US2003225149A1PendingUtilityA1
Process for preparing highly functionalized gamma-butyrolactams and gamma-amino acids
Priority: Apr 30, 2002Filed: Feb 13, 2003Published: Dec 4, 2003
Est. expiryApr 30, 2022(expired)· nominal 20-yr term from priority
C07D 207/38C07D 401/04C07C 229/18C07C 227/22C07C 229/08
42
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Claims
Abstract
The invention relates to a process for preparing highly functionalized γ-butyrolactams and γ-amino acids by reductive amination of mucohalic acid or its derivatives, and discloses a process for preparing pregabalin, a GABA analog with desirable medicinal activity.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A process for preparing a compound of formula I
wherein:
R 1 is H, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, (CH 2 ) n -aryl, heterocyclo, (CH 2 ) n -heterocyclo, heteroaryl, or (CH 2 ) n -heteroaryl, wherein n is 0, 1, 2, or 3; and
R 2 and R 2′ are each independently H, straight or branched (C 1 -C 6 )alkyl, a straight or branched (C 2 -C 7 )alkenyl, (C 3 -C 7 )cycloalkyl, alkylcycloalkyl, alkylalkoxy, alkylphenyl, alkyphenoxy, phenyl or substituted phenyl;
comprising:
(a) treating mucochloric or mucobromic acid 1 wherein X is Cl or Br with R′OH, wherein R′ is (C 1 -C 6 )alkyl, —CH 2 -phenyl, or —CH 2 -substituted phenyl in the presence of acid to provide 2A
(b) conjugate addition of R 2 R 2′ CM 0 wherein R 2 and R 2′ are as defined above and wherein M 0 is MgBr, CuBr, or B(OH) 2 , to 2A, to provide 3A
(c) hydrogenation of 3A to provide 4A
(d) reductive amination of 4A under hydrogenation conditions using ammonium formate or R 1 NH 2 , wherein R 1 is H, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, (CH 2 ) n -aryl, heterocyclo, (CH 2 ) n -heterocyclo, heteroaryl, or (CH 2 ) n -heteroaryl, wherein n is 0, 1, 2, or 3, followed by hydrolyisis
2 . The process of claim 1 , step (a) wherein R′OH is benzyl alcohol.
3 . The process of claim 1 , step (b), wherein R 2 R 2 CM 0 is
4 . The process of claim 1 , step (c) using Pd/C as a catalyst in the presence of triethyl amine.
5 . The process of claim 1 , step (d) wherein the reductive amination is effected under hydrogenation conditions using ammonium formate, triethyl amine, and Pd/C.
6 . A process for preparing pregabalin
comprising:
(a) treating mucochloric or mucobromic acid 1 wherein X is Cl or Br with benzyl amine in the presence of acid, to provide 2
(b) conjugate addition of
wherein M 1 is MgBr, CuBr, or
wherein M 2 is B(OH) 2 , to 2 to provide 3B, wherein “———” is absent or is a bond;
(c) hydrogenation of 3B to provide 4B
(d) reductive amination of 4B using ammonium formate, followed by hydrolyisis
7 . A process for preparing a compound of formula I
wherein:
R 1 is H, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, (CH 2 ) n -aryl, heterocyclo, (CH 2 ) n -heterocyclo, heteroaryl, or (CH 2 ) n -heteroaryl, wherein n is 0, 1, 2, or 3; and
R 2 and R 2′ are each independently H, straight or branched (C 1 -C 6 )alkyl, a straight or branched (C 2 -C 7 )alkenyl, (C 3 -C 7 )cycloalkyl, alkylcycloalkyl, alkylalkoxy, alkylphenyl, alkyphenoxy, phenyl or substituted phenyl;
comprising:
(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 R 1 NH 2 , wherein R 1 is (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, (CH 2 ) n -aryl, heterocyclo, (CH 2 ) n -heterocyclo, heteroaryl, or (CH 2 ) n -heteroaryl, wherein n is 0, 1, 2, or 3, and an acid catralyst, to provide 2C
(b) conjugate addition of R 2 R 2′ M 0 wherein M 0 is MgBr, CuBr, or B(OH) 2 , to 2C to provide 3C
(c) hydrogenation of 3C to provide 4C
(d) hydrolysis of 4C
8 . The process of step (a) of claim 7 , wherein the R 1 NH 2 is benzylamine or 1-phenylethyl amine.
9 . The process of step (a) of claim 7 , wherein the reducing agent is selected from sodium triacetoxy borohydride, sodium cyanoborohydride, triethyl silane, Ti(OiPr) 4 /NaBH 3 CN, borohydride exchange resin, Zn/acetic acid, sodioum borohydride/magnesium perchlorate, or zinc borohydride/zinc chloride.
10 . The process of step (a) of claim 7 , wherein the reducing agent is sodium triacetoxy borohydride.
11 . The process of step (a) of claim 7 , wherein the acid catalyst is selected from acetic acid, trichloroacetic acid, trifluoroacetic acid, formic acid, magnesium chloride, magnesium triflate, boron trifluoride etherate, AlCl 3 , FeCl 3 , ZnCl 2 , AlBr 3 , ZnBr 2 , TiCl 4 , SiCl 4 and SnCl 4 .
12 . The process of step (a) of claim 7 , wherein the acid catalyst is acetic acid.
13 . The process of step (a) of claim 7 , wherein the stochiometry of the reaction components is:
(a) 1 equivalents of mucochloric acid; (b) 1 to 5 equivalents of amine; (c) 1 to 10 equivalents of reducing agent; and (d) HOAc sufficient to maintain a pH of about 2 to about 7.
14 . The process of step (a) of claim 7 , wherein the stochiometry of the reaction components is:
(a) 1 equivalents of mucochloric acid; (b) 1 to 3 equivalents of amine; (c) 1 to 5 equivalents of reducing agent; and (d) HOAc sufficient to maintain a pH of about 3 to about 6.
15 . The process of step (a) of claim 7 , wherein the stochiometry of the reaction components is:
(a) 1 equivalents of mucochloric acid; (b) 1 to 2 equivalents of amine; (c) 1 to 3 equivalents of reducing agent; and (d) HOAc sufficient to maintain a pH of about 4 to about 5.
16 . The process of step (a) of claim 7 , wherein contacting comprises mixing in a liquid at a sufficient concentration and at sufficient temperatures and for sufficient times to allow formation of the resulting product.
17 . The process of step (a) of claim 7 , wherein the liquid is a polar non protic solvent and combinations or mixtures thereof.
18 . The process of step (a) of claim 7 , wherein the solvent is selected from tetrahydrofuran, acetonitrile, nitromethane, chloroform, methylene chloride, monochloro ethane, 1,1, or 1,2 dichloroethane, 1,1,1 or 1,1,2 tricholoroethane, or 1,1,1,2, or 1,1,2,2 tetrachloroethane, or combinations or mixtures thereof.
19 . The process of step (a) of claim 7 , wherein the temperature is from about −25° C. to about 50° C.
20 . The process of step (a) of claim 7 , wherein the temperature is from about 0° C. to about 40° C.
21 . The process of step (a) of claim 7 , wherein the temeperature is form about 10° C. to about 30° C.
22 . The process of step (a) of claim 7 , wherein the temperature is from about 12.5° C. to about 27.5° C.
23 . The process of step (a) of claim 7 , wherein the time is from about 30 minutes to about 5 days.
24 . The process of step (a) of claim 7 , wherein the time is from about 1 hour to about 3 days.
25 . The process of step (a) of claim 7 , wherein the time is from about 6 hours to 48 hours.
26 . The process of step (a) of claim 7 , wherein the time is from about 12 hours to 36 hours.
27 . The process of step (b) of claim 7 as provided in claim 3 .
28 . The process of step (c) of claim 7 as provided in claim 4 .
29 . A process for preparing pregabalin
comprising:
(a) reductive amination of mucochloric or mucobromic acid 1 wherein X is Cl or Br using sodium triacetoxy borohydride in the presence of benzylamine or 1-phenyl-ethylamine to provide 2D
(b) conjugate addition of
to provide 3B, wherein “———” is absent or is a bond;
(c) hydrogenation of 3D to provide 4D
(d) base hydrolysis of 4D
30 . A process for reductively aminating mucohalic acid, comprising:
(a) contacting mucochloric or mucobromic acid 1 wherein X is Cl or Br with sodium triacetoxyborohydride, acetic acid, and R 3 NH 2 , wherein R 3 is H, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, (CH 2 ) n -aryl, heterocyclo, (CH 2 ) n -heterocyclo, heteroaryl, or (CH 2 ) n -heteroaryl, wherein n is 0, 1, 2, or 3; to provide 2EJoin the waitlist — get patent alerts
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