FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
As amended by the Patents (Amendment) Act, 2005
&
The Patents Rules, 2003
As amended by the Patents (Amendment) Rules, 2005 PROVISIONAL SPECIFICATION
(See section 10 and rule 13) TITLE OF THE INVENTION
A process for the preparation of Benazepril Hydrochloride
INVENTORS
Names : 1) Desai Parimal Hansmukh
2) Salvi Narendra Jagganath
3) Patravale Bharat Sunilkumar and
4) Parab Seema Susheel
Nationality : all Indian Nationals
Address : all of Aarti Healthcare Limited
D-53/D-60, MIDC, Phase II, Kalyan Shil Road
Dombivli (E), District Thane - 421204 Maharashtra, India
APPLICANTS
Name : Aarti Healthcare Limited
Nationality: Indian Company
Address : 71, Udyog Kshetra, 2nd Floor
Mulund Goregaon Link Road
Mulund (W), Mumbai - 400080
Maharashtra, India
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the nature of this invention:

FIELD OF THE INVENTION:
The invention relates to a process for the preparation of benazepril hydrochloride.
The invention also relates to a process for the preparation of protected 3(S)-amino-2,3,4,5-tetrahydro-2-oxo-lH-l-benazazepin-l-acetic acid, an intermediate of Benazepril hydrochloride in high yield with high enantiomeric purity.
Benazepril hydrochloride is known by the chemical name as 3-[(l-(ethoxycarbonyl)-3-phenyl-(l S)-propyl)amino]-2,3,4,5-tetrahydro-2-oxo-1 H-[ 1 ]-10(3 S)-benzazepine-1 -acetic acid monohydrochloride salt of the formula (I)

Formula (I)
Benazepril is an orally active ACE inhibitor and useful in the treatment of hypertension, chronic heart failure and progressive chronic renal insufficiency.
BACKGROUND OF THE INVENTION:
Benazepril and its synthesis were first disclosed in US 4,410,520. The synthetic route consist of reductive amination of ethyl 2-oxo-4-phenyl butyrate using (3S)-3-amino-l-carboxymethyl-2,3,4,5-tetrahydro-lH-benzazepin-2-one in the presence of sodium cyanoborohydride to obtain benazapril in a 7:3 diastereoisomeric ratio. Benazepril isomers are treated with hydrochloric acid gas followed by crystallization to isolate benazapril hydrochloride in the diastereoisomeric ratio of 95:5. Sodium cyanoborohydride is a toxic reagent. Moreover the yield obtained is very low about 25 %.
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US 4785089 teaches that aromatic p-nitro- or p-halo-sulfonic esters of ethyl(R)-2-hydroxy-4-phenylbutyrate give better results than the trifluoromethane sulfonic acid ester of ethyl-(R)-2-hydroxy-4-phenylbutyrate when used in the synthesis of ACE inhibitors like benazepril. The process consists of alkylation of benzofused lactam with p-nitro or p-halo sulfonic ester of ethyl-(R)-2-hydroxy-4-phenylbutyrate at 75-80° C for about 9 hours. The yield of l-Carboxymethyl-3S-[(lS-ethoxycarbonyl-3-phenylpropyl)amino]-2,3,4,5-tetrahydro-lH-[l]-benzapin-2-one is 83.6%. However, on a commercial scale the process results into low overall yield.
WO03 092698 describes a process for the preparation of benazepril hydrochloride by reacting (3S)-3-amino-l-t-butoxy carbonyl methyl-2,3,4,5-tetrahydro-lH-benzazepin-2-one with 3-benzoyl acrylic acid ester to obtain Michael adduct. The adduct is further transformed into 3-[[l-(ethoxycarbonyl)-3-hydroxy-3-phenyl propyl] amino]-1-t-butoxycarbonyl methyl-2,3,4,5-tetrahydro-lH-benzazepin-2-one by catalytic hydrogenation in the presence of hydrogen donor like ammonium formate. 3-[[l-(ethoxycarbonyl)-3-hydroxy-3-phenyl propyl]amino]-1 -t-butoxycarbonyl methyl-2,3,4,5-tetrahydro-lH-benzazepin-2-one formed is crystallized to obtain its S,S-isomer by using solvent mixture of acetone and acetic acid. The isomer is esterified with carbonyldiimidazole and ethanol to obtain ethyl 3-(1-t-butoxycarbonyl methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)-2-oxo-6-phenyl-[l,3]oxazinan-4-carboxylateone which is subjected to catalytic reduction to obtain 3-[[l-(ethoxycarbonyl)-3-phenyl propyl]amino]-l-t-butoxycarbonyl methyl-2,3,4,5-tetrahydro-lH-benzazepin-2-one. This is further treated with hydrochloric acid gas to obtain benazepril hydrochloride. The process is lengthy and not cost-effective on commercial ground
WOO 179176 describes a process for the preparation of 3-[(l'-(alkoxy carbonyl)-3'-phenyl propyl )amino]-2-oxo-[l]-benzazepine and derivatives thereof. In this process benazepril is prepared by reacting 3-bromo-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one with ethyl (+) 2-amino-4-phenylbutyric ester or L-homophenylalanine ethyl ester in the presence of phase transfer catalyst. The condensation results into 39.5% of SS, 40.31% of
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SR isomer and 19% of side product. The process avoids racemization and also involves fewer steps in the synthesis. However it results into too low yield, which is not desirable on industrial scale
WO2005/009972 discloses a process for the preparation of benazepril comprising of chiral resolution of t-butyloxycarbonylmethyl-3-amio-2,3,4,5-tetrahydro-lH-[l]benzazepine-2-one using tartaric acid in the presence of ethanol. The resolution does not involve inversion or racemization due to which the undesired (S,R) optically active form cannot get converted into desired (S,S) form and thus results into low yield. Further the process involves condensation of Triflates with l-tert-butoxycarbonylmethyl-3-S-amino-2,3,4,5-tetrahydro-l-H(l)-benzazepine-2-one in the presence of methylene dichloride as solvent. The trfluoromethane sulfonic acid released during the reaction is not recycled or reused.
US 5,066,801 discloses preparation of sulfonic acid esters which involves reaction of ethyl(-)-R-2-hydroxy-4-phenylbutyrate with 4-nitrobenzenesulfonylchloride in the presence of toluene and base to obtain an oily residue which requires purification. Further the process discloses condensation of above mentioned sulfonic acid esters with 1-tert-butoxycabonylmethyl-3-S-amino-2,3,4,5-tetrahydro-lH-(l)-benzazepin-2-one in the absence of solvent. The precipitated n-methyl morpholine salt of p- benzene sulfonic acid is dissolved in ethyl acetate and water and separated out. Thus the p-nitrobenzene sulfonic acid can not be recycled. Further evaporation of ethyl acetate yields an oily residue having a low diastereomeric ratio of SS:SR 96:4 whereas the crude product obtained after solvolysis is required to be purified twice
In the prior art processes, the resolution of benazepril uses chirally active organic acids such as tartaric acid as resolving agent in the presence of alcohol as a solvent and the resolution carried out without inversion leaves the undesired (S,R) isomer unutilized and results into low yield. The process for the preparation of sulfonic acid esters of ethyl(R)-2-hyrodxy-Y-pehnyl butyrate involves the use of toluene as a solvent, which results into an oily residue and requires further treatment with combination of solvents or column
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purification. The condensation step is reported to be carried out with or without solvent involving elaborative work up and does not provide scope of recycling the sulfonic acid used in the process.
OBJECTS OF THE INVENTION :
An object of the invention is to provide a process for the preparation of benazepril hydrochloride in high yield and high enantiomeric purity.
Another object of the invention is to provide a process for the preparation of benazepril hydrochloride where the process is economical and eco-friendly.
Another object of the invention is to provide a process for the preparation of benazepril hydrochloride where the process is simple, efficient, easy and convenient to carry out.
Another object of the invention is to provide a process for the preparation of chiral protected 3(S)-amino-2,3,4,5-tetrahydro-2-oxo-lH-l-benazazepin-l-acetic acid, an intermediate of benazepril hydrochloride in high yield.
Another object of the invention is to provide a process for the preparation of chiral protected 3(S)-amino-2,3,4,5-tetrahydro-2-oxo-lH-l-benazazepin-l-acetic acid, an intermediate of benazepril hydrochloride in high enantiomeric purity.
DETAILED DESCRIPTION OF THE INVENTION :
The invention provides a process for the preparation of benazepril hydrochloride of the formula (I),
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Formula (I)
the process comprising
(a) preparation of ethyl(+)-R-2-(4-nitrobenzenesulfonyloxy)-4-phenyl butyrate of the
formula (V),


OEt

Formula (V)
by treating p-toluene sulfonyl chloride of the formula (VI) with R-(+) Ethyl hydroxyl
-4-phenyl butyrate of the formula (VII);


Formula (VI)

Formula (VII)

in the presence of an organic base such as triethyl amine and organic solvents such as aromatic hydrocarbons selected from toluene or benzene or halogenated hydrocarbons selected from dichloromethane, dichloroethane or chloroform at -5 C to +5 C followed by addition of water, extracting the compound of the formula (V) using a solvent selected from aromatic hydrocarbons selected from toluene or
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benzene or halogenated hydrocarbons selected from dichloromethane, dichloroethane or chloroform and distilling out the solvent from the extract to obtain oily residue comprising the compound of the formula (V),
(b) purifying the compound of the formula (V) by precipitating it as solid on addition of solvent such as normal or branched chain C5-C7 alkane and isolating pure solid of compound of the formula (V),
(c) resolving chiral protected tert-butyl ester of 3(S)-amino-2,3,4,5-tetrahydro-2-oxo-lH-1-benazazepin-l-acetic acid of the formula (II),

Formula (II)
by treating racemic mixture ofamines such as tert butyl ester of 3-amino 2,3,4,5
tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid of the formula (III),

Formula (III)
with chitally active organic acids such as L (+) tartaric acid in the presence of
aldehyde in an organic solvent to obtain (S,S) distereomeric salt of tert butyl ester of
3-amino-2,3,4,5 tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid of the formula
(IV);

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Formula (IV)
converting the (S,S) distereomeric salt of tert butyl ester of 3-(S)-amino-2,3,4,5 tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid of the formula (IV) into chiral free base, tert butyl ester of 3-amino- 2,3,4,5 tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid of the formula (II), by treating it with base such as liquid ammonia in an organic solvent such as halogenated hydrocarbons selected from dichloromethane, dichloroethane or chlroform at pH in the range of 9 to 11;

Formula (II)
and isolating the compound of formula (II) by extracting it in aromatic hydrocarbons selected from toluene or benzene or halogenated hydrocarbons selected from dichloromethane, dichloroethane or chloroform followed by distilling out the solvent to obtain the residue followed by treatment with anti-solvent selected from normal or branched chain alkanes such as n-hexane or n-heptane;
(d) preparation of benazepril base of formula (VIII),

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Formula (VIII)
by condensing compound of the formula (II) with ethyl(+)-R-2-(4-nitrobenzenesulfonyloxy)-4-phenyl butyrate of the formula (V) in the presence of base such as salt of n-methyl morpholene and an organic solvent selected from ethyl acetate, methyl acetate, ethyl propionate or methyl propionate at reflux temperature to obtain benazepril base of formula (VIII) and (e) preparation of benazepril hydrochloride of the formula (I) by treating benazepril base of the formula (VIII) with acetic acid and hydrochloric acid.
The invention also provides a process for the preparation of chiral protected tert butyl ester of 3(S)-amino-2,3,4,5-tetrahydro-2-oxo-lH-l-benazazepin-l-acetic acid of the formula (II), an intermediate of benazepril hydrochloride,

Formula (II)
the process comprises of
(a) treating racemic mixture of amines such as tert butyl ester of 3-amino-2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepine-l -acetic acid of the formula (III),
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Formula (III)
with chirally active organic acids such as L (+) tartaric acid in the presence of aldehyde in an organic solvent to obtain (S,S) distereomeric salt of tert butyl ester of 3-(S)-amino-2,3,4,5 tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid of the formula
(IV);

(b) converting (S,S) distereomeric salt of tert butyl ester of 3-amino-2,3,4,5 tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid of the formula (IV) into chiral free base, tert butyl ester of 3-amino- 2,3,4,5 tetrahydro-2-oxo-lH-l-benzazepine-l-acetic acid of the formula (II), by treating it with base such as liquid ammonia in an organic solvent such as halogenated hydrocarbons selected from dichloromethane, dichloroethane or chloroform at pH in the range of 9 to 11;

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and
(c) isolating the compound of formula (II) by extracting it in aromatic hydrocarbons
selected from toluene or benzene or halogenated hydrocarbons selected from
dichloromethane, dichloroethane or chlroform, followed by distilling out the solvent
to obtain the residue followed by treatment with anti-solvent selected from normal or
branched chain alkanes such as n-hexane or n-heptane.
The aldehyde is selected from aromatic or aliphatic aldehydes selected from benzaldehyde, butryldehyde, salicyldehyde, etc. The organic solvent used in the resolution of chiral amine is selected from C1 to C4 normal or branched chain alcohol such as isopropyl alcohol or ethyl alcohol or chlorinated hydrocarbon such as dichloromethane, dichloroethane or chloroform. The base used in the resolution of chiral amine is selected from liquid ammonia or ammonium hydroxide. The compound of the formula (V) is prepared by treating the compound of the formula (VI) with the compound of the formula (VII) at 0 to -5° C.
According to the invention there is also provided chiral protected tert-butyl ester of 3(S)-amino-2,3,4,5-tetrahydro-2-oxo-lH-l-benazazepin-l-acetic acid, an intermediate of Benazepril hydrochloride in high yield of 80-82% and in high enantiomeric purity of 99%.
According to the invention there is also provided benazepril hydrochloride in high yield of 90 to 96 % with high purity of 98 to 99.9 %.
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According to the invention, aldehyde is used in the preparation of chiral protected tert-butyl ester of 3(S)-amino-2,3,4,5-tetrahydro-2-oxo-lH-l-benazazepin-l-acetic acid causing inversion. Due to the inversion, the desired (S,S) diastereomeric salt of chiral amine is precipitated out leaving undesired (S,R) diastereomeric salt in reaction mixture. The undesired isomer reacts with the aldehyde present in reaction mixture to form Schiff base due to which the chirality of undesired isomer gets disturbed. The Schiff base is cleaved to release the chiral amine as racemate along with the aldehyde. The racemic mixture of chiral amine again reacts with chirally active acid present in the reaction mixture to obtain (S,S) distereomeric salt. Thus products are obtained in high chemical and optical yield with high enantiomeric purity. The condensation of the compound of formula (II) and the compound of formula (V) is carried out in the presence of base such as salt of n-methyl morpholene and an organic solvent selected from ethyl acetate, methyl acetate, ethyl propionate or methyl propionate at reflux temperature. The sulfonic acid formed during the condensation gets precipitated out as salt of n-methyl morpholene in the reaction mixture and conveniently isolated by filtration. The salt of n-methyl morpholene is further broken down easily by treating with hydrochloric acid and the sulfonic acid freed can be reused in the process. The benazepril hydrochloride thus prepared does not require any purification. Thus the method is economical and eco-friendly. The process steps are very simple and convenient to carry out.

(Shilpa Gharve )
of Khaitan & Co
Agent for the Applicants
Dated this 19th day of May 2006
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