(ES+):521.5(100%).
Step F. 2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-N-isopropyl-N-[1 -(4-
phenyl-1H-imidazol-2-yl)-ethyl]-propionamide
A solution of (2-(4-hydroxy-2,6-dimethyl-phenyl)-1 -{isopropyl-[1 -(4-
phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-ethyl)-carbamic acid tert-butyl ester
(0.13 g, 0.25 mmol) in trifluoroacetic acid (5 ml_) was stirred at room
tempertaure for 2 h. Upon removal of the solvents, the residue was purified by
preparative LC and lyophilized to yield the TFA salt of the title compound as a
white powder.
1H NMR (300 MHz, CDCI3): 5 0.48 (3H, d), 1.17 (3H, d), 1.76 (3H, d),
2.28 (6H, s), 3.19 (2H, m), 3.74 (1H, m), 4.70 (1H, m), 4.82 (1H, q), 6.56 (2H,
s), 7.45 (4H, m), 7.74 (2H, m)
MS(ES+):421.2(100%).
Example 4
(3,4-Dimethoxy-benzyl)-[1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amine
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A solution of 1-(4-phenyl-1 H-imidazol-2-yl)-ethylamine (0.061 g, 0.33
mmol) of Example 3, and 0.55 g (0.33 mmol) of 3,4-dimethoxybenzaldehyde in
5 mL of anhydrous methanol was stirred at room temperature for 1 h and then
cooled to about 0-10°C in an ice bath for 1 h. The reaction was treated
carefully with 0.019 g (0.49 mmol) of sodium borohydride in one portion and
maintained at about 0-10°C for 21 h. Cold 2M aqueous HCI was added
dropwise (30 drops), the mixture was stirred for 5 min, and then partially
concentrated in vacuo unheated. The residual material was taken up in EtOAc
to yield a suspension that was treated with 5 mL of cold 3M aqueous NaOH
and stirred vigorously until clear. The phases were separated and the aqueous
layer was extracted three times additional with EtOAc. The combined extracts
were dried over MgSO4, filtered, and concentrated to yield (3,4-dimethoxy-
benzyl)-[1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amine as a light yellow oil (HPLC:
87% @ 254nm and 66% @ 214 nm).
MS (ES+) (relative intensity): 338.1 (100) (M+1)
This sample was of sufficient quality to use in the next reaction without
further purification.
Example 5
5-(fr2-Amino-3-(4-carbamovl-2,6-dimethvl-phenvl)-propionvn-n-(4-phenvl-
1 H-imidazol-2-vl)-ethvn-amino)-methvl)-2-methoxy-benzoic acid

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STEP A. 2-Methoxy-5-{[1-(4-phenyl-1 H-imidazol-2-yl)-ethylamino]-methyl}-
benzoic acid methyl ester
Using the procedures described for Example 4, substituting 5-formyl-2-
methoxy-benzoic acid methyl ester (WO 02/22612) for 3,4-
dimethoxybenzaldehyde, 2-methoxy-5-{[1 -(4-phenyl-1 H-imidazol-2-yl)-
ethylamino]-methyl}-benzoic acid methyl ester was prepared.
STEP B. 5-({[2-terf-Butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl-
phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-
methoxy-benzoic acid methyl ester
Using the procedure of Example 3 for the conversion of Cpd 3d to Cpd
3e, substituting 2-methoxy-5-{[1-(4-phenyl-1 H-imidazol-2-yl)-ethylamino]-
methyl}-benzoic acid methyl ester for Cpd 3d and substituting 2-tert-
Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid for 2-
tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid,
Cpd 5a was prepared.
STEP C. 5-({[2-terf-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-
phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-
methoxy-benzoic acid
5-({[2-tert-Butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)-
propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-
benzoic acid methyl ester was dissolved in an ice-chilled (0-10°C), mixed
solvent system of THF (10 ml_) and MeOH (5 mL). A LiOHH2O/water
suspension (2.48 M; 3.77 mL) was added dropwise, then the reaction was
allowed to warm to room temperature and stirred overnight. The resulting
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mixture was cooled in an ice bath and the basic solution was neutralized with
2N citric acid until slightly acidic. The mixture was concentrated under reduced
pressure to remove the volatile materials, after which time the remaining
aqueous phase was extracted with EtOAc (3 x 26 mL). These combined
organic phases were dried over MgSO4, filtered, and concentrated under
reduced pressure to yield a pale yellowish white solid. This crude material was
dissolved in a 10% MeOH/CH2CI2 solution and adsorbed onto 30 g of silica.
The adsorbed material was divided and chromatographed on an ISCO normal
phase column over two runs, using a 40 g Redi-Sep column for both runs. The
solvent system was a gradient MeOH/CH2CI2 system as follows: Initial 100%
CH2CI2, 98%-92% over 40 min; 90% over 12 min, and then 88% over 13 min.
The desired product eluted cleanly between 44-61 min. The desired fractions
were combined and concentrated under reduced pressure to yield 5-{{[2-tert-
butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-
phenyl-1 H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid, Cpd
5b, as a white solid.
STEP D. 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1 -
(4-phenyl-1H-innidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid
A portion of Cpd 5b (0.27g, 0.41 mmol) was dissolved in EtOAc (39 mL)/
THF (5 mL), filtered, and subsequently treated with gaseous HCI for 15 min.
After completion of the HCI addition, the reaction was slowly warmed to room
temperature and a solid precipitate formed. After 5 h the reaction appeared
>97% complete by LC (@214nm; 2.56 min.). The stirring was continued over 3
d, then the solid was collected and rinsed with a small amount of EtOAc. The
resulting solid was dried under high vacuum under refluxing toluene for 2.5 h to
yield Cpd 5c as a white solid di-HCI salt.
Example 6
4-f2-Amino-2-r{1-r4-(2-cvano-phenvl)-1H-imidazol-2-vn-ethyl}(3,4-
dimethoxv-benzvl)-carbamovn-ethvl}-3.5-dimethvl-benzamide
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STEP A: {1 -[2-(2-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-ethyl}-carbamic
acid terf-butyl ester
Compound 6a was prepared according to Example 3 using the
appropriate reagents, starting materials and methods known to those skilled in
the art.
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STEP B. {1-[4-(2-Bromo-phenyl)-1h-imidazol-2-yl]-ethyl}-carbamic acid
tert-butyl ester
Following the procedure described in Example 3 for the conversion of
Compound 3a to Compound 3b, and using the appropriate reagents and
methods known to those skilled in the art, Cpd 6b, was prepared.
STEP C. 1-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-ethylamine
Using the procedure described for the conversion of Cpd 3e to 3f,
Compound 6c was prepared.
STEP D. [1-[{1-[4-(2-Bromo-phenyl)-1 H-imidazol-2-yl]-ethyl}-(3,4-
dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-
ethyl]-carbamic acid terf-butyl ester
Using the procedure described in Example 5, STEP B, and substituting
1-[4-(4-bromo-phenyl)-1 H-imidazol-2-yl]-ethylamine for 1-(4-phenyl-1 H-
imidazol-2-yl)-ethylamine, the product was prepared.
STEP E. {2-(4-Carbamoyl-2,6-dimethyl-phenyl)-1 -[{1 -[4-(2-cyano-phenyl)-
1H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-
carbamic acid ferf-butyl ester
To a solution of [1-[{1-[4-(2-bromo-phenyl)-1 H-imidazol-2-yl]-ethyl}-(3,4-
dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyt)-ethyl]-
carbamic acid terf-butyl ester (294 mg; 0.4 mmol) in DMF (2 ml_) was added
Zn(CN)2 (28 mg; 0.24 mmol). The resulting mixture was degassed with Argon
for 5 min, then Pd(PPh3)4 (92 mg; 0.08 mmol) was added neat, and the system
was immediately warmed to 100°C. After heating for 6 h, the reaction was
cooled to room temperature and partitioned between EtOAc and water. The
organic phase was dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude material was subjected to reverse phase HPLC
(water/ acetonitrile/ 0.1% TFA). The fractions of interest were combined,
basified with saturated aqueous NaHCO3 and extracted twice with EtOAc. The
EtOAc extracts were combined, dried over Na2SO4, filtered, and concentrated
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to yield {2-(4-carbamoyl-2,6-dimethyl-phenyl)-1 -[{1 -[4-(2-cyano-phenyl)-1 H-
imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-carbamic acid
fert-butyl ester (HPLC: 96% @ 254 nm and 97% @ 214 nm). This sample was
of sufficient quality to use in the next reaction without further purification.
STEP F. 4-{2-Amino-2-[{1-[4-(2-cyano-phenyl)-1 H-imidazol-2-yl]-ethyl}-(3,4-
dimethoxy-benzyl)-carbamoyl]-ethyI}-3,5-dimethyl-benzamide
{2-(4-carbamoyl-2,6-dimethyl-phenyl)-1 -[{1 -[4-(2-cyano-phenyl)-1 H-
imidazol-2-yl]-ethyl}-(3,4-dimethoxy-benzyl)-carbamoyl]-ethyl}-carbamic acid
tert-butyl ester may be BOC-deprotected using the procedure described in*
Example 3 for the conversion of Cpd 3e to Cpd 3f to yield the title compound.
Example 7
3-(2-f1-rr2-Amino-3-(4-carbamovl-2,6-dimethvl-phenyl)-propionvn-(3,4-
dimethoxv-benzvl)-amino1-ethyl}-1H-imidazol-4-yl)-benzoic acid

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STEP A. 1-[4-(3-Bromo-phenyl)-1H-imidazol-2-yl]-ethylamine
Using the procedure described in Example 6, and the appropriately
substituted starting materials and reagents, 1-[4-(3-bromo-phenyl)-1H-imidazol-
2-yl]-ethylamine was prepared.
STEP B. {1-[4-(3-Bromo-phenyl)-1 H-imidazol-2-yl]-ethylH3,4-dimethoxy-
benzyl)-amine
Using the procedure described in Example 4, and substituting 1-[4-(3-
bromo-phenyl)-1 H-imidazol-2-yl]-ethylamine for 1-(4-phenyl-1 H-imidazol-2-yl)-
ethylamine, the product was prepared.
STEP C. [1-[{1-[4-(3-Bromo-phenyl)-1 H-imidazol-2-yl]-ethyl}-(3,4-
dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-
ethyl]-carbamic acid terf-butyl ester
Using the procedure of Example 3 for the conversion of Cpd 3d to Cpd
3e, substituting {1-[4-(3-Bromo-phenyl)-1 H-imidazol-2-yl]-ethyl}-(3,4-dimethoxy-
benzyl)-amine for Cpd 3d and substituting 2-terf--Butoxycarbonylamino-3-(4-
carbamoyl-2,6-dimethyl-phenyl)-propionic acid for 2-terf-Butoxycarbonylamino-
3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid, the product was prepared.
Step D. 3-(2-{1-[[2-ferf-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-
phenyl)-propionyl]-(3,4-dimethoxy-benzyl)-amino]-ethyl}-1H-imidazol-4-
yl)-benzoic acid
To a solution of [1 -[{1 -[4-(3-bromo-phenyl)-1 H-imidazol-2-yl]-ethyl}-(3,4-
dimethoxy-benzyl)-carbamoyl]-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-
carbamic acid tert-butyl ester (290 mg; 0.40 mmol) in DMF (5mL) was added
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K2CO3 (262 mg; 1.9 mmol) and the resulting mixture was degassed with Argon
for 5 min. At this time, Pd(OAc)2 (8.9 mg; 0.04 mmol) and 1,1-
bis(diphenylphosphino) ferrocene (46 mg; 0.083 mmol) were added. Carbon
monoxide was then bubbled through the resulting mixture for 10 min at room
temperature, the reaction was capped, and warmed to 100°C for 6 h. After
cooling to room temperature the mixture was partitioned between EtOAc and
water, filtered through Celite, and then separated. The aqueous phase was
then washed with a second portion of EtOAc. The aqueous phase was then
acidified to pH 5 with 2N citric acid and the resulting aqueous solution extracted
with EtOAc (4x). These latter EtOAc extracts were combined, dried over
Na2SO4, filtered, and concentrated under reduced pressure to yield the crude
product (HPLC: 87% at 254 nm).
Step E. 3-(2-{1-[[2-Amino -3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-
(3,4-dimethoxy-benzyl)-amino]-ethyl}-1 H-imidazol-4-yl)-benzoic acid
3-(2-{1-[[2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-
phenyl)-propionyl]-(3,4-dimethoxy-benzyl)-amino]-ethyl}-1H-imidazol-4-yl)-
benzoic acid may be BOC-de-protected using the procedure described in
Example 3 for the conversion of Cpd 3e to Cpd 3f to yield the title compound.
Example 8
4-(2-Amino-2-fr2-hvdroxv-1-(4-phenyl-1 H-imidazol-2-vl)-ethyl]-isopropyl-
carbamoyl)-ethvl)-3,5-dimethvl-benzamide

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STEP A. [2-Benzyloxy-1-(2-oxo-2-phenyl-ethylcarbamoyl-ethyl]-carbamic
acid tert butyl ester
The product was prepared using the procedure described in Example 3
and substituting N--BOC-L-serine benzyl ester for N--CBZ-L-alanine.
STEP B. [2-Benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethyl]-carbamic acid
tert butyl ester
By the procedure described in Example 3 for the conversion of Cpd 3a
to Cpd 3b, [2-benzyloxy-1-(2-oxo-2-phenyl-ethylcarbamoyl-ethyl]-carbamic acid
tert butyl ester was converted to the product.
STEP C. [2-Benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethylamine
[2-benzyloxy-1-(4-phenyl-1 H-imidazol-2-yl-ethyl]-carbamic acid tert butyl
ester may be BOC-deprotected using the procedure described in Example 3 for
the conversion of Cpd 3e to Cpd 3f to give the product.
STEP D. [2-Benzyloxy-1-(4-phenyl-1 H-imidazol-2-yl-ethyl]-isopropyl-amine
By the procedure described in Example 3 for the conversion of Cpd 3c
to Cpd 3d, [2-benzyloxy-1-(4-phenyl-1H-imidazol-2-yl-ethylamine was
converted to the product.
STEP E. [1-{[2-Benzyloxy-1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-isopropyl-
carbamoyl}-2-(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-
butyl ester
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Using the procedure of Example 3 for the conversion of Cpd 3d to Cpd
3e, substituting [2-benzyloxy-1-(4-phenyl-1 H-imidazol-2-yl-ethyl]-isopropyl-
amine for Cpd 3d and substituting 2-tert-Butoxycarbonylamino-3-(4-carbamoyl-
2,6-dimethyl-phenyl)-propionic acid for 2-tert-butoxycarbonylamino-3-(4-
hydroxy-2,6-dimethyl-phenyl)-propionic acid, the product was prepared.
STEP F. 4-(2-Amino-2-{[2-hydroxy-1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-
isopropyl-carbamoyl}-ethyl)-3,5-dimethyl-benzamide (TFA salt). A solution
of [1 -{[2-benzyloxy-1 -(4-phenyl-1 H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-2-
(4-carbamoyl-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester, (0.287
g, 0.439 mmol), in chloroform (10 ml_) was cooled in an ice bath and treated
with 0.62 mL (4.4 mmol) of iodotrimethylsilane. The reaction, which
immediately clouded, was warmed slowly to room temperature while stirring.
After 16 h, the reaction was cooled in an ice bath to 5-10°C and treated with
100 mL of MeOH. The quenched mixture was stirred at 5-10°C for 30 min,
removed from the ice bath and stirred for an additional 30 min, and
concentrated in vacuo to yield an orange residue that was subjected to reverse
phase HPLC (water/ acetonitrile / 0.1% TFA). The fractions of interest were
combined and the sample was lyophilized to yield 4-(2-amino-2-{[2-hydroxy-1-
(4-phenyl-1 H-imidazol-2-yl)-ethyl]-isopropyl-carbamoyl}-ethyl)-3,5-dimethyl-
benzamide (TFA salt) as a white powder (HPLC: 99% @ 254 nm and 100% @
214 nm)
MS (ES+) (relative intensity): 464.1 (100) (M+1).
Example 9
84
(S)-2-tert-Butoxvcarbonvlamino-3-(2,6-dimethvl-4-
trifluoromethanesulfonylphenyl)-propionic acid methyl ester


WO 2006/099060 PCT/US2006/008450

STEP A. (S)-2-terf-Butoxycarbonylamino-3-(2,6-dimethyl-4-
trifluoromethanesulfonylphenyl)-propionic acid methyl ester
Into a cool solution of Boc-L-(2,6-diMe)Tyr-OMe (7.0 g, 21.6 mmol;
Sources: Chiramer or RSP AminoAcidAnalogues) and N-
phenyltrifluoromethanesulfonimide (7.9 g, 22.0 mmol) in dichloromethane (60
mL) was added triethylamine (3.25 mL, 23.3 mmol). The resulting solution was
stirred at 0°C for 1 h and slowly warmed to room temperature. Upon
completion, the reaction was quenched by addition of water. The separated
organic phase was washed with 1N NaOH aqueous solution, water and dried
over Na2SO4 overnight. After filtration and evaporation, the residue was
purified by flash column chromatography (eluent: EtOAc-hexane: 3:7) to yield
the desired product as a clear oil.
1H NMR (300 MHz, CDCI3): δ 1.36 (9H, s), 2.39 (6H, s), 3.06 (2H, 6,J =
7.7 Hz), 3.64 (3H, s), 4.51-4.59 (1H, m), 5.12 (1H, d, J= 8.5 Hz), 6.92 (2H, s)
MS (ES+) (relative intensity): 355.8 (100) (M-Boc)+.
STEPB. (S)-4-(2-tert-Butoxycarbonylamino-2-methoxycarbonylethyl)-3,5-
dimethylbenzoic acid
To a suspension of (S)-2-tert-butoxycarbonylamino-3-(2,6-dimethyl-4-
trifluoromethanesulfonylphenyl)-propionic acid methyl ester (9.68 g, 21.3
mmol), K2CO3(14.1 g, 0.102 mol), Pd(OAc)2 (0.48 g, 2.13 mmol) and 1,1'-
bis(diphenylphosphino)ferrocene (2.56 g, 4.47 mmol) in DMF (48 ml_) was
bubbled in gaseous CO for 15 min. The mixture was heated to 60°C for 8 h
with a CO balloon. The cool mixture was partitioned between NaHCO3 and
EtOAc, and filtered. The aqueous layer was separated, acidified with 10% citric
acid aqueous solution, extracted with EtOAc, and finally dried over Na2SO4.
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Filtration and concentration of the filtrate resulted in a residue. The residue
was recrystallized from EtOAc-hexanes to yield the desired product.
1H NMR (300 MHz, CDCI3): 8 1.36 (9H, s), 2.42 (6H, s), 3.14 (2H, J= 7.4
Hz), 3.65 (3H, s), 4.57-4.59 (1H, m), 5.14 (1H, d, J= 8.6 Hz), 7.75 (2H, s)
MS(ES+) (relative intensity): 251.9 (100) (M-Boc)+.
STEP C. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-
dimethylphenyl)propionic acid methyl ester
Into a stirring solution of (S)-4-(2-tert-butoxycarbonylamino-2-
methoxycarbonylethyl)-3,5-dimethylbenzoic acid (3.00 g, 8.54 mmol), PyBOP
(6.68 g, 12.8 mmol) and HOBt(1.74g, 12.8 mmol) in DMF (36 ml_) was added
DIPEA (5.96 ml_, 34.2 mmol) and NH4CI (0.92 g, 17.1 mmol). The resulting
mixture was stirred at rt for 40 min before being partitioned between aqueous
NH4CI solution and EtOAc. The separated organic phase was washed
sequentially with 2N citric acid aqueous solution, saturated aqueous NaHCO3
solution, and brine, then dried over Na2SO4 overnight. After filtration and
concentration, the residue was purified by flash column chromatography
(eluent: EtOAc) to yield the product.
1H NMR (300 MHz, CDCI3): 5 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J =
7.2 Hz), 3.65 (3H, s), 4.53-4.56 (1H, m), 5.12 (1H, d, J= 8.7 Hz), 5.65 (1H, br
s), 6.09(1 H, brs), 7.46 (2H, s)
MS(ES+) (relative intensity): 250.9 (100) (M-Boc)+.
STEP D. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-
dimethylphenyl)propionic acid
Into an ice-cooled solution of methyl ester from Step C (2.99 g, 8.54
mmol) in THF (50 ml_) was added an aqueous LiOH solution (1N, 50 mL) and
stirred at 0°C. Upon consumption of the starting materials, the organic solvents
were removed and the aqueous phase was neutralized with cooled 1N HCI at
0°C, and extracted with EtOAc, and dried over Na2SO4 overnight. Filtration and
evaporation to dryness yielded the title acid (S)-2-tert-butoxycarbonylamino-3-
(4-carbamoyl-2,6-dimethylphenyl)propionicacid.
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1H NMR (300 MHz, DMSO-d6): δ 1.30 (9H, s), 2.32 (6H, s), 2.95(1 H, dd,
J = 8.8, 13.9 Hz), 3.10 (1H, dd, J= 6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23
(2H, m), 7.48 (2H,s), 7.80(1 H,s)
MS(ES+) (relative intensity): 236.9 (6) (M-Boc)+.
Example 10
(Z)-2-Ben2vloxvcarbonvlamino-3-(4-carbamovl-2,6-dimethyl-
phenyl)acrylic acid methyl ester

STEP A. Trifluoromethanesulfonic acid 4-bromo-3,5-dimethyl-phenyl ester
To a cooled (0°C) solution of 4-bromo-3,5-dimethylphenol (3.05 g, 15.2
mmol) in pyridine (8 ml_) was added trifluoromethanesulfonic anhydride (5.0 g,
17.7 mmol) dropwise. After completion of addition, the resulting mixture was
stirred at 0°C for 15 min and at room temperature overnight. The reaction was
then quenched by addition of water, then extracted with EtOAc. The EtOAc
extracts were washed with water, 2/V HCI (2 x ), brine and dried over MgSO4.
Filtration and evaporation to dryness yield the product (10a) as a colorless oil.
1H NMR (300 MHz, CDCI3): 5 2.45 (6H, s), 7.00 (2H, s).
STEP B. 4-Bromo-3,5-dimethylbenzoic acid
Into a solution of trifluoro-methanesulfonic acid 4-bromo-3,5-dimethyl-
phenyl ester (6.57 g, 19.7 mmol) in DMF (65 mL) were added K2CO3 (13.1 g,
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94.7 mmol), Pd(OAc)2 (0.44 g, 1.97 mmol) and 1,1'-
bis(diphenylphosphino)ferrocene (2.29 g, 4.14 mmol). The resulting mixture
was bubbled in gaseous CO for 10 min and was then heated to 60°C for 7.5 h
with a CO balloon. The cooled mixture was partitioned between aqueous
NaHCO3 and EtOAc, and filtered. The aqueous phase layer was separated,
acidified with aqueous 6/V HCI, extracted with EtOAc, and then dried over
Na2SO4. Filtration and concentration of the filtrate resulted in the crude
product (10b) as a brown residue, which was used in the next step without
further purification.
STEP C. 4-Formyl-3,5-dimethyl-benzoic acid
A solution of 4-bromo-3,5-dimethylbenzoic acid (0.92 g, 4 mmol) in THF
(10 mL) was cooled down to -100C with N2(l)-Et2O bath and added n-
butyllithium (1.6 M in hexanes, 5 ml_, 8 mmol) slowly. After completion of
addition, the reaction mixture was warmed to -78OC and DMF (0.74 ml_, 8
mmol) was added dropwise. The resulting mixture was stirred at - 78OC for 1.5
h and allowed to warm to -209C, followed by the addition of 2N aqueous HCI
(30 ml_). The organic phase was separated and the aqueous phase was
extracted with EtOAc, the combined organic phases were dried over MgSO4.
The solvent was removed and the resulting residue was purified by flash
column chromatography (eluent: EtOAc-hexanes~1:1) to yield 4-formyl-3,5-
dimethyl-benzoic acid (10c).
1H NMR (300 MHz, CDCI3): 5 2.65 (6H, s), 7.82 (2H, s), 10.67(1 H, s).
STEP D. 4-Formyl-3,5-dimethyl-benzamide
To a solution of 4-formyl-3,5-dimethyl-benzoic acid ( 0.15 g, 0.85 mmol)
in DMF (6 mL) were added PyBOP (1.0 g, 1.92 mmol), HOBt (0.26 g, 1.92
mmol), DIPEA (0.89 mL, 5.12 mmol) and NH4CI (0.14 g, 2.56 mmol). The
resulting mixture was stirred at room temperature for 1 h, and quenched by
addition of brine, then extracted with EtOAc. The organic phase was washed
with 2N aqueous HCI, saturated NaHCO3, brine and then dried over MgSO4.
The solvent was removed to yield the crude product (10d), which was used in
the next step without further prurification.
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STEP E. (Z)-2-Benzyloxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-
phenyl)acrylic acid methyl ester
Into a solution of N-(benzyloxycarbonyl)-a-phosphinoglycine trimethyl
ester (0.46 g, 1.4 mmol) in DCM (5 mL) was added DBU (0.21 mL, 1.4 mmol).
After stirring for 10 min, a solution of the above made 4-formyl-3,5-dimethyl-
benzamide in DCM (5 mL) was added dropwise. The resulting mixture was
stirred at room temperature for 5.5 h and the solvent was removed by rotary
evaporation. The residue was dissolved in EtOAc and washed with 1N
aqueous HCI, brine and then dried over MgSO4. The solvent was removed and
the residue purified by flash column chromatography (eluent: EtOAc-
hexanes~1:1) to yield (Z)-2-te/f-butoxycarbonylamino-3-(4-carbamoyl-2,6-
dimethyl-phenyl)acrylic acid methyl ester (10e) as a white solid.
MS(ES+) (relative intensity): 383.4 (10%)(M+1).
Example 11
(Z)-2-Benzvloxvcarbonvlamino-3-(4-carbamoyl-2,6-dimethvl-
phenyl)acrylic acid methyl ester

STEP A. 4-Hydroxy-3,5-dimethyl-benzamide
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Using the procedure described in Example 10, Step D, 4-hydroxy-3,5-
dimethyl-benzamide (11a) was prepared as a yellowish solid.
1H NMR (300 MHz, CDCI3): δ 2.82 (6H, s), 5.51 (1H, brs), 5.90 (1H, br
s), 7.48 (2H, s);
MS(ES+) (relative intensity): 166.2 (8%)(M+1).
STEP B. Trifluoromethanesulfonic acid 4-carbamoyl-2,6-dimethyl-phenyl
ester
Into a solution of 4-hydroxy-3,5-dimethyl-benzamide (3.72 g, 22.5 mmol)
and N-phenyltrifluoromethanesulfoniunimide (9.4 g, 25 mmol) in DCM (80 mL
was added TEA (3.48 mL, 25 mmol) at room temperature, then the resulting
mixture was stirred at room temperature overnight. After the reaction was
quenched by addition of water, the separated organic phase was washed with
1N NaOH, water and then dried over MgSO4. The solvent was removed and
the residue purified by flash column chromatography (eluent: EtOAc-
hexanes~1:1) to yield trifluoromethanesulfonic acid 4-carbamoyl-2,6-dimethyl-
phenyl ester (11 b) as a white solid.
1H NMR (300 MHz, CDCI3): 5 2.42 (6H, s), 6.28 (2H, br s), 7.57 (2H, s)
MS(ES+) (relative intensity): 298.1 (63%)(M+1).
STEP C. 4-Formyl-3,5-dimethyl-benzamide
Into a solution of trifluoro-methanesulfonic acid 4-carbamoyl-2,6-
dimethyl-phenyl ester (1.49 g, 5 mmol), Pd(OAc)2 (0.037 g, 0.15 mmol), DPPP
(0.062 g, 0.15 mmol) and TEA (1.74 mL, 12.5 mmol) in DMF (25 mL) was
bubbled CO (gas) for 10 min, then triethylsilane (1.6 mL, 10 mmol) was added.
The resulting mixture was stirred at 75°C under a CO gas balloon for 6.5 hr.
After cooling to room teperature, the reaction was quenched by addition of
water, then extracted with EtOAc. The EtOAc extracts were washed with water,
brine and then dried over MgSO4. After filtration and evaporation, the residue
was purified by column chromatograpghy (eluent, EtOAc-hexanes~1:1) to yield
4-formyl-3,5-dimethyl-benzamide (11c) as a yellowish solid.
1H NMR (300 MHz, CDCI3): 5 2.65 (6H, s), 5.75 (1H, br s), 6.13 (1H, br
s),7.52(2H, s), 10.64(1 H, s).
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STEP D. (Z)-2-Benzyloxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-
phenyl)acrylic acid methyl ester
The title compound was prepared as described in Example 10, Step E.
Example 12 Optical Rotation Measurements
The optical rotation of a representative sample of the compound of
formula (la), prepared as in Example 1, was measured as [a] D = -12 (c 1.5,
MeOH).
The optical rotation of a representative sample of the compound of
formula (la), prepared as in Example 9, from commercially purchased (S)-N-
BOC-Tyr-OMe was measured as [] D = -10.8 (c 1.7, MeOH).
While the foregoing specification teaches the principles of the present
invention, with examples provided for the purpose of illustration, it will be
understood that the practice of the invention encompasses all of the usual
variations, adaptations and/or modifications as come within the scope of the
following claims and their equivalents.
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We Claim:
1. A process for the preparation of a compound of formula (I)

wherein
is C6-10aryl or a heteroaryl selected from the group consisting of
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl,
benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl,
isoquinolinyl and quinazolinyl;
each R41P is independently selected from C1-6alkyl, C-1-6alkoxy or fluoro;
RJ and RK are each independently selected from hydrogen or C1-6alkyl;
alternatively, RJ and RK are taken together with the nitrogen atom to which they
are bound to form a five to seven membered heterocyclyl;
Pg1 is a nitrogen protecting group;
comprising

reacting a compound of formula (X), wherein Xp is selected from OH,
CN, -CO2H, -C(O)-CI or-C(O)-OC1-4alkyl and wherein Yp is selected from Br,
Cl or I, to yield the corresponding compound of formula (XII);
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WO 2006/099060 PCT/US2006/008450

reacting the compound of formula (XII) with a suitably substituted
compound of formula (XVIII); in the presence of palladium catalyst; in the
presence of an organic or inorganic base; in an organic solvent; at a
temperature greater than about room temperature; to yield the corresponding
compound of formula (XIX);

reacting the compound of formula (XIX) with hydrogen or a source of
hydrogen; in the presence of a catalyst; in a solvent; at a temperature greater
than about room temperature; to yield the corresponding compound of formula
(XX);

reacting the compound of formula (XX) with an aqueous base; in an
organic solvent; to yield the corresponding compound of formula (I).
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2. The process as in Claim 1, wherein
is phenyl;
the phenyl is substituted with a R41P group at the 2-position and a
second R41P group at the 4- position;
each R41P is independently selected from C1-2alkyl, C1-2alkoxy or fluoro;
RJ and RK are each independently selected from hydrogen or C1-4alkyl;
alternatively, RJ and RK are taken together with the nitrogen atom to which they
are bound to form a five to seven membered heterocyclyl; and
Pg1 is a nitrogen protecting group.
3. The process as in Claim 1, wherein is phenyl; the phenyl is
substituted with a R41P group at the 2-position and a second R41P group at the
4- position; each R41P is methyl; RJ and RK are each hydrogen; and Pg1 is a t-
butoxycarbonyl.
4. A process for the preparation of a compound of formula (I)

wherein
i
is C6-ioaryl or a heteroaryl selected from the group consisting of
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl,
benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl,
isoquinolinyl and quinazolinyl;
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each R41P is independently selected from C1-6alkyl, C1-6alkoxy or fluoro;
RJ and RK are each independently selected from hydrogen or C1-6alkyl;
alternatively, RJ and RK are taken together with the nitrogen atom to which they
are bound to form a five to seven membered heterocyclyl;
Pg1 is a nitrogen protecting group;
F
reacting the compound of formula (XIX) with hydrogen or a source of
hydrogen; in the presence of a catalyst; in a solvent; at a temperature greater
than about room temperature; to yield the corresponding compound of formula
(XX);

reacting the compound of formula (XX) with an aqueous base; in an
organic solvent; to yield the corresponding compound of formula (I).
5. A process for the preparation of a compound of formula (la)

comprising
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WO 2006/099060 PCT/US2006/008450

reacting a compound of formula (Xa), wherein Xp is selected from OH,
CN, -CO2H, -C(O)-CI or-C(O)-OC1.4alkyl and wherein Yp is selected from Br,
Cl or I, to yield the corresponding compound of formula (Xlla);
3
reacting the compound of formula (Xlla) with a suitably substituted
compound of formula (XVIIIa); in the presence of palladium catalyst; in the
presence of an organic or inorganic base; in an organic solvent; at a
temperature greater than about room temperature; to yield the corresponding
compound of formula (XlXa);

reacting compound of formula (XlXa) with hydrogen gas, at a pressure
sufficient to hydrogenate; in the presence of a suitable chiral catalyst; at a
temperature greater than about room temperature; in an organic solvent; to
yield the corresponding compound of formula (XXa);
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reacting the compound of formula (XXa) with an aqueous base; in an
organic solvent; to yield the corresponding compound of formula (la).
6. The process as in Claim 5, wherein Xp is -OH and wherein Yp is Br.
7. The processas in Claim 6, further comprising
reacting the compound of formula (Xa), with a triflating reagent; in the
presence of an organic or inorganic base; to yield the corresponding compound
of formula (Xla);

reacting the compound of formula (Xla) with carbon monoxide and a
suitable source of ammonia; in the presence of a palladium catalyst in
combination with a suitable ligand; or in the presence of a palladiunrligand
complex; at a temperature in the range of from about 50°C to about 160°C; in
an organic solvent; to yield the corresponding compound of formula (XII).
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8. The process as in Claim 5, wherein the compound of formula (Xlla) is
reacted with the compound of formula (XVIIIa) in the presence of Pd2(dba)3
and P(o-toluene)3.
9. The process as in Claim 5, wherein the chiral catalyst is [Rh(cod)(R,R-
DIPAMP)]+BF4".
10. A process for the preparation of the compound of formula (la)

reacting compound of formula (XlXa) with hydrogen gas, at a pressure
sufficient to hydrogenate; in the presence of a suitable chiral catalyst; at a
temperature greater than about room temperature; in an organic solvent; to
yield the corresponding compound of formula (XXa);

reacting the compound of formula (XXa) with an aqueous base; in an
organic solvent; to yield the corresponding compound of formula (la).
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11. A product prepared according to the process of Claim 1.
12. A product prepared according to the process of Claim 4.
13. A product prepared according to the process of Claim 5.
14. A product prepared according to the process of Claim 10.
15. A process for the preparation of compounds of formula (II)

wherein
is C6-10aryl or a heteroaryl selected from the group consisting of
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolinyl, benzofuryl, benzothienyl,
benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolizinyl, quinolinyl,
isoquinolinyl and quinazolinyl;
each R41P is independently selected from C1.6alkyl, C1-6alkoxy or fluoro;
RJ and RK are each independently selected from hydrogen or C1-4alkyl;
alternatively, RJ and RK are taken together with the nitrogen atom to which they
are bound to form a five to seven membered heterocyclyl;
R1 is selected from the group consisting of hydrogen, C1-6alkyl,
cycloalkyl, heterocyclyl, aryl(C1-6)alkyl, and heteroaryl(C1-6)alkyl;
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WO 2006/099060 ' PCT/US2006/008450
wherein when R1 is phenyl(C1-6)alkyl, phenyl is optionally fused to a
heterocyclyl or cycloalkyl;
wherein when R1 is C1-2alkyl, said C1-2alkyl is optionally substituted with
one to two substituents independently selected from the group
consisting of C1.6alkoxy, aryl, cycloalkyl, heterocyclyl, hydroxy, cyano,
amino, C1-6alkylamino, (C1-6alkyl)2amino, trifluoromethyl, and carboxy;
and further, wherein when R1 is C3.6alkyl, said C3-6alkyl is optionally
substituted with one to three substituents independently selected from
the group consisting of C1-6alkoxy, aryl, cycloalkyl, heterocyclyl, hydroxy,
cyano, amino, Ci-6alkylamino, (C1-6alkyl)2amino, trifluoromethyl, and
carboxy;
wherein the cycloalkyl and heterocyclyl of C1-2alkyl and C3-6alkyl are
optionally substituted with one to two substituents independently
selected from the group consisting of C1-6alkyl, hydroxy(C1.6)alkyl, C1--
6alkoxy, hydroxy, cyano, amino, C1-6alkylamino, (C1-6alkyl)2amino,
trifluoromethyl, carboxy, aryl(C1-6)alkoxycarbonyl, C1-6alkoxycarbonyl,
aminocarbonyl, C1-6alkylaminocarbonyl, (C1-6alkyl)2aminocarbonyl, and
aminosulfonyl;
furthermore, wherein the cycloalkyl and heterocyclyl of R1 are optionally
substituted with one to two substituents independently selected from the
group consisting of C1-6alkyl, hydroxy(C1-6)alkyl, C1-6alkoxy, hydroxy,
cyano, amino, C1-6alkylamino, (C1-6alkyl)2amino, trifluoromethyl, carboxy,
aryl(Ci-6)alkoxycarbonyl, Ci-6alkoxycarbonyl, aminocarbonyl, C1-
6alkylaminocarbonyl, (C1-6alkyl)2aminocarbonyl, and aminosulfonyl;
furthermore, wherein the aryl and heteroaryl portion of the R1
substituents aryl(C1-6)alkyl and heteroaryl(C1-6)alkyl, are optionally
substituted with one to three R11 substituents independently selected
from the group consisting of C1-6alkyl; hydroxy(C1-6)alkyl; C1-6alkoxy; C6-
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10aryl(C1-6)alkyl; C1-6aryl(C1-6)alkoxy; C6-10aryl; heteroaryl optionally
substituted with one to two substituents independently selected from the
group consisting of C1-4alkyl, C1-4alkoxy, and carboxy; cycloalkyl;
heterocyclyl; C6-10oaryloxy; heteroaryloxy; cycloalkyloxy; heterocyclyloxy;
amino; C1-6alkylamino; (C1-6alkyl)2amino; C3.6cycloalkylaminocarbonyl;
hydroxy(C1-6)alkylaminocarbonyl; C6-10arylaminocarbonyl wherein C6.
10aryl is optionally substituted with carboxy or C1-4alkoxycarbonyl;
heterocyclylcarbonyl; carboxy; C1-6alkylcarbonyloxy; Cv6alkoxycarbonyl;
C1-6alkylcarbonyl; C1-6alkylcarbonylamino; aminocarbonyl; C1-
6alkylaminocarbonyl; (C1-6alkyl)2aminocarbonyl; cyano; halogen;
trifluoromethyl; trifluoromethoxy; and hydroxy;
provided that no more than one R11 substituent is selected from the
group consisting of C1-6aryl(C1-6)alkyl; C6-10aryl(C1-6)alkoxy; C6-10aryl;
heteroaryl optionally substituted with one to two substituents
independently selected from the group consisting of C1-4alkyl, C1-4alkoxy,
and carboxy; cycloalkyl; heterocyclyl; C6-10aryloxy; heteroaryloxy;
cycloalkyloxy; C6-10arylaminocarbonyl, heterocyclylcarbonyl; and
heterocyclyloxy;
R2 is hydrogen, C1-8alkyl, hydroxy(C1-8)alkyl, C6-10aryl(C1-6)alkoxy(C1-
6)alkyl, or C1-6aryKC1-8alkyl;
wherein the C6-10aryl group in the C6-10aryl-containing substituents of R2
is optionally substituted with one to two substituents independently
selected from the group consisting of C1-6alkyl, C1-6alkoxy, hydroxy,
amino, C1-6alkylamino, (C1-6alkyl)2amino, aminocarbonyl, C1-
6alkylaminocarbonyl, (C1-6alkyl)2aminocarbonyl, cyano, fluoro, chloro,
bromo, trifluoromethyl, and trifluoromethoxy; and, wherein the C1-6alkyl
and C1.6alkoxy substituents of aryl are optionally substituted with
hydroxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, or aryl;
A is selected from the group consisting of aryl, ring system a-1, a-2, a-3,
and a-4, optionally substituted with R3 and R5;
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wherein A-B is selected from the group consisting of N-C, C-N, N-N and
C-C; wherein D-E is selected from the group consisting of O-C, S-C, and O-
N; and wherein F-G is selected from the group consisting of N-0 and C-O;
R3 is one to two substituents independently selected from the group
consisting of C1-6alkyl, aryl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl,
heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl(C2-6)alkenyl, heteroaryl(C2-6)alkynyl,
amino, C1-6alkylamino, (C1-6alkyl)2amino, arylamino, heteroarylamino, aryloxy,
heteroaryloxy, trifluoromethyl, and halogen;
wherein the aryl and heteroaryl, as well as the aryl and heteroaryl of
aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, heteroaryKC1-6alkyl,
heteroaryl(C2-6)alkenyl, heteroaryl(C2-6)alkynyl, arylamino,
heteroarylamino, aryloxy, and heteroaryloxy, are optionally substituted
with one to five fluoro substituents or one to three substituents
independently selected from the group consisting of C1-6alkyl,
hydroxy(C1-6)alkyl, C1-6aikoxy, C6-10aryl(C1-6)alkyl, C6-10oaryl(C1-6)alkoxy,
C6-10oaryl, C6-10oaryloxy, heteroaryl(C1-6)alkyl, heteroaryl(C1-6)alkoxy,
heteroaryl, heteroaryloxy, C6-10arylamino, heteroarylamino, amino, C1-
6alkylamino, (C1-6alkyl)2amino, carboxy(C1-6)alkylamino, carboxy, C1-
6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino,
aminocarbonyl, C1-6alkylaminocarbonyl, (C1-6alkyl)2aminocarbonyl,
carboxy(C1-6)alkylaminocarbonyl, cyano, halogen, trifluoromethyl,
trifluoromethoxy, hydroxy, C1-6alkylsulfonyl, and C1-6alkylsulfonylamino;
provided that not more than one R3 is selected from the group consisting
of aryl, heteroaryl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl,
heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl(C2-6)alkenyl, heteroaryl(C2-
6)alkynyl, arylamino, heteroarylamino, aryloxy, and heteroaryloxy;
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WO 2006/099060 PCT/US2006/008450
and wherein C1-6alkyl, and C1-6alkyl of aryKC1-6alkyl and heteroaryl(C1-
6)alkyl, are optionally substituted with a substituent selected from the
group consisting of hydroxy, carboxy, C1-4alkoxycarbonyl, amino, C1--
6alkylamino, (C1-6alkyl)2amino, aminocarbonyl, (C1-6alkylaminocarbonyl,
di(C1-4)alkylaminocarbonyl, aryl, heteroaryl, arylamino, heteroarylamino,
aryloxy, heteroaryloxy, aryl(C1-4)alkoxy, and heteroaryl(C1-4)alkoxy;
R5 is a substituent on a nitrogen atom of ring A selected from the group
consisting of hydrogen and C1-4alkyl;
Ra and Rb are independently selected from the group consisting of
hydrogen, C1-6alkyl, and C1-6alkoxycarbonyl; alternatively, when Raand Rbare
each other than hydrogen, Raand Rbare optionally taken together with the
nitrogen atom to which they are both attached to form a five to eight membered
monocyclic ring;
and pharmaceutically acceptable enantiomers, diastereomers,
racemates, and salts thereof;
comprising

reacting a compound of formula (X), wherein Xp is selected from OH,
CN, -CO2H, -C(O)-CI or -C(O)-OC1-4alkyl and wherein Yp is selected from Br,
Cl or I, to yield the corresponding compound of formula (XII);
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WO 2006/099060 PCT/US2006/008450

reacting the compound of formula (XII) with a suitably substituted
compound of formula (XVIII), wherein Pg1 is a nitrogen protecting group; in the
presence of palladium catalyst; in the presence of an organic or inorganic base;
in an organic solvent; at a temperature greater than about room temperature; to
yield the corresponding compound of formula (XIX);

reacting the compound of formula (XIX) with hydrogen or a source of
hydrogen; in the presence of a catalyst; in a solvent; at a temperature greater
than about room temperature; to yield the corresponding compound of formula
(XX);

reacting the compound of formula (XX) with an aqueous base; in an
organic solvent; to yield the corresponding compound of formula (I);
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reacting the compound of formula (I), to yield the corresponding
compound of formula (II).
16. The process as in Claim 15, wherein
is phenyl;
the phenyl is substituted with a R41P group at the 2-position and a
second R41P group at the 4- position;
each R41P is independently selected from C1-2alkyl, C1-2alkoxy or fluoro;
RJ and RK are each independently selected from hydrogen or C1-4alkyl;
alternatively, RJ and RK are taken together with the nitrogen atom to which they
are bound to form a five to seven membered heterocyclyl; and
Pg1 is a nitrogen protecting group.
17. The process as in Claim 15, wherein is phenyl; the phenyl is
substituted with a R41P group at the 2-position and a second R41P group at the
4- position; each R41P is methyl; RJ and RK are each hydrogen; and Pg1 is a t-
butoxycarbonyl.
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18. A product prepared according to the process of Claim 15.

The present invention is directed to novel processes for the
preparation of opioid modulators (agonists and antagonists) and
intermediates in their synthesis. The opioid modulators are useful for
the treatment and prevention of as pain and gastrointestinal
disorders.

Documents:

03419-kolnp-2007-abstract.pdf

03419-kolnp-2007-claims.pdf

03419-kolnp-2007-correspondence others 1.1.pdf

03419-kolnp-2007-correspondence others 1.2.pdf

03419-kolnp-2007-correspondence others.pdf

03419-kolnp-2007-description complete.pdf

03419-kolnp-2007-form 1 1.1.pdf

03419-kolnp-2007-form 1.pdf

03419-kolnp-2007-form 2.pdf

03419-kolnp-2007-form 3.pdf

03419-kolnp-2007-form 5.pdf

03419-kolnp-2007-gpa.pdf

03419-kolnp-2007-international publication.pdf

03419-kolnp-2007-international search report.pdf

03419-kolnp-2007-pct priority document notification.pdf

03419-kolnp-2007-pct request form.pdf

3419-KOLNP-2007-(01-02-2013)-ANNEXURE TO FORM 3.pdf

3419-KOLNP-2007-(01-02-2013)-CORRESPONDENCE.pdf

3419-KOLNP-2007-(23-08-2012)-ABSTRACT.pdf

3419-KOLNP-2007-(23-08-2012)-AMANDED CLAIMS.pdf

3419-KOLNP-2007-(23-08-2012)-ANNEXURE TO FORM 3.pdf

3419-KOLNP-2007-(23-08-2012)-DESCRIPTION (COMPLETE).pdf

3419-KOLNP-2007-(23-08-2012)-EXAMINATION REPORT REPLY RECEIVED.pdf

3419-KOLNP-2007-(23-08-2012)-FORM-1.pdf

3419-KOLNP-2007-(23-08-2012)-FORM-2.pdf

3419-KOLNP-2007-(23-08-2012)-OTHERS -1.pdf

3419-KOLNP-2007-(23-08-2012)-OTHERS.pdf

3419-KOLNP-2007-(23-08-2012)-PETITION UNDER RULE 137.pdf

3419-kolnp-2007-form 18.pdf


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Patent Number 256363
Indian Patent Application Number 3419/KOLNP/2007
PG Journal Number 24/2013
Publication Date 14-Jun-2013
Grant Date 07-Jun-2013
Date of Filing 13-Sep-2007
Name of Patentee JANSSEN PHARMACEUTICA N.V.
Applicant Address TURNHOUTSEWEG 30, B-2340, BEERSE
Inventors:
# Inventor's Name Inventor's Address
1 CHAOZHONG CAI 129 BANBURY AVENUE, NORTH WALES, PA 19403
2 WEI HE 2002 KESTRAL CIRCLE, AUDUBON, PA 19403
PCT International Classification Number C07D 211/60
PCT International Application Number PCT/US2006/008450
PCT International Filing date 2006-03-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/661,784 2005-03-14 U.S.A.