Title of Invention

PROCESS FOR PREPARING 5-(1, 3-OXAZOL-2-YL) BENZOIC ACID DERIVATIVES

Abstract Disclosed are compounds of formula III and a process to prepare a compound of formula III wherein R1, R2, R3 and R6 are defined herein, using a zinc chloride/optionally substituted oxazole adduct and an compound of formula I. Further disclosed are methods of using compounds of formula III to prepare compounds useful in the treatment of Alzheimer's disease and related conditions. (FIG). nil
Full Text PROCESS FOR PREPARING 5-(1,3-OXAZOL-2-YL) BENSOIC
ACID DERIVATIVES
BACKGROUND OF THE INVENTION
This non-provisional application claims priority from U.S.
Provisional Application S.N. 60/390,285 filed June 20, 2002, and
U.S. Provisional Application 60/450,478 filed February 27, 2003.
Field of the Invention
The invention relates to processes for the preparation of
oxazolyl esters which are useful in preparing pharmaceutically
active compounds. The invention further comprises methods of
preparing the final active compounds. The invention further
comprises compounds useful in the preparation of compounds and
pharmaceutical compositions to treat Alzheimer"s disease and
related conditions.
Description of the Related Art
Synthesis 583 (1996) discloses the coupling of aryl halides
or aryl triflates with an oxazol-2-yl zinc chloride to provide
the corresponding aryl oxazolyl. The invention provides a
method for performing the coupling that unexpectedly affords
improved yields and in many cases, shorter reaction times.
The methods described herein are also suitable for the
preparation of compounds and./or intermediates disclosed in WO
02/02512.
SUMMARY OF INVENTION
In a first aspect, the invention provides processes for
preparing compounds of formula III:

wherein:
R3. is C1-C6 alkoxy, or C1-C6 alkoxyphenyl;

R2 and R3 are independently H; phenyl optionally substituted
with C1-C4 alkyl, C1-C4 alkoxy, or dialkylamino; or C1-C4
alkyl; or
R2 and R3 and the carbons to which they are attached form a
benzo ring, which is optionally substituted with C1-C4
alkyl, C1-C4 alkoxy, or dialkylamino; and
R6 is C1-C6 alkoxy, C1-C6 alkoxyphenyl or NR4R5; wherein
R4 and R5 are independently C1-C6 alkyl or -C1-C6
alkylphenyl;
comprising forming a reaction mixture comprising
a compound of formula I:

X is Br, I, OTf, or OMs;
a compound of formula II:
a catalyst, an optional additive, and at least one solvent.
In a second aspect, the invention provides compounds of
formula III-a:
wherein:
R11 is OH, imidazolyl, halogen, -OC(O)CH3, -OC(O)C2-C4 alkyl,

R2 and R3 are independently H; phenyl optionally substituted
with C1-C4 alkyl, C1-C4 alkoxy, or dialkylamino; or C1-C4
alkyl; or
R2 and R3 and the carbons to which they are attached form a
benzo ring, which is optionally substituted with C1-C4
alkyl, C1-C4 alkoxy, or dialkylamino; and
R6 is C1-C6 alkoxy, C1-C6 alkoxyphenyl, or NR4R5 where R4 and R5
are independently C1-C6 alkyl or -C1-C6 alkylphenyl.
Compounds of formula III-a are useful in preparing
pharmaceutically active compounds. For example, the compounds
of formula III-a are useful in preparing various compounds
pharmaceutically active compounds disclosed in published
international application WO 02/02512.
In a third aspect, the invention provides processes for
preparing compounds of formula XX:

wherein
R10 is - (CH2)1-2-S (O)0-2-(C1-C6 alkyl), or
C1-C10 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from halogen, -OH, =O, -SH,
-C=N, -CF3, -C1-C3 alkoxy, amino, mono- or
dialkylamino, -N(R)C(O)R" - , -OC (=0)-amino and -OC(=O)-
mono- or dialkylamino, or
C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally
substituted with 1, 2, or 3 groups independently
selected from halogen, -OH, -SH, -Cs=N, -CF3, C1-C3
alkoxy, amino, and mono- or dialkylamino, or
aryl, heteroaryl, heterocyclyl, -C1-C6 alkyl-aryl, -C1-C6
alkyl-heteroaryl, or -C1-C6 alkyl-heterocyclyl, where
the ring portions of each are optionally substituted
with 1, 2, 3, or 4 groups independently selected from
halogen, -OH, -SH, -C=N, -NR105R"105, -CO2R, -N(R)COR",
or -N(R)SO2R", -C(=0) - (C1-C4) alkyl, -SO2-amino, -SO2-
mono or dialkylamino, -C(=O)-amino, -C(=O)-mono or
dialkylamino, -SO2-(C1-C4) alkyl, or
C1-C6 alkoxy optionally substituted with 1, 2, or 3
groups which are independently selected from
halogen, or
C3-C7 cycloalkyl optionally substituted with 1, 2, or
3 groups independently selected from halogen,
OH, -SH, -C=N, -CF3/ C1-C3 alkoxy, amino, -Ci-Cs
alkyl and mono- or dialkylamino, or
C1-C10 alkyl optionally substituted with 1, 2, or 3
groups independently selected from halogen, -OH,
-SH, -C=N, -CF3, -C1-C3 alkoxy, amino, mono- or
dialkylamino and -C1-C3 alkyl, or
C2-C10 alkenyl or C2-C10 alkynyl each of which is
optionally substituted with 1, 2, or 3 groups
independently selected from halogen, -OH, -SH,
-GºN, -CF3/ C1-C3 alkoxy, amino, C1-C6 alkyl and
mono- or dialkylamino; and the heterocyclyl group
is optionally further substituted with oxo;
R and R" independently are hydrogen, C1-C10 alkyl, C1-
C10 alkylaryl or C1-C10 alkylheteroaryl ;
R20 is selected from the group consisting of H; C1-C6 alkyl,
optionally substituted with 1, 2, or 3 substituents that
are independently selected from the group consisting of Cx-
C3 alkyl, halogen, -OH, -SH, -GºN, -CF3, C1-C3 alkoxy, and -
NR1-aR1-b; - (CH2)0-4-aryl; - (CH2)0-4-heteroaryl; C2-C6 alkenyl;
C2-C6 alkynyl; -CONRN-2RN-3; -SO2NRn-2RN-3; -CO2H; and -CO2- (C1-
C4 alkyl); wherein
R1-a and Rx-b are independently -H or C1-C6 alkyl;
R30 is selected from the group consisting of H; C1-C6 alkyl,
optionally substituted with 1, 2, or 3 substituents
independently selected from the group consisting of C1-C3
alkyl, halogen, -OH, -SH, -CºN, -CF3, C1-C3 alkoxy, and -NR1-
aR1-b; - (CH2) 0-4-aryl; - (CH2)0-4-heteroaryl; C2-C6 alkenyl; C2-
C6 alkynyl; -CO-NRN-2RN-3; -SO2-NRN-2RN-3; -CO2H; and - CO-O-
(C1-C6alkyl);
or
R20, R30 and the carbon to which they are attached form a
carbocycle of three thru seven carbon atoms, wherein one
carbon atom is optionally replaced by a group selected
from-O-, -S-, -SO2-, or -NRN-2-;
RN-2 and RN-3 at each occurrence are independently selected
from the group consisting of -C1-C8 alkyl optionally
substituted with 1, 2, or 3 groups independently
selected from the group consisting of -OH, -NH2,
phenyl and halogen; -C3-C8 cycloalkyl; - (C1-C2 alkyl)-
(C3-C8 cycloalkyl); - (C1-C6 alkyl)-O-(C1-C3 alkyl); -C2-
C6 alkenyl; -C2-C6 alkynyl; -C1-C6 alkyl chain with one
double bond and one triple bond; aryl; heteroaryl;
heterocycloalkyl;
or
Rn-2, Rn-3 and the nitrogen to which they are attached form a
5, 6, or 7 membered heterocycloalkyl or heteroaryl
group, wherein said heterocycloalkyl or heteroaryl
group is optionally fused to a benzene, pyridine, or
pyrimidine ring, and said groups are unsubstituted or
substituted with 1, 2, 3, 4, or 5 groups that at each
occurrence are independently C1-C6 alkyl, C1-C6 alkoxy,
halogen, halo C1-C6 alkyl, halo C1-C6 alkoxy, -CN, -
NO2, -NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl) (C1-C6 alkyl),
-OH, -C(O)NH2/ -C(O)NH(C1-C6 alkyl) , -C(O)N(C1-C6
alkyl) (C1-C6 alkyl), C1-C6 alkoxy C1-C6 alkyl, C1-C6
thioalkoxy, and C1-C6 thioalkoxy C1-C6 alkyl;
RC is hydrogen, - (CR245R250)0-4-aryl, - (CR245R250)0-4-heteroaryl,
(CR245R250)0-4-heterocyclyl, - (CR245R250)0-4-aryl-heteroaryl,
(CR245R250)0-4-aryl-heterocyclyl, - (CR245R250)0-4-aryl-aryl,
- (CR245R250)0-4-heteroaryl-aryl, - (CR245R250)0-4-heteroaryl -
heterocyclyl, - (CR245R250)0-4-heteroaryl-heteroaryl,
(CR245R250)0-4-heterocyclyl-heteroaryl, - (CR245R250)0-4-
heterocyclyl-heterocyclyl, - (CR24SR250)0-4-heterocyclyl-aryl,
-[C(R255) (R260)1-3-CO-N-(R255)2, -CH(aryl)2, -CH (heteroaryl) 2,
-CH (heterocyclyl) 2, -CH (aryl) (heteroaryl) , - (CH2) 0-1-
CH( (CH2)0-6-OH) - (CH2)0-1-aryl, - (CH2)0-1-CH ( (CH2) 0-6-OH- (CH2) 0-1-
heteroaryl, -CH(-aryl or -heteroaryl)-CO-O(C1-C4 alkyl), -
CH(-CH2-OH) -CH(OH) -phenyl-NO2, (C1-C6 alkyl)-O-(C1-C6 alkyl)-
OH; -CH2-NH-CH2-CH(-O-CH2-CH3)2, - (CH2)0-6-C (=NR235) (NR235R240),
or
C1-C10 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of
R205, -OC=ONR235R240, -S (=O)0-2 (C1-C6 alkyl), -SH,
-NR235C=ONR235R24o, -C=ONR235R240; and -S (=O) 2NR235R240, or
- (CH2)0-3- (C3-C8) cycloalkyl wherein the cycloalkyl is
optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of
R205, -CO2H, and -CO2- (C1-C4 alkyl), or
cyclopentyl, cyclohexyl, or cycloheptyl ring fused to aryl,
heteroaryl, or heterocyclyl wherein one, two or three
carbons of the cyclopentyl, cyclohexyl, or cycloheptyl
is optionally replaced with a heteroatom independently
selected from NH, NR215/ 0, or S(=O)0-2/ and wherein the
cyclopentyl, cyclohexyl, or cycloheptyl group can be
optionally substituted with one or two groups that are
independently R205, =O, -CO-NR235R240, or -SO2- (C1-C4
alkyl), or
C2-C10 alkenyl or C2-C10 alkynyl, each of which is optionally
substituted with 1, 2, or 3 R205 groups, wherein
each aryl and heteroaryl is optionally substituted with 1,
2, or 3 R200/ and wherein each heterocyclyl is
optionally substituted with 1, 2, 3, or 4 R210;
R200 at each occurrence is independently selected from -OH, -NO2,
halogen, -CO2H, C=N, - (CH2)0-4-CO-NR220R225, - (CH2)0-4-CO-(C1-C12
alkyl) , - (CH2)0-4-CO- (C2-C12 alkenyl) , - (CH2)0-4-CO- (C2-C12
alkynyl) , - (CH2)0-4-CO- (C3-C7 cycloalkyl) , - (CH2)0-4-CO-aryl,
- (CH2)0-4-CO-heteroaryl, - (CH2)0-4-CO-heterocyclyl, -(CH2)0-4-
CO-O-R215, - (CH2)0-4-SO2-NR220R225, - (CH2)0-4-SO- (C1-C8 alkyl), -
(CH2)0-4-SO2. (C1-C12 alkyl), - (CH2)0-4-SO2-(C3-C7 cycloalkyl),
- (CH2)0-4-N(H or R215) -CO-O-R215, - (CH2)0-4-N(H or R215) -CO-
N(R215)2, -(CH2)0-4-N-CS-N(R215)2, - (CH2)0-4-N (-H or R21S) -CO-
R220, -(CH2)o-4-NR220R225, -(CH2)0-4-O-CO-(C1-C6 alkyl), -(CH2)0-
4-O-P(O) -(OR240)2, -(CH2)0-4-O-CO-N(R215)2, - (CH2)0-4-O-CS-
N(R215)2, - (CH2)0-4-O- (R215) , -(CH2)0-4-O- (R215)-COOH, - (CH2)0-4-
S-(R215) , - (CH2)0-4-O-(C1-C6 alkyl optionally substituted with
1, 2, 3, or 5 -F) , C3-C7 cycloalkyl, - (CH2)0-4-N (H or R215) -
SO2-R220, -(CH2)0-4- C3-C7 cycloalkyl, or
C1-C10 alkyl optionally substituted with 1, 2, or 3 R205
groups, or
C2-C10 alkenyl or C2-C10 alkynyl, each of which is optionally
substituted with 1 or 2 R205 groups, wherein
the aryl and heteroaryl groups at each occurrence are
optionally substituted with 1, 2, or 3 groups that are
independently R205/ R210/ or
C1-C6 alkyl substituted with 1, 2, or 3 groups that
are independently R205 or R210; and wherein
the heterocyclyl group at each occurrence is optionally
substituted with 1, 2, or 3 groups that are
independently R210;
R205 at each occurrence is independently selected from C1-C6
alkyl, halogen, -OH, -O-phenyl, -SH, -CºN, -CF3, C1-C6
alkoxy, NH2, NH(C1-C6 alkyl) or N- (C1-C6 alkyl) (C1-C6 alkyl);
R210 at each occurrence is independently selected from halogen,
C1-C6 alkoxy, C1-C6 haloalkoxy, -NR220R225, OH, ON, -CO-(C1-C4
alkyl), _SO2-NR235R240, -CO-NR235R240, -SO2-(C1-C4 alkyl), =O, or
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C7
cycloalkyl, each of which is optionally substituted
with 1, 2, or 3 R205 groups;
R215 at each occurrence is independently selected from C1-C6
alkyl, - (CH2)0-2-(aryl) , C2-C6 alkenyl, C2-C6 alkynyl, C3-C7
cycloalkyl, and - (CH2) 0-2- (heteroaryl) , - (CH2)0-2-
(heterocyclyl), wherein
the aryl group at each occurrence is optionally substituted
with 1, 2, or 3 groups that are independently R205 or
R210, and wherein
the heterocyclyl and heteroaryl groups at each occurrence
are optionally substituted with 1, 2, or 3 R210;
R220 and R225 at each occurrence are independently selected from -
H, -C3-C7 cycloalkyl, - (C1-C2 alkyl)-(C3-C7 cycloalkyl), -
(C1-C6 alkyl)-O-(C1-C3 alkyl), -C2-C6 alkenyl, -C2-C6
alkynyl, -C1-C6 alkyl chain with one double bond and one
triple bond, -aryl, -heteroaryl, and -heterocyclyl, or
-C1-C10 alkyl optionally substituted with -OH, -NH2 or
halogen, wherein
the aryl, heterocyclyl and heteroaryl groups at each
occurrence are optionally substituted with 1, 2, or 3
K270 groups
R235 and R240 at each occurrence are independently H, or C1-C6
alkyl;
R245 and R250 at each occurrence are independently selected from -
H, C1-C4 alkyl, C1-C4 alkylaryl, C1-C4 alkylheteroaryl, C1-C4
hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, - (CH2)0-4-C3-C7
cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and phenyl; or
R245 and R250 are taken together with the carbon to which they are
attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon
atoms, where one carbon atom is optionally replaced by a
heteroatom selected from -O-, -S-, -SO2-, and -NR220-;
R255 and R260 at each occurrence are independently selected from -
H, -(CH2)1-2-S(O)0-2-(C1-C6 alkyl),-(C1-C4 alkyl)-aryl, - (C1-
C4 alkyl)-heteroaryl, - (C1-C4 alkyl)-heterocyclyl, -aryl, -
heteroaryl, -heterocyclyl, - (CH2)1-4-R265- (CH2)0-4-aryl,
- (CH2)1-4-R265- (CH2)0-4-heteroaryl, - (CH2)1-4-R265- (CH2)0-4-
heterocyclyl, or
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or - (CH2)0-4-C3-C7
cycloalkyl, each of which is optionally substituted
with 1, 2, or 3 R205 groups, wherein
each aryl or phenyl is optionally substituted with 1, 2, or
3 groups that are independently R205/ R210, or
C1-C6 alkyl substituted with 1, 2, or 3 groups that
are independently R205 or R210, and wherein
each heterocyclyl is optionally substituted with 1, 2, 3,
or 4 R210;
R265 at each occurrence is independently -0-, -S- or -N(C1-C6
alkyl)-;
R270 at each occurrence is independently R205/ halogen C1-C6
alkoxy, C1-C6 haloalkoxy, NR235R240, -OH, -GºN, -CO- (C1-C4
alkyl), .SO2-NR235R240, -CO-NR235R240, -SO2-(C1-C4 alkyl), =O, or
C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or - (CH2)0-4-C3-C7
cycloalkyl, each of which is optionally substituted
with 1, 2, or 3 R205 groups;
comprising forming a reaction mixture comprising a compound of
formula III-a
wherein
R1 is OH, imidazolyl, halogen, -OC(O)CH3, -OC(O)CF3, or

R2 and R3 are independently H, phenyl, or C1-C4 alkyl; or
R2 and R3 and the carbons to which they are attached form a
benzo ring which is optionally substituted with C1-C4
alkyl, C1-C4 alkoxy, or dialkylamino; and
R6 is C1-C6 alkoxy or NR4R5; wherein
R4 and R5 are independently C1-C6 alkyl;
and a compound of formula VIII

in a solvent with an optional base and an optional
additive, such as, for example, a ligand for the catalyst used
in the formulation of compounds of formula I.
Compounds of formula VIII can be prepared, for example, as
according to procedures described in published international
application WO 02/02512.
In still another aspect, the invention provides a process
for converting compounds of formula III into compounds of
formula III-a.
In yet another aspect, the invention provides compound of
formula III-a:
wherein
R1 is OH, imidazolyl, halogen, -OC(O)CH3, -OC(O)CF3, or

R2 and R3 are independently H, phenyl, or C1-C4 alkyl; or
R2 and R3 and the carbons to which they are attached form a
benzo ring which is optionally substituted with C1-C4
alkyl, C1-C4 alkoxy, or dialkylamino; and
R6 is C1-C6 alkoxy or NR4R5; wherein
R4 and R5 are independently C1-C6 alkyl.
The compounds of Formula III-a are useful in preparing the
pharmaceutically active compounds disclosed in WO 02/02512.
In another aspect, the invention provides a process for the
preparation of the zinc chloride/oxazole adduct of formula II.
DETAILED DESCRIPTION OF THE INVENTION
As noted above, in one aspect, the invention provides
methods of preparing compounds of formula III using compounds of
formula II.
In a preferred method for preparing compounds of formula
III using compounds of formula II, the catalyst is a transition
metal catalyst. More preferably, it is a Pt or Pd catalyst.
Even more preferably, it is a Pd(O) catalyst. Still more
preferably, the catalyst is Pd(PPh3)4, PdCl2 (PPh3) 2, PdCl2, PdCl2
and PPh3, or Pd(OCOCH3)2. Most preferably the catalyst is
Pd(PPh3)4.
In a preferred method the reaction is carried out in a
solvent. More preferably, the method is carried out in at least
one polar, aprotic solvent. Still more preferably, the solvent
is tetrahydrofuran, tetramethyltetrahydrofuran, glyme, methyl t-
butyl ether, or mixtures thereof. Even more preferably, the
solvent is tetrahydrofuran.
In a preferred method the reaction is carried out at a
temperature of from about 25°C to about the refluxing
temperature of the solvent used. More preferably, the
temperature is about 30°C to about 75°C. Even more preferably,
the temperature is about 40°C to about 60°C. Still more
preferably, the temperature is 45-55°C.
All of the reagents can preferably be combined at once,
i.e., at nearly the same time, or within a short time of each
other. In an alternative method, the reaction mixture is formed
by combining the compound of formula I, the compound of formula
II, the catalyst and any additional additive (if necessary) over
a period of about 0.5 hours to about 4 hours, wherein this
period is also known as the addition time. More preferably, the
addition time is about 1 hour to about 3 hours. Even more
preferably, the addition time is about 1.5 hours to about 2.5
hours. Most preferably it is 2 hours. It should be noted that
the compound of formula I may be added to a mixture containing
the compound of formula II, or vice versa.
For example, the compound of formula II can be added to the
reaction mixture, e.g. a solution, comprising the compound of
formula I and the catalyst. Or, the compound of formula I, and
the catalyst, can be added to the reaction mixture, e.g. a
solution, comprising the compound of formula II.
In a preferred method the transition metal catalyst is
present in 0.01 to 20 mole percent, based on the amount of the
compound of formula I. More preferably the catalyst is present
in 0.1 to 10 mole percent, based on the amount of the compound
of formula I. Even more preferably, the catalyst is present in
1 to 7 mole percent, based on the amount of the compound of
formula I.
In a preferred method, after all of the compounds and
reagents have been combined, thereby forming the reaction
mixture, the reaction mixture is heated at the temperatures
mentioned above for about 0.5 to about 24 hours. More
preferably, the reaction mixture is heated for about 0.5 to
about 4 hours. Even more preferably, the reaction mixture is
heated for about 0.5 to about 2.25 hours.
In a preferred method, the compound of formula II is used
in an excess from 1.001 to 10 equivalents, based on the amount
of compound of formula I. Preferably, the compound of formula
II is used in an excess from 1.01 to 5 equivalents, based on the
amount of compound of formula I. Even more preferably, the
compound of formula II is used in an excess from 1.05 to 4
equivalents, based on the amount of compound of formula I.
Still more preferably, the second compound is used in an excess
from 1.1 to 1.7 equivalents, based on the amount of compound of
formula I. In a most preferred embodiment, about 3 equivalents
are utilized.
In a preferred method of preparing compounds of formula
III,
X is Br;
R2 and R3 are independently H, methyl or ethyl;
Rs is NR4R5 where R4 and R5 are both C3 alkyl; and
R1 is C1-C4 alkyl.
In this aspect, R1 is more preferably methyl or ethyl.
In another aspect, the invention provides an improved
method for preparing the zinc chloride/oxazole adduct of formula
II.
In a preferred aspect, the compound of formula II is
prepared using solid ZnCl2. Preferably, 1.1 to about 10
equivalents of ZnCl2 based on the amount of the particular
oxazole used is used to prepare the compound of formula II.
More preferably, 1.1 to about 5 equivalents of ZnCl2 is used.
Even more preferably, about 2.5 to about 3.5 equivalents of
ZnCl2 is used.
Preferred compounds of formula III and formula III-a
include compounds wherein R2 and R3 are independently H, methyl,
or phenyl; or R2/ R3 and the carbons to which they are attached
form a benzo ring. More preferably, R2 and R3 are independently
H or methyl. Even more preferably, R2 and R3 are both H.
More preferred compounds of formula III and formula III-a
include compounds wherein R6 is NR4R5 where R4 and R5 are both C3
alkyl or R4 and R5 are independently C1-C4 alkyl or benzyl.
Preferably, R4 and R5 are both C3 alkyl. Alternatively, R4 and.
R5 are independently C1-C4 alkyl or benzyl.
Even more preferred compounds of formula Ill-a include
compounds wherein R6 is NR4R5 where R4 and R5 are both C3 alkyl or
R4 and R5 are independently C1-C4 alkyl or benzyl. Preferably R4
and R5 are both C3 alkyl. Alternatively, R4 and R5 are
independently C1-C4 alkyl or benzyl; and Ri is OH.
Even more preferred compounds of formula III include
compounds wherein R6 is NR4R5 wherein R4 and R5 are both C3 alkyl
or R4 and R5 are independently C1-C4 alkyl or benzyl. Preferably
R4 and R5 are both C3 alkyl. Alternatively, R4 and R5 are
independently C1-C4 alkyl or benzyl; and R1 is C1-C4 alkoxy, more
preferably R1 is methyl or ethyl. Even more preferably, R1 is
methyl.
Even more preferred compounds of formula III-a include
compounds wherein R6 is NR4R5 where R4 and R5 are both C3 alkyl or
R4 and R5 are independently C1.-C4 alkyl or benzyl. Preferably R4
and R5 are both C3 alkyl. Alternatively, R4 and R5 are
independently C1-C4 alkyl or benzyl; and R1 is halogen, more
preferably R1 is chloro.
Even more preferred compounds of formula III-a include
compounds wherein
R6 is NR4R5; wherein
R4 and R5 are both C3 alkyl or R4 and R5 are independently
C1-C4 alkyl or benzyl.
Preferably R4 and R5 are both C3 alkyl. Alternatively, R4
and R5 are independently C1-C4 alkyl or benzyl; and
R1
In another aspect, preferred compounds of formula III and
formula III-a are those compounds wherein R6 is C1-C6 alkoxy or
C1-C6 alkoxyphenyl, more preferably R6 is C1-C4 alkoxy or
benzyloxy. Still more preferably, R6 is methoxy or ethoxy.
Even more preferably, R6 is methoxy.
Other preferred compounds of formula III-a include those
where R2 and R3 are independently H, phenyl, or C1-C4 alkyl; or
R2 and R3 and the carbons to which they are attached form a
benzene ring which is optionally substituted with C1-C4 alkyl,
C1-C4 alkoxy, or dialkylamino; and R6 is C1-C6 alkoxy or NR4R5;
wherein R4 and R5 are independently C1-C6 alkyl;
Still other preferred compounds of formula III-a include
those compounds wherein R2 and R3 are independently H, phenyl,
ox C1-C4 alkyl.
Other preferred compounds of formula III-a are those
wherein R6 is NR4R5 wherein R4 and R5 are C1-C6 alkyl.
Still other preferred compounds of formula Ill-a are those
wherein R2 and R3 are independently H, phenyl, or C1-C4 alkyl;
and R6 is NR4R5; wherein R4 and R5 are Ci-CG alkyl.
Still other preferred compounds of formula Ill-a are those
wherein R1 is OH.
Still other preferred compounds of formula Ill-a are those
wherein R1 is OH; and R2 and R3 are independently H, phenyl, or
C1-C4 alkyl. More preferably when R1 is OH, R2 and R3 are
independently H, methyl or ethyl. Also preferred when R1 is OH
are compounds wherein R2 and R3 are independently H or phenyl.
Still other preferred compounds of formula Ill-a are those
wherein R1 is OH; and R2 and R3 are independently H, phenyl, or
C1-C4 alkyl. More preferably R2 and R3 are independently H,
methyl or ethyl. Also preferred are the compounds wherein R2
and R3 are independently H or phenyl; and
R6 is NR4R5; wherein R4 and R5 are C1-C6 alkyl. More preferably,
R4 and R5 are both C3 alkyl. Also preferred is when R4 and R5
are both C2 alkyl. Also preferred is when R4 and R5 are both C4
alkyl.
As noted above, the invention provides a process for
preparing a compound of formula XX.
In one aspect, the process for preparing compounds of
formula XX is carried out in a solvent. Preferably, the solvent
is THF, DMF, CH2Cl2, CHC13, or a mixture thereof. Useful co-
solvents include hexanes, heptane, n-methylpyrrolidine,
trifluoroethane, tetramethyltetrahydrofuran, and cyclohexane.
The optional base is typically an amine, preferably a
tertiary amine. Examples of suitable amine bases are selected
from pyridine, collidine, di-tertiarybutyl pyridine,
triethylamine, diisopropylethylamine, dimethylamino pyridine,
lutidine and mixtures thereof.
The optional additive is typically am amide coupling agent.
Examples of suitable amide coupling agents are 1, 2, or 3 of the
following 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (also known as EDC and/or EDCI), 1-
hydroxybenzotriazole hydrate (HOBT), benzotriazole, l-hydroxy-7-
azabenzotriazole (HOAT), O-(7-azabenzotriazol-l-yl)-N,N,N",N" ,-
tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-1-
yl-N,N,N",N"-tetramethyluronium hexafluorophosphate (HBTU),
PYBop, Bop, BopCl, or 1,3-dicyclohexylcarbodiimide (DCC).
The reaction is preferably carried out for about 0.5 to
about 24 hours. More preferred reaction times are about 2 hours
to about 16 hours.
Preferably, the reaction is carried out a temperature of
about -5°C to about 70°C. More preferably at a temperature of
about 0°C to about 50°C. Even more preferably, at a temperature
of about 15°C to about 40°C. Still more preferably at a
temperature of about 20°C to about. 40°C.
In another aspect, the compound of formula III-a is used in
excess, based on the amount of the compound of formula VIII.
Preferably about 1.01 to about 5 equivalents of the compound of
formula Ill-a are used. More preferably, from about 1.1 to
about 3 equivalents of the compound of formula Ill-a are used.
In another aspect, when the optional base is present, it is
used 1) catalytically, 2) in a one to one ratio based on the
amount of the compound of formula Ill-a, or 3) in excess. If
used catalytically about 0.01 to about 0.99 equivalents based on
the amount of the compound of formula Ill-a can be used. If
used in excess, there are 1.0001 to about 30 equivalents of base
are used. More preferably, 1.001 to about 20 equivalents of
base are used. Still more preferably, 1.01 to about 10
equivalents of base are used. More preferably, 1.1 to about 5
equivalents of base are used. However, one skilled in the art
will recognize that the exact amount of base (or even
substituting a different base) may be varied without deviating
from the scope of the invention.
If any of the additives are added, one skilled in the art
will recognize the appropriate amount of the additive that
should be added. The use of such reagents is known in the art
of organic synthesis and medicinal chemistry. It is also known
in the art of peptide synthesis and amide couplings.
Definitions
By "alkyl" and "C1-C6 alkyl" in the present invention is
meant straight or branched chain alkyl groups having 1-6 carbon
atoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-
butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl,
hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. It is understood
that in cases where an alkyl chain of a substituent (e.g. of an
alkyl, alkoxy or alkenyl group) is shorter or longer than 6
carbons, it will be so indicated in the second "C" as, for
example, "C1-C10" indicates a maximum of 10 carbons.
By "alkoxy" and "C1-C6 alkoxy" in the present invention is
meant straight or branched chain alkyl groups having 1-6 carbon
atoms, attached through at least one divalent oxygen atom, such
as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,
sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy,
hexoxy, and 3-methylpentoxy.
By the term "halogen" in the present invention is meant
fluorine, bromine, chlorine, and iodine.
By the term, "OTf" is meant -OSO2CF3.
By the term, "OMs" is meant -OSO2CH3.
By the term "halogen" in the present invention is meant
fluorine, bromine, chlorine, and/or iodine.
"Alkenyl" and "C2-C6 alkenyl" means straight and branched
hydrocarbon radicals having from 2 to 6 carbon atoms and from
one to three double bonds and includes, for example, ethenyl,
propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the
like.
"Alkynyl" and "C2-C6 alkynyl" means straight and branched
hydrocarbon radicals having from 2 to 6 carbon atoms and one or
two triple bonds and includes ethynyl, propynyl, butynyl,
pentyn-2-yl and the like.
As used herein, the term "cycloalkyl" refers to saturated
carbocyclic radicals having three to twelve carbon atoms. The
cycloalkyl can be monocyclic, or a polycyclic fused system.
Examples of such radicals include cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl. Preferred cycloalkyl groups are
cyclopentyl, cyclohexyl, and cycloheptyl. The cycloalkyl groups
herein are unsubstituted or, as specified, substituted in one or
more substitutable positions with various groups. For example,
such cycloalkyl groups may be optionally substituted with, for
example, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano,
nitro, amino, mono (C1-C6) alkylamino, di(C1-C6) alkylamino, C2-
C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy,
amino (C1-C6) alkyl, mono (C1-C6) alkylamino(C1-C6) alkyl or di(C1-
C6) alkylamino (C1-C6) alkyl.
By "aryl" is meant an aromatic carbocyclic group having a
single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or
multiple condensed rings in which at least one is aromatic,
(e.g., 1, 2, 3, 4-tetrahydronaphthyl, naphthyl), which is
optionally mono-, di-, or trisubstituted. Preferred aryl groups
of the present invention are phenyl, 1-naphthyl, 2-naphthyl,
indanyl, indenyl, dihydronaphthyl, tetralinyl or 6,7,8,9-
tetrahydro-5H-benzo [a] cycloheptenyl. The aryl groups herein are
unsubstituted or, as specified, substituted in one or more
substitutable positions with various groups. For example, such
aryl groups may be optionally substituted with, for example, C1-
C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino,
mono(C1-C6) alkylamino, di (C1-C6) alkylamino, C2-C6alkenyl, C2-
C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino (C1-C6) alkyl,
mono (C1-C6) alkylamino (C1-C6) alkyl or di (C1-C6) alkylamino (C1-
C6) alkyl.
By "heteroaryl" is meant one or more aromatic ring systems
of 5-, 6-, or 7-membered rings which includes fused ring systems
of 9-11 atoms containing at least one and up to four heteroatoms
selected from nitrogen, oxygen, or sulfur. Preferred heteroaryl
groups of the present invention include pyridinyl, pyrimidinyl,
quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl,
pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl,
phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,
thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,
oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl,
cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl,
chromanyl, tetrahydroisoquinolinyl, isoindolinyl,
isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,
isobenzothienyl, benzoxazolyl, pyridopyridinyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl,
benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl,
pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-
oxide, tetrahydroguinolinyl, dihydroquinolinyl,
dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,
dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl,
benzoxazolinonyl, pyrrolyl N-oxide, , pyrimidinyl N-oxide,
pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide,
indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,
quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-
oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide,
thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide,
benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-
oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-
oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide,
benzothiopyranyl S,S-dioxide. The heteroaryl groups herein are
unsubstituted or, as specified, substituted in one or more
substitutable positions with various groups. For example, such
heteroaryl groups may be optionally substituted with, for
example, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano,
nitro, amino, mono (C1-C6) alkylamino, di(C1-C6) alkylamino, C2-
C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy,
amino (C1-C6) alkyl, mono (C1-C6) alkyl amino (C1-C6) alkyl or di(C1-
C6) alkylamino (C1-C6) alkyl.
By "heterocycle", "heterocycloalkyl" or "heterocyclyl" is
meant one or more carbocyclic ring systems of 4-, 5-, 6-, or 7-
membered rings which includes fused ring systems of 9-11 atoms
containing at least one and up to four heteroatoms selected from
i nitrogen, oxygen, or sulfur. Preferred heterocycles of the
present invention include morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide,
piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl,
tetrahydropyranyl, piperidinyl, tetrahydrofuranyl,
tetrahydrothienyl, homopiperidinyl, homomorpholinyl,
homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,
oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide.
The heterocycle groups herein are unsubstituted or, as
specified, substituted in one or more substitutable positions
with various groups. For example, such heterocycle groups may
be optionally substituted with, for example, C1-C6 alkyl, C1-C6
alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-
C6) alkyl amino, di (C1-C6) alkyl amino, C2-C6 alkenyl, C2-C6alkynyl,
C1-C6 haloalkyl, C1-C6 haloalkoxy, amino (C1-C6) alkyl, mono (Ci-
C6) alkylamino (C1-C6) alkyl, di(C1-C6) alkylamino (C1-C6) alkyl or =O.
The invention provides methods of converting compounds of
formula III into compounds of formula III-a. Such methods are
outlined in schemes B and C (wherein Xx is as defined below) and
are discussed in more detail below. Methods for converting an
ester into an amide are well known in the art. Such methods
include, for example, base hydrolysis using LiOH, NaOH, or KOH
as the base, or acid hydrolysis using HC1, H2SO4, H3PO4, triflic
acid, para-toluene sulfonic acid, or HNO3. The invention also
contemplates the use of two or more acids in combination or two
or more bases in combination to effect the hydrolysis. Other
methods will be readily apparent to one of skill in the art.
The conversion of the acid into the acid chloride is
preferably accomplished by using S0Cl2, SO2Cl2, or oxalyl
chloride. Other reagents known in the art can be conveniently
used to effect this transformation. :
The conversion of the acid into the imidazolyl compound is
preferably carried out using carbonyl diimidazole (CDI.)
The conversion of the acid into an acid anhydride is
accomplished by treating the acid with another acid anhydride,
such as acetic anhydride (thereby forming a mixed anhydride), or
the conversion can be effected by dehydrating two acid molecules
through the use of heat or another dehydrating agent. Treatment
with an acid anhydride is more preferable. On an industrial
scale, heating is one preferred method of preparing the
anhydride.
The processes of the invention are outlined in the
following Schemes.
The oxazolyl ester III can be used in situ or isolated.
Those skilled in the art when trying to remove zinc salts often
add acid so the zinc salts precipitate. Here if acid is added,
the desired oxazolyl ester III will protonate and will also
precipitate. Therefore, it is preferred to work-up the reaction
by adding saturated ammonium chloride solution to the crude
reaction mixture and extracting with a suitable organic solvent
such as ethyl acetate. This work up method allows for the
partition of the oxazolyl ester III into the organic phase with
the zinc salts remaining in the aqueous phase.
Scheme A illustrates the preparation of the ZnCl2/oxazole
adduct. The scheme discloses the use of solid ZnCl2. Solutions
of ZnCl2 can be used, but solid ZnCl2 is preferred. The
alkyllithium base used can be n-butyllithium t-butyllithium,
sec-butyllithium, or methyllithium. N-butyl lithium is
preferred. The lithiation of oxazoles has been described in
Hodges, et al. , J. Org. Chem. 1991, 56, 449; and Whitney, S. E.,
et al. , J. Org. Chem. 1991, 56, 3058 and in references cited
therein.
Scheme B illustrates a reaction between a compound of
formula I (wherein R6 is di-n-propylamine, X is Br, and R1 is
alkoxy) and a zinc chloride/oxazole adduct of formula II to form
a coupled product of formula III. The ester is then hydrolyzed
or otherwise cleaved to form the carboxylic acid.
Scheme C illustrates the conversion of a carboxylic acid of
formula IV into an acid halide or an imidazolide (compound of
formula V wherein X1 is Cl or imidazolyl, respectively), or an
acid anhydride (compound of formula VI) . Scheme C further
illustrates the coupling of the acid (IV) , acid chloride (or
bromide) (V), acid anhydride (VI) or imidazolide (V) with the
amine of formula VIII to generate a compound of formula X. The
arnine and/or alcohol in compounds of formula VIII may be
protected before the coupling reaction is performed. One of
skill in the art can determine the need for the use of
protecting groups. See for example, "Protective Groups in
Organic Synthesis, third edition" by Wuts and Green. These
couplings are also known to those of skill in the art. The
coupled compounds of formula X are generally disclosed in
International Publication WO 02/02512 based on PCT/US01/21012
International Publication WO02/02512 further discloses that
the substituted amines of formula X are prepared by reacting the
RN acid, acid halide, anhydride or carbonyl imidazole compound
with the corresponding amine of formula VIII.
Schemes D and E disclose a method for preparing one
possible amine of formula VIII.
Scheme F illustrates a coupling of a compound of formula I
with an amine of formula VIII to form the amide of formula XI.
In this scheme, it should be noted that the compound of formula
I has not been coupled to the zinc chloride/oxazole adduct
before being coupled to the amine of formula VIII. Compound XI
can then be coupled to the zinc chloride/oxazole adduct to form
compound XII. The protecting group can then be removed to form
the compound of formula X.
All temperatures are in degrees Celsius.
CDI refers to 1,1"-carbonyldiimidazole.
MTBE refers to methyl t-butyl ether.
TLC refers to thin-layer chromatography.
HPLC refers to high pressure liquid chromatography.
Chromatography (column and flash chromatography) refers to
purification/separation of compounds expressed as (support,
eluent) . It is understood that the appropriate fractions are
pooled and concentrated to give the desired compound(s) .
NMR refers to nuclear (proton) magnetic resonance
spectroscopy, chemical shifts are reported in ppm (d) downfield
from TMS.
CMR refers to C-13 magnetic resonance spectroscopy,
chemical shifts are reported in ppm (5) downfield from TMS.
MS refers to mass spectrometry expressed as m/e, m/z or
mass/charge unit. [M + H]+ refers to the positive ion of a
parent plus a hydrogen atom. El refers to electron impact. CI
refers to chemical ionization. FAB refers to fast atom
bombardment.
ESMS refers to electrospray mass spectrometry.
THF refers to tetrahydrofuran.
Ether refers to diethyl ether.
Saline refers to an aqueous saturated solution of sodium
chloride.
Tetrakis (triphenylphosphine) Palladium refers to Pd(PPh3)4.
Pharmaceutically acceptable refers to those properties
and/or substances which are acceptable to the manufacturing
pharmaceutical chemist from a physical/chemical point of view
regarding composition, formulation and stability.
When solvent pairs are used, the ratios of solvents used
are volume/volume (v/v) .
When the solubility of a solid in a solvent is used the
ratio of the solid to the solvent is weight/volume (wt/v) .
Dichlorobis (triphenyl-phosphine)palladium (II) refers to
(PdCl2(PPh3)2)•
Triphenylphosphine oxide refers to Ph3PO.
Prot refers to a protecting group or hydrogen. Protecting
groups are well known to those skilled in the art. Further
information on protecting groups can be found in, "Protective
Groups in Organic Synthesis, third edition" by Wuts and Green.
Palladium(O) catalysts are those catalysts containing
palladium with an oxidation state of zero. Palladium(O)
catalysts include, but are not limited to: Pd(PPh3)4,
PdCl2(PPh3)2, PdCl2, PdCl2 and PPh3, Pd(OCOCH3)2, and ((o-
Tol)3P)2PdCl2. One skilled in the art will recognize that some
of the fore-mentioned palladium(O) catalysts contain palladium
in an oxidized state, for example, Pd(II)Cl2. One skilled in
the art readily recognizes that the palladium(O) species can be
generated in situ through the use of butyllithium, DIBAL-H or
other reagents known in the art of organic synthesis. See for
example, Negishi, et al. , J. Chem. Soc, Chem Commun. 1986,
133 8. The preferred palladium(O) catalyst is Pd(PPh3)4-
EXAMPLES
Starting materials are generally readily available from
commercial sources, such as Sigma-Aldrich Corp. (St. Louis, MO),
or may be prepared as described herein. The processes shown in
the above schemes and set forth below in the Examples are not to
be construed as limiting the invention in scope or spirit to the
specific reagents and conditions shown in them. Those having
skill in the art will recognize that the starting materials,
reagents and conditions may be varied and additional steps
employed in the processes of the invention and to produce
compounds encompassed by the invention. In some cases,
protection of reactive functionalities may be necessary to
achieve the desired transformations. In general, such need for
protecting groups, as well as the conditions necessary to attach
and remove such groups, will be apparent to those skilled in the
art of organic synthesis. Unless otherwise stated in the
schemes below, the variables are as defined above.
All references mentioned in this application are
incorporated by reference, in their entirety.
All reagents are of commercial grade unless otherwise
noted. All reactions are stirred or otherwise agitated. Unless
otherwise stated, none of the solvents were degassed.
PREPARATION 1 t-Butyl(lS,2R)-l-(3,5-difluorobenzyl)-3-{[l-(3-
ethynylphenyl)cyclopropyl]amino}-2-
hydroxypropylcarbamate
Part (A) - Preparation of brotnophenylcyclopropylnitrile (2)
A mixture of 1-bromo-2-chloroethane (120 ml) , 3-bromobenzyl
cyanide (1, 25 g) and benzyl-triethylammonium chloride (1.1 g)
is stirred at 40° while aqueous sodium hydroxide (50%, 120 g) is
added dropwise over approximately 20 min. The reaction
temperature rises to about 80° during the addition of the
aqueous base. The reaction mixture is stirred very vigorous
while the temperature slowly drops to 50° (over about 3 hr).
After 3 hours, the reaction mixture is cooled down to 20-25°,
water (100 ml) is added and the mixture stirred for 5 min. The
organic phase is separated and the aqueous phase is extracted
with dichloromethane (3 x) . The combined organic phases are
washed with water and dilute hydrochloric acid. The organic
phase is then dried over magnesium sulfate, filtered and
concentrated. The concentrate is purified by a high vacuum
fractionation using short-path set-up and single receiver. The
fractions with bp = 108-115°/ 0.1-0.05 mm Hg are collected;
after cooling to 20-25° this liquid solidified.
Part (B) - Preparation of bromoamide (3)
The bromophenylcyclopropylnitrile, ((2), part (A), 5.9 g;
26.6 mmol), is dissolved in methanol (150 ml). Potassium
hydroxide (25% aqueous solution, 0.68 ml) and hydrogen peroxide
(30%, 35 ml) are added and the reaction mixture is heated at 55°
for 5 hr. The mixture is concentrated to give the crude
bromoamide.
Part (C) - Preparation of bromoacid (4)
The crude bromoamide ((3), part (B)) is slurried in
methanol (10 ml) and sodium hydroxide (10% aqueous, 150 ml) is
added. The reaction mixture is refluxed for 4.5 hr. The
reaction mixture is then cooled to 20-25°, acidified to pH = 2
with hydrochloric acid (15%) and concentrated. The resulting
precipitated (6.8 g) is collected by filtration.
Part (D) - Preparation of acid chloride (5)
Thionyl chloride (2.73 ml) and benzotriazole (4.47 g) are
dissolved in dry dichloromethane (25 ml.) 22.2 ml (1.25
equivalents) are then added portionwise over several minutes to
the crude bromoacid ((4), part (C) , 6.8 g) in dichloromethane
(120 ml.) Before the addition is complete, benzotriazole
hydrochloride started separating out as a white solid. The
reaction mixture is stirred for an additional 15 min and then
the solids are filtered off. The filtrate is stirred with
anhydrous magnesium sulfate (2 g) to destroy an excess reagent.
The solids are filtered off and the filtrate is concentrated
under reduced pressure and dried under high vacuum for
approximately 1 hr to afford the desired product (6.6 g.)
Part (E) - Preparation of bromoamine (6)
The crude acid chloride ((5), part (D) ) , is dissolved in
dry acetone (40 ml) , cooled to -10° and treated with sodium
azide (4 g in 15 ml of water) . After stirring for 1 hr at -10°
the mixture is allowed to warm to 0° and is poured into cold
water (300 ml) . The azide is extracted into smallest possible
amount of toluene (about 40 ml) . The toluene phase is separated
and washed with water and dried over Na2SO4. The solids are
filtered off and the filtrate is heated cautiously at 100° for 1
hr. Concentrated hydrochloric acid (about 25 ml) is added
through the condenser and the mixture is refluxed for 15 min.
On cooling a precipitate forms and is filtered off. The
filtrate is slightly concentrated, cooled down and an additional
portion of precipitate is collected. The combined solids are
dried to give the desired product (4.1 g) as the hydrochloride
salt.
Part (F) - Preparation of the 3, 5-dif luorobenzyl-bromo compound
(7)
The crude bromoamine ((6), part (E) , 2 g; 8 mmol) is
dissolved in saturated sodium carbonate (20 ml) and extracted
with dichloromethane (5 x 10 ml) . The combined extracts are
dried, and concentrated. The extract containing the bromoamine
(1.68 g, 7.92 mmol) is dissolved in isopropanol (20 ml) and BOC
protected-3, 5-difluorobenzylepoxide (ii, International
Publication WO02/02512, EXAMPLE 3, 2.36 g, 7.92 mmol) is added.
The mixture is heated to 80° in a sealed tube for 16 hours. The
reaction mixture is concentrated to afford the crude 3,5-
difluorobenzyl-bromo compound (3.9 g)•
Part (G) - Preparation of silyl compound (8)
Crude 3,5-difluorobenzyl-bromo compound ((7), part (F), 3.9
g; 7.0 mmol; 1 equivalent) is dissolved in triethylamine (20
ml.) Dichlorobis(triphenyl-phosphine)palladium (II) (0.196 g,
0.28 mmol; 0.04 equivalents) and CuI (0.068 g; 0.36 mmol; 0.05
equivalents) are then added. The reaction mixture is heated to
reflux and trimethylsilyl acetylene (0.82 g, 1.2 ml, 8.2 mmol,
1.2 equivalent) is added in one portion. The reaction mixture
is refluxed for 3 hr under nitrogen, then it is cooled to 20-25°
before partitioning between aqueous saturated sodium carbonate
and ethyl acetate. The organic phase is separated and the
aqueous phase is extracted with ethyl acetate (3 x 25 ml). The
combined organic extracts are washed with brine, dried over
Na2SO4, filtered and concentrated to give the desired silyl
compound.
Part (H) - Preparation of BOC protected-acetylene compound (8a)
Tetrabutylammonium fluoride (1M in THF, 8 ml) is added to a
solution of the crude silyl compound ((8), part (G)) in THF (5
ml). The reaction mixture is stirred for 1 hr at 20-25° and
then concentrated. The concentrate is dissolved in ether (3 0
ml) , washed with brine, dried over Na2SO4, filtered, and
concentrated. The crude product is purified by flash
chromatography (silica gel; ethyl acetate/hexane, 2/3 mixture)
to give the title compound.
EXAMPLE 1 Methyl 1-[3-[(Dipropylamino)carbonyl]-5-(1,3-
oxazol-2-yl)]benzoate
Compound 13 may be prepared as follows. n-Butyl lithxium
(1.4 equivalents) is added drop wise over 30 min to a stirrred,
-78° mixture of 1,3-oxazole (1.3 equivalents) in THF, whil_e
maintaining the mixture at a temperature below about -55°C . The
mixture is stirred for 3 0 min and then solid zinc chloride: (3
equivalents ) is added in 3-10 portions over about 10-15
minutes. The cooling bath is then removed, the reaction mixture
is allowed to warm to 20-25° and then the reaction is stirrred
for an additional 10 min. Next, the zinc chloride-oxazoles
adduct, 12, is added over a period of 2 hr to a mixture of
methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (10,
WO02/02512, PREPARATION 3) and tetrakis(triphenylphosphines)
palladium (5 mole %) in THF at 50°. Once the addition is
complete, the reaction is stirred at 50° until no methyl 3 -
bromo-5- [ (dipropylamino) carbonyl]benzoate 10 is observed by HPLC
(usually about 1 hour.)
HPLC retention time =3.9 min (column: 15 cm luna
phenylhexyl; acetonitrile/water, 0.2M ammonium formate; 65/35, X
= 210 nm; 1.0 mL/min).
The reaction mixture is cooled to 20-25 ° and methyl t-
butyl ether and hydrochloric acid (IN) are added. The phatses
are separated and the aqueous phase is extracted three tiines
with methyl t-butyl ether. The combined organic phases arre
concentrated under reduced pressure to give a solid. The
product is purified using silica gel chromatography (ethyl
acetate/octane, 25/75 to ethyl acetate/octane 50/50) to give the
title compound in 84% yield; NMR (ds-DMSO) 8.50, 8.28, 8.10,
7.94, 7.44, 3.90, 3.38-3.14, 1.62-1.49 and 0.99-0.67 6; CMR (ds-
DMSO) 168.56, 164.99, 159.29, 140.98, 138.77, 130.95, 128. 41,

127.69, 126.53, 54.91, 52.67, 50.14, 45.93, 21.46, 20.27, 11.30
and 10 .80 5.
EXAMPLE 2 Methyl 1- [3- [ (dipropylamino) carbonyl] -5- (1,3-
oxazol-2-yl)]benzoate

In a preferred aspect, 13 may be prepared as follows.
n-Butyllithium (405 mL, 1.0 moles, 1.4 equivalents) is
added dropwise over approximately 3 0 min. to oxazole (50.32 g,
0.73 moles, 1.3 equivalents) in -78° THF, while maintaining the
mixture at a temperature below about -55°C. Zinc chloride solid
(3 00 g, 2.2 moles, 3 equivalents) is added in 3-10 portions over
about 10-15 minutes and the reaction mixture is warmed to 20-25°
by removing the cold bath.
Once at 20-25°, the reaction is stirred for an additional
10 min. and then methyl 3-bromo-5-
[ (dipropylamino) carbonyl]benzoate (10, 155 g, 0.45 moles, 1
equivalents) and tetrakis (triphenylphosphine) Palladium (5 mole
%) are added. The reaction mixture is then heated to reflux and
stirred until the starting material has been consumed. Once
judged complete by HPLC, the reaction mixture is cooled to 20-
25° and the crude reaction mixture is concentrated to dryness.
To the resulting solid material is added NH4C1 and EtOAc. The
phases are separated and the aqueous phase is extracted with
ethyl acetate. The organic layers are combined and washed with
saturated aqueous ammonium chloride. The solvent is removed
under reduced pressure to give the title compound.
HPLC retention time = 3.5 min (column: 15 cm luna
phenylhexyl; acetonitrile/water, 60/40; X = 210 nin; 1.0 mL/min) .
This material may be purified using silica gel
cliromatography (ethyl acetate/octane, 25/75 to ethyl
Acetate/octane 50/50) or be used without purification in the
next step.
An alternative work up for the above reaction is as
follows.
Once the reaction is complete, the reaction mixture is
cooled to 20-25°C and concentrated to afford a solid. EtOAc (1
L) and sat NH4Cl (1 L) were added to the solid. The layers were
separated and the aqueous layer was extracted with EtOAc (2 x
100 mL.) The combined organic layers were then washed with sat
NH4C1 (2 x 100 mL), and concentrated to afford the desired
product.
EXAMPLE 3 1-[3-[(Dipropylamino)carbonyl]-5-(1,3-oxazol-2-
yl)]benzoic acid (14)

Aqueous sodium hydroxide (2N, 120 mL, 4 equivalents) is
added portionwise to a mixture of methyl 1- [3-
[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)]benzoate (13,
EXAMPLE 2) in methanol (300 mL) at 20-25°. The resultant slurry
is stirred at 2 0-25° for 1 hr at which time the reaction is
judged to be complete by HPLC. Water is then added (3 volumes
based on methanol) , the layers are separated and the aqueous
layer is extracted with MTBE until no triphenylphosphine oxide
could be detected in the aqueous layer by HPLC. The pH of the
aqueous layer is adjusted to less than one with concentrated
hydrochloric acid and the product is extracted into ethyl
acetate (200 mL). The ethyl acetate phase is separated and is
subsequently distilled under reduced pressure while adding
octane, which causes precipitation of the acid. The resulting
solids are collected by filtration and dried under reduced
pressure to give the title compound.
HPLC retention time =1.1 min (column: 15 cm luna
phenylhexyl; acetonitrile/water; 60/40; X = 210 nm; 1.0 mL/min).
EXAMPLE 4 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{ [1-(3-
ethynylphenyl)cyclopropyl] amino}butan-2-ol (17)
Acetyl chloride (84 mL, 1.18 moles, 15 equivalents based on
the protected 3,5-difluorobenzyl compound) is added slowly to
stirred methanol (250 mL) . (Alternatively, HCl or TFA may be
utilized.) The mixture is stirred for at least 15 min at which
time t-butyl(lS,2R)-1-(3,5-difluorobenzyl)-3-{[l-(3-
ethynylphenyl) cyclopropyl] amino} -2-hydroxypropylcarbamate
(WO02/02512, PREPARATION 1, 37.8 g, 0.08 moles, 1 equivalent)
dissolved in methanol (100 mL) is added slowly. The mixture is
then stirred at 20-25° until the reaction is judged to be
complete by HPLC. Once complete, the methanol is removed under
reduced pressure and the resulting residue is dissolved in water
(500 mL) . This mixture is washed with MTBE (2 x 200 mL) and the
combined organic phases are washed with hydrochloric acid (IN,
100 mL) . The pH of the combined aqueous phases is adjusted to
greater than 10 with base and then extracted with MTBE (2 x 2 00
mL) . The combined organic phases are then concentrated to
dryness under reduced pressure to give the title compound.
HPLC retention time = 3.9 min (column: 15 cm luna
phenylhexyl; acetonitrile/water, 0. 2M ammonium formate; 65/35, X
=210 ran; 1.0 mL/min).
This product can then be dissolved in THF and used without
purification in the coupling reaction.
EXAMPLE 5 N1-{ (1S,2R) -1-(3 , 5-dif luorobenzyl) -3- [(3-
ethylbenzyl)amino]-2-hydroxypropyl} - 5 - (1, 3 -
oxa.zol-2-yl) -N3,N3-dipropylisophthalamide (19)
Solid 1- [3- [ (dipropylamino) carbonyl] -5- (1, 3-oxazol-2-
yl)]benzoic acid (14, EXAMPLE 3,1.0 equivalents) is added slowly
to CDI (1.3 equivalents).in room temperature THF. The resulting
mixture is stirred for at least 1 hr at which time it is added
slowly over 1 hr to a -35° mixture of (2R,3S)-3-amino-4-(3,5-
difluorophenyl) -1-[(3-ethylbenzyl)amino]butan-2-ol (18,
International Publication WO02/02512, 1.0 equivalent) in THF.
After this addition, the reaction is warmed to 0° and stirred
until complete by HPLC. Once judged complete, the contents are
poured into hydrochloric acid (IN) and the aqueous phase is
separated and extracted with ethyl acetate. The combined
organic phases are washed with saturated sodium bicarbonate and
the solvent removed under reduced pressure. The crude product is
purified using silica gel chromatography to afford the title
compound.
EXAMPLE 6 N1- { (1S,2R)-1- (3,5-difluorobenzyl)-3-{ll-(3-
ethynylphenyl)cyclopropyl] amino}-2-
hydroxypropyl)-5-(1,3-oxazol-2-yl)-N3,N3-
dipropylisophthalamide (20)

Solid 1-[3-[(Dipropylamino)carbonyl]-5-(1,3-oxazol-2-
yl)]benzoic acid (14, EXAMPLE 3, 23 g, 0.08 moles, 1.0
equivalent is added slowly to a mixture of CDI (14. 6 g, 0.09
moles, 1.3 equivalents) in THF (150 mL) . The resultant mixture
is stirred at 20-25° for at least 1 hr at which time it is added
slowly over 1 hr to a -35° mixture of (2R,3S) -3-amino-4-(3,5-
difluorophenyl) -l-{ [1- (3-ethynylphenyl) cyclopropyl]amino}butan-
2-ol (17, EXAMPLE 4, 28 g, 0.08 moles, 1.0 equivalent) in THF
(300 mL) . After this addition is complete, the reaction is
allowed to warm to 0°. Once judged complete, the reaction
mixture is poured into hydrochloric acid (IN, 500 mL.) The
aqueous phase is then separated and extracted with ethyl acetate
(2 x 500 mL) . The combined organic extracts are washed with
saturated sodium bicarbonate (250 mL) and then concentrated.
The crude product is purified using silica gel chromatography to
afford the title compound.
HPLC retention time = 4.7 min (column: 15 cm luna phenylhexyl,
acetonitrile/water, 0.2 ammonium formate, 65/35, A = 210 nm, 1.0
mL/min) .
The invention and the manner and process of making and
using it, are now described in such full, clear, concise and
exact terms as to enable any person skilled in the art to which
it pertains, to make and use the same. It is to be understood
that the foregoing describes preferred embodiments of the
present invention and that modifications may be made therein
without departing from the spirit or scope of the present
invention as set forth in the claims. To particularly point out
and distinctly claim the subject matter regarded as invention,
the following claims conclude this specification.
WE CLAIM :
1. A process for preparing a compound of the formula
III: •

wherein:
R1 is C1-C6 alkoxy or OH;
R2 is H, phenyl, or C1-C4 alkyl;
R3 is H, phenyl, or C2-C4 alkyl;or
R2 and R3 and the carbons to which they are attached form a
benzo ring, which is optionally substituted with C1-C4 alkyl,
C1-C4 alkoxy, or dialkylamino; and
R6 is C1-C6 alkoxy or NR4R5; wherein
R4 and R5 are independently C1-C6 alkyl;
comprising:
forming a reaction mixture comprising a compound of
formula I:
wherein X is Br, I," OTf, or OMs;
a compound of formula II:
a catalyst and at least one solvent.
2. A process as claimed in claim 1, wherein the
catalyst is a transition metal catalyst.
3. A process as claimed in claim 2 wherein the
transition metal catalyst is Pd(PPh3)4, PdCl2 (PPh3) 2, PdCl2, PdCl2
and PPh3, or Pd(OCOCH3)2.
4. A process as claimed in claim 3, wherein the catalyst
is Pd(PPh3)4.
5. A process as claimed in claim 1 wherein the method is
conducted in the presence of at one additional polar, aprotic
solvent.
6. A process as claimed in claim 5, wherein the polar,
aprotic solvent is tetrahydrofuran, tetramethyltet-
rahydrofuran, glyme, methyl t-butyl ether, or a mixture
thereof.
7. A process as claimed in claim 6, wherein the polar,
aprotic solvent is tetrahydrofuran.
8. A process as claimed in claim 1, wherein the reaction
is performed at a temperature of from about 25°C to about the
refluxing temperature of the solvent used.
9. A process as claimed in claim 8 wherein the
temperature is about 30°C to about 75°C.
10. A process as claimed in claim 9, wherein the
temperature is about 4 0°C to about 60°C.
11. A process as claimed in claim 10, wherein the
reaction mixture is formed by combining I, II and the catalyst,
and any additional optional additives, at once or within a
short time of each other.
12. A process as claimed in claim 10, wherein the
reaction mixture is formed over a period of about 0.5 hours to
about 4 hours.
13. A process as claimed in claim 12, wherein the time is
about 1 hour to about 3 hours.
14. A process as claimed in claim 13, wherein the time is
about 1.5 hours to about 2.5 hours.
15. A process as claimed in claim 1 wherein the
transition metal catalyst is present in 0.01 to 20 mole
percent, based on the amount of the compound of formula I.
16. A process according to claim 15, wherein the
transition metal catalyst is present in 0.1 to 10 mole percent,
based on the amount of the compound of formula I.
17. A process as claimed in claim 16, wherein the
transition metal catalyst is present in 1 to 7 mole percent,
based on the amount of the compound of formula I.
18. A process as claimed in claim 17, wherein the
reaction mixture is heated for about 24 hours.
19. A process as claimed in claim 18, wherein the
reaction mixture is heated for about 0.5 to about 8 hours.
20. A process as claimed in claim 19, wherein the
reaction mixture is heated for about 0.5 to about 4 hours.
21. A process as claimed in claim 20, wherein the
reaction mixture is heated for about 0.5 to about 2.25 hours.
22. A process as claimed in claim 1, wherein the compound
of formula II is used in an excess from 1.001 to 10
equivalents, based on the compound of formula I.
23. A process as claimed in claim 22, wherein the
compound of formula II is used in an excess from 1.01 to 5
equivalents, based on the compound of formula I.
24. A process as claimed in claim 23, wherein the
compound of formula II is used in an excess of 3 equivalents,
based on the compound of formula I.
25. A process as claimed in claim 1, wherein
X is Br;
R2 and R3 are independently H, methyl or ethyl;
R6 is NR4R5; wherein
R4 and R5 are both C3 alkyl; and
R1 is C1-C4 alkyl.
Disclosed are compounds of formula III and a process to prepare a compound of formula III wherein R1, R2, R3 and
R6 are defined herein, using a zinc chloride/optionally substituted oxazole adduct and an compound of formula I. Further disclosed
are methods of using compounds of formula III to prepare compounds useful in the treatment of Alzheimer"s disease and related
conditions.

Documents:

1935-kolnp-2004-granted-abstract.pdf

1935-kolnp-2004-granted-assignment.pdf

1935-kolnp-2004-granted-claims.pdf

1935-kolnp-2004-granted-correspondence.pdf

1935-kolnp-2004-granted-description (complete).pdf

1935-kolnp-2004-granted-examination report.pdf

1935-kolnp-2004-granted-form 1.pdf

1935-kolnp-2004-granted-form 13.pdf

1935-kolnp-2004-granted-form 18.pdf

1935-kolnp-2004-granted-form 3.pdf

1935-kolnp-2004-granted-form 5.pdf

1935-kolnp-2004-granted-gpa.pdf

1935-kolnp-2004-granted-letter patent.pdf

1935-kolnp-2004-granted-reply to examination report.pdf

1935-kolnp-2004-granted-specification.pdf


Patent Number 214082
Indian Patent Application Number 01935/KOLNP/2004
PG Journal Number 05/2008
Publication Date 01-Feb-2008
Grant Date 30-Jan-2008
Date of Filing 16-Dec-2004
Name of Patentee PHARMACIA & UPJOHN COMPANY
Applicant Address 301,HENRIETTA STREET, KALAMAZOO USA.
Inventors:
# Inventor's Name Inventor's Address
1 REEDER MICHAEL R 7793 PERCHERON STREET KALAMAZOO USA
2 IMBORDINO RICK J 8155 HERUTAGE KALA-MAZOO USA.
PCT International Classification Number C07D263/32
PCT International Application Number PCT/US2003/019585
PCT International Filing date 2003-06-20
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/450, 478 2003-02-27 U.S.A.
2 60/390, 285 2002-06-20 U.S.A.