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US 2008/0076818 A1Published application
Novel processes for the preparation of dpp iv inhibitors
AssigneeGlenmark Pharmaceuticals S.A.
InventorsAbraham Thomas, V.S. Lingam, Ashok Kadam, Suresh Kadam, Shantaram Phatangare, Deepak Ukride
Life of this patent
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Abstract
The present invention relates to novel processes for preparing DPP-IV inhibitors having the structure of formula I, and pharmaceutically acceptable salt thereof, which are useful for treatment of Type 2 diabetes.
Claims49
A process for preparing a compound of formula V,
- and stereoisomers thereof, wherein X is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl, and R is a C1-C4 alkyl, comprising the step of condensing the compound of formula II
- with a glyoxalic acid ester.
A process for preparing a compound of formula VI,
- stereoisomers thereof, wherein X is a substituted or unsubstituted cycloalkyl substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl substituted or unsubstituted aralkyl substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl, and R is a C1-C4 alkyl, comprising the step of reducing imino group of the compound of formula V
A process for preparing a compound of formula VII,
- stereoisomers thereof, wherein X is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl or substituted or unsubstituted heteroarylalkyl, and R is a C1-C4 alkyl, PG is a nitrogen protecting group, comprising the step of introducing nitrogen protecting group to the compound of formula VI.
A process for preparing a compound of formula VIII,
- stereoisomers thereof, wherein X is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl, and PG is a nitrogen protecting group, comprising the step of hydrolyzing the compound of formula VII.
A process for preparing a compound of formula IX,
- and stereoisomers thereof, wherein X is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl, PG is nitrogen protecting group, and Y is CH2 or CF, comprising the step of coupling the compound of formula VIII with prolinamide derivative.
A process for preparing a compound of formula X,
- and stereoisomers thereof, wherein X is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl and PG is nitrogen protecting group, and Y is CH2 or CHF, comprising the step of converting carboxamide of the compound of formula IX to nitrile.
A process for preparing a compound of formula X,
- and stereoisomers thereof, wherein X is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl and PG is nitrogen protecting group, and Y is CH2 or CF, comprising the step of coupling the compound of formula VIII
- with 2S-cyanopyrrolidine derivative.
A process for preparing a compound of formula I,
- pharmaceutically acceptable salts, stereoisomers thereof, wherein X is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl, and Y is CH2 or CHF,
- which process comprises the steps of:
- (a) condensing the compound of formula II with a glyoxalic acid ester
- to give a compound of formula V,
- wherein R is C1-C4 alkyl,
- (b) reducing the imino group of the compound of the formula V to give an amine of formula VI,
- (c) N-protecting the compound of formula VI to give a glycine ester derivative of formula VII,
- (d) hydrolyzing the compound of formula VII to give the glycine derivative of the formula VIII,
- (e) coupling the compound of formula VIII with a prolinamide derivative to give a dipeptide derivative of formula IX,
- (f) converting the compound of formula IX to a nitrile derivative of formula X,
- alternatively, coupling the compound of formula VIII with a 2S-cyanopyrrolidine derivative to give a compound of formula X, and
- (h) deprotecting the compound of formula X to a compound of formula I, which is optionally converted to a pharmaceutically acceptable salt.
9 more elements
A process for preparing a compound of formula A,
- stereoisomers thereof, wherein L is a leaving group, Y is CHF, and R2 is CN, which process comprises the steps of:
- a) protecting an amide of formula XI
- with a suitable nitrogen protecting group (PG) in ether solvent to form a compound of formula XII
- b) protecting the compound of formula XII with a suitable hydroxy protecting group (Pg1) in presence of a base selected as pyridine to form a compound of formula XIII
- c) dehydrating the compound of formula XIII in presence of a suitable dehydrating agent selected as phosphorous oxychloride and a base selected as pyridine to form a compound of formula XIV
- d) deprotecting the compound of formula XIV with ammonia in methanol to form a compound of formula XV
- e) fluorinating the compound of formula XV with a suitable fluorinating agent selected as diethylamino sulfurtrifluoride in dichloromethane to form a compound of formula XVI
- f) deprotecting the compound of formula XVI and coupling it with an acetyl compound L2C(O)CH2L, (wherein L2 is a leaving group) in presence of p-toluenesulfonic acid and acetonitrile to form a compound of formula A.
5 more elements
A process for preparing a compound of formula A,
- wherein L is a leaving group, Y is CHF and R2 is CN, comprising the steps of:
- a) converting an ester of formula XVIII in presence of a base and dichloromethane
- to a compound of formula XIX
- wherein L1 is a leaving group other than a halogen,
- b) aminating the compound of formula XIX with ammonia in methanol to form a compound of formula XX
- c) fluorinating the compound of formula XX with a fluorinating agent selected as tetrabutylammonium fluoride in a solvent system selected as tetrahydrofuran and water to form a compound of formula XXI
- d) dehydrating the compound of formula XXI with a suitable dehydrating agent selected as phosphorous oxychloride in presence of imidazole in pyridine to form a compound of formula XVI
- e) deprotecting the compound of formula XVI and coupling it with an acetyl compound L2C(O)CH2L, (wherein L2 is a leaving group) in presence of p-toluenesulfonic acid and a base in acetonitrile to form a compound of formula A.
5 more elements
A compound selected from
- stereoisomers thereof, wherein X is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl, Y is CH2 or CHF, and PG is a suitable nitrogen protecting group.
A compound selected from
- stereoisomers thereof, wherein PG is nitrogen protecting group, Pg1 is oxygen protecting group, and L1 is a leaving group.
A pharmaceutical composition comprising:
- (a) a compound of the formula
- or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein X is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl, and Y is CH2 or CF, and
- (b) a compound selected from
- wherein PG is a suitable nitrogen protecting group selected from tert-butyloxycarbonyl, benzyloxy carbonyl, or benzyl, and X, R and Y are as defined, wherein the compound in component (b) is present in an amount up to 0.2% based upon 100% total weight of components (a) and (b).
1 more element
Dependencies are inferred from the claim text.