This invention relates an Improved Process For Preparation Of Ramipril. FIELD OF INVENTION
Particularly, this invention relates to an improved process for Manufacturing a key intermediate of Ramipril named as (S,S,S)-2-azobicyclo [3,3,0] octane-3-carboxylic acid benzyl ester hydrochloride [(S,S,S)-enantiomer)] by resolution of its racemate. More particularly, the present invention provides a process for separation of diastereomeric mixture of key intermediate, (S,S,S)- enantiomer, of Ramipril in its pure form.
Still more particularly, this invention provides a process that is high yielding, ecofriendly, commercially viable and easy to operate. BACKROUND OF THE INVENTION
Ramipril is known for having a long lasting, intense hypotensive action. This is one of the powerful inhibitor of angiotensin- converting enzyme (ACE inhibitor) and is used for controlling high blood pressure of various origins. It can be combined with other antihypotensive, vasodilating or diuretic compounds. Synthesis of Ramipril involves a common intermediate namely 2- azabicyclo [3,3,0] octane-3-carboxylic acid of formula I. This common intermediate is a racemic mixture of (S,S,S) and (R,R,R)-enantiomers, out of that (S,S,S)-being the desired enantiomer for getting Ramipril. These enantiomers are inseparable by known separation techniques due to their zwitterionic nature.
(Formula Removed)
Typically these enantiomers are converted to respective esters, which are used further for synthesis of Ramipril.
The prior art known to the inventor include US 4,587,258, which advocates conversion of a compound of formula I to its ethyl ester (II a), which is further purified by column chromatography to get enantiomerically pure cis-endo and cis-exo epimers that are further converted to Ramipril through a sequence of reactions. The process suffers from the disadvantage of chromatographic operation, which is very tedious, expensive and can not be used industrially.
EP 0115345 and TL 25(40) 4479-82 (1984) describe a process for resolution of racemic optically active bicyclic imino-alpha-carboxylic acid ester to get (S,S,S)-enantiomer by a process involving conversion of racemic ester into its salt with optically active N-acylated R- or S- aminocarboxylic acids which contain a phenyl nucleus, from the series phenylalanine, phenylglycine, beta-phenyl-alpha-aminobutyric acid, 3,4-dihydroxyphenylalanine, beta phenylserine and tyrosine, crystallizing such salts, decomposing them and isolating the desired enantiomer which can be further converted to Ramipril.
US patent No. 6,407,262 ('262). In accordance with column nos. 1 to 4 of this patent, the existing prior art reported two approaches that are followed for the synthesis of ramipril. The first approach utilizes the reaction of racemic amino esters of formula II, wherein R is benzyl or ethyl with a compound of formula III using known amide formation methods as described in the patents: CA 1,338,162; EP 79022; US 9,977,380; ES 549789 and ES 2004804 to prepare a racemic mixture of compound of formula IV where in R has the meaning as given above. This route gives a 1:1 mixture of diastereomers from which the desired isomer is separated
using silica gel chromatography. Further, the protecting group has to be removed either by hydrogenolysis or treatment with an acid or base to yield Ramipril. The disadvantage of this approach is that it involves two additional steps to install the protecting group in formula II and to remove the ester group from formula IV. Further, the racemic mixture has to be purified by costly and hard to implement silica gel column chromatography to give enantiomerically pure (S,S,S)-compound. Additionally the yield is low.
(Formula Removed)
In approach II, enantiomerically pure amino ester (II) is either prepared by targeted enantioselective synthesis. When the compound of formula IV is prepared by coupling compound of formula II with the compound of formula III, the ester protecting group R is removed by hydrogenolysis or treatment with an acid or base. However, this route is associated with certain difficulties. The efficient large scale enantioselective synthesis of chirally pure compound of formula II is not reported. The reported enantioeselective routes appear to be very low yielding (13% even as low as 5.5%) proving the process unfeasible for commercial implementation. Further, it is obtained by resolution using expensive reagents like (S)-l- (1-naphthyl) ethylamine or by using N- acyl derivatives of optically active R or S amino acids containing a phenyl nucleus, which again is an expensive method. In some cases ester has also been resolved using mandelic acid but in lower yield. Unfortunately these routes require a sequence of steps mentioned as herein before. Hence using these methods becomes cost extensive, time consuming, and less efficient. US 6,407,262 describes a process in which the resolution of penultimate step of Ramipril ie, benzyl Ramipril, has been done using solvent selected from a group consisting of nitrile solvent (C2-C4), alcohols ( C1 C6), aromatic hydrocarbon solvents (C6 C8 ), ether solvents (C3-C10), ketone solvent ( C3-C6), Ester solvent ( C2-C7), and hydrocarbon solvents (C5-C10), or mixture thereof and adding if desired acid such as maleic acid mandelic acid or benzoic acid or fumaric acid or methsne sulfonic acid or toluene sulfonic acid or halo acids or sulphuric acid or phosphoric acid as resolving agent. The preferred esterifying group is benzyl and preferred acid is maleic acid. The reaction is carried out at -50°C to 50°C. the acid can be replaced by base. The seeding may have to be implemented for precipitation of title compound.
It is always advantageous to purify/ resolve the lower intermediates as compared to
higher ones as the purification/ resolution losses in yield at higher stages contribute
more to the cost due to value addition.
Though maleic acid is a cheaper alternative, the process becomes uneconomical when
it is done at penultimate step due to yield losses of a value added advanced
intermediate.
Thus there is a still a need to find some suitable resolution method which should be
employed at a less advanced (less expensive) intermediate, like amino ester of
formula II, and that uses inexpensive resolving agents in suitable solvents. This is the
aim of this invention.
SUMMARY OF THE INVENTION
The main aim of the present invention is to provide an improved Process For
Preparation Of Ramipril.
The other object of this invention is to provide an improved process for
manufacturing a key intermediate of Ramipril named as (S,S,S)-2-azobicyclo [3,3,0]
octane-3-carboxylic acid benzyl ester hydrochloride [(S,S,S)-enantiomer)] by
resolution of its racemate.
Another object of this invention is to provide a process for separation of
diastereomeric mixture of key intermediate, (S,S,S)- enantiomer, of Ramipril in its
pure form.
Yet other object of this invention is to provide an improved a process that is high
yielding, ecofriendly, commercially viable and easy to operate.
STATEMENT OF INVENTION:
According to this invention, there is provided a process for preparation of Ramipril comprising,
(a) converting bicyclic amino acid of formula I to its racemic ester of formula II by
any conventional method,
(b) treating the said racemic ester of formula II, obtained in step (a) at a temperature
in the range of 0.0 to 40°C, with an organic acid in solvent exemplified by ester
solvents (up to C3), ketonic solvents, halogenated hydrocarbons solvents, hydrocarbons solvents, ethereal solvents or mixture thereof to precipitate salt of desired enantiomer,
(c) decomposing of above salt at a temperature in the range of 0.0 to 30°C, to get the
desired enantiomerically pure bicyclic amino ester of formula lib,
(d) reacting enantiomerically pure bicyclic amino ester of formula lib with a
compound of formula III to give benzyl Ramipril of formula Iva in a conventional
manner, and
(e) debenzylating IVa by conventional methods to get Ramipril.
Organic acids used in step b) may be tartaric acids or substituted tartaric acids like,, L- tartaric acid, (-) dibenzoyl-L-tartaric acid; maleic acid or substituted maleic acid. Solvents used may be ester solvents like, ethyl acetate, propyl acetate; ketonic solvents like, acetone, methyl isobutyl ketone, methyl ethyl ketone; halogenated hydrocarbons like, chloroform, dichloromethane; hydrocarbons like, hexanes, heptanes, xylenes, toluene, benzene, cyclohexane; ethereal solvents like diethylether, diisopropyl ether, methyl tertiary butyl ether tetrahydrofuran.
The reactions in step (b) and (c) is carried out at a temperature in the range of 0.0 to 15°C.
The invention is further illustrated by non-limiting examples, which should not
construe the scope of the invention.
EXAMPLE-1
Step 1-Preparation of (S,S,S)-amino benzyl ester dibenzoyl-L-tartarate salt
To a solution of bicyclo amino ester of formula II (100 g) in DM-water (3 Ltr),
decolorizing carbon (6 g) was added. After 10 minute stirring at room temperature,
filter the carbon through hyflo and adjust pH 10.5-11.0 with 10% (w/v) aqueous
sodium hydroxide solution. Extract the product with dichloromethane. Solvent was
evaporated under vacuum to get oily residue. Add ethyl acetate (300 mL) to the
residue and stir to get clear solution. Add dropwise a solution of (-) dibenzoyl-L-
tartaric acid (132 g) in ethyl acetate (200 mL). Continue stirring for 1 hour at 10-15°C
and then filter to get product (salt of S,S,S-enantiomer) as a white solid (100 g).
Step2- Preparation of (S,S,S)-enantiomer of amino benzyl ester hydrochloride
To the suspension of dibenzoyl-L-tartarate salt (S,S,S-enantiomer) from Example 1
(100 g) in DM-water (200 mL), is added 30% (w/v) aqueous sodium hydroxide
solution to adjust pH 11.0-11.5. Product is extracted with dichloromethane and dried
over sodium sulphate. Solvent is evaporated under vacuum to get oily residue. Add
diisopropyl ether (300 mL) and stir to get clear solution. Adjust pH 1.5-2.0 with 25%
HC1 gas in diisopropyl ether. Continue stirring for 1 hour at 10-15°C and then filter to
get product lib as white crystalline solid (40 g). the said compound of formula lib is
converted to ramipril by any known methods.
ADVANTAGES:
The product obtained is highly pure.
Yields of the resolved compounds are very high.
Inexpensive resolving agents (acids) are used for resolution at an early stage.
Process of resolution involves very simple operations like stirring, crystallization, filtration etc. which do not require any special plant and machinery for scale-up. Makes use of commercially available ingredients. Process is very easy to operate at large scale.

WE CLAIM:
1. A process for preparation of Ramipril comprising,
(a) converting bicyclic amino acid of formula I to its racemic ester of formula
II by any conventional method,
(b) treating the said racemic ester of formula II, obtained in step (a), at a
temperature in the range of 0.0 to 40°C, with an organic acid in solvent
exemplified by ester solvents (up to C3), ketonic solvents, halogenated
hydrocarbons solvents, hydrocarbons solvents, ethereal solvents or mixture
thereof to precipitate salt of desired enantiomer,
(c) decomposing of above salt at a temperature in the range of 0.0 to 30°C to
get the desired enantiomerically pure bicyclic amino ester of formula lib,
(d) reacting enantiomerically pure bicyclic amino ester of formula lib with a
compound of formula III to give benzyl Ramipril of formula Iva in a
conventional manner, and
(e) debenzylating IVa by conventional methods to get Ramipril.

2. A process as claimed in claim 1 wherein the organic acids used in step b) is
tartaric acids or substituted tartaric acids like,, L- tartaric acid, (-) dibenzoyl-
L-tartaric acid; maleic acid or substituted maleic acid.
3. A process as claimed in claim 1 wherein the solvents used are ester solvents
like, ethyl acetate, propyl acetate; ketonic solvents like, acetone, methyl
isobutyl ketone, methyl ethyl ketone; halogenated hydrocarbons like,
chloroform, dichloromethane; hydrocarbons like, hexanes, heptanes, xylenes,
toluene, benzene, cyclohexane; ethereal solvents like diethylether, diisopropyl
ether, methyl tertiary butyl ether tetrahydrofuran.
4. A process as claimed in any preceding claims wherein the reactions in step (b)
and (c) is carried out at a temperature in the range of 0.0 to 15°C.
5. A process for preparation of Ramipril substantially as herein described