Process for the preparation of ramipril

Patent metadata

Field	Value
Publication number	US-10112973-B2
Application number	US-201515317362-A
Country	US
Kind code	B2
Filing date	Jun 8, 2015
Priority date	Jun 11, 2014
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

Abstract

An enantioselective process for the production of (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid and its conversion into Ramipril is provided.

First claim

The invention claimed is:

1. A process for preparing a compound of formula (VI)

wherein:
R1 is CO 2 R4 or CN;
R2 is (C1-C4)alkyl;
R3 is
(C1-C4)alkyl, wherein one, two or three hydrogen atoms are optionally replaced by fluorine, (C1-C4)alkoxy, or
phenyl;

R4 is (C1-C4)alkyl; and
Ar is
phenyl, optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, (C1-C4)alkoxy and (C1-C4)alkyl, or
1-naphthyl;

comprising
reacting a chiral amine of formula (IV)

wherein:
R1 is CO 2 R4 or CN;
R4 is (C1-C4)alkyl; and
Ar is
phenyl, optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, (C1-C4)alkoxy and (C1-C4)alkyl, or
1-naphthyl;

with a 2-acylamino-acrylic acid ester of formula (V)

wherein:
R2 is (C1-C4)alkyl; and
R3 is
(C1-C4)alkyl, wherein one, two or three hydrogen atoms are optionally replaced by fluorine, (C1-C4)alkoxy, or
phenyl,

to produce the compound of formula (VI).

2. A compound of formula (VI)

wherein:
R1 is CO 2 R4 or CN;
R2 is (C1-C4)alkyl;
R3 is
(C1-C4)alkyl, wherein one, two or three hydrogen atoms are optionally replaced by fluorine, (C1-C4)alkoxy, or
phenyl;

R4 is (C1-C4)alkyl; and
Ar is
phenyl, optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, (C1-C4)alkoxy and (C1-C4)alkyl, or
1-naphthyl.

3. The compound according to claim 2 , wherein the carbon atom bearing the R1 group is in the (S) configuration.

4. A compound of formula (VIIa)

wherein:
R2 is (C1-C4)alkyl;
R3 is
(C1-C4)alkyl, wherein one, two or three hydrogen atoms are optionally replaced by fluorine, (C1-C4)alkoxy, or
phenyl; and

R4 is (C1-C4)alkyl.

5. The compound of claim 4 , wherein the carbon atom bearing the CO 2 R4 group is in the (S) configuration.

6. A compound of formula (VIIb)

wherein:
R2 is (C1-C4)alkyl; and
R3 is
(C1-C4)alkyl, wherein one, two or three hydrogen atoms are optionally replaced by fluorine, (C1-C4)alkoxy, or
phenyl.

7. The compound of claim 6 , wherein the carbon atom bearing the CN group is in the (R) configuration.

8. The compound according to claim 2 , wherein R1 is CO 2 R4.

9. The compound according to claim 2 , wherein R2 is methyl or ethyl.

10. The compound according to claim 2 , wherein R3 is methyl, ethyl, propyl, butyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, or phenyl.

11. The compound according to claim 2 , wherein R4 is methyl or ethyl.

12. The compound according to claim 2 , wherein Ar is phenyl, 4-methoxyphenyl, 4-chlorophenyl or 1-naphthyl.

13. The compound according to claim 4 , wherein R2 is methyl or ethyl.

14. The compound according to claim 4 , wherein R3 is methyl, ethyl, propyl, butyl, trifluoromethyl, methoxy, ethoxy, propoxy, butoxy, or phenyl.

15. The compound according to claim 4 , wherein R4 is methyl or ethyl.

16. The process of claim 1 , further comprising steps (B-1a), (B-1b), (C), and (D):
(B-1a) hydrolysing the chiral imine moiety in the compound of formula (VI)
to produce a chiral ketone of formula (VII),

wherein:
R1 is CO 2 R4 or CN;
R2 is (C1-C4)alkyl;
R3 is
(C1-C4)alkyl, wherein one, two or three hydrogen atoms are optionally replaced by fluorine, (C1-C4)alkoxy, or
phenyl; and

R4 is (C1-C4)alkyl;
followed by
(B-1b) hydrolysing the chiral ketone of formula (VII) to produce a chiral amino acid of formula (VIII), or a salt thereof,

which is in equilibrium with a chiral bicyclic amino acid of formula (IX), or a salt thereof,

and
(C) converting the chiral bicyclic amino acid of formula (IX) or salt thereof, from the mixture of the chiral amino acid of formula (VIII) or salt thereof, and the chiral bicyclic amino acid of formula (IX) or salt thereof, by catalytic hydrogenation into a compound of formula (IIIa), or a salt thereof,

and
(D) converting the compound of formula (IIIa) or salt thereof into a compound of formula (I)

17. The process of claim 1 , further comprising steps (B-2), (C), and (D):
(B-2) hydrolysing the chiral imine in the compound of formula (VI) to produce a chiral amino acid of formula (VIII), or a salt thereof,

which is in equilibrium with a chiral bicyclic amino acid of formula (IX), or a salt thereof,

and
(C) converting the chiral bicyclic amino acid of formula (IX) or salt thereof, from the mixture of the chiral amino acid of formula (VIII) or salt thereof, and the chiral bicyclic amino acid of formula (IX) or salt thereof, by catalytic hydrogenation into a compound of formula (IIIa), or a salt thereof,

and
(D) converting the compound of formula (IIIa) or salt thereof into a compound of formula (I)

Assignees

• Sanofi Aventis Deutschland

Inventors

• Kretzschmar Gerhard
• Oehme Jan
• Rossen Kai

Classifications

• C07K5/06026 Primary

  the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala · CPC title

• C07C255/46

  to carbon atoms of non-condensed rings · CPC title

• C07C2601/10

  the ring being unsaturated · CPC title

• C07C249/02

  of compounds containing imino groups · CPC title

• C07C251/20

  having carbon atoms of imino groups being part of rings other than six-membered aromatic rings · CPC title