Title of Invention

METHODS FOR MINIMIZING THIOAMIDE IMPURITES

Abstract Methods for minimizing the formation of thioamide compounds using decoy agents during reactions, such as thionations of carbonyl compounds containing nitrile groups, are provided.
Full Text

BACKGROUND OF THE INVENTION
Progesterone receptor modulators can be prepared by thionation of carbonyl
compounds. The thionation of benzoxazin-2-ones using either 2,4-bis(4-
methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) or
phosphorous pentasulfide is known (US Patent No. 6,436,929). See, Scheme 1.

Such compounds are useful for contraception, hormone replacement therapy,
synchronization of estrus, and in the treatment of conditions including hormone
neoplastic diseases, adenocarcinomas, and carcinomas.
However, certain impurities formed during thionation are difficult to remove.
What is needed in the art are methods for reducing or eliminating the formation of
impurities.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides methods for preventing, reducing
or minimizing the formation of thioamide impurities.
In another aspect, the present invention provides methods for preventing,
reducing or minimizing the formation of thioamide impurities using a decoy agent.
In a further aspect, the present invention provides methods for preventing,
reducing or minimizing the formation of thioamide impurities during thionation of a
carbonyl compound comprising a nitrile group.
In yet another aspect, the present invention provides methods for preventing
the formation of thioamide impurities of the structure, wherein Y, R7-R9 are defined
below:


In still a further aspect, the present invention provides methods for preventing

the formation of thioamide impurities of the structure, wherein R1 , R7 , and R8 are
defined below:

In another aspect, the present invention provides methods for preventing the
formation of thioamide impurities of the structure, wherein R1-R5 are defined below:

In another aspect the invention provides for the use of a decoy agent
containing a nitrile group in a method for preparing a compound having the formula:
wherein:
R1 is C1 to C6 alkyl or substituted C1 to C6 alkyl;
R2 and R3 are, independently, H, C1 to C6 alkyl, or substituted C1 to C6 alkyl;
or R2 and R3 are fused to form a ring comprising -CH2(CH2)nCH2-,
-CH2CH2C(CH3)2CH2CH2-, -O(CH2)pCH2-, -O(CH2)qO-, -CH2CH2OCH2CH2-, or
-CH2CH2NR6CH2CH2-;

n is 1 to 5;
p is 1 to 4;
q is 1 to 4;
R4 is H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted C, to C6 alkyl, C2
to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, or substituted C2 to C6
alkynyl;
R5 is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted
C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
R6 is H or C1 to C6 alkyl;
X is O, S, or absent;
or a pharmaceutically acceptable salt thereof;
the method comprising reacting a thionating agent with a carbonyl compound
having the formula

wherein R1—R6, n, p, q, and X are as defined above;
wherein the decoy agent prevents or reduces thionation of the one or more
nitrile groups present in the carbonyl compound.
The thionating agent may be selected from the group consisting of hydrogen
sulfide, Lawesson's reagent, phosphorus pentasulfide, and diethyldithiophosphate.
The decoy agent may be an aryl nitrile selected from the group consisting of
benzonitrile, p-chlorobenzonitrile, p-ethoxybenzonitrile, p-methoxybenzonitrile, o-
nitrobenzonitrile, p-acetylbenzonitrile, p-methylbenzonitrile, p-fluorobenzonitrile, and
1,3-dicyanobenzene.
Alternatively the decoy agent may be a heteroaryl nitrile selected from the
group consisting of N-methyl-2-pyrrolecarbonitrile, 2-thiophenecarbonitrile, 2-
cyanopyridine, 3-cyanopyridine and 4-cyanopyridine.

The decoy agent may alternatively be an aliphatic nitrile selected from the
group consisting of acetonitrile, propionitrile, butyronitrile, isobutyronitrile,
chloroacetonitrile, trichloroacetonitrile and malononitrile.
In one embodiment the molar ratio of said decoy agent to said carbonyl
compound is greater than 1:1.
In a further embodiment the thionation reaction can be carried out in a solvent
selected from the group consisting of tetrahydrofuran, 1,2-dimethoxyethane,
methylene chloride, and toluene.
Other aspects and advantages of the present invention are described further in
the following detailed description of the preferred embodiments thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides methods for minimizing the formation of
thioamide compounds using decoy agents. Specifically, the present invention
provides methods for adding decoy agents to avoid undesirable side reactions.
I. Definitions
The term "alkyl" is used herein to refer to both straight- and branched-chain
saturated aliphatic hydrocarbon groups having 1 to about 10 carbon atoms, and
desirably 1 to about 8 carbon atoms. The term "alkenyl" is used herein to refer to
both straight- and branched-chain alkyl groups having one or more carbon-carbon
double bonds and containing about 2 to about 10 carbon atoms. Desirably, the term
alkenyl refers to an alkyl group having 1 or 2 carbon-carbon double bonds and having
2 to about 6 carbon atoms. The term "alkynyl" group is used herein to refer to both
straight- and branched-chain alkyl groups having one or more carbon-carbon triple
bond and having 2 to about 8 carbon atoms. Desirably, the term alkynyl refers to an
alkyl group having 1 or 2 carbon-carbon triple bonds and having 2 to about 6 carbon
atoms.
The term "cycloalkyl" is used herein to refer to an alkyl group as previously
described that is cyclic in structure and has about 4 to about 10 carbon atoms, and
desirably about 5 to about 8 carbon atoms.

The terms "substituted alkyl", "substituted alkenyl", "substituted alkynyl", and
"substituted cycloalkyl" refer to alkyl, alkenyl, alkynyl, and cycloalkyl groups,
respectively, having one or more substituents the same or different including, without
limitation, halogen, CN, OH, NO2, amino, aryl, heterocyclic, alkoxy, aryloxy,
alkylcarbonyl, alkylcarboxy, and arylthio which groups are optionally substituted.
These substituents can be attached to any carbon of an alkyl, alkenyl, or alkynyl group
provided that the attachment constitutes a stable chemical moiety.
The term "aryl" as used herein as a group or part of a group refers to an
aromatic system which can include a single ring or multiple aromatic rings fused or
linked together where at least one part of the fused or linked rings forms the
conjugated aromatic system e.g. having 6 to 14 carbon atoms. The aryl groups can
include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl,
tetrahydronaphthyl, phenanthryl, indene, benzonaphthyl, fluorenyl, and carbazolyl.
The term "substituted aryl" refers to an aryl group which is substituted with
one or more substituents the same or different including halogen, CN, OH, NO2,
amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkyloxy, alkylcarbonyl,
alkylcarboxy, aminoalkyl, and arylthio, which groups can be optionally substituted.
Desirably, a substituted aryl group is substituted with 1,2,3 or 4 substituents.
The term "heterocyclic" or "heteroaryl" as used herein refers to a stable 4- to
10-membered monocyclic or multicyclic heterocyclic ring which is saturated, partially
unsaturated, or wholly unsaturated. The heterocyclic ring has carbon atoms and one
or more heteroatoms including nitrogen, oxygen, and sulfur atoms. Desirably, the
heterocyclic ring has 1 to about 4 heteroatoms in the backbone of the ring. When the
heterocyclic ring contains nitrogen or sulfur atoms in the backbone of the ring, the
nitrogen or,sulfur atoms can be oxidized. The term "heterocyclic" also refers to
multicyclic rings in which a heterocyclic ring is fused to an aryl ring e.g. of 6 to 14
carbon atoms. The heterocyclic ring can be attached to the aryl ring through a
heteroatom or carbon atom provided the resultant heterocyclic ring structure is
chemically stable.
A variety of heterocyclic or heteroaryl groups are known in the art and
include, without limitation, oxygen-containing rings, nitrogen-containing rings,
sulfur-containing rings, mixed heteroatom-containing rings, fused heteroatom

containing rings, and combinations thereof. Oxygen-containing rings include, but are
not limited to, furyl, tetrahydrofuranyl, pyranyl, pyronyl, and dioxinyl rings.
Nitrogen-containing rings include, without limitation, pyrrolyl, pyrazolyl, imidazolyl,
triazolyl, pyridyl, piperidinyl, 2-oxopiperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl,
piperazinyl, azepinyl, triazinyl, pyrrolidinyl, and azepinyl rings. Sulfur-containing
rings include, without limitation, thienyl and dithiolyl rings. Mixed heteroatom
containing rings include, but are not limited to, oxathiolyl, oxazolyl, thiazolyl,
oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxazinyl, oxathiazinyl,
morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, oxepinyl, thiepinyl, and
diazepinyl rings. Fused heteroatom-containing rings include, but are not limited to,
benzofuranyl, thionapthene, indolyl, benazazolyl, purindinyl, pyranopyrrolyl,
isoindazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzopyranyl, quinolinyl,
isoquinolinyl, benzodiazonyl, napthylridinyl, benzothienyl, pyridopyridinyl,
benzoxazinyl, xanthenyl, acridinyl, and purinyl rings.
The term "substituted heterocyclic" or "substituted heteroaryl" as used herein
refers to a heterocyclic group having one or more substituents the same or different
including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy,
aryloxy, alkyloxy, alkylcarbonyl, alkylcarboxy, aminoalkyl, and arylthio, which
groups can be optionally substituted. Desirably, a substituted heterocyclic group is
substituted with 1,2, 3 or 4 substituents.
The term "alkoxy" as used herein refers to the O(alkyl) group, where the point
of attachment is through the oxygen-atom and the alkyl group is optionally
substituted.
The term "aryloxy" as used herein refers to the O(aryl) group, where the point
of attachment is through the oxygen-atom and the aryl group is optionally substituted.
The term "alkyloxy" includes hydroxyalkyl and as used herein refers to the
alkylOH group, where the point of attachment is through the alkyl group.
The term "arylthio" as used herein refers to the S(aryl) group, where the point
of attachment is through the sulfur-atom and the aryl group can be optionally
substituted.

The term "alkylcarbonyl" as used herein refers to the C(O)(alkyl) group,
where the point of attachment is through the carbon-atom of the carbonyl moiety and
the alkyl group is optionally substituted.
The term "alkylcarboxy" as used herein refers to the C(O)O(alkyl) group,
where the point of attachment is through the carbon-atom of the carboxy moiety and
the alkyl group is optionally substituted.
The term "aminoalkyl" includes alkylamino and as used herein refers to both
secondary and tertiary amines where the point of attachment is through the nitrogen-
atom and the alkyl groups are optionally substituted. The alkyl groups can be the
same or different.
The term "thioalkoxy" or "thioalkyl" as used herein refers to the S(alkyl),
where the point of attachment is through the sulfur-atom and the alkyl group is
optionally substituted.
The term "halogen" as used herein refers to Cl, Br, F, or I groups.
The term "amide" as used herein refers to the C(O)NH2 group, where the point
of attachment is through the carbon-atom. Similarly, the term "thioamide" as used
herein refers to a C(S)NH2 substituent.
The term "nitrile" or "cyano" as used herein refers to a CN group.
The term "ketone" as used herein refers to the C(O) group, where the points of
attachment are through the carbon-atom. Similarly, the term "aldehyde" as used
herein refers to the C(O)H, where the point of attachment is through the carbon-atom.
The term "lactone" as used herein refers to a ring having an ester moiety in the
backbone of the ring. The lactone ring can be optionally substituted with any
substituent that forms a stable bond to the ring.
The terms "carbamate" and "urethane" are used herein interchangeably to
refer to a N-C(O)0 group, where the point of attachments are through the nitrogen
and oxygen atoms.
The term "carbonate" is used herein to refer to a O-C(O)-O group.
The term "enone" is used therein to refer to a molecule that contains an alkene
group, i.e., -C=C-, and a ketone group. Desirably, the enone is C=C-C(O), where the
point of attachments are through the carbon-atom of the alkene and the carbon-atom
of the carbonyl.

The term "enaminone" is used herein to refer to a molecule that contains the -
N-C=C-C(O) group, where the point of attachments are through the carbon-atom of
the alkene and the carbon-atom of the carbonyl.
The term "purified" or "pure" as used herein refers to a compound that
contains less than about 10% impurity. Desirably, the term "purified" or "pure" refers
to a compound that contains less than about 5% impurity, more desirably, less than
about 2% impurity, and most desirably less than 1% impurity. The term "purified" or
"pure" can also refer to a compound that contains about 0% impurity. In one
embodiment, the impurity is a thioamide.
n. The Decoy Agent
Methods are provided for preventing or minimizing the formation of
impurities such as thioamides. Desirably, the present invention provides methods for
preventing or minimizing the formation of thioamide impurities during thionations of
carbonyl compounds containing nitrile groups. The method utilizes a decoy agent
containing a nitrile group. See, Scheme 2.

Without wishing to be bound by theory, the inventors have hypothesized that
thioamide impurities are formed by addition of hydrogen sulfide (H2S), a H2S by-
product, or a dithiaphosphetane by-product such as a Lawesson's reagent by-product,
among others, to a nitrile moiety. See, Scheme 3. Therefore, the inventors have
found that the addition of a decoy agent in the reaction mixture that prevents or
minimizes the formation of the thioamide impurity is advantageous.


The decoy agent used in the present invention competes with the nitrile
substituent of the carbonyl compound during thionation. In one embodiment, the
decoy agent competes with the nitrile substituent for reaction with H2S, an H2S by-
product formed during the reaction, or a Lawesson's agent by-product formed during
thionation of a carbonyl compound having a nitrile compound attached thereto.
However, the decoy agent desirably reacts only minimally or does not react with
actual thionating reagent.
The term "decoy agent" as used herein is distinguishable from "scavengers",
"trapping agents" or "mopping reagents". As known to those of skill in the art,
scavengers, trapping agents or mopping reagents are used to remove excess reagents,
products, or other formed impurities. For example, H2S can be scavenged with lead
acetate, trapped with molecular sieves, or mopped with water. A decoy agent,
however, is intentionally added to redirect any side reactions and is a sacrificial
reagent which protects the product from being a source of a contaminant
One of skill in the art would readily be able to select a suitable decoy agent
depending on the reaction conditions, cost of decoy agent, reactivity of the decoy
agent, reactivity of the carbonyl compound, and reactivity of the carbonyl group of

the carbonyl compound. Desirably, the decoy agent is similar in structure to the
nitrile group of the carbonyl compound.
Electron withdrawing substituents attached to the decoy agent can increase the
reactivity of the decoy agent, and specifically, the reactivity of a nitrile group on the
decoy agent. Desirably, the electron withdrawing substituent includes a halogen, and
more desirably chlorine. Desirably, the decoy agent is chloroacetonitrile (ClCH2CN),
trichloroacetonitrile, or 1,3-dicyanobenzene.
In one embodiment, the carbonyl compound contains a very reactive carbonyl
group and a less reactive nitrile group, whereby the carbonyl group easily reacts with
the thionating compound. In this case, a less reactive decoy agent can be utilized
during the thionation reaction to prevent formation of the thioamide impurity.
However, more reactive decoy agents can be utilized with reactive carbonyl
compounds. Typically, acetonitrile is utilized if the carbonyl group of the carbonyl
compound easily reacts with the thionating agent
In another embodiment, the carbonyl compound contains a reactive carbonyl
group and a reactive nitrile group. In this case, a moderately reactive decoy agent can
be utilized during the thionation reaction to prevent formation of the thioamide
impurity. Typically, moderately reactive decoy agents such as benzonitrile, p-
chlorobenzonitrile, p-methylbenzonitrile, 1,3-dicyanobenzene, 3- and 4-
cyanopyridines and malononitrile can be utilized.
In a further embodiment the carbon-containing compound contains a less
reactive carbonyl group and a highly reactive nitrile. In this case, a highly reactive
decoy agent can be utilized during the thionation reactive to prevent formation of the
thioamide impurity. Typically, highly reactive decoy agents such as N-methyl-2-
pyrrolecarbonitrile, 2-thiophenecarbonitrile, 2-cyanopyridine, chloroacetonitrile and
trichloroacetonitrile can be utilized.
Examples of decoy agents that can be used according to the present invention
include, without limitation, aryl nitriles including benzonitrile, p-chlorobenzonitrile,
p-ethoxybenzonitrile, p-methoxybenzonitrile, o-nitrobenzonitrile, p-
acetylbenzonitrile, p-methylbenzonitrile, p-fluorobenzonitrile, and 1,3-
dicyanobenzene; aliphatic nitriles such as acetonitrile (CH3CN), propionitrile,
butyronitrile, iosbutyronitrile, chloroacetonitrile, trichloroacetonitrile and

malononitrile; a nitrile compound having one or more electron withdrawing
substituents; or heteroaryl nitriles including N-methyl-2-pyrrolecarbonitrile, 2-
thiophenecarbonitrile, and 2-cyanopyridine. However, while some decoy agents may
be utilized, it may be cost-prohibitive for the use thereof. For example, CH3CN is an
inexpensive, low-boiling, common reagent with twice the moles of nitrile groups as
compared to N-methyl-2-pyrrolecarbonitrile. Further, while 2-thiophenecarbonitrile
is twice as reactive as benzonitrile, it is considerably more expensive. More
desirably, the decoy agent is similar in structure to N-methyl-2-pyrrolecarbonitrile
and is acetonitrile or 2-thiophenecarbonitrile.
A molar excess of the decoy agent is typically added to the reaction mixture,
where the reaction mixture contains a compound having a nitrile moiety, i.e., moles of
decoy agent are greater than moles of nitrile compound. However, less than a 1:1
ratio of decoy agent to the compound having a nitrile moiety, i.e., moles of decoy
agent are less than moles of nitrile compound, can also be utilized. In one
embodiment, greater than an about 10 molar excess of decoy agent is utilized. In
another embodiment, greater than an about 20 molar excess; in a further embodiment,
greater than an about 40 molar excess; and in still another embodiment, greater than a
100 molar excess of decoy agent is utilized. In one embodiment, the decoy agent can
be utilized as the solvent. One of skill in the art would readily be able to determine
the amount of decoy agent required depending on the reaction being performed,
reagents utilized, and reactivity of the decoy agent
HI. The Method of the Invention
The present invention thereby provides methods for preventing or minimizing
the formation of thioarnide impurities. Typically, the thioamide impurities formed
according to the present invention include thioamide groups attached at any location
on the backbone of the thioamide molecule.
In one embodiment, the thioamide impurity contains a thioamide group of the
structure:


In another embodiment, the thioamide impurity is of the structure:

wherein Y is O or S; R7 is H, NH2, NHR10, N(R10)2, C(O)R10, C(S)R10, C1 to C6 alkyl,
substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6
alkynyl, substituted C2 to C6 alkynyl, C3 to C6 cycloalkyl, substituted C3 to C6
cycloalkyl, C1 to C6 thioalkyl, substituted C1 to C6 thioalkyl, C1 to C6 alkoxy,
substituted C1 to C6 alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R8 is C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6
alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted
C3 to C6 cycloalkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, aryl, substituted
aryl, heteroaryl, or substituted heteroaryl; or R7 and R8 are fused to form (i) a
saturated carbon-based 4 to 8 membered ring; (ii) an unsaturated carbon-based 4 to 8
membered ring; or (iii) a 4 to 8 heterocyclic ring containing 1 to 3 heteroatoms
selected from among O, N, and S; wherein rings (i)-(iii) are optionally substituted by
1 to 3 substituents selected from among H, C1 to C6 alkyl, substituted C1 to C6 alkyl,
C2 to C6 alkenyl, substituted C2 to C1 alkenyl, C2 to C6 alkynyl, substituted C2 to C6
alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, C1 to C6 alkoxy,
substituted C1 to C6 alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C1 to C6 aminoalkyl, and substituted C1 to C6 aminoalkyl; R9 is absent, C1 to C6 alkyl,
substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6
alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8
cycloalkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, aryl, substituted aryl,
heteroaryl, or substituted heteroaryl; R10 is selected from among H, C1 to C6 alkyl,
substituted C1 to C6 alkyl, aryl, substituted aryl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, substituted C1 to C6 aminoalkyl, C1 to C6 thioalkyl,
substituted C1 to C6 thioalkyl, NH2, NHR11, and N(R11)2; and R11 is selected from
among H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, C1 to C6
alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, substituted C1 to C6
aminoalkyl, C1 to C6 thioalkyl, substituted C1 to C6 thioalkyl, and NH2.

In a further embodiment, the thioamide impurity is of the structure:
or a combination thereof,
wherein, R7 is H, NH2, NHR10, N(R10)2, C(O)R10, C(S)R10, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl,
substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, C1 to
C6 thioalkyl, substituted C1 to C6 thioalkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R8 is C1 to C6
alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to
C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8
cycloalkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, aryl, substituted aryl,
heteroaryl, or substituted heteroaryl; or R7 and R8 are fused to form (i) a saturated
carbon-based 4 to 8 membered ring; (ii) an unsaturated carbon-based 4 to 8 membered
ring; or (iii) a 4 to 8 heterocyclic ring containing 1 to 3 heteroatoms selected among
O, N, and S; wherein rings (i)-(iii) are optionally substituted by 1 to 3 substituents
selected from among H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl,
substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C1 to C8
cycloalkyl, substituted C3 to C8 cycloalkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C1 to C6 aminoalkyl,
and substituted C1 to C6 aminoalkyl; R9 is absent, C1 to C6 alkyl, substituted C1 to C6
alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2
to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C6 cycloalkyl, C1 to C6 alkoxy,
substituted C1 to C6 alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R10 is selected from among H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl,
substituted aryl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl,
substituted C1 to C6 aminoalkyl, C1 to C6 thioalkyl, substituted C1 to C6 thioalkyl,
NH2, NHR11 and N(R11)2; and R11 is selected from among H, C1 to C6 alkyl,
substituted C1 to C6 alkyl, aryl, substituted aryl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, substituted C1 to C6 aminoalkyl, C1 to C6 thioalkyl,
substituted C1 to C6 thioalkyl, and NH2.
In still a further embodiment, the thioamide impurity contains a thioamide
group that is attached to a pyrrole ring or to a substituent of a pyrrole ring. The

thioamide impurity can therefore have the following thioamide substituent, where R1
is C1 to C6 alkyl or substituted C1 to C6 alkyl.

In another embodiment, the thioamide impurity is of the structure:

wherein, R1 is selected from among C1 to C6 alkyl or substituted C1 to C6 alkyl. and
R7 and R8 are defined above.
In still a further embodiment, the thioamide impurity is of the structure:

wherein, R1 is selected from among C1 to C1 alkyl or substituted C1 to C6 alkyl. R2
and R3 are independently selected from among H, C1 to C6 alkyl, or substituted C1 to
C6 alkyl; or R2 and R3 are fused to form a ring including -CH2(CH2)nCH2-, -
CH2CH2C(CH3)2CH2CH2-, -O(CH2)pCH2-, -O(CH2)qO-, -CH2CH2OCH2CH2-, or -
CH2CH2NR6CH2CH2-, n is 1,2,3,4, or 5, p is 1,2, 3, or 4, and q is 1,2,3, or 4; R4 is
selected from among H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted C1 to C6
alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, or substituted
C2 to C6 alkynyl; R5 is selected from among H, C1 to C6 alkyl, substituted C1 to C6
alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted
C1 to C6 aminoalkyl; R6 is selected from among H or C1 to C1 alkyl; C1 is selected
from among O or S; and X is absent or is selected from among O or S.

In still a further embodiment, the thioamide impurity is of the structure:

wherein, R1-R5, X, and Q are defined above.
The carbonyl compound containing a nitrile group utilized in the present
invention contains at least one carbonyl and at least one nitrile group. The present
invention also provides for carbonyl compounds having more than 1 carbonyl group,
e.g., 2, 3, 4, 5, or 5 carbonyl groups and more, more than 1 nitrile group, e.g., 2,3,4,
or 5 nitrile groups and more, or a combination thereof.
In one embodiment, the carbonyl compound is of the structure;

wherein, R7 is H, NH2, NHR10, N(R10)2, C(O)R10, C(S)R10, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl,
substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, C1 to
C6 thioalkyl, substituted C1 to C6 thioalkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R8 is C1 to C6
alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to
C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C6 cycloalkyl, substituted C3 to C8
cycloalkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, aryl, substituted aryl,
heteroaryl, or substituted heteroaryl; or R7 and R8 are fused to form (i) a saturated
carbon-based 4 to 8 membered ring; (ii) an unsaturated carbon-based 4 to 8 membered
ring; or (iii) a 4 to 8 heterocyclic ring containing 1 to 3 heteroatoms selected from
among O, N, and S; wherein rings (i)-(iii) are optionally substituted by 1 to 3
substituents selected from among H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to
C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6
alkynyl, C3 to C6 cycloalkyl, substituted C3 to C8 cycloalkyl, C1 to C6 alkoxy,
substituted C1 to C6 alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

C1 to C6 aminoalkyl, and substituted C1 to C6 aminoalkyl; R9 is absent, C1 to C6 alkyl,
substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6
alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8
cycloalkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, aryl, substituted aryl,
heteroaryl, or substituted heteroaryl; R10 is selected from among H, C1 to C6 alkyl,
substituted C1 to C6 alkyl, aryl, substituted aryl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, C1 to C6 aminoalkyl, substituted C1 to C6 aminoalkyl, C1 to C6 thioalkyl,
substituted C1 to C6 thioalkyl, NH2, NHR11, and N(R11)2; and R11 is selected from
among H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, C1 to C6
alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, substituted C1 to C6
aminoalkyl, C1 to C6 thioalkyl, substituted C1 to C6 thioalkyl, and NH2.
In a further embodiment, the carbonyl compound is of the structure:

wherein, R1 is C1 to C6 alkyl or substituted C1 to C6 alkyl; R7 and R8 are defined
above.
In yet another embodiment, the carbonyl compound is of the structure:

wherein, R1 is C1 to C6 alkyl or substituted C1 to C6 alkyl; R2 and R3 are,
independently, H, C1 to C6 alkyl, or substituted C1 to C6 alkyl; or R2 and R3 are fused
to form a ring comprising -CH2(CH2)nCH2-, -CH2CH2C(CH3)2CH2CH2-, -
O(CH2)pCH2-, -O(CH2)qO-, -CH2CH2OCH2CH2-, or -CH2CH2NR6CH2CH2-; n is 1 to
5; p is 1 to 4; q is 1 to 4; R4 is H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, or
substituted C2 to C6 alkynyl; R5 is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to
C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6

aminoalkyl; R6 is H or C1 to C6 alkyl; X is O, S, or absent; or a pharmaceutically
acceptable salt thereof.
In still a further embodiment, the carbonyl compound is of the structure:

wherein, R1-R5 and X are defined above.
Typically, the decoy agent utilized is in the presence of a solvent. One of skill
in the art would readily be able to select a suitable solvent for use with the decoy
agent depending on the other reagents utilized and reaction conditions, among others.
Desirably, the solvent does not react with any of the reagents utilized in the reaction
and does not contain any peroxides. In one embodiment, the solvent includes
tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), toluene, and methylene
chloride, among others.
The decoy agent can be utilized at any temperature that facilitates the reaction
and can readily be determined by one of skill in the art. Desirably, the decoy agent is
utilized at least room temperature, and more desirably at the boiling point of the
solvent.
When the decoy agent is utilized in a thionation reaction, the reaction is
performed using a thionating agent. Several thionating agents that replace O-atoms
with S-atoms are known in the art and include, without limitation, phosphorus
pentasulfide (P4S10), hydrogen sulfide, Lawesson's reagent, and
dialkyldithiophosphates such as diethyldithiophosphate (See, Phosphorous and Sulfur
1985,25,297). See, Scheme 4.


Desirably, the thionating agent does not react with the decoy reagent. The
thionation can also be performed with thionating by-products that agents are formed
during the reaction and include:

In one embodiment, the present invention provides a method for preventing or
minimizing the formation of thioamide impurities during thionation of a nitrile
compound containing a carbonyl group including performing the thionation in the
presence of a decoy agent having a nitrile group.
In another embodiment, the present invention provides a product prepared by
the method of the present invention.
The resulting compounds of the present invention can be formulated in a
physiologically compatible carrier and used as PR modulators as described in US
Patent Nos. 6,509,334; 6,391,907; 6,417,214; and 6,407,101, which are hereby
incorporated by reference. The invention further provides kits comprising the
product.
The following examples are provided to illustrate the invention and do not
limit the scope thereof. One skilled in the art will appreciate that although specific
reagents and conditions are outlined in the following examples, modifications can be
made which are meant to be encompassed by the spirit and scope of the invention.
EXAMPLES
EXAMPLE 1 - REACTIVITY OF DECOY AGENTS
One mmol of the aromatic nitrile decoy agents set forth in Table 1 were
reacted at reflux with the thionating agent diethyl dithiophosphate (0.2 mL) in wet
THF (6 mL) to give the respective thioamides.


This example illustrates that 2-thiophenecarbonitrile was the most reactive
with the thionating agent.
EXAMPLE 2 - USE OF DECOY AGENT DURING THIONATION
Acetonitrile (21 kg, 512 mol) was utilized as decoy agent in a thionation of 5-
(4,4-dimethyl-2-oxo-1,4-dihydro-benzoxazin-6-yl)-l-methyl-1H-pyrrole-2-
carbonitrile (34 kg, 126 mol), i.e., a 4:1 molar ratio, using Lawesson's reagent (28.3
kg, 70 mol) in DME (505 kg) at reflux to give 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-
benzoxazm-6-yl)-l-methyl-1H-pyrrole-2-carbonitrile (26.7 kg; 74% yleld).
The crude reaction mixture of 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-
benzoxazin-6-yl)-l-methyl-1H-pyrrole-2-carbomtrile contained only about 2.6% of 5-
(4,4^imethyl-2-tm^xo-1,4-dihydro-benzoxazine)-l-methyl-pyrrole-2-thioamide
impurity. After recrystallization, the purified 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-
berizoxazin-6-yl)-l-methyl-1H-pyrrole-2-carbonitrile was about 99.90% pure.
When the reaction was performed in the absence of the decoy agent, the
thioamide impurity was present at about 11 to about 12%.
EXAMPLE 3 - COMPETITION BETWEEN 2-THIOPHENECARBONITRILE
AND ALKYL NITRILES
2-Thiophenecarbonitrile (1 rnmol) was reacted at reflux with diethyl
dithiophosphate (200 µL) in wet THF (6 mL) and in the presence of the aliphatic

nitrites (1 mmol) set forth in Table 2. The conversion of the undesired thiophene-2-
carbothioic acid amide was then measured.

This example illustrates that conversion of a reactive nitrile, such as 2-
thiophene carbonitrile, to the thioamide impurity is high when no decoy agent is
utilized. However, conversion to the thioamide impurity is decreased when decoy
agents are utilized.
EXAMPLE 4 - COMPETITION BETWEEN 2-THIOPHENECARBONITRILE
AND ACETONITRILE
2-Thiophenecarbonitrile (1 mmol) was reacted at reflux with diethyl
dithiophosphate (200 µL) in wet THF and acetonitrile using the molar equivalents set
form in Table 3. The conversion of the undesired thiophene-2-carbothioic acid amide
was then measured.


This example illustrates that conversion to the thioamide impurity decreased
as the amount of acetonitrile increased.
EXAMPLE 5 - EFFECT OF ACETONITRILE ON THE FORMATION OF
THIOAMIDE IMPURITIES
The nitrile set forth in Table 4 was reacted at reflux with diethyl
dithiophosphate (200 µL) in wet THF (5 mL) and acetonitrile (1 mL = 20 molar
equivalents). The control set contained 6 mL THF and no acetonitrile. After 5 hours
at 66 oC, the mixtures were subjected to GC/MS analysis to detect the presence of
thioamide impurity.

This example illustrates that conversion to the thioamide impurity was
suppressed in samples containing acetonitrile. Further, samples containing
acetonitrile and p-methoxybenzonitrile had very little conversion to the thioamide
impurity.
EXAMPLE 6 - USE OF DECOY AGENT DURING THIONATION
A 2-L flask was charged with 1,2-dimethoxyethane (2.1 L) and 5-
(spiro[cyclohexane-1,3'-[3H]indole]-2'-oxo-5'-yl)-1H-pyrrole-l-methyl-2-
carbonitrile (150 g, 0.49 mol), followed by Lawesson's reagent (119 g, 0.295 mol)
and acetonitrile (0.3 L, 5.75 mol), i.e., a 12:1 molar ratio of decoy agent to nitrile
compound. The suspension was heated to reflux and kept for 1 hour. Upon cooling to
ambient temperature, water (2.51 L) was added to the suspension at a rate to maintain
the temperature below 30 °C. The yellow-greenish precipitate was filtered on a fritted
funnel. The solid was transferred back to the reaction flask and slurried in water (0.75

L) overnight. The yellow suspension was filtered, washed with water (0.45 L) and
dried to give 154 g (98% yleld, 99.0% purity by HPLC area, mp 269-271.5 °C, 0.60%
thioamide impurity) of 5-(2 '-thioxospiro[cyclohexane-l ,3 '-[3H]indol]-5 '-yl)-l -
methyl-1H-pyrrole-2-carbonitrile.
EXAMPLE 7 - USE OF DECOY AGENT DURING THIONATION (SCALE-UP)
In this example, a larger scale production of [5-(2'-thioxospiro[cyclohexane-
1,3 '-[3H]indol]-5'-yl)-1-methyl-1H-pyrrole-2-carbonitrile] was performed.
A 100-gal vessel was charged with 1,2-dimethoxyethane (155.1 kg, 178.8 L)
and 5-(spiro[cyclohexane-1,3'-[3H]indole]-2'-oxo-5'-yl)-1H-pyrrole-1-methyl-2-
carbonitrile (12.78 kg), followed by Lawesson's reagent (10.14 kg) and acetonitrile
(20.1 kg, 25.6 L). The contents of the vessel was heated to reflux and kept for 1 hour.
The orange-brown solution was cooled to 70 °C and a sample was withdrawn for the
reaction completion test that showed less than 0.2% of the starting material. The batch
was cooled to ambient temperature and water (213.9 kg) was charged at a rate to
maintain temperature between 23 and 29 °C. The yellow-greenish suspension was
filtered on a 0.3 SQM PSL filter/dryer. The solids were slurried in water (63.9 kg) on
the filter/dryer for 15 minutes. The yellow suspension was transferred into a 100-gal
vessel and the filter was rinsed with water (2 x 10 kg) into the vessel. The slurry was
stirred at 1S-26 °C for 12 hours, filtered on a 0.3 SQM PSL filter/dryer and washed
with water (2 x 19.2 kg). The solids were dried in a vacuum oven at initially 2O-30 °C
and then at 45 °C to give 12.8 kg of crude 5-(2'-thioxospiro[cyclohexane-1,3'-
[3H]indol]-5'-yl)-1-methyl-1H-pyrrole-2-carbonitrile (95% yleld, 0.45% thioamide
impurity).
All publications cited in this specification are incorporated herein by reference
herein. While the invention has been described with reference to a particularly
preferred embodiment, it will be appreciated that modifications can be made without
departing from the spirit of the invention. Such modifications are intended to fell
within the scope of the appended claims.

WE CLAIM:
1. A method for reducing the formation of thioamide impurities during thionation
of a carbonyl compound comprising a nitrile group, comprising performing said thionation in
the presence of a decoy agent comprising a nitrile group.
2. The method as claimed in claim 1, wherein the moles of said decoy
agent Is greater than the moles of said carbonyl compound. - •
3. The method as claimed in claim 1, wherein the moles of said decoy
agent is less than the moles of said carbonyl compound.
4. The method as claimed in any one of claims 1 to 3, wherein said
thioamide impurity is of the structure:

wherein:
Y is O or S;
R7 is H, NH2, NER10, NCR10)2, C(O)R10, C(S)R10, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl C2 to C6 alkynyl,
substituted C2 to C6 alkynyl, C3 to C6 cycloalkyl, substituted C3 to C8 cycloalkyl, C1 to
C6 tbioalkyl, substituted C1 to C6 thioalkyl C1 to C6 alkoxy, substituted C1 to C6
alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R8 is C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2
to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl,
substituted C3 to C6 cycloalkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; or
R7 and R8 are fused to form:
(i) a saturated carbon-based 4 to 8 membered ring;
(ii) an unsaturated carbon-based 4 to 8 membered ring; or

(iii) a 4 to 8 heterocyclic ring containing 1 to 3 heteroatoms selected from
the group consisting of O, N, and S;
wherein rings (i)-(m) are optionally substituted by 1 to 3 substituents
selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2
to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6
alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, C1 to C6 alkoxy,
substituted C1 to C6 alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C1 to C6 aminoalkyl, and substituted C1 to C6 aminoalkyl;
R9 is absent, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl,
substituted C2 to C6 alkenyl, C2 to C8 alkynyl, substituted C2 to C6 alkynyl, C3 to C8
cycloalkyl, substituted C3 to C6 cycloalkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R10 is selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to
C6 alkyl, aryl, substituted aryl, C1 to C6 alkoxy, substituted C1 to C8 alkoxy, C1 to C6
aminoalkyl, substituted C1 to C6 aminoalkyl, C1 to C6 thioalkyl, substituted C1 to C6
thioalkyl, NH2, NHR11, and N(R11)2; and
R11 is selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to
C6 alkyl, aryl, substituted aryl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6
aminoalkyl, substituted C1 to C6 aminoalkyl, C1 to C6 thioalkyl, substituted C1 to C6
mioalkyl, and NH2.
5. The method as claimed in claim 4, wherein said thioamide impurity is
of the structure:

wherein:
R1 is C1 to C6 alkyl or substituted C1 to C6 alkyl;
R7 is H, NH2, NHR10, N(R10)2, C(O)R10, C(S)R10, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl,

substituted C2 to C8 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, C1 to
C6 thioalkyl, substituted C1 to C6 thioalkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R8 is C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2
to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl,
substituted C3 to C8 cycloalkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; or
R7 and R8 are fused to form:
(i) a saturated carbon-based 4 to 8 membered ring;
(ii) an unsaturated carbon-based 4 to 8 membered ring; or
(iii) a 4 to 8 heterocyclic ring containing 1 to 3 heteroatoms selected from
the group consisting of O, N, and S;
wherein rings (i)-(iii) are optionally substituted by 1 to 3 substituents
selected from the group consisting of H, C1 to C8 alkyl, substituted C1 to C8 alkyl, C2
to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl substituted C2 to C6
alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, C1 to C6 alkoxy,
substituted C1 to C6 alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C1 to C6 aminoalkyl, and substituted C1 to C6 arninoalkyl;
R10 is selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to
C6 alkyl, aryl substituted aryl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6
aminoalkyl, substituted C1 to C6 aminoalkyl, C1 to C6 thioalkyl substituted C1 to C6
thioalkyl, NH2,NHR11, and N(R11)2; and
R11 is selected from the group consisting of H, C1 to C8 alkyl, substituted C1 to
C6 alkyl, aryl, substituted aryl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6
aminoalkyl, substituted C1 to C6 arninoalkyl, C1 to C6 thioalkyl, substituted C1 to C6
thioalkyl, and NH2-
6. The method as claimed in claim 4, wherein said thioamide impurity is
of the structure:


wherein:
R1 is C1 to C6 alkyl or substituted C1 to C6 alkyl;
R2 and R3 are., independently, H, C1 to C6 alkyl, or substituted C1 to C6 alkyl;
or R2 and R3 are fused to form a ring comprising -CH2(CH2)nCH2-,
-CH2CH2C(CH3)2CH2CH2- -O(CH2)pCH2-> -O(CH2)qO-, -CH2CH2OCH2CH2-, or
-CH2CH2NR6CH2CH2-;
n is 1 to 5;
p is 1 to 4;
q is 1 to 4;
R4 is H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2
to C6 alkenyl, substituted C2 to C1 alkenyl, C2 to C6 alkynyl, or substituted C2 to C6
alkynyl;
R5 is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted
C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;
R6 is H or C1 to C6 alkyl;
Q is O or S;
X is O, S, or absent;
or a pharmaceutically acceptable salt thereof.
7. The method as claimed in any one of claims 1 to 3, wherein said
carbonyl compound is a ketone, enone, aldehyde, ester, lactone, amide, carbamate,
carbonate, or enaminone.
8. The method as claimed in claim 7, wherein said carbonyl compound is

of the structure:


wherein:
R7 is H, NH2, NHR10, N(R10)2, C(O)R10, C(S)R10, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to Co alkenyl, C2 to C6 alkynyl,
substituted C2 to C8 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C6 cycloalkyl, C1 to
C6 thioalkyl, substituted C1 to C6 thioalkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R8 is C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C8 alkenyl, substituted C2
to C6 alkenyl, C2 to C8 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl.
substituted C3 to C8 cycloalkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; or
R7 and R8 are fused to form:
(i) a saturated carbon-based 4 to 8 membered ring;
(ii) an unsaturated carbon-based 4 to 8 membered ring; or
(iii) a 4 to 8 heterocyclic ring containing 1 to 3 heteroatoms selected from
the group consisting of O, N, and S;
wherein rings (i)-(iii) are optionally substituted by 1 to 3 substituents
selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2
to C6 alkenyl, substituted C2 to C1 alkenyl C2 to C6 alkynyl, substituted C2 to C6
alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, C1 to C6 alkoxy,
substituted C1 to C6 alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C1 to C6 aminoalkyl, and substituted C1 to C6 aminoalkyl;
R9 is absent, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl,
. substituted C2 to C6 alkenyl, C2 to C8 alkynyl, substituted C2 to C6 alkynyl, C3 to C8
cycloalkyl, substituted C3 to C8 cycloalkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R10 is selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to
C6 alkyl, aryl, substituted aryl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6
aminoalkyl, substituted C1 to C6 aminoalkyl, C1 to C6 thioalkyli substituted C1 to C6
thioalkyl, NH2, NHR11, andN(R11)2; and

R11 is selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to
C6 alkyl, aryl, substituted aryl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6
aminoalkyl, substituted C1 to C6 aminoalkyl, C1 to C6 tbioalkyl, substituted C1 to C6
thioalkyl, and NH2.
9 The method as claimed in claim 7, wherein said carbonyl compound is
of the structure:

wherein:
R1 is C1 to C6 alkyl or substituted C1 to C6 alkyl;
R7 is H, NH2, NHR10, N(R10)2, C(O)R10, C(S)R10, C1 to C6 alkyl, substituted
C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl,
substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C6 cycloalkyl, C1 to
C6 tbioalkyl, substituted C1 to C6 tbioalkyl, C1 to C6 alkoxy, substituted C1 to C6
alkoxy, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R8 is C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2
to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C6 cycloalkyl,
substituted C3 to C6 cycloalkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; or
R7 and R8 are fused to form:
(i) a saturated carbon-based 4 to 8 membered ring;
(ii) an unsaturated carbon-based 4 to 8 membered ring; or
(iii) a 4 to 8 heterocyclic ring containing 1 to 3 heteroatoms selected from
the group consisting of O, N, and S;
wherein rings (i)-(iii) are optionally substituted by 1 to 3 substituents
selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2
to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6
alkynyl, C3 to C6 cycloalkyl, substituted C3 to C8 cycloalkyl, C1 to C6 alkoxy,

substituted C1 to C6 alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
C1 to C6 aminoalkyl, and substituted C1 to C6 aminoalkyl;
R10 is selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to
C6 alkyl, aryl, substituted aryl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6
aminoalkyl, substituted C1 to C6 aminoalkyl, C1 to C6 thioalkyl, substituted C1 to C6
thioalkyl, NH2, NHR11, and N(R11)2; and
R11 is selected from the group consisting of H, C1 to C8 alkyl, substituted C1 to C6
alkyl, aryl, substituted aryl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6
aminoalkyl, substituted C1 to C6 aminoalkyl, C1 to C6 thioalkyl, substituted C1 to C6
thioalkyl, and NH2.
10. The method as claimed in claim 7, wherein said carbonyl compound is
of the structure:

wherein:
R1 is C1 to C6 alkyl or substituted C1 to C6 alkyl;
R2 and R3 are, independently, H, C1 to C6 alkyl, or substituted C1 to C6 alkyl;
or R2 and R3 are fused to form a ring comprising -CH2(CH2)nCH2-,
-CH2CH2C(CH3)2CH2CH2-, -O(CH2)pCH2-, -O(CH2)qO-, -CH2CH2OCH2CH2-, or
-CH2CH2NR6CH2CH2-;
n is 1 to 5;
p is 1 to 4;
q is 1 to 4;
R4 is H, OH, NH2, CN, halogen, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2
to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, or substituted C2 to C6
alkynyl;
Rs is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted
C1 to C6 alkoxy, C1 to C6 aminoalkyl, or substituted C1 to C6 aminoalkyl;

R6 is H or C1 to C6 alkyl;
X is O, S, or absent;
or a pharmaceutically acceptable salt thereof.
1|. The method as claimed in any one of claims 1 to 10, wherein said decoy
agent is acetonitrile.
12. The method as claimed in any one of claims 1 to 10, wherein said decoy
agent comprises an electron withdrawing substituent
13. The method as claimed in claim 12, wherein said decoy agent is
chloroacetonitrile or trichloroacetonitrile.
14. The method as claimed in any one of claims 1 to 10, wherein said decoy
agent is an aryl nitrile selected from the group consisting of benzonitrile, p-
chlorobenzonitrile, p-ethoxybenzonitrile, p-methoxybenzonitrile, o-nitrobenzonitrile,
p-acerylbenzonitrile, p-methylbenzonitrile, p-fluorobenzonitrile, and 1,3-
dicyanobenzene.
15. The method as claimed in any one of claims 1 to 10, wherein said decoy
agent is a heteroaryl nitrile selected from the group consisting of N-methyl-2-
pyrrolecafbonitrile, 2-thiophenecarbonitrile, 2-cyanopyridine, 3-cyanopyridine and 4-
cyanopyridine.
16. The method as claimed in any one of claims 1 to 15, wherein said
thionation is performed with a thionating agent selected from the group consisting of
hydrogen sulfide, Lawesson's reagent, phosphorus pentasulfide, and
diethyldithiophosphate.


(54) Title: METHODS FOR MINIMIZING THIOAMIDE IMPURITIES
(57) Abstract; Methods for minimizing the formation of thioamide compounds using decoy agents during reactions, such as thionations
of carbonyl compounds containing nitrile groups, are provided.

Documents:

02862-kolnp-2006 abstract.pdf

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02862-kolnp-2006 correspondence others.pdf

02862-kolnp-2006 description(complete).pdf

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02862-kolnp-2006 form-3.pdf

02862-kolnp-2006 form-5.pdf

02862-kolnp-2006 gpa.pdf

02862-kolnp-2006 international publication.pdf

02862-kolnp-2006 international search authority report.pdf

02862-kolnp-2006 pct other document.pdf

02862-kolnp-2006 priority document.pdf

02862-kolnp-2006-correspondence-1.1.pdf

02862-kolnp-2006-form-3-1.1.pdf

2862-KOLNP-2006-ABSTRACT.pdf

2862-KOLNP-2006-AMANDED CLAIMS.pdf

2862-KOLNP-2006-CANCELLED PAGES.pdf

2862-KOLNP-2006-CORRESPONDENCE.pdf

2862-KOLNP-2006-DESCRIPTION (COMPLETE).pdf

2862-KOLNP-2006-EXAMINATION REPORT.pdf

2862-KOLNP-2006-FORM 1.pdf

2862-KOLNP-2006-FORM 13 1.1.pdf

2862-KOLNP-2006-FORM 13.pdf

2862-KOLNP-2006-FORM 18 1.1.pdf

2862-kolnp-2006-form 18.pdf

2862-KOLNP-2006-FORM 2.pdf

2862-KOLNP-2006-FORM 3 1.1.pdf

2862-KOLNP-2006-FORM 3.pdf

2862-KOLNP-2006-FORM 5.pdf

2862-KOLNP-2006-GPA.pdf

2862-KOLNP-2006-GRANTED-ABSTRACT.pdf

2862-KOLNP-2006-GRANTED-CLAIMS.pdf

2862-KOLNP-2006-GRANTED-DESCRIPTION (COMPLETE).pdf

2862-KOLNP-2006-GRANTED-FORM 1.pdf

2862-KOLNP-2006-GRANTED-FORM 2.pdf

2862-KOLNP-2006-GRANTED-SPECIFICATION.pdf

2862-KOLNP-2006-INTERNATIONAL PUBLICATION.pdf

2862-KOLNP-2006-INTERNATIONAL SEARCH REPORT.pdf

2862-KOLNP-2006-OTHERS 1.1.pdf

2862-KOLNP-2006-OTHERS.pdf

2862-KOLNP-2006-PCT REQUEST FORM.pdf

2862-KOLNP-2006-PETITION UNDER RULE 137.pdf

2862-KOLNP-2006-REPLY TO EXAMINATION REPORT 1.1.pdf

2862-KOLNP-2006-REPLY TO EXAMINATION REPORT.pdf


Patent Number 255317
Indian Patent Application Number 2862/KOLNP/2006
PG Journal Number 07/2013
Publication Date 15-Feb-2013
Grant Date 12-Feb-2013
Date of Filing 04-Oct-2006
Name of Patentee WYETH
Applicant Address FIVE GIRALDA FARMS MADISON,NJ 07940
Inventors:
# Inventor's Name Inventor's Address
1 WILK BOGDAN KAZIMIERZ 6 CONRAD LANE,NEW CITY,NY 10956
PCT International Classification Number C07D 413/04
PCT International Application Number PCT/US2005/013657
PCT International Filing date 2005-04-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/560,403 2004-04-08 U.S.A.