An Improved Process for the Preparation of cis endo benzyl-2-a?abicyclo[3.3.0}octane-3-carboxylate hydrochloride
Field of Invention:
The present invention provides an improved process for the preparation of cisendo benzyl-2-azabicyclo [3.3.0]octane-3-carboxylate hydrochloride which is an valuable intermediate of Ramiro.
More specifically the present invention provides an improved method of resolving racemic benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride to obtain optically pure cisendo benzyl-2-azabicyclo[3,3.0]octane-3-carboxylate hydrochloride, a key intermediate of Ramipril. The intermediate enzyl-2-azabicyclo[3^.0]octane-3-carboxylate hydrochloride and Ramipril may be represented by the formula's 4 and 1 respectively:

— H
H H
i
H

.C00CH2-Ph
. HCI

COOH
H5C2OOC CH3 "•,
H IH.

Ramipril is pharmaceutically useful, in particular, as Antihypertensive.

Background of Invention:
In accordance with the prior art, described in EP 0 115 345 Bl, method of preparation of cisendo benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride is provided by resolving racemic mixture of benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate by crystallization of diastereomeric salts, which process comprises:
a. preparing the salts of the racemic esters with optically active N acylated R-or S-
aminocarboxylic acids which contain a phenyl nucleus from the series, phenyl alanine,
phenyl glycine, p-phenyl-a-aminobutyric acid, 3,4-dihydroxy phenyl alanine, P-
phenylserine and tyrosine;
b. rrecrystallizing them from an aprotic organic solvent or an alcohol;
c. decomposing the precipitated, optically homogenous diastereomeric salts in a manner
known per se;
d. isolating the desired enantiomers and converting the latter into free acid by saponification
or hydrogenolysis in a manner known per se.
The prior art procedure describes the usage of expensive amino acids rendering the process less cost friendly.
Furthermore amino acids apart from being expensive are also relatively commercially less accessible. Due to the aforementioned reasons the cost for the preparation of the final drug Ramipril, escalates considerably.
As the compound formula 1 (Ramipril) is a useful anti-hypertensive, it is important to have a cost effective, commercially viable and industrially scaleable process for preparing one of its key intermediate of formula 4 (wherein the key raw materials of intermediate of formula 4 are also easily accessible and cost effective).

Therefore, the main objective of the present invention is to develop a process for preparing the compound of formula 4, which is cost effective, commercially viable and easily scaleable.
Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of
compound of formula 4, which comprises, reacting racemic benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride of formula 2 with L (+)Mandelic acid to give S,S,S diastereomeric salt of benzyl-2-azabicyclo[3.3.0]pctane-3-carboxylate hydrochloride of formula 3 which on reaction with alkali hydroxide or alkali carbonate and subsequently with hydrochloric acid affords optically pure title compound of formula 4. The process may schematically be represented as follows:


H
. HCI

\^ o

STEPl



CHsCOOPh
\^ o

STEP 2

H H

.C00CH2-Ph

H

HCI

The present invention is directed to a cost effective and industrially viable process.
Detailed Description of The Invention
The present invention provides an improved process for the preparation of optically pure, cis endo benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride which is an valuable intermediate of Ramipril. The title compound of formula 4 is prepared by a two step process, which comprises: Stepl
a. treatment of a suspension of racemic benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate
hydrochloride in halogenated solvent selected from dichloromethane, ethylene dichloride
or chloroform or in an organic solvent selected from alkyl acetates wherein alkyl group
consists of C1-C5 carbon atoms preferably ethyl acetate, with a solution of alkali
hydroxide selected from potassium hydroxide or sodium hydroxide or a alkali carbonate
selected from potassium carbonate or sodium carbonate preferably sodium carbonate, till
a clear solution is obtained;
b. separating the organic phase from the resultant biphasic system, accompanied by
distillation of solvent;
c. dissolving the residue obtained in step b) in ketone solvent selected from C3 to Cu
ketones, selected from acetone, propanone, 2-methylbutyl ketone, acetyl acetone, ethyl
methyl ketone, diethyl ketone, diisopropyl ketone, diisobutyl ketone and the like or
aliphatic nitriles selected from acetonitrile and the like, preferably acetone followed by
addition of L(+) Mandelic acid;

d. stirring the reaction mixture at a temperature of 0-3 0°C preferably 0-10°C for a time
period of 15 minutes to 2 hours preferably 20-30 minutes;
e. isolation of S,S,S diastereomeric salt of benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate
hydrochloride of formula 3 obtained in step d by conventional methods.
Step 2
a. treatment of a suspension of S,S,S diastereomeric salt of benzyI-2-
azabicyclo[3.3.0]octane-3-carboxyIate hydrochloride of formula 3 in halogenated solvent
selected from dichloromethane, ethylene dichloride or chloroform or in an organic
solvent selected from alkyl acetates wherein alkyl group consists of C1-C5 carbon atoms
preferably ethyl acetate, with alkali hydroxide selected from sodium hydroxide or
potassium hydroxide or alkali carbonate selected from potassium carbonate or sodium
carbonate preferably sodium carbonate till a clear solution is obtained;
b. separating the organic phase from the resultant biphasic system, accompanied by
distillation of solvent;
c. dissolving the residue obtained in step b in ketone solvent selected from C3 to Cn
ketones, selected from acetone, propanone, 2-methylbutyl ketone, acetyl acetone, ethyl
methyl ketone, diethyl ketone, diisopropyl ketone, diisobutyl ketone and the like or
aliphatic nitriles selected from acetonitrile and the like, preferably acetone followed by
dropwise addition of hydrochloric acid at a temperature of 0-30°C preferably 0-10°C ,
till pH 1.5-2.5 preferably 2.0;
d. filtering the suspension obtained in step c) to obtain the title compound of formula 4.

The present invention is described in detail in the examples below, which are provided by way of illustration only and does not limit the scope of the invention.
Example 1 Stepl
A suspension of racemic benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride (100 g), in dichloromethane (1.0 L) is stirred at 27°C for 5 minutes and then cooled to 5-6°C. The pH of the reaction mixture is adjusted to 9.8 by the drop wise addition of 10% sodium carbonate solution. Of the resultant biphasic system the organic phase is separated and aqueous phase is extracted with dichloromethane (2 xl50 ml). Both the organic phases are then combined and washed with 2% sodium carbonate and then with water and subjected to distillation under reduced pressure. The residue obtained is then dissolved in acetone (135 ml). To the resultant solution, a solution of L (+) Mandelic acid (40 g) in acetone (135 ml) is added and the reaction mixture cooled to 5-8°C for 25 minutes. The obtained suspension is filtered and washed with chilled acetone to yield the intermediate S,S,S diastereomeric salt of benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride of formula 3 (34 g).
[a]D^° =+15.3° (c-1, in water).
Step 2
A suspension of S,S,S diastereomeric salt of benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride of formula 3 (34 g), in dichloromethane (400 ml) is stirred at 27°C for 10 minutes and then cooled to 5-6°C. The pH of the reaction mixture is adjusted to 10.3 by addition of 10% sodium carbonate solution. Of the resultant biphasic system the organic phase is separated and aqueous phase is extracted with dichloromethane (2 x 100 ml). Both the organic phases are then combined and washed with water and subjected to distillation under reduced pressure. To the residue obtained acetone (115 ml) is added and the reaction mixture is cooled to 5-6°C. Upon

completion of this step Hydrochloric acid is added dropwise till pH~2 and the reaction mixture is stirred at the same temperature for 20 minutes. The suspension obtained is then filtered and washed with chilled acetone to yield the title compound (21.5 g)

We claim
1. An improved process for the preparation of casino benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride of formula 4, which comprises, reacting racemic benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride of formula 2 with alkali hydroxide/ alkali carbonate and subsequently with L (+)Mandelic acid at a temperature of 0-3 0°C and in presence of a solvent to give S, S,S diastereomeric salt of benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride formula 3 which on reaction with alkali hydroxide/ alkali carbonate and subsequently with hydrochloric acid in presence of a solvent, at 0-30°C affords optically pure title compound of formula 4.


The process as claimed in claim 1 wherein the title compound of formula 4 is prepared by a two step process, comprising preparation of S,S,S diastereomeric salt of benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride of formula 3 and its subsequent conversion to optically pure benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride of formula 4.
The process as claimed in claim 1 and 2 wherein preparation of S,S,S diastereomeric salt of benzyI-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride comprises:
a. treatment of a suspension of racemic benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate
hydrochloride in halogenated solvent selected from dichloromethane, ethylene
dichloride or chloroform or in an organic solvent selected from alkyl acetates wherein
alkyl group consists of C1-C5 carbon atoms preferably ethyl acetate, with a solution
of alkali hydroxide selected from potassium hydroxide or sodium hydroxide or a
alkali carbonate selected from potassium carbonate or sodium carbonate preferably
sodium carbonate, till a clear solution is obtained;
b. separating the organic phase from the resultant biphasic system, accompanied by
distillation of solvent;
c. dissolving the residue obtained in step b) in ketone solvent selected from C3 to Can
ketones, selected from acetone, propanone, 2-methylbutyl ketone, acetyl acetone,
ethyl methyl ketone, diethyl ketone, isopropyl ketone, isobutyl ketone and the like
or aliphatic nitrides selected acetonitrile and the like, preferably acetone followed by
addition of L(+) Mandelic acid;
d. stirring the reaction mixture at a temperature of 0-30°C preferably 0-10°C for a time
period of 15 minutes to 2 hours preferably 20-30 minutes;
e. isolation of S,S,S diastereomeric salt of benzyl-2-azabicyclo[3.3.0]octane-3-
carboxylate hydrochloride of formula 3 obtained in step d by conventional methods.

4. The process as claimed in claim 1 -3 wherein preparation of optically pure benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride of formula 4 comprises:
a. treatment of a suspension of S,S,S diastereomeric salt of benzyl-2-
azabicyclo[3.3.0]octane-3-carboxylate hydrochloride of formula 3 in halogenated
solvent selected from dichloromethane, ethylene dichloride or chloroform or in an
organic solvent selected from alkyl acetates wherein alkyl group consists of C1-C5
carbon atoms preferably ethyl acetate, with alkali hydroxide selected from sodium
hydroxide or potassium hydroxide or alkali carbonate selected from potassium
carbonate or sodium carbonate preferably sodium carbonate till a clear solution is
obtained;
b. separating the organic phase from the resultant biphasic system, accompanied by
distillation of solvent;
c. dissolving the residue obtained in step b) in ketone solvent selected from C3 to Cn
ketones, selected from acetone, propanone, 2-methylbutyl ketone, acetyl acetone,
ethyl methyl ketone, diethyl ketone, diisopropyl ketone, diisobutyl ketone and the like
or aliphatic nitriles selected from acetonitrile and the like, preferably acetone
followed by drop wise addition of hydrochloric acid at a temperature of 0-3 0°C
preferably 0-10°C , till pH 1.5-2.5 preferably 2.0;
d. filtering the suspension obtained in step c) to obtain the title compound of formula 4.

A. process according to claims 1-4 wherein the cis endo benzyl-2-azabicyclo[3.3.0]octane-3-carboxylate hydrochloride of formula 4 prepared by process descried therein is an intermediate used for the preparation of Ramipril.
6. An improved process for the preparation of cis endo benzyl-2-carboxylate hydrochloride of formula 4 as herein described v\ examples.