FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PROCESS FOR THE PREPARATION OF NICARDIPINE OR SALT THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for the preparation of nicardipine or salt thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides a process for the preparation of Nicardipine or salt thereof.
Nicardipine hydrochloride of formula I is chemically known as 2-(benzyl-methyl amino) ethyl methyl-1, 4-dihydro - 2, 6-dimethyl-4-(m-nitrophenyl)- 3, 5-pyridine dicarboxylate monohydrochloride. Nicardipine hydrochloride is indicated for the management of patients with chronic stable angina (effort-associated angina) and for the treatment of hypertension.

Formula I
U.S. Patent No. 3,985,758 disclosed the process of preparation of nicardipine and salt thereof wherein the process involves reaction of 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitro phenyl)-1,4-dihydropyridine-5-carboxylic acid with N-(2-hydroxyethyl)-N-benzyl-methylamine and N,N'-dicyclohexylcarbodiimide to get nicardipine which is then converted to its hydrochloride salt form.
U.S. Patent No. 4,769,465 and European patent EP202625 provides the process for the preparation of nicardipine hydrochloride involving partial hydrolysis of dimethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and the reaction of the obtained 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-
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dihydropyridine-5-carboxylic acid either with N-(2-hydroxyethyl)-N-benzyl-methylamine or with N-(2-haloethyl)-N-benzyl-methylamine which then converted to its hydrochloride salt.
U.S. Patent No. 4,705,797 disclosed the diester of 1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid or the stereoisomers or pharmaceutically acceptable acid addition salts thereof prepared from the aromatic aldehydes and esters of acetoacetic and 3-aminocrotonic acids.
In J. Am. Chem. Soc. 76, 4920-23, 1954, disclosed the process of preparation of N-(2-chloroethyl)-N-benzyl-methylamine, an useful intermediate in the synthesis of nicardipine or salt thereof.
Several other processes are known in the art for preparation of nicardipine and related compounds or salts thereof such as in U.S. Patent Nos. 4,673,564, 5,310,917, 5,245,039, 4,600,778 and European patent application Nos. 445987 A3, 245680 A3, 1682101 A2.
Several PCT applications like WO 2007054969, WO 2006134606, WO 2006059332 and WO 9635668 (and its equivalents) disclosed the use of 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid as an Intermediates for the preparation of lercanidipine, and process for the same. Japanese Patent application JP 2971091 B2 discloses the use of 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid as an Intermediates for the preparation of nicardipine.
Present inventors while working on the process for preparation of nicardipine or salt thereof have found that thionyl chloride can be used as an effective halogenating agent for obtaining 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid chloride intermediate involved in the synthesis of Nicardipine. The process of the present invention provides
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improved yields and the formation of fewer reaction byproducts. The improved purity of the compounds of the invention avoids the use of chromatographic columns to isolate the desired final product. The compounds can be obtained directly as the hydrochloride salt with a high degree of purity.
In one aspect there is provided a process for the preparation of nicardipine or salt thereof. The process includes step of:
a) reacting 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid with thionyl chloride in one or more organic solvent to produce 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid chloride;
b) reacting said 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid chloride with N-benzyl-N-methylethanolamine ;
c) isolating Nicardipine salt thereof.
The process of present invention involves reacting 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid with halogenating agent in an aprotic solvent to produce 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid chloride. N-benzyl-N-methylethanolamine is added to the acid chloride and the reaction mass is stirred at temperature of 0-20 °C. After completion of reaction solvent was removed to get syrupy mass. Further the syrupy mass was dissolved in ethyl acetate and washed with saturated brine. Ethyl acetate layer was extracted with hydrochloric acid solution and dried over anhydrous sodium sulphate, concentrated, filtered and dried to get Nicardipine hydrochloride.
Alternatively nicardipine salts are prepared from the free base. The non-limiting examples of salts include for example, hydrochloric, sulfuric, maleic, succinic, citric, methanesulfonic and toluenesulfonic acids, and the like.
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More particularly it relates to use of thionyl chloride as a halogenating agent. The non-limiting examples of halogenating agent include for example, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, oxalyl chloride, and the like.
The non-limiting examples of one or more organic solvents may includes chloroform, dichloromethane, dichloroethane, chlorobenzene, 1,1,1-trichloroethane, ethyl acetate, methyl acetate, tetrahydrofuran, dioxane, N,N-dimethyl-formamide, dimethylcarbonate, toluene, xylene, an alkane, a cycloalkane and mixtures thereof.
Removing the solvents may include, for example, one or more of filtration, filtration under vacuum, distillation, distillation under vacuum, evaporation, decantation and centrifugation.
In another aspect there is provided a process for Nicardipine or salt thereof, having purity of 99 % or more.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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Example 1. Preparation of nicardipine hydrochloride
Thionyl chloride (4.58 gm), was added, at -10° C, to a stirred suspension of 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3 carboxylic acid (11.62 gm ) in 65 ml of dichloromethane and 16 ml of N.N-dimethylformamide . To this was added N-benzyl-N-methylethanolamine (6.42 gm.) in one lot at 0-20 °C & stirred at room temperature for 18-20 hrs. Solvent was removed completely under reduced pressure to get a thick syrupy mass. The syrupy mass was dissolved in ethyl acetate (500 ml) and washed with saturated brine solution. Ethyl acetate layer was further extracted with 10% hydrochloric acid solution and nicardipine hydrochloride was isolated from the reaction mass thereof. Yield: 8.2 gm HPLC purity 99.05 %
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WE CLAIM:
1. A process for the preparation of nicardipine or salt thereof. The process
comprising:
a) reacting 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid with a thionyl chloride in one or more organic solvent to produce 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid chloride;
b) reacting said 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid chloride with N-benzyl-N-methylethanolamine ;
c) isolating Nicardipine salt thereof.

2. The method according to claim 2, wherein the one or more organic solvents may includes chloroform, dichloromethane, dichloroethane, chlorobenzene, 1,1,1-trichloroethane, ethyl acetate, methyl acetate, tetrahydrofuran, dioxane, N,N-dimethyl-formamide, dimethylcarbonate, toluene, xylene, an alkane, a cycloalkane and mixtures thereof.
3. The method according to claim 2, wherein the Nicardipine or salt thereof is having the purity 99.0 % or more.
4. The method according to claim 5, wherein the Nicardipine or salt thereof is Nicardipine hydrochloride, having purity of 99.0 % or more.

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Abstract:
The present invention provides a process for the preparation of nicardipine or salt thereof. More particularly it relates to a process for the preparation of nicardipine, using 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine -3-carboxylic acid intermediate and thionyl chloride as halogenating agent.
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