Title of Invention	A NOVEL PROCESS FOR THE PREPARATION OF CILAZAPRIL
Abstract	Cilazapril is prepared in good yield using ethyl R-2-(nitro or halo substituted benzene sulfonyloxy)-4-phenyl butyrate. Thus, (1S,9S)-t-butyl octahydro-10-oxo-9-amino-6H-pyrJdazino[1,2-a][1,2]diazepine-1-carboxylate Is reacted with ethyl R-2-(4-nitro benzene su!fonyloxy)-4-phenyl butyrate in the presence of N-methyl morpholine followed by treatment with hydrogen chloride to give cilazapril.

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The present invention relates to a process for preparation of cilazapril. BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of cilazapril. chemically, (1S.9S)-9-[[(1S)-1-(ethoxycarbonyl)-3- phenylpropyl]amino]octahydro-10-oxo-6H-pyridazino[1,2-a][1,2]diazepine-1 -carboxylic acid. Cilazapril is known as an excellent antihypertensive agent and its structure is shown in formula I. Process for preparation of cilazapril is disclosed in US 4,512,924 and J. Chem. Soc. Perkin Trans 1, 1986. 1011-1019. According to the prior art process, cilazapril is prepared by reacting ethyl (R)-2-{trifluoromethane sulfonyloxy)-4-phenyl butyrate with (1S,9S)-t-butyl octahydro-10-oxo-9-amino-6H-pyridazino[1.2-a][1,2]diazepine-1-carboxylate of fonnula III followed by solvolysis. Ethyl (R)-2-(trifluoromethane sulfonyloxy)-4-phenyl butyrate used in the prior art process is prepared from ethyl (R)-2-hydroxy"4-phenyl butyrate and triflic anhydride. It is very difficult to isolate ethyl (R)-2-(trifluoromethane sulfonyloxy)-4-phenyl butyrate from the reaction mixture in pure form by usual processes like solvent extraction, distillation, crystallization, etc., and requires chromatographic separation as reported in J. Chem. Soc. Perkin Trans 1,1986, 1011-1019. Moreover, the use of triflic anhydride is associated with handling Elifficulties. The present invention discloses a process for preparation of cilazapril in good yield using nitro or halo substituted phenyl sulfonic ester of formula II. These sulfonic esters are easily prepared from nitro or halo substituted phenyl sulfonyl chloride and ethyl (R)-2-hydroxy-4"phenyl butyrate as described for example in US 4,785,089 and no chromatographic separation is required to isolate these esters. The object of the present invention is to provide a process for preparation of cilazapril using an intermediate, which is obtainable in pure form by a commercial means. DESCRIPTION OF THE INVENTION The present invention provides a process for preparing cilazapril of fomnula I: I b) treating the said compound of the formula IV with an acid. The preferred nitro substituted phenyl is mono or dinitro phenyl such as 2-, 3- or 4- nitro phenyl or 2,4-dinitro phenyl. The most preferred nitro substituted phenyl is 4-nitro phenyl or 2.4-dinitro phenyl. The preferred halo substituted phenyl is bromo phenyl, trichjoro phenyl or pentafluoro phenyl. ^ The step (a) is carried out under general conditions in the temperature range from about OPC to the boiling point of the mixture, preferably in the range from 20°C to about 100°C. The step may be carried out with or without a solvent. The preferable solvent is chlorinated lower alkane such as chloroform, methylene chloride; acyclic or cyclic ether such as diethyl ether, dioxane, 1,2-dimethoxyethane or tetrahydrofuran; lower alkane carbonitrile such as acetonitrile; ester of a lower alkanoic acid such as ethyl acetate; tertiary amide such as N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N-eihylpiperidone or hexamethylposphoramide. The suitable acid acceptor to neutralize the strong acid HOSO2-R formed in the reaction may be an inorganic base such as a bicarbonate, carbonate or hydroxide 'of an alkali metal; an organic quaternary ammoniumsalt such as tetrabutyl ammonium salt; an organic tertiary base such as triethylamine, N-ethylpiperidine, N-methylmorpholine, N-ethy!morpholine, pyridine or quinoline. In step (b), cilazapril tert-butyl ester is treated with an acid, preferably hydrogen haiide to give cilazapril. Of the hydrogen halides, hydrogen chloride is the preferred one. Cilazapril produced may be in the form of free cilazapril or cilazapril hydrate, preferably monohydrate. The invention will now be further described by the following examples, which is illustrative rather than limiting. Example 1 (1 S,9S)-t-Butyl octahydro-10-oxo-9-amino-6H-pyridazino[1,2-a][1.2] diazepine-1-carboxylate (50 gm) is added to ethyl R-2-(4-nitro benzene sulfonyloxy)-4-phenyl butyrate (83 gm) and N-methylmorpholine (21 gm),and stirred for 12 hours at 80°C to 85°C. After completion of the reaction, methylene chloride (300 ml) and water (150 ml) are added to the reaction mass and the pH of the reaction mass is adjusted to 8.5 to 8.8 with 1N sodium carbonate solution. The separated organic.layer is washed with water (300 ml), the layer is dried with sodium sulfate and passed over celite. The methylene chloride layer is cooled to -5°C to 0°C and passed dry hydrochloric acid gas for 3 hours. Then the temperature is slowly raised to 20°C to 25*'C and stirred for 20 hours. The solvent is distilled off completely under vacuum. Then water (200 ml) and diisopropyl ether (100 ml) are added to the reaction mass and extracted with IN hydrochloric acid solution (200 ml). The layers are separated and the pH of the aqueous layer is adjusted to 4.2-4.4 with aqueous sodium hydroxide. Then the precipitated solid is filtered to give 70 gm of cilazapril monohydrate. Example 2 (1 S,9S)-t-Butyl octahydro-10-oxo-9-amino-6H-pyridazino[1.2-a]I1,2] diazepine-l-carboxylate (50 gm) is added to a mixture of ethyl R-2-(4-nitro benzene sulfonyloxy)-4-phenyl butyrate (83 gm), metiiylene chloride (250 ml) and N-methylmorpholine (21 gm) and stirred for 10 hours at 80°C to 85°C. After completion of the reaction, a further amount of methylene chloride (300 ml) and water (150 mi) are added to the reaction mass. Then the pH of the reaction mass is adjusted to 8.5 to 8.8 with 1N sodium carbonate solution. The organic layer is separated, washed with water (300 ml), dried with sodium sulfate and passed over celite. The methylene chloride layer is cooled to -5°C to 0°C and passed dry hydrochloric acid gas for 2 hours. Then the temperature is slowly raised to 20°C to 25°C and stirred for 18 hours. The solvent is distilled completely under vacuum. Then water (175 ml) and diisopropyl ether (75 ml) are added to the reaction mass and extracted with IN hydrochloric acid solution (175 ml). The layers are separated and the pH of the aqueous layer is adjusted to 4.2 - 4.4 with aqueous sodium hydroxide. The precipitated solid is filtered to give 69.2 gm of cilazapril monohydrate. We claim: 1) A process for preparing cilazapril of formula I: which comprises: a) reacting (1S,9S)-t-butyl octahydro-10-oxo-9-amino-6H-pyridazino[1,2" a][1,2]diazepine-1-carboxylate of formula III: wherein R is halo or nitro substituted phenyl group, in the presence of an acid acceptor selected from inorganic bases, organic quaternary ammonium salts and organic tertiary bases with or without using a solvent to give cilazapril tert-butyl ester of the formula IV: and b) treating the said compound of the formula IV with an acid selected from hydrogen halides to hydrolyze the tert-butyj ester group. 2) The process according to claim 1, wherein the nitro substituted phenyl is 2-, 3- or 4- nitro phenyl or 2,4-dinitrc) phenyl. 3) The process according to claim 2. wherein the nitro substituted phenyl is 4- nitro phenyl or 2,4-dinitro phenyl. 4) The process according to claim 1, wherein halo substituted phenyl is bromo phenyl, trichloro phenyl or pentafluoro phenyl. 5) The process according to claim 1, wherein the reaction in step (a) is carried out without using a solvent. 6) The process according to claim 1, wherein the solvent in step (a) is selected from chloroform, methylene chloride, diethyl ether, dioxane, t2- dimethoxyethane, tetrahydrofuran, acetonitrile, ethylacetate, N,N- dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N- ethylpiperidone and hexamethylposphoramide. 7) The process according to claim 6, wherein the solvent is methylene chloride. 8) The process according to claim 1, wherein the acid acceptor in step (a) is selected from bicarbonate, carbonate and hydroxide of an alkali metal; a tetrabutyl ammonium salt, triethylamine, N-ethylpiperidine, N-methylmorpholine. N-ethylmorpholine, pyridine and quinoline. 9) The process according to claim 8, wherein the bicarbonate is sodium ' bicarbonate and the carbonate is sodium carbonate. 10) The process according to claim 8, wherein the acid acceptor is triethylamine. N-ethylpiperidine or N-methylmorpholine. 11)The process according to claim 1, wherein the hydrogen halide in step (b) is hydrogen chloride or hydrogen bromide. 12) The process according to claim 11. wherein the hydrogen halide is hydrogen chloride.

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