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(12) Patent Application Publication (10) Pub. No.: US 2003/0225149 A1 Blazecka Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2003/0225149 A1 Blazecka Et Al US 2003O2251.49A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0225149 A1 Blazecka et al. (43) Pub. Date: Dec. 4, 2003 (54) PROCESS FOR PREPARING HIGHLY (52) U.S. Cl. ......................... 514,400; 514/419; 514/561; FUNCTIONALIZED 514/567; 548/339.1; 548/495; GAMMA-BUTYROLACTAMS AND 562/443; 562/553 GAMMA-AMINO ACDS (57) ABSTRACT (76) Inventors: Peter G. Blazecka, Windsor (CA); The invention relates to a process for preparing highly James Guy Davidson III, Howell, MI functionalized Y-butyrolactams and Y-amino acids by reduc (US); Ji Zhang, Ann Arbor, MI (US) tive amination of mucohalic acid or its derivatives, and discloses a process for preparing pregabalin, a GABA ana Correspondence Address: log with desirable medicinal activity. Heidi M. Berwen Warner-Lambert Company 2800 Plymouth Road Ann Arbor, MI 48105 (US) X O (21) Appl. No.: 10/365,430 O - - - - - - - - - - - - - - - (22) Filed: Feb. 13, 2003 X Related U.S. Application Data Michi.d (60) Provisional application No. 60/376.991, filed on Apr. X = Br, Cl O 30, 2002. Publication Classification Me OH (51) Int. Cl.' .................. A61K 31/4172; A61K 31/405; Me NH2 A61K 31/198; CO7C 229/06; Pregabalin CO7C 229/38; CO7D 233/66; CO7D 209/18 US 2003/0225149 A1 Dec. 4, 2003 PROCESS FOR PREPARING HIGHLY SUMMARY OF THE INVENTION FUNCTIONALIZED GAMMA-BUTYROLACTAMS AND GAMMA-AMINO ACIDS 0006 These and other needs are met by the present invention which provides a process for preparing a com CROSS REFERENCE TO RELATED pound of formula I APPLICATIONS 0001. This application claims benefit of priority from U.S. Provisional Application No. 60/376,991, filed on Jun. 14, 2002. OH FIELD OF THE INVENTION R2 NHR 0002 The invention relates to a process for preparing highly functionalized Y-butyrolactams and Y-amino acids by reductive amination of mucohalic acid or its derivatives, and discloses a process for preparing pregabalin, a GABA ana 0007 wherein: log with desirable medicinal activity. 0008 R is H., (C-C)alkyl, (C-C)cycloalkyl, BACKGROUND OF THE INVENTION aryl, (CH2)-aryl, heterocyclo, (CH2)-heterocyclo, heteroaryl, or (CH)-heteroaryl, wherein n is 0, 1, 2, 0003 Pregabalin (3-Aminomethyl-5-methyl-hexanoic or 3; and acid) is a 3-substituted Y-aminobutyric acid (GABA) analog that exhibits an array of useful medicinal properties, as 0009 R and R are each independently H, straight disclosed in WO93/23383 and U.S. Pat. No. 6,306,910, both or branched (C-C)alkyl, a straight or branched of which are assigned to the same assignee as the instant (C-C)alkenyl, (C-C)cycloalkyl, alkylcycloalkyl, application. alkylalkoxy, alkylphenyl, alkyphenoxy, phenyl or Substituted phenyl, 0010 comprising: 0011 (a) treating mucochloric or mucobromic acid 1 wherein X is C1 or Br with ROH, wherein R" is (C-C)alkyl, -CH2-phenyl, or -CH-Sub Stituted phenyl, in the presence of acid to provide Pregabalin 0004 Synthetic approaches to pregabalin generally com O O X X mence from a linear precursor. For instance, WO 93/23383 ROH O -- O; discloses a route commencing from 5-methyl-hexanoic acid H that requires 8 transformations. A recently disclosed alter X X native Strategy commences with the enantioSelective conju OH OR gate addition of S-C methylbenzyl amine to 2-Methylene 1. 2A succinic acid dimethyl ester (Michael J. Mayer, Trip Report, Synthetic Pathways 9" Symposium on the Latest Trends in Organic Synthesis, Albany Molecular Sciences Technical 0012 (b) conjugate addition of RRCMo. Report Vol. 5, No. 19 (2001), p. 9; also available at http:// wherein R and R2 are as defined above and albmolecular.logical.net/features/tekrepS/vol05/no19/last wherein Mo is MgBr, CuBr, or B(OH), to 2A, to visited Feb. 6, 2003). The reaction provides a mixture of provide 3A diastereomers, which can be separated, and the requSite diastereomer is then converted to pregabalin via 6 additional O O StepS. X X R2RCMo 0005. A shortcoming of either of these approaches, par O --> O; ticularly in Scale-up and production contexts, is that they R2 require a multitude of Steps and purification operations. AS X a result, there is a need for a process for Synthesizing OR i R ORi pregabalin and other 3-Substituted Y amino acids that mini 2A 3A mizes the total number of Synthetic transformations and Simplifies purification StepS. US 2003/0225149 A1 Dec. 4, 2003 0013 (c) hydrogenation of 3A to provide 4A 0018 (b) conjugate addition of O -e- O; and OR OR 0014) (d) reductive amination of 4A under hydro genation conditions using ammonium formate or RNH, wherein R is H., (C-C)alkyl, (C- C.)cycloalkyl, aryl, (CH-)-aryl, heterocyclo, (CH2)-heterocyclo, heteroaryl, or (CH2)-het eroaryl, wherein n is 0, 1, 2, or 3, followed by 0020 wherein M is B(OH), to 2 to provide 3B, wherein hydrolyisis 66 is absent or is a bond; O O H), RNH2 O HCONH4, Ho R2 Hydrolysis R2 OR OR Me OR 4A 2 O 3B 0.015 What is also provided is a process for preparing pregabalin NH2 Pregabalin He- O; and OR OR 0016 comprising: 3B 4B 0017 (a) treating mucochloric or mucobromic acid 1 wherein X is C1 or Br with ROH, wherein R" is (C-C)alkyl or -CH2-aryl, in the presence of acid, to provide 2 0022 (d) reductive amination of 4B using ammo nium formate, followed by hydrolyisis O O O X X ROH X O --> O; H Me H), HCO2NH4, O Hydroloysis - Pregabalin. X X Me OH OR 4B US 2003/0225149 A1 Dec. 4, 2003 0023. What is also provided is a process for preparing a 0030) (c) hydrogenation of 3C to provide 4C compound of formula I NR --> NR1; and OH R2 NHR 0031) (d) hydrolysis of 4C 0024 wherein: 0025 R is H., (C-C)alkyl, (C-C)cycloalkyl, aryl, (CH2)-aryl, heterocyclo, (CH2)-heterocyclo, heteroaryl, or (CH2)-heteroaryl, wherein n is 0, 1, 2, Hydrolysis or 3; and NR --> I. 0026 R and R are each independently H, straight or branched (C-C)alkyl, a straight or branched (C-C)alkenyl, (C-C)cycloalkyl, alkylcycloalkyl, alkylalkoxy, alkylphenyl, alkyphenoxy, phenyl or Substituted phenyl, 0032) What is also provided is a process for preparing 0027 comprising: pregabalin 0028 (a) reductive amination of mucochloric or mucobromic acid 1 wherein X is Cl or Br, using a reducing agent in the presence of ammonium formate or RNH, wherein R is (C-C)alkyl, (C-C7)cycloalkyl, aryl, (CH2)-aryl, heterocyclo, (CH)-heterocyclo, heteroaryl, or (CH)-het NH2 eroaryl, wherein n is 0, 1, 2, or 3, and an acid Me catralyst, to provide 2C Pregabalin O O 0033 comprising: X X o - I - NR: 0034 (a) reductive amination of mucochloric or RNH2 1s mucobromic acid 1 wherein X is C1 or Br using a reducing agent in the presence of benzylamine or X X 1-phenyl-ethylamine to provide 2D OH 1. 2C O O X X H or Me: 0029 (b) conjugate addition of RRCM, H wherein Mo is MgBr, CuBr, or B(OH), to 2C to o - Benzylonline amine or - || N provide 3C X 1-Phenyl-ethylamine X Ph OH 1. 2D 0035 (b) conjugate addition of NR -> NR1; Me r Me US 2003/0225149 A1 Dec. 4, 2003 0036) wherein M is MgBr, CuBr, or 0039) ; and 0040 (d) hydrolysis of 4D Hydrolysis Me Yr. --> Pregabalin. Me 0037 wherein M is B(OH), to 2 to provide 3B, wherein 0041 What is also provided is a process for reductively ss is absent or is a bond; aminating mucohalic acid, comprising: 0042 (a) contacting mucochloric or mucobromic acid 1 wherein X is Cl or Br with a reducing agent, an acid catalyst, and RNH2, wherein R is H, (C-C)alkyl, (C-C)cycloalkyl, aryl, (CH2)-aryl, heterocyclo, (CH2)-heterocyclo, heteroaryl, or (CH-)-heteroaryl, wherein n is 0, 1, 2, or 3; to provide 2E O O X X R3NH2. 3. X X OH 1. 2E DETAILED DESCRIPTION OF THE INVENTION 0043. The invention processes for preparing 3-substituted Yaminobutyric acids disclosed herein possess a number of advantages. Firstly, they give rise to 3-Substituted Y-amino butyric acids in a minimum number of Steps and under mild 3D conditions. Secondly, they make use of generally inexpen Sive and readily available reagents. Thirdly, they exploit the Synthetic potential of mucohalic acid. 0044) Mucochloric acid 1 (2,3-dichloro-4-oxo-2- butenoic acid) and mucobromic acid (2,3-dibromo-4-oxo-2- butenoic acid) are commercially available and inexpensive 0038 (c) hydrogenation of 3D to provide 4D Starting materials. Both molecules are characterized by the presence of a carbon-carbon double bond with Z configu ration, two halogen atoms, and two carbonyl groups. This high degree of functionality makes both mucochloric and mucobromic acid particularly useful building blocks for the Synthesis of a variety of biologically active heterocycles, Such as Substituted 1,5-dihydropyrrol-2-ones, pyrrolidines, and Y-lactams, and Y-amino acids Such as pregabalin. O O Cl Br O O Cl Br OH OH Mucochloric Acid Mucobromic Acid US 2003/0225149 A1 Dec. 4, 2003 0.045. Mucobromic and mucochloric acid surprisingly have not been commonly employed in organic Synthesis as -continued C-4 building blocks. Presumably, this is because of the many O O reactive sites in the molecules, their poor Stability under basic conditions, and the perception among those of ordi Step E OH nary skill in the art of the difficulties associated with the NR --- Selective manipulation of the halogen atoms in the presence R2 R NHR of the other functional groups.
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