Title of Invention	AN IMPROVED PROCESS FOR THE SYNTHESIS OF 1,4 DIHYDROPYRIDINE 3,5 DICARBOXYLIC ACID DERIVATIVES
Abstract	Disclosed herein is a simple and efficient process for the synthesis of lercanidipine hydrochloride, wherein 1,1 ,N-trimethyl-N-(3,3 -diphenylpropyl)-2-aminoethylacetoacetate and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester are subjected to a simple Michael addition under mild reaction conditions to obtain 1,5 diketo compound of formula C, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercamidipine in good yield and high purity. The invention further discloses an alternate process for the synthesis of lercanidipine hydrochloride wherein, 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester is converted into 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester by reacting with an ammonia source. 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester undergoes cyclisation with the active methylene group of compound (A) in presence of catalytic amount of acid source to give lercarnidipine hydrochloride.

Title of Invention

AN IMPROVED PROCESS FOR THE SYNTHESIS OF 1,4 DIHYDROPYRIDINE 3,5 DICARBOXYLIC ACID DERIVATIVES

Abstract

Disclosed herein is a simple and efficient process for the synthesis of lercanidipine hydrochloride, wherein 1,1 ,N-trimethyl-N-(3,3 -diphenylpropyl)-2-aminoethylacetoacetate and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester are subjected to a simple Michael addition under mild reaction conditions to obtain 1,5 diketo compound of formula C, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercamidipine in good yield and high purity. The invention further discloses an alternate process for the synthesis of lercanidipine hydrochloride wherein, 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester is converted into 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester by reacting with an ammonia source. 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester undergoes cyclisation with the active methylene group of compound (A) in presence of catalytic amount of acid source to give lercarnidipine hydrochloride.

Full Text	COMPETE AFTER PROVISIONAL LEFT ON 23 JAN 2007 FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule l3) 1. TITLE OF THE INVENTION: "An Improved process for the synthesis of 1,4 dihydropyridine 3,5 dicarboxylic acid derivatives" 2. APPLICANT (a) NAME: CIPLA LTD. (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India 3.PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be formed. Technical field of the Invention The present invention relates to an improved process for the synthesis of 1,4-dihydropyridine-3,5- dicarboxylic acid derivatives like lacidipine, isradipine and more particularly for the synthesis of lercanidipine hydrochloride. Background of the invention Dihydropyridine derivatives are well established for prophylaxis and treatment of various cardiovascular diseases. The asymmetrical diesters of l,4-dihydropyridines-3,5-dicarboxylic acid of the general formula I wherein R1,R2,R3 are as defined in the table, were found to be effective as very short-acting, potent and vasoselective antihypertensive agents, useful for intravenous as well as oral administration. Diesters of l,4-dihydropyridines-3,5 dicarboxylic acid of the general formula I are known to be synthesised using Hantzsch synthesis as shown in Scheme-I o R1 o Table Rl R2 R3 p8 CH3 ^y^^N^&^A C2H5 C2H5 N—0 CH3 (CH3)2CH Scheme I -R/R' Various processes for the synthesis of l,4-dihydropyridine-3,5-dicarboxylic acid derivatives are disclosed in the prior art they are all associated with numerous disadvantages. As the technology evolves, need for an efficient and economical process arises. The present invention provides a simple and efficient process for the synthesis of 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives like lacidipine, isradipine and more particularly for the synthesis of lercanidipine hydrochloride. 3 ij Lercanidipine Hydrochloride (II) Lercanidipine Hydrochloride (l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate) of the formula (II) which is a calcium-channel blocker used for the treatment of mild to moderate hypertension. Lercanidipine slows the movement of calcium through cells, which has two results. It decreases the rate at which the heart beats and also has a widening effect on blood vessels. This combination causes blood pressure to be reduced. Lercanidipine causes fewer vasodilatory adverse effects than other calcium-channel blockers. It is also being promoted for the treatment of isolated systolic hypertension (ISH) in elderly patients. Lercanidipine was first disclosed in patent US4705797, it describes the synthesis as in Scheme-II wherein the aminoalcohol (1) is esterified with diketene to form the corresponding acetoacetate (2), which is further coupled with 3-nitrobenzaldehyde to give l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl -a-acetyl 3-nitrocinnamate (3),which is further cyclised with methyl 3-aminocrotonate. Lercanidipine Hydrochloride Scheme-II 4 The process disclosed in the patent has several disadvantages. It employs use of hazardous material like diketene. The process leads to several by-products in the final step, which requires cumbersome purification technique like column chromatography. The process results in Lercanidipine hydrochloride hemihydrate, which is hygroscopic in nature. The overall yield of the process is 23%. These disadvantages make the process not suitable for industrial scale up. Hence there is a need for an industrially suitable process that avoids the use of the hazardous reagent also eliminates the need for column purification. WO 9635668 discloses an alternate process (Scheme-Ill) for the synthesis of lercanidipine hydrochloride H,COOC COOH Lercanidipine Hydrochloride (4) (D Scheme-Ill which comprises converting (4) to its acid chloride derivative and further reacting it with (1) in aprotic solvent leading to anhydrous lercanidipine hydrochloride which has low hygroscopicity. The disadvantage of this process is that it employs the use of a monocarboxylic acid (4) as a starting material which is not commercially available and the synthesis of this intermediate is difficult, it is prepared by hydrolysis of its diester which also lead to dicarboxylic acid derivative as an impurity and further purification is required to isolate the intermediate (4). Solution of these problems associated with prior art becomes the objects of the present invention. Hence, the present invention provides industrially viable and economically feasible process thereby eliminating the all the above-mentioned shortcomings. Summary of the Invention The present invention provides a simple and efficient process for the synthesis of lercanidipine hydrochloride is described in Scheme-A, wherein the compound of formula A 5 and compound of formula B are subjected to a simple Michael addition reaction leading to a 1,5 diketo compound of formula C, the reaction conditions employed are mild which results in lesser impurity formation and gives a product with high purity. The resulting diketo compound, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercanidipine in good yield and high purity. Lercamidipine is isolated as hydrochloride salt by quenching the residue with chilled hydrochloric acid and precipitated from a ketonic solvent; preferably methyl isobutyl ketone. Scheme A OMe Michael Addition Reaction lj OMe + (A) Lercanidipine Hydrochloride (II) Scheme- A The reaction is carried out at a temperature of ambient to reflux temperature of the solvent used. The solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ter.butanol or ethers such as diglyme. The base is selected from the group comprising inorganic bases such as sodium and potassium alkoxides and organic bases such as diethyl amine, triethyl amine diisopropyl amine, di-n-propyl amine and piperidine. The ammonia source is selected from the group consisting of alcoholic ammonia, aqueous ammonia, ammonium carbonate ammonium chloride and ammonium acetate. In another aspect the present invention provides an alternate process for the synthesis of lercanidipine hydrochloride of formula (II) (Scheme A) wherein, the compound of formula (B) is converted to an imine ester of formula (D) in an alcoholic solvent at a temperature of 40-60°C by reacting it with an ammonia source. Compound (D) undergoes cyclisation with the active methylene group of compound (A) in an alcoholic solvent, in presence of catalytic amount of acid source to give Lercanidipine The ammonia source is selected from aqueous ammonia, alcoholic ammonia, ammonium carbonate ammonium chloride and ammonium acetate. The alcoholic solvent is selected from the group consisiting of methanol, ethanol or isopropanol. The said reaction is carried out at ambient temperature to reflux temperature of the solvent used. As used herein the word 'ambient temperature' means to refer a temperature of 25-30°C. The acid source is selected from the group consisting of mineral acids or organic acids. Compound of formula (A) can be prepared following the teaching of US4705797 as shown below 7 \ // OH (A) Compound of formula A can also be synthesized by using a diketene acetone adduct as disclosed in the application WO2005107374. Alternatively compound of formula A can also be prepared using acyl meldrums acid as shown below wherein the tert. alcohol (N-methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol) is reacted with easily available non hazardous acyl meldrums acid (5-Acetyl-2,2-dimethyl- [l,3]dioxane-4,6-dione) in toluene at reflux temperature to get compound of formula A, thereby providing a cost effective safe and non hazardous process. 0 Acyl Meldrums Acid (A) The following specific examples presented to illustrate the best mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious set forth in the description. Example 1 5-Acetyl-2,2-dimethyl-[l,3]dioxane-4,6-dione (15 gm, 0.0806 mol) was reacted with N- methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol (26.4 gm., 0.088 mol ) in toluene (150 8 ml ) at reflux temperature for 2-3 hrs. The reaction mass was then cooled to ambient temperature and extracted twice with IN HC1 (100 ml). The organic layer was discarded and the combined aqueous layer was extracted thrice with dichloromethane (75 ml). Combined organic layer was washed with water (50 ml) and dried over sodium sulphate it was further concentrated to obtain l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) as an brown yellowish oil (30 gm.) having HPLC Purity : 98 % Example 2 Method I: To the stirred solution of sodium methoxide (2.12g, 0.04 mol ) in methanol ( 75 ml) kept under stirring was added 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (8.12 gm, 0.033 mol) at ambient temperature under argon atmosphere. Stirred the reaction mass for 10 min and a solution of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (10 gm, 0.0262 mol) prepared in methanol ( 25ml) was charged drop wise in 10 min. Refluxed the reaction mass for 3 hrs and organic layer was evaporated under reduced pressure. The obtained residue was quenched with chilled water (150 ml) below 10°C and extracted thrice with dichloromethane (100ml). Combined organic layer was washed with water (50 ml) dried over sodium sulfate and concentrated to get 12 gms of 1,5 diketo compound of formula C. HPLC purity : 98% Method II: To the stirred solution of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (15 gm, 0.0393 mol) in isopropanol ( 50 ml), diethyl amine (8.7 g, 0.11811 mol) was added at ambient temperature. The reaction mass was then refluxed for 5 hrs and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (9.8 gm, 0.0393 mol) was added to the reaction mass in one lot at reflux temperature. It was then refluxed for 18 hr and organic layer was evaporated to obtain oil. It was then cooled to room temperature and quenched with 2N hydrochloride acid solution (250 ml). The reaction Mass was stirred for 30 min and extracted thrice with dichloromethane (75 ml). Combined extract was washed twice with 9 water (50 ml), dried over sodium sulfate and concentrated to get 20 gm of 1,5 diketo compound of formula C HPLC purity : 98%. Method III: To a cleaned and thoroughly dried flask was charged freshly prepared l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) ( 25 gm, 0.0656 mol) with diglyme (100 ml) under inert atmosphere at ambient temperature. The reaction mass was stirred for 10 min at same temperature and freshly prepared fused Potassium fluoride (30 gm, 0.516 mol) was charged to the reaction mass at same temperature. Stirred the reaction mass at room temperature for 2 hrs and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (16.33 gm, 0.0656 mol) was charged portion wise in 5 to 6 hrs under stirring. The reaction mass was then stirred for 18 hrs and it was then quenched with saturated ammonium chloride solution (500 ml) below 10°C .Extracted the reaction mass thrice with dichloromethane (200ml ). Combined all organic layer and washed six times with water (100 ml). Dried organic layer over sodium sulphate and evaporated to obtain 35 gms of 1,5 diketo compound of formula C HPLC purity : 98% Example 3 To a 15 % methanolic ammonia solution (150 ml) was charged 1,5 diketo compound of formula C (25 gm, 0.03968 mol) at ambient temperature and stirred for 18 hrs at to get complete conversion. The methanolic layer was concentrated under reduced pressure and obtained residue was quenched in chilled IN Hydrochloride acid . It was then stirred for 15 min at 20-25°C and extracted thrice with methylene dichloride (50 ml). Combined extract was then washed with water and concentrated to obtain oil. This oil was then dissolved in methyl isobutyl ketone (200 ml) at 50°C and cooled gradually to ambient temperature till complete precipitation of solid. The resulting solid was filtered and washed with methyl isobutyl ketone (50 ml) and dried under vacuum at 50°C to get 20 g of Methyl 1,1,N-trimethylN-(3,3-diphenyl-propyl)-2-aminoethyll,4-dihydro-2,6-dimethyl-4-(3nitrophenyl) -pyridine-,3,5-dicarboxylate HPLC Purity: 99.5%. 10 Example 4 Synthesis of 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester (D) Method I: 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (10 gm, 0.40 mol) was suspended in methanol (100 ml) at ambient temperature . To this solution 33% aqueous ammonia solution was added ( 30 ml) below 35°C. The reaction mass was then stirred as such for 24 hrs and quenched with water (200 ml). The resulting solid was filtered and washed with waterand dried to get 9 gm of the titled compound (D). Yield : 90%, HPLC purity : 99% + Method II : To the solution of 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (25 gm, 0.10 mol) and methanol ( 100 ml ) ammonium Carbonate (50 gm, 0.52 mol) was added and reaction mass was warmed to 40-50°C. The reaction mass was then kept at same temperature for 6 hrs. Additional amount of ammonium carbonate (50 gm, 0.52 mol) was added and it was kept at same temperature for 18 hrs. Cooled to room temperature and quenched with water (250ml) below 25°C. The resulting solid was filtered washed with water and dried to get 18 gm of compound D. HPLC purity : 98% + Example 5 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester (D) (15 gm, 0.0604 mol) andl,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (20.5 gm, 0.059 mol) was stirred in isopropanol at ambient temperature. The reaction mass was then refluxed for 48 hrs and organic layer was evaporated to obtain a brown sticky residue. This residue was stirred with IN Hydrochloric acid solution (200 ml) for 30 min at ambient temperature. It was then extracted thrice with methylene dichloride (250 ml). Combined extract was then washed with water and concentrated to obtain oil. This oil was then dissolved in methyl 11 isobutyl ketone (250 ml) at 50°C and cooled gradually to ambient temperature. It was then stirred for 2 days to get Precipitation of solid. It was then filtered and washed with methyl isobutyl ketone ( 25 ml), weight of Lercanidipine Hydrochloride ( 28 gm ), HPLC Purity: 99.5%. 12 We claim, 1. A process for preparation of lercarnidipine hydrochloride of formula II N^, Lercariidipine Hydrochloride (II) comprising the steps of :- a) reacting compound of formula A (A) b) with compound of formula B to obtain 1, 5 diketo compound of formula C; OMe ,NOj c) cyclizing the compound of formula C in presence of an ammonia source d) quenching the reaction mass with hydrochloric acid; and e) precipitating lercarnidipine hydrochloride using methyl isobutyl ketone. 2. The process as claimed in claim 1, wherein the said reaction is carried out at a temperature of 25-30°C to reflux temperature of the solvent used. 3. The process as claimed in claim 1, wherein the said reaction is carried out in organic solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ter.butanol or ethers such as diglyme. 13 4. The process as claimed in claim 1, wherein said base is selected from the group comprising inorganic bases such as sodium and potassium alkoxides and organic bases such as diethyl amine, triethyl amine, diisopropyl amine, di-n-propyl amine and piperidine. 5. The process as claimed in claim 1, wherein said ammonia source is selected from the group consisting of alcoholic ammonia, aqueous ammonia, ammonium carbonate, ammonium chloride and ammonium acetate. 6. A process for preparation of lercarnipidine hydrochloride comprising the steps of: a) reacting the compound of B using ammonia source in an alcoholic solvent at a temperature of 40-60°C to obtain imine ester of formula D; OMe (D) b) cyclizing the compound of formula D with active methylene group of compound of formula A in an alcoholic solvent in presence of catalytic amount of acid source to obtain lercarnidipine hydrochloride. 7. The process as claimed in claim 6, wherein said ammonia source is selected from aqueous ammonia, alcoholic ammonia, ammonium carbonate, ammonium chloride and ammonium acetate. 8. The process as claimed in claim 6, wherein said alcoholic solvent is selected from the group consisiting of methanol, ethanol or isopropanol. 9. The process as claimed in claim 6, wherein said reaction is carried out at temperature of 25-30°C to reflux temperature of the solvent used. 10. The process as claimed in claim 6, wherein said acid source is selected from the group consisting of mineral acids or organic acids. 11. A process for preparation of compound of formula A comprising the steps of: 14 a. reacting N-methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol with 5- Acetyl-2,2-dimethyl-[l,3]dioxane-4,6-dione in toluene at reflux temperature for 2-4 hrs; b. extracting the reaction mass with hydrochloric acid, and discarding the organic layer c. extracting the aqueous layer with dichloromethane and concentrating to isolate compound of formula A. 12. The process for preparation of lercamidipine hydrochloride is substantially as described herein with reference to the description and forgoing examples 1 to 5. Dated this 23rd day of January 2007 15 ABSTRACT: Disclosed herein is a simple and efficient process for the synthesis of lercanidipine hydrochloride, wherein 1,1 ,N-trimethyl-N-(3,3 -diphenylpropyl)-2-aminoethylacetoacetate and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester are subjected to a simple Michael addition under mild reaction conditions to obtain 1,5 diketo compound of formula C, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercamidipine in good yield and high purity. The invention further discloses an alternate process for the synthesis of lercanidipine hydrochloride wherein, 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester is converted into 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester by reacting with an ammonia source. 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester undergoes cyclisation with the active methylene group of compound (A) in presence of catalytic amount of acid source to give lercamidipine hydrochloride. 16 COMPETE AFTER PROVISIONAL LEFT ON 23 JAN 2007 FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule l3) 1. TITLE OF THE INVENTION: "An Improved process for the synthesis of 1,4 dihydropyridine 3,5 dicarboxylic acid derivatives" 2. APPLICANT (a) NAME: CIPLA LTD. (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India 3.PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be formed. Technical field of the Invention The present invention relates to an improved process for the synthesis of 1,4-dihydropyridine-3,5- dicarboxylic acid derivatives like lacidipine, isradipine and more particularly for the synthesis of lercanidipine hydrochloride. Background of the invention Dihydropyridine derivatives are well established for prophylaxis and treatment of various cardiovascular diseases. The asymmetrical diesters of l,4-dihydropyridines-3,5-dicarboxylic acid of the general formula I wherein R1,R2,R3 are as defined in the table, were found to be effective as very short-acting, potent and vasoselective antihypertensive agents, useful for intravenous as well as oral administration. Diesters of l,4-dihydropyridines-3,5 dicarboxylic acid of the general formula I are known to be synthesised using Hantzsch synthesis as shown in Scheme-I o R1 o Table Rl R2 R3 p8 CH3 ^y^^N^&^A C2H5 C2H5 N—0 CH3 (CH3)2CH Scheme I -R/R' Various processes for the synthesis of l,4-dihydropyridine-3,5-dicarboxylic acid derivatives are disclosed in the prior art they are all associated with numerous disadvantages. As the technology evolves, need for an efficient and economical process arises. The present invention provides a simple and efficient process for the synthesis of 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives like lacidipine, isradipine and more particularly for the synthesis of lercanidipine hydrochloride. 3 ij Lercanidipine Hydrochloride (II) Lercanidipine Hydrochloride (l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate) of the formula (II) which is a calcium-channel blocker used for the treatment of mild to moderate hypertension. Lercanidipine slows the movement of calcium through cells, which has two results. It decreases the rate at which the heart beats and also has a widening effect on blood vessels. This combination causes blood pressure to be reduced. Lercanidipine causes fewer vasodilatory adverse effects than other calcium-channel blockers. It is also being promoted for the treatment of isolated systolic hypertension (ISH) in elderly patients. Lercanidipine was first disclosed in patent US4705797, it describes the synthesis as in Scheme-II wherein the aminoalcohol (1) is esterified with diketene to form the corresponding acetoacetate (2), which is further coupled with 3-nitrobenzaldehyde to give l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl -a-acetyl 3-nitrocinnamate (3),which is further cyclised with methyl 3-aminocrotonate. Lercanidipine Hydrochloride Scheme-II 4 The process disclosed in the patent has several disadvantages. It employs use of hazardous material like diketene. The process leads to several by-products in the final step, which requires cumbersome purification technique like column chromatography. The process results in Lercanidipine hydrochloride hemihydrate, which is hygroscopic in nature. The overall yield of the process is 23%. These disadvantages make the process not suitable for industrial scale up. Hence there is a need for an industrially suitable process that avoids the use of the hazardous reagent also eliminates the need for column purification. WO 9635668 discloses an alternate process (Scheme-Ill) for the synthesis of lercanidipine hydrochloride H,COOC COOH Lercanidipine Hydrochloride (4) (D Scheme-Ill which comprises converting (4) to its acid chloride derivative and further reacting it with (1) in aprotic solvent leading to anhydrous lercanidipine hydrochloride which has low hygroscopicity. The disadvantage of this process is that it employs the use of a monocarboxylic acid (4) as a starting material which is not commercially available and the synthesis of this intermediate is difficult, it is prepared by hydrolysis of its diester which also lead to dicarboxylic acid derivative as an impurity and further purification is required to isolate the intermediate (4). Solution of these problems associated with prior art becomes the objects of the present invention. Hence, the present invention provides industrially viable and economically feasible process thereby eliminating the all the above-mentioned shortcomings. Summary of the Invention The present invention provides a simple and efficient process for the synthesis of lercanidipine hydrochloride is described in Scheme-A, wherein the compound of formula A 5 and compound of formula B are subjected to a simple Michael addition reaction leading to a 1,5 diketo compound of formula C, the reaction conditions employed are mild which results in lesser impurity formation and gives a product with high purity. The resulting diketo compound, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercanidipine in good yield and high purity. Lercamidipine is isolated as hydrochloride salt by quenching the residue with chilled hydrochloric acid and precipitated from a ketonic solvent; preferably methyl isobutyl ketone. Scheme A OMe Michael Addition Reaction lj OMe + (A) Lercanidipine Hydrochloride (II) Scheme- A The reaction is carried out at a temperature of ambient to reflux temperature of the solvent used. The solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ter.butanol or ethers such as diglyme. The base is selected from the group comprising inorganic bases such as sodium and potassium alkoxides and organic bases such as diethyl amine, triethyl amine diisopropyl amine, di-n-propyl amine and piperidine. The ammonia source is selected from the group consisting of alcoholic ammonia, aqueous ammonia, ammonium carbonate ammonium chloride and ammonium acetate. In another aspect the present invention provides an alternate process for the synthesis of lercanidipine hydrochloride of formula (II) (Scheme A) wherein, the compound of formula (B) is converted to an imine ester of formula (D) in an alcoholic solvent at a temperature of 40-60°C by reacting it with an ammonia source. Compound (D) undergoes cyclisation with the active methylene group of compound (A) in an alcoholic solvent, in presence of catalytic amount of acid source to give Lercanidipine The ammonia source is selected from aqueous ammonia, alcoholic ammonia, ammonium carbonate ammonium chloride and ammonium acetate. The alcoholic solvent is selected from the group consisiting of methanol, ethanol or isopropanol. The said reaction is carried out at ambient temperature to reflux temperature of the solvent used. As used herein the word 'ambient temperature' means to refer a temperature of 25-30°C. The acid source is selected from the group consisting of mineral acids or organic acids. Compound of formula (A) can be prepared following the teaching of US4705797 as shown below 7 \ // OH (A) Compound of formula A can also be synthesized by using a diketene acetone adduct as disclosed in the application WO2005107374. Alternatively compound of formula A can also be prepared using acyl meldrums acid as shown below wherein the tert. alcohol (N-methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol) is reacted with easily available non hazardous acyl meldrums acid (5-Acetyl-2,2-dimethyl- [l,3]dioxane-4,6-dione) in toluene at reflux temperature to get compound of formula A, thereby providing a cost effective safe and non hazardous process. 0 Acyl Meldrums Acid (A) The following specific examples presented to illustrate the best mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious set forth in the description. Example 1 5-Acetyl-2,2-dimethyl-[l,3]dioxane-4,6-dione (15 gm, 0.0806 mol) was reacted with N- methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol (26.4 gm., 0.088 mol ) in toluene (150 8 ml ) at reflux temperature for 2-3 hrs. The reaction mass was then cooled to ambient temperature and extracted twice with IN HC1 (100 ml). The organic layer was discarded and the combined aqueous layer was extracted thrice with dichloromethane (75 ml). Combined organic layer was washed with water (50 ml) and dried over sodium sulphate it was further concentrated to obtain l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) as an brown yellowish oil (30 gm.) having HPLC Purity : 98 % Example 2 Method I: To the stirred solution of sodium methoxide (2.12g, 0.04 mol ) in methanol ( 75 ml) kept under stirring was added 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (8.12 gm, 0.033 mol) at ambient temperature under argon atmosphere. Stirred the reaction mass for 10 min and a solution of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (10 gm, 0.0262 mol) prepared in methanol ( 25ml) was charged drop wise in 10 min. Refluxed the reaction mass for 3 hrs and organic layer was evaporated under reduced pressure. The obtained residue was quenched with chilled water (150 ml) below 10°C and extracted thrice with dichloromethane (100ml). Combined organic layer was washed with water (50 ml) dried over sodium sulfate and concentrated to get 12 gms of 1,5 diketo compound of formula C. HPLC purity : 98% Method II: To the stirred solution of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (15 gm, 0.0393 mol) in isopropanol ( 50 ml), diethyl amine (8.7 g, 0.11811 mol) was added at ambient temperature. The reaction mass was then refluxed for 5 hrs and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (9.8 gm, 0.0393 mol) was added to the reaction mass in one lot at reflux temperature. It was then refluxed for 18 hr and organic layer was evaporated to obtain oil. It was then cooled to room temperature and quenched with 2N hydrochloride acid solution (250 ml). The reaction Mass was stirred for 30 min and extracted thrice with dichloromethane (75 ml). Combined extract was washed twice with 9 water (50 ml), dried over sodium sulfate and concentrated to get 20 gm of 1,5 diketo compound of formula C HPLC purity : 98%. Method III: To a cleaned and thoroughly dried flask was charged freshly prepared l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) ( 25 gm, 0.0656 mol) with diglyme (100 ml) under inert atmosphere at ambient temperature. The reaction mass was stirred for 10 min at same temperature and freshly prepared fused Potassium fluoride (30 gm, 0.516 mol) was charged to the reaction mass at same temperature. Stirred the reaction mass at room temperature for 2 hrs and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (16.33 gm, 0.0656 mol) was charged portion wise in 5 to 6 hrs under stirring. The reaction mass was then stirred for 18 hrs and it was then quenched with saturated ammonium chloride solution (500 ml) below 10°C .Extracted the reaction mass thrice with dichloromethane (200ml ). Combined all organic layer and washed six times with water (100 ml). Dried organic layer over sodium sulphate and evaporated to obtain 35 gms of 1,5 diketo compound of formula C HPLC purity : 98% Example 3 To a 15 % methanolic ammonia solution (150 ml) was charged 1,5 diketo compound of formula C (25 gm, 0.03968 mol) at ambient temperature and stirred for 18 hrs at to get complete conversion. The methanolic layer was concentrated under reduced pressure and obtained residue was quenched in chilled IN Hydrochloride acid . It was then stirred for 15 min at 20-25°C and extracted thrice with methylene dichloride (50 ml). Combined extract was then washed with water and concentrated to obtain oil. This oil was then dissolved in methyl isobutyl ketone (200 ml) at 50°C and cooled gradually to ambient temperature till complete precipitation of solid. The resulting solid was filtered and washed with methyl isobutyl ketone (50 ml) and dried under vacuum at 50°C to get 20 g of Methyl 1,1,N-trimethylN-(3,3-diphenyl-propyl)-2-aminoethyll,4-dihydro-2,6-dimethyl-4-(3nitrophenyl) -pyridine-,3,5-dicarboxylate HPLC Purity: 99.5%. 10 Example 4 Synthesis of 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester (D) Method I: 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (10 gm, 0.40 mol) was suspended in methanol (100 ml) at ambient temperature . To this solution 33% aqueous ammonia solution was added ( 30 ml) below 35°C. The reaction mass was then stirred as such for 24 hrs and quenched with water (200 ml). The resulting solid was filtered and washed with waterand dried to get 9 gm of the titled compound (D). Yield : 90%, HPLC purity : 99% + Method II : To the solution of 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (25 gm, 0.10 mol) and methanol ( 100 ml ) ammonium Carbonate (50 gm, 0.52 mol) was added and reaction mass was warmed to 40-50°C. The reaction mass was then kept at same temperature for 6 hrs. Additional amount of ammonium carbonate (50 gm, 0.52 mol) was added and it was kept at same temperature for 18 hrs. Cooled to room temperature and quenched with water (250ml) below 25°C. The resulting solid was filtered washed with water and dried to get 18 gm of compound D. HPLC purity : 98% + Example 5 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester (D) (15 gm, 0.0604 mol) andl,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (20.5 gm, 0.059 mol) was stirred in isopropanol at ambient temperature. The reaction mass was then refluxed for 48 hrs and organic layer was evaporated to obtain a brown sticky residue. This residue was stirred with IN Hydrochloric acid solution (200 ml) for 30 min at ambient temperature. It was then extracted thrice with methylene dichloride (250 ml). Combined extract was then washed with water and concentrated to obtain oil. This oil was then dissolved in methyl 11 isobutyl ketone (250 ml) at 50°C and cooled gradually to ambient temperature. It was then stirred for 2 days to get Precipitation of solid. It was then filtered and washed with methyl isobutyl ketone ( 25 ml), weight of Lercanidipine Hydrochloride ( 28 gm ), HPLC Purity: 99.5%. 12 We claim, 1. A process for preparation of lercarnidipine hydrochloride of formula II N^, Lercariidipine Hydrochloride (II) comprising the steps of :- a) reacting compound of formula A (A) b) with compound of formula B to obtain 1, 5 diketo compound of formula C; OMe ,NOj c) cyclizing the compound of formula C in presence of an ammonia source d) quenching the reaction mass with hydrochloric acid; and e) precipitating lercarnidipine hydrochloride using methyl isobutyl ketone. 2. The process as claimed in claim 1, wherein the said reaction is carried out at a temperature of 25-30°C to reflux temperature of the solvent used. 3. The process as claimed in claim 1, wherein the said reaction is carried out in organic solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ter.butanol or ethers such as diglyme. 13 4. The process as claimed in claim 1, wherein said base is selected from the group comprising inorganic bases such as sodium and potassium alkoxides and organic bases such as diethyl amine, triethyl amine, diisopropyl amine, di-n-propyl amine and piperidine. 5. The process as claimed in claim 1, wherein said ammonia source is selected from the group consisting of alcoholic ammonia, aqueous ammonia, ammonium carbonate, ammonium chloride and ammonium acetate. 6. A process for preparation of lercarnipidine hydrochloride comprising the steps of: a) reacting the compound of B using ammonia source in an alcoholic solvent at a temperature of 40-60°C to obtain imine ester of formula D; OMe (D) b) cyclizing the compound of formula D with active methylene group of compound of formula A in an alcoholic solvent in presence of catalytic amount of acid source to obtain lercarnidipine hydrochloride. 7. The process as claimed in claim 6, wherein said ammonia source is selected from aqueous ammonia, alcoholic ammonia, ammonium carbonate, ammonium chloride and ammonium acetate. 8. The process as claimed in claim 6, wherein said alcoholic solvent is selected from the group consisiting of methanol, ethanol or isopropanol. 9. The process as claimed in claim 6, wherein said reaction is carried out at temperature of 25-30°C to reflux temperature of the solvent used. 10. The process as claimed in claim 6, wherein said acid source is selected from the group consisting of mineral acids or organic acids. 11. A process for preparation of compound of formula A comprising the steps of: 14 a. reacting N-methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol with 5- Acetyl-2,2-dimethyl-[l,3]dioxane-4,6-dione in toluene at reflux temperature for 2-4 hrs; b. extracting the reaction mass with hydrochloric acid, and discarding the organic layer c. extracting the aqueous layer with dichloromethane and concentrating to isolate compound of formula A. 12. The process for preparation of lercamidipine hydrochloride is substantially as described herein with reference to the description and forgoing examples 1 to 5. Dated this 23rd day of January 2007 15 ABSTRACT: Disclosed herein is a simple and efficient process for the synthesis of lercanidipine hydrochloride, wherein 1,1 ,N-trimethyl-N-(3,3 -diphenylpropyl)-2-aminoethylacetoacetate and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester are subjected to a simple Michael addition under mild reaction conditions to obtain 1,5 diketo compound of formula C, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercamidipine in good yield and high purity. The invention further discloses an alternate process for the synthesis of lercanidipine hydrochloride wherein, 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester is converted into 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester by reacting with an ammonia source. 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester undergoes cyclisation with the active methylene group of compound (A) in presence of catalytic amount of acid source to give lercamidipine hydrochloride. 16 COMPETE AFTER PROVISIONAL LEFT ON 23 JAN 2007 FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule l3) 1. TITLE OF THE INVENTION: "An Improved process for the synthesis of 1,4 dihydropyridine 3,5 dicarboxylic acid derivatives" 2. APPLICANT (a) NAME: CIPLA LTD. (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India 3.PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be formed. Technical field of the Invention The present invention relates to an improved process for the synthesis of 1,4-dihydropyridine-3,5- dicarboxylic acid derivatives like lacidipine, isradipine and more particularly for the synthesis of lercanidipine hydrochloride. Background of the invention Dihydropyridine derivatives are well established for prophylaxis and treatment of various cardiovascular diseases. The asymmetrical diesters of l,4-dihydropyridines-3,5-dicarboxylic acid of the general formula I wherein R1,R2,R3 are as defined in the table, were found to be effective as very short-acting, potent and vasoselective antihypertensive agents, useful for intravenous as well as oral administration. Diesters of l,4-dihydropyridines-3,5 dicarboxylic acid of the general formula I are known to be synthesised using Hantzsch synthesis as shown in Scheme-I o R1 o Table Rl R2 R3 p*8 CH3 ^y^^N^&^A C2H5 C2H5 N—0 CH3 (CH3)2CH Scheme I -R/R' Various processes for the synthesis of l,4-dihydropyridine-3,5-dicarboxylic acid derivatives are disclosed in the prior art they are all associated with numerous disadvantages. As the technology evolves, need for an efficient and economical process arises. The present invention provides a simple and efficient process for the synthesis of 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives like lacidipine, isradipine and more particularly for the synthesis of lercanidipine hydrochloride. 3 ij Lercanidipine Hydrochloride (II) Lercanidipine Hydrochloride (l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate) of the formula (II) which is a calcium-channel blocker used for the treatment of mild to moderate hypertension. Lercanidipine slows the movement of calcium through cells, which has two results. It decreases the rate at which the heart beats and also has a widening effect on blood vessels. This combination causes blood pressure to be reduced. Lercanidipine causes fewer vasodilatory adverse effects than other calcium-channel blockers. It is also being promoted for the treatment of isolated systolic hypertension (ISH) in elderly patients. Lercanidipine was first disclosed in patent US4705797, it describes the synthesis as in Scheme-II wherein the aminoalcohol (1) is esterified with diketene to form the corresponding acetoacetate (2), which is further coupled with 3-nitrobenzaldehyde to give l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl -a-acetyl 3-nitrocinnamate (3),which is further cyclised with methyl 3-aminocrotonate. Lercanidipine Hydrochloride Scheme-II 4 The process disclosed in the patent has several disadvantages. It employs use of hazardous material like diketene. The process leads to several by-products in the final step, which requires cumbersome purification technique like column chromatography. The process results in Lercanidipine hydrochloride hemihydrate, which is hygroscopic in nature. The overall yield of the process is 23%. These disadvantages make the process not suitable for industrial scale up. Hence there is a need for an industrially suitable process that avoids the use of the hazardous reagent also eliminates the need for column purification. WO 9635668 discloses an alternate process (Scheme-Ill) for the synthesis of lercanidipine hydrochloride H,COOC COOH Lercanidipine Hydrochloride (4) (D Scheme-Ill which comprises converting (4) to its acid chloride derivative and further reacting it with (1) in aprotic solvent leading to anhydrous lercanidipine hydrochloride which has low hygroscopicity. The disadvantage of this process is that it employs the use of a monocarboxylic acid (4) as a starting material which is not commercially available and the synthesis of this intermediate is difficult, it is prepared by hydrolysis of its diester which also lead to dicarboxylic acid derivative as an impurity and further purification is required to isolate the intermediate (4). Solution of these problems associated with prior art becomes the objects of the present invention. Hence, the present invention provides industrially viable and economically feasible process thereby eliminating the all the above-mentioned shortcomings. Summary of the Invention The present invention provides a simple and efficient process for the synthesis of lercanidipine hydrochloride is described in Scheme-A, wherein the compound of formula A 5 and compound of formula B are subjected to a simple Michael addition reaction leading to a 1,5 diketo compound of formula C, the reaction conditions employed are mild which results in lesser impurity formation and gives a product with high purity. The resulting diketo compound, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercanidipine in good yield and high purity. Lercamidipine is isolated as hydrochloride salt by quenching the residue with chilled hydrochloric acid and precipitated from a ketonic solvent; preferably methyl isobutyl ketone. Scheme A OMe Michael Addition Reaction lj OMe + (A) Lercanidipine Hydrochloride (II) Scheme- A The reaction is carried out at a temperature of ambient to reflux temperature of the solvent used. The solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ter.butanol or ethers such as diglyme. The base is selected from the group comprising inorganic bases such as sodium and potassium alkoxides and organic bases such as diethyl amine, triethyl amine diisopropyl amine, di-n-propyl amine and piperidine. The ammonia source is selected from the group consisting of alcoholic ammonia, aqueous ammonia, ammonium carbonate ammonium chloride and ammonium acetate. In another aspect the present invention provides an alternate process for the synthesis of lercanidipine hydrochloride of formula (II) (Scheme A) wherein, the compound of formula (B) is converted to an imine ester of formula (D) in an alcoholic solvent at a temperature of 40-60°C by reacting it with an ammonia source. Compound (D) undergoes cyclisation with the active methylene group of compound (A) in an alcoholic solvent, in presence of catalytic amount of acid source to give Lercanidipine The ammonia source is selected from aqueous ammonia, alcoholic ammonia, ammonium carbonate ammonium chloride and ammonium acetate. The alcoholic solvent is selected from the group consisiting of methanol, ethanol or isopropanol. The said reaction is carried out at ambient temperature to reflux temperature of the solvent used. As used herein the word 'ambient temperature' means to refer a temperature of 25-30°C. The acid source is selected from the group consisting of mineral acids or organic acids. Compound of formula (A) can be prepared following the teaching of US4705797 as shown below 7 \ // OH (A) Compound of formula A can also be synthesized by using a diketene acetone adduct as disclosed in the application WO2005107374. Alternatively compound of formula A can also be prepared using acyl meldrums acid as shown below wherein the tert. alcohol (N-methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol) is reacted with easily available non hazardous acyl meldrums acid (5-Acetyl-2,2-dimethyl- [l,3]dioxane-4,6-dione) in toluene at reflux temperature to get compound of formula A, thereby providing a cost effective safe and non hazardous process. 0 Acyl Meldrums Acid (A) The following specific examples presented to illustrate the best mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious set forth in the description. Example 1 5-Acetyl-2,2-dimethyl-[l,3]dioxane-4,6-dione (15 gm, 0.0806 mol) was reacted with N- methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol (26.4 gm., 0.088 mol ) in toluene (150 8 ml ) at reflux temperature for 2-3 hrs. The reaction mass was then cooled to ambient temperature and extracted twice with IN HC1 (100 ml). The organic layer was discarded and the combined aqueous layer was extracted thrice with dichloromethane (75 ml). Combined organic layer was washed with water (50 ml) and dried over sodium sulphate it was further concentrated to obtain l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) as an brown yellowish oil (30 gm.) having HPLC Purity : 98 % Example 2 Method I: To the stirred solution of sodium methoxide (2.12g, 0.04 mol ) in methanol ( 75 ml) kept under stirring was added 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (8.12 gm, 0.033 mol) at ambient temperature under argon atmosphere. Stirred the reaction mass for 10 min and a solution of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (10 gm, 0.0262 mol) prepared in methanol ( 25ml) was charged drop wise in 10 min. Refluxed the reaction mass for 3 hrs and organic layer was evaporated under reduced pressure. The obtained residue was quenched with chilled water (150 ml) below 10°C and extracted thrice with dichloromethane (100ml). Combined organic layer was washed with water (50 ml) dried over sodium sulfate and concentrated to get 12 gms of 1,5 diketo compound of formula C. HPLC purity : 98% Method II: To the stirred solution of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (15 gm, 0.0393 mol) in isopropanol ( 50 ml), diethyl amine (8.7 g, 0.11811 mol) was added at ambient temperature. The reaction mass was then refluxed for 5 hrs and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (9.8 gm, 0.0393 mol) was added to the reaction mass in one lot at reflux temperature. It was then refluxed for 18 hr and organic layer was evaporated to obtain oil. It was then cooled to room temperature and quenched with 2N hydrochloride acid solution (250 ml). The reaction Mass was stirred for 30 min and extracted thrice with dichloromethane (75 ml). Combined extract was washed twice with 9 water (50 ml), dried over sodium sulfate and concentrated to get 20 gm of 1,5 diketo compound of formula C HPLC purity : 98%. Method III: To a cleaned and thoroughly dried flask was charged freshly prepared l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) ( 25 gm, 0.0656 mol) with diglyme (100 ml) under inert atmosphere at ambient temperature. The reaction mass was stirred for 10 min at same temperature and freshly prepared fused Potassium fluoride (30 gm, 0.516 mol) was charged to the reaction mass at same temperature. Stirred the reaction mass at room temperature for 2 hrs and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (16.33 gm, 0.0656 mol) was charged portion wise in 5 to 6 hrs under stirring. The reaction mass was then stirred for 18 hrs and it was then quenched with saturated ammonium chloride solution (500 ml) below 10°C .Extracted the reaction mass thrice with dichloromethane (200ml ). Combined all organic layer and washed six times with water (100 ml). Dried organic layer over sodium sulphate and evaporated to obtain 35 gms of 1,5 diketo compound of formula C HPLC purity : 98% Example 3 To a 15 % methanolic ammonia solution (150 ml) was charged 1,5 diketo compound of formula C (25 gm, 0.03968 mol) at ambient temperature and stirred for 18 hrs at to get complete conversion. The methanolic layer was concentrated under reduced pressure and obtained residue was quenched in chilled IN Hydrochloride acid . It was then stirred for 15 min at 20-25°C and extracted thrice with methylene dichloride (50 ml). Combined extract was then washed with water and concentrated to obtain oil. This oil was then dissolved in methyl isobutyl ketone (200 ml) at 50°C and cooled gradually to ambient temperature till complete precipitation of solid. The resulting solid was filtered and washed with methyl isobutyl ketone (50 ml) and dried under vacuum at 50°C to get 20 g of Methyl 1,1,N-trimethylN-(3,3-diphenyl-propyl)-2-aminoethyll,4-dihydro-2,6-dimethyl-4-(3nitrophenyl) -pyridine-,3,5-dicarboxylate HPLC Purity: 99.5%. 10 Example 4 Synthesis of 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester (D) Method I: 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (10 gm, 0.40 mol) was suspended in methanol (100 ml) at ambient temperature . To this solution 33% aqueous ammonia solution was added ( 30 ml) below 35°C. The reaction mass was then stirred as such for 24 hrs and quenched with water (200 ml). The resulting solid was filtered and washed with waterand dried to get 9 gm of the titled compound (D). Yield : 90%, HPLC purity : 99% + Method II : To the solution of 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (25 gm, 0.10 mol) and methanol ( 100 ml ) ammonium Carbonate (50 gm, 0.52 mol) was added and reaction mass was warmed to 40-50°C. The reaction mass was then kept at same temperature for 6 hrs. Additional amount of ammonium carbonate (50 gm, 0.52 mol) was added and it was kept at same temperature for 18 hrs. Cooled to room temperature and quenched with water (250ml) below 25°C. The resulting solid was filtered washed with water and dried to get 18 gm of compound D. HPLC purity : 98% + Example 5 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester (D) (15 gm, 0.0604 mol) andl,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (20.5 gm, 0.059 mol) was stirred in isopropanol at ambient temperature. The reaction mass was then refluxed for 48 hrs and organic layer was evaporated to obtain a brown sticky residue. This residue was stirred with IN Hydrochloric acid solution (200 ml) for 30 min at ambient temperature. It was then extracted thrice with methylene dichloride (250 ml). Combined extract was then washed with water and concentrated to obtain oil. This oil was then dissolved in methyl 11 isobutyl ketone (250 ml) at 50°C and cooled gradually to ambient temperature. It was then stirred for 2 days to get Precipitation of solid. It was then filtered and washed with methyl isobutyl ketone ( 25 ml), weight of Lercanidipine Hydrochloride ( 28 gm ), HPLC Purity: 99.5%. 12 We claim, 1. A process for preparation of lercarnidipine hydrochloride of formula II N^, Lercariidipine Hydrochloride (II) comprising the steps of :- a) reacting compound of formula A (A) b) with compound of formula B to obtain 1, 5 diketo compound of formula C; OMe ,NOj c) cyclizing the compound of formula C in presence of an ammonia source d) quenching the reaction mass with hydrochloric acid; and e) precipitating lercarnidipine hydrochloride using methyl isobutyl ketone. 2. The process as claimed in claim 1, wherein the said reaction is carried out at a temperature of 25-30°C to reflux temperature of the solvent used. 3. The process as claimed in claim 1, wherein the said reaction is carried out in organic solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ter.butanol or ethers such as diglyme. 13 4. The process as claimed in claim 1, wherein said base is selected from the group comprising inorganic bases such as sodium and potassium alkoxides and organic bases such as diethyl amine, triethyl amine, diisopropyl amine, di-n-propyl amine and piperidine. 5. The process as claimed in claim 1, wherein said ammonia source is selected from the group consisting of alcoholic ammonia, aqueous ammonia, ammonium carbonate, ammonium chloride and ammonium acetate. 6. A process for preparation of lercarnipidine hydrochloride comprising the steps of: a) reacting the compound of B using ammonia source in an alcoholic solvent at a temperature of 40-60°C to obtain imine ester of formula D; OMe (D) b) cyclizing the compound of formula D with active methylene group of compound of formula A in an alcoholic solvent in presence of catalytic amount of acid source to obtain lercarnidipine hydrochloride. 7. The process as claimed in claim 6, wherein said ammonia source is selected from aqueous ammonia, alcoholic ammonia, ammonium carbonate, ammonium chloride and ammonium acetate. 8. The process as claimed in claim 6, wherein said alcoholic solvent is selected from the group consisiting of methanol, ethanol or isopropanol. 9. The process as claimed in claim 6, wherein said reaction is carried out at temperature of 25-30°C to reflux temperature of the solvent used. 10. The process as claimed in claim 6, wherein said acid source is selected from the group consisting of mineral acids or organic acids. 11. A process for preparation of compound of formula A comprising the steps of: 14 a. reacting N-methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol with 5- Acetyl-2,2-dimethyl-[l,3]dioxane-4,6-dione in toluene at reflux temperature for 2-4 hrs; b. extracting the reaction mass with hydrochloric acid, and discarding the organic layer c. extracting the aqueous layer with dichloromethane and concentrating to isolate compound of formula A. 12. The process for preparation of lercamidipine hydrochloride is substantially as described herein with reference to the description and forgoing examples 1 to 5. Dated this 23rd day of January 2007 15 ABSTRACT: Disclosed herein is a simple and efficient process for the synthesis of lercanidipine hydrochloride, wherein 1,1 ,N-trimethyl-N-(3,3 -diphenylpropyl)-2-aminoethylacetoacetate and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester are subjected to a simple Michael addition under mild reaction conditions to obtain 1,5 diketo compound of formula C, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercamidipine in good yield and high purity. The invention further discloses an alternate process for the synthesis of lercanidipine hydrochloride wherein, 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester is converted into 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester by reacting with an ammonia source. 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester undergoes cyclisation with the active methylene group of compound (A) in presence of catalytic amount of acid source to give lercamidipine hydrochloride. 16

Full Text

COMPETE AFTER PROVISIONAL
LEFT ON 23 JAN 2007
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"An Improved process for the synthesis of 1,4 dihydropyridine 3,5 dicarboxylic
acid derivatives"
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956 (c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be formed.

Technical field of the Invention
The present invention relates to an improved process for the synthesis of 1,4-dihydropyridine-3,5- dicarboxylic acid derivatives like lacidipine, isradipine and more particularly for the synthesis of lercanidipine hydrochloride.
Background of the invention
Dihydropyridine derivatives are well established for prophylaxis and treatment of various cardiovascular diseases. The asymmetrical diesters of l,4-dihydropyridines-3,5-dicarboxylic acid of the general formula I wherein R1,R2,R3 are as defined in the table, were found to be effective as very short-acting, potent and vasoselective antihypertensive agents, useful for intravenous as well as oral administration. Diesters of l,4-dihydropyridines-3,5 dicarboxylic acid of the general formula I are known to be synthesised using Hantzsch synthesis as shown in Scheme-I
o R1 o

Table

Rl R2 R3
p*8 CH3 ^y^^N^&^A C2H5 C2H5

N—0 CH3 (CH3)2CH
Scheme I

-R/R'

Various processes for the synthesis of l,4-dihydropyridine-3,5-dicarboxylic acid derivatives are disclosed in the prior art they are all associated with numerous disadvantages. As the technology evolves, need for an efficient and economical process arises. The present invention provides a simple and efficient process for the synthesis of 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives like lacidipine, isradipine and more particularly for the synthesis of lercanidipine hydrochloride.
3

ij
Lercanidipine Hydrochloride (II)
Lercanidipine Hydrochloride (l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate) of the formula (II) which is a calcium-channel blocker used for the treatment of mild to moderate hypertension. Lercanidipine slows the movement of calcium through cells, which has two results. It decreases the rate at which the heart beats and also has a widening effect on blood vessels. This combination causes blood pressure to be reduced. Lercanidipine causes fewer vasodilatory adverse effects than other calcium-channel blockers. It is also being promoted for the treatment of isolated systolic hypertension (ISH) in elderly patients.
Lercanidipine was first disclosed in patent US4705797, it describes the synthesis as in Scheme-II wherein the aminoalcohol (1) is esterified with diketene to form the corresponding acetoacetate (2), which is further coupled with 3-nitrobenzaldehyde to give l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl -a-acetyl 3-nitrocinnamate (3),which is further cyclised with methyl 3-aminocrotonate.

Lercanidipine Hydrochloride

Scheme-II

4

The process disclosed in the patent has several disadvantages. It employs use of hazardous
material like diketene. The process leads to several by-products in the final step, which
requires cumbersome purification technique like column chromatography. The process
results in Lercanidipine hydrochloride hemihydrate, which is hygroscopic in nature. The
overall yield of the process is 23%. These disadvantages make the process not suitable for
industrial scale up.
Hence there is a need for an industrially suitable process that avoids the use of the hazardous
reagent also eliminates the need for column purification.
WO 9635668 discloses an alternate process (Scheme-Ill) for the synthesis of lercanidipine
hydrochloride

H,COOC
COOH
Lercanidipine Hydrochloride

(4)

(D

Scheme-Ill
which comprises converting (4) to its acid chloride derivative and further reacting it with (1) in aprotic solvent leading to anhydrous lercanidipine hydrochloride which has low hygroscopicity. The disadvantage of this process is that it employs the use of a monocarboxylic acid (4) as a starting material which is not commercially available and the synthesis of this intermediate is difficult, it is prepared by hydrolysis of its diester which also lead to dicarboxylic acid derivative as an impurity and further purification is required to isolate the intermediate (4).
Solution of these problems associated with prior art becomes the objects of the present invention. Hence, the present invention provides industrially viable and economically feasible process thereby eliminating the all the above-mentioned shortcomings.
Summary of the Invention
The present invention provides a simple and efficient process for the synthesis of lercanidipine hydrochloride is described in Scheme-A, wherein the compound of formula A
5

and compound of formula B are subjected to a simple Michael addition reaction leading to a 1,5 diketo compound of formula C, the reaction conditions employed are mild which results in lesser impurity formation and gives a product with high purity. The resulting diketo compound, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercanidipine in good yield and high purity. Lercamidipine is isolated as hydrochloride salt by quenching the residue with chilled hydrochloric acid and precipitated from a ketonic solvent; preferably methyl isobutyl ketone. Scheme A

OMe
Michael Addition Reaction

lj OMe
+ (A)

Lercanidipine Hydrochloride (II)

Scheme- A

The reaction is carried out at a temperature of ambient to reflux temperature of the solvent used. The solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ter.butanol or ethers such as diglyme.
The base is selected from the group comprising inorganic bases such as sodium and potassium alkoxides and organic bases such as diethyl amine, triethyl amine diisopropyl amine, di-n-propyl amine and piperidine.
The ammonia source is selected from the group consisting of alcoholic ammonia, aqueous ammonia, ammonium carbonate ammonium chloride and ammonium acetate.
In another aspect the present invention provides an alternate process for the synthesis of lercanidipine hydrochloride of formula (II) (Scheme A) wherein, the compound of formula (B) is converted to an imine ester of formula (D) in an alcoholic solvent at a temperature of 40-60°C by reacting it with an ammonia source. Compound (D) undergoes cyclisation with the active methylene group of compound (A) in an alcoholic solvent, in presence of catalytic amount of acid source to give Lercanidipine
The ammonia source is selected from aqueous ammonia, alcoholic ammonia, ammonium
carbonate ammonium chloride and ammonium acetate.
The alcoholic solvent is selected from the group consisiting of methanol, ethanol or
isopropanol.
The said reaction is carried out at ambient temperature to reflux temperature of the solvent
used.
As used herein the word 'ambient temperature' means to refer a temperature of 25-30°C.
The acid source is selected from the group consisting of mineral acids or organic acids.
Compound of formula (A) can be prepared following the teaching of US4705797 as shown
below
7

\ //

OH

(A)
Compound of formula A can also be synthesized by using a diketene acetone adduct as
disclosed in the application WO2005107374.
Alternatively compound of formula A can also be prepared using acyl meldrums acid as
shown below
wherein the tert. alcohol (N-methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol) is reacted
with easily available non hazardous acyl meldrums acid (5-Acetyl-2,2-dimethyl-
[l,3]dioxane-4,6-dione) in toluene at reflux temperature to get compound of formula A,
thereby providing a cost effective safe and non hazardous process.

0

Acyl Meldrums Acid

(A)

The following specific examples presented to illustrate the best mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious set forth in the description.
Example 1
5-Acetyl-2,2-dimethyl-[l,3]dioxane-4,6-dione (15 gm, 0.0806 mol) was reacted with N-
methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol (26.4 gm., 0.088 mol ) in toluene (150
8

ml ) at reflux temperature for 2-3 hrs. The reaction mass was then cooled to ambient temperature and extracted twice with IN HC1 (100 ml). The organic layer was discarded and the combined aqueous layer was extracted thrice with dichloromethane (75 ml). Combined organic layer was washed with water (50 ml) and dried over sodium sulphate it was further concentrated to obtain l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) as an brown yellowish oil (30 gm.) having HPLC Purity : 98 %
Example 2 Method I:
To the stirred solution of sodium methoxide (2.12g, 0.04 mol ) in methanol ( 75 ml) kept under stirring was added 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (8.12 gm, 0.033 mol) at ambient temperature under argon atmosphere. Stirred the reaction mass for 10 min and a solution of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (10 gm, 0.0262 mol) prepared in methanol ( 25ml) was charged drop wise in 10 min. Refluxed the reaction mass for 3 hrs and organic layer was evaporated under reduced pressure. The obtained residue was quenched with chilled water (150 ml) below 10°C and extracted thrice with dichloromethane (100ml). Combined organic layer was washed with water (50 ml) dried over sodium sulfate and concentrated to get 12 gms of 1,5 diketo compound of formula C. HPLC purity : 98%
Method II:
To the stirred solution of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (15 gm, 0.0393 mol) in isopropanol ( 50 ml), diethyl amine (8.7 g, 0.11811 mol) was added at ambient temperature. The reaction mass was then refluxed for 5 hrs and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (9.8 gm, 0.0393 mol) was added to the reaction mass in one lot at reflux temperature. It was then refluxed for 18 hr and organic layer was evaporated to obtain oil. It was then cooled to room temperature and quenched with 2N hydrochloride acid solution (250 ml). The reaction Mass was stirred for 30 min and extracted thrice with dichloromethane (75 ml). Combined extract was washed twice with
9

water (50 ml), dried over sodium sulfate and concentrated to get 20 gm of 1,5 diketo compound of formula C HPLC purity : 98%.
Method III:
To a cleaned and thoroughly dried flask was charged freshly prepared l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) ( 25 gm, 0.0656 mol) with diglyme (100 ml) under inert atmosphere at ambient temperature. The reaction mass was stirred for 10 min at same temperature and freshly prepared fused Potassium fluoride (30 gm, 0.516 mol) was charged to the reaction mass at same temperature. Stirred the reaction mass at room temperature for 2 hrs and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (16.33 gm, 0.0656 mol) was charged portion wise in 5 to 6 hrs under stirring. The reaction mass was then stirred for 18 hrs and it was then quenched with saturated ammonium chloride solution (500 ml) below 10°C .Extracted the reaction mass thrice with dichloromethane (200ml ). Combined all organic layer and washed six times with water (100 ml). Dried organic layer over sodium sulphate and evaporated to obtain 35 gms of 1,5 diketo compound of formula C HPLC purity : 98%
Example 3
To a 15 % methanolic ammonia solution (150 ml) was charged 1,5 diketo compound of formula C (25 gm, 0.03968 mol) at ambient temperature and stirred for 18 hrs at to get complete conversion. The methanolic layer was concentrated under reduced pressure and obtained residue was quenched in chilled IN Hydrochloride acid . It was then stirred for 15 min at 20-25°C and extracted thrice with methylene dichloride (50 ml). Combined extract was then washed with water and concentrated to obtain oil. This oil was then dissolved in methyl isobutyl ketone (200 ml) at 50°C and cooled gradually to ambient temperature till complete precipitation of solid. The resulting solid was filtered and washed with methyl isobutyl ketone (50 ml) and dried under vacuum at 50°C to get 20 g of Methyl 1,1,N-trimethylN-(3,3-diphenyl-propyl)-2-aminoethyll,4-dihydro-2,6-dimethyl-4-(3nitrophenyl) -pyridine-,3,5-dicarboxylate HPLC Purity: 99.5%.
10

Example 4
Synthesis of 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester (D)
Method I:
2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (10 gm, 0.40 mol) was suspended in methanol (100 ml) at ambient temperature . To this solution 33% aqueous ammonia solution was added ( 30 ml) below 35°C. The reaction mass was then stirred as such for 24 hrs and quenched with water (200 ml). The resulting solid was filtered and washed with waterand dried to get 9 gm of the titled compound (D). Yield : 90%, HPLC purity : 99% +
Method II :
To the solution of 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (25 gm, 0.10 mol) and methanol ( 100 ml ) ammonium Carbonate (50 gm, 0.52 mol) was added and reaction mass was warmed to 40-50°C. The reaction mass was then kept at same temperature for 6 hrs. Additional amount of ammonium carbonate (50 gm, 0.52 mol) was added and it was kept at same temperature for 18 hrs. Cooled to room temperature and quenched with water (250ml) below 25°C. The resulting solid was filtered washed with water and dried to get 18 gm of compound D. HPLC purity : 98% +
Example 5
3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester (D) (15 gm, 0.0604 mol) andl,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (20.5 gm, 0.059 mol) was stirred in isopropanol at ambient temperature. The reaction mass was then refluxed for 48 hrs and organic layer was evaporated to obtain a brown sticky residue. This residue was stirred with IN Hydrochloric acid solution (200 ml) for 30 min at ambient temperature. It was then extracted thrice with methylene dichloride (250 ml). Combined extract was then washed with water and concentrated to obtain oil. This oil was then dissolved in methyl
11

isobutyl ketone (250 ml) at 50°C and cooled gradually to ambient temperature. It was then stirred for 2 days to get Precipitation of solid. It was then filtered and washed with methyl isobutyl ketone ( 25 ml), weight of Lercanidipine Hydrochloride ( 28 gm ), HPLC Purity: 99.5%.
12

We claim,
1. A process for preparation of lercarnidipine hydrochloride of formula II

N^,

Lercariidipine Hydrochloride (II)
comprising the steps of :-
a) reacting compound of formula A

(A)
b) with compound of formula B to obtain 1, 5 diketo compound of formula C;

OMe
,NOj

c) cyclizing the compound of formula C in presence of an ammonia source
d) quenching the reaction mass with hydrochloric acid; and
e) precipitating lercarnidipine hydrochloride using methyl isobutyl ketone.

2. The process as claimed in claim 1, wherein the said reaction is carried out at a temperature of 25-30°C to reflux temperature of the solvent used.
3. The process as claimed in claim 1, wherein the said reaction is carried out in organic solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ter.butanol or ethers such as diglyme.
13

4. The process as claimed in claim 1, wherein said base is selected from the group comprising inorganic bases such as sodium and potassium alkoxides and organic bases such as diethyl amine, triethyl amine, diisopropyl amine, di-n-propyl amine and piperidine.
5. The process as claimed in claim 1, wherein said ammonia source is selected from the group consisting of alcoholic ammonia, aqueous ammonia, ammonium carbonate, ammonium chloride and ammonium acetate.
6. A process for preparation of lercarnipidine hydrochloride comprising the steps of:
a) reacting the compound of B using ammonia source in an alcoholic solvent at a
temperature of 40-60°C to obtain imine ester of formula D;

OMe (D)
b) cyclizing the compound of formula D with active methylene group of compound of formula A in an alcoholic solvent in presence of catalytic amount of acid source to obtain lercarnidipine hydrochloride.
7. The process as claimed in claim 6, wherein said ammonia source is selected from aqueous ammonia, alcoholic ammonia, ammonium carbonate, ammonium chloride and ammonium acetate.
8. The process as claimed in claim 6, wherein said alcoholic solvent is selected from the group consisiting of methanol, ethanol or isopropanol.
9. The process as claimed in claim 6, wherein said reaction is carried out at temperature of 25-30°C to reflux temperature of the solvent used.
10. The process as claimed in claim 6, wherein said acid source is selected from the group consisting of mineral acids or organic acids.
11. A process for preparation of compound of formula A comprising the steps of:
14

a. reacting N-methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol with 5-
Acetyl-2,2-dimethyl-[l,3]dioxane-4,6-dione in toluene at reflux temperature
for 2-4 hrs;
b. extracting the reaction mass with hydrochloric acid, and discarding the
organic layer
c. extracting the aqueous layer with dichloromethane and concentrating to
isolate compound of formula A.
12. The process for preparation of lercamidipine hydrochloride is substantially as described herein with reference to the description and forgoing examples 1 to 5.
Dated this 23rd day of January 2007

15

ABSTRACT:
Disclosed herein is a simple and efficient process for the synthesis of lercanidipine hydrochloride, wherein 1,1 ,N-trimethyl-N-(3,3 -diphenylpropyl)-2-aminoethylacetoacetate and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester are subjected to a simple Michael addition under mild reaction conditions to obtain 1,5 diketo compound of formula C, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercamidipine in good yield and high purity. The invention further discloses an alternate process for the synthesis of lercanidipine hydrochloride wherein, 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester is converted into 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester by reacting with an ammonia source. 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester undergoes cyclisation with the active methylene group of compound (A) in presence of catalytic amount of acid source to give lercamidipine hydrochloride.
16
COMPETE AFTER PROVISIONAL
LEFT ON 23 JAN 2007
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"An Improved process for the synthesis of 1,4 dihydropyridine 3,5 dicarboxylic
acid derivatives"
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956 (c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be formed.

Technical field of the Invention
The present invention relates to an improved process for the synthesis of 1,4-dihydropyridine-3,5- dicarboxylic acid derivatives like lacidipine, isradipine and more particularly for the synthesis of lercanidipine hydrochloride.
Background of the invention
Dihydropyridine derivatives are well established for prophylaxis and treatment of various cardiovascular diseases. The asymmetrical diesters of l,4-dihydropyridines-3,5-dicarboxylic acid of the general formula I wherein R1,R2,R3 are as defined in the table, were found to be effective as very short-acting, potent and vasoselective antihypertensive agents, useful for intravenous as well as oral administration. Diesters of l,4-dihydropyridines-3,5 dicarboxylic acid of the general formula I are known to be synthesised using Hantzsch synthesis as shown in Scheme-I
o R1 o

Table

Rl R2 R3
p*8 CH3 ^y^^N^&^A C2H5 C2H5

N—0 CH3 (CH3)2CH
Scheme I

-R/R'

Various processes for the synthesis of l,4-dihydropyridine-3,5-dicarboxylic acid derivatives are disclosed in the prior art they are all associated with numerous disadvantages. As the technology evolves, need for an efficient and economical process arises. The present invention provides a simple and efficient process for the synthesis of 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives like lacidipine, isradipine and more particularly for the synthesis of lercanidipine hydrochloride.
3

ij
Lercanidipine Hydrochloride (II)
Lercanidipine Hydrochloride (l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate) of the formula (II) which is a calcium-channel blocker used for the treatment of mild to moderate hypertension. Lercanidipine slows the movement of calcium through cells, which has two results. It decreases the rate at which the heart beats and also has a widening effect on blood vessels. This combination causes blood pressure to be reduced. Lercanidipine causes fewer vasodilatory adverse effects than other calcium-channel blockers. It is also being promoted for the treatment of isolated systolic hypertension (ISH) in elderly patients.
Lercanidipine was first disclosed in patent US4705797, it describes the synthesis as in Scheme-II wherein the aminoalcohol (1) is esterified with diketene to form the corresponding acetoacetate (2), which is further coupled with 3-nitrobenzaldehyde to give l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl -a-acetyl 3-nitrocinnamate (3),which is further cyclised with methyl 3-aminocrotonate.

Lercanidipine Hydrochloride

Scheme-II

4

The process disclosed in the patent has several disadvantages. It employs use of hazardous
material like diketene. The process leads to several by-products in the final step, which
requires cumbersome purification technique like column chromatography. The process
results in Lercanidipine hydrochloride hemihydrate, which is hygroscopic in nature. The
overall yield of the process is 23%. These disadvantages make the process not suitable for
industrial scale up.
Hence there is a need for an industrially suitable process that avoids the use of the hazardous
reagent also eliminates the need for column purification.
WO 9635668 discloses an alternate process (Scheme-Ill) for the synthesis of lercanidipine
hydrochloride

H,COOC
COOH
Lercanidipine Hydrochloride

(4)

(D

Scheme-Ill
which comprises converting (4) to its acid chloride derivative and further reacting it with (1) in aprotic solvent leading to anhydrous lercanidipine hydrochloride which has low hygroscopicity. The disadvantage of this process is that it employs the use of a monocarboxylic acid (4) as a starting material which is not commercially available and the synthesis of this intermediate is difficult, it is prepared by hydrolysis of its diester which also lead to dicarboxylic acid derivative as an impurity and further purification is required to isolate the intermediate (4).
Solution of these problems associated with prior art becomes the objects of the present invention. Hence, the present invention provides industrially viable and economically feasible process thereby eliminating the all the above-mentioned shortcomings.
Summary of the Invention
The present invention provides a simple and efficient process for the synthesis of lercanidipine hydrochloride is described in Scheme-A, wherein the compound of formula A
5

and compound of formula B are subjected to a simple Michael addition reaction leading to a 1,5 diketo compound of formula C, the reaction conditions employed are mild which results in lesser impurity formation and gives a product with high purity. The resulting diketo compound, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercanidipine in good yield and high purity. Lercamidipine is isolated as hydrochloride salt by quenching the residue with chilled hydrochloric acid and precipitated from a ketonic solvent; preferably methyl isobutyl ketone. Scheme A

OMe
Michael Addition Reaction

lj OMe
+ (A)

Lercanidipine Hydrochloride (II)

Scheme- A

The reaction is carried out at a temperature of ambient to reflux temperature of the solvent used. The solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ter.butanol or ethers such as diglyme.
The base is selected from the group comprising inorganic bases such as sodium and potassium alkoxides and organic bases such as diethyl amine, triethyl amine diisopropyl amine, di-n-propyl amine and piperidine.
The ammonia source is selected from the group consisting of alcoholic ammonia, aqueous ammonia, ammonium carbonate ammonium chloride and ammonium acetate.
In another aspect the present invention provides an alternate process for the synthesis of lercanidipine hydrochloride of formula (II) (Scheme A) wherein, the compound of formula (B) is converted to an imine ester of formula (D) in an alcoholic solvent at a temperature of 40-60°C by reacting it with an ammonia source. Compound (D) undergoes cyclisation with the active methylene group of compound (A) in an alcoholic solvent, in presence of catalytic amount of acid source to give Lercanidipine
The ammonia source is selected from aqueous ammonia, alcoholic ammonia, ammonium
carbonate ammonium chloride and ammonium acetate.
The alcoholic solvent is selected from the group consisiting of methanol, ethanol or
isopropanol.
The said reaction is carried out at ambient temperature to reflux temperature of the solvent
used.
As used herein the word 'ambient temperature' means to refer a temperature of 25-30°C.
The acid source is selected from the group consisting of mineral acids or organic acids.
Compound of formula (A) can be prepared following the teaching of US4705797 as shown
below
7

\ //

OH

(A)
Compound of formula A can also be synthesized by using a diketene acetone adduct as
disclosed in the application WO2005107374.
Alternatively compound of formula A can also be prepared using acyl meldrums acid as
shown below
wherein the tert. alcohol (N-methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol) is reacted
with easily available non hazardous acyl meldrums acid (5-Acetyl-2,2-dimethyl-
[l,3]dioxane-4,6-dione) in toluene at reflux temperature to get compound of formula A,
thereby providing a cost effective safe and non hazardous process.

0

Acyl Meldrums Acid

(A)

The following specific examples presented to illustrate the best mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious set forth in the description.
Example 1
5-Acetyl-2,2-dimethyl-[l,3]dioxane-4,6-dione (15 gm, 0.0806 mol) was reacted with N-
methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol (26.4 gm., 0.088 mol ) in toluene (150
8

ml ) at reflux temperature for 2-3 hrs. The reaction mass was then cooled to ambient temperature and extracted twice with IN HC1 (100 ml). The organic layer was discarded and the combined aqueous layer was extracted thrice with dichloromethane (75 ml). Combined organic layer was washed with water (50 ml) and dried over sodium sulphate it was further concentrated to obtain l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) as an brown yellowish oil (30 gm.) having HPLC Purity : 98 %
Example 2 Method I:
To the stirred solution of sodium methoxide (2.12g, 0.04 mol ) in methanol ( 75 ml) kept under stirring was added 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (8.12 gm, 0.033 mol) at ambient temperature under argon atmosphere. Stirred the reaction mass for 10 min and a solution of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (10 gm, 0.0262 mol) prepared in methanol ( 25ml) was charged drop wise in 10 min. Refluxed the reaction mass for 3 hrs and organic layer was evaporated under reduced pressure. The obtained residue was quenched with chilled water (150 ml) below 10°C and extracted thrice with dichloromethane (100ml). Combined organic layer was washed with water (50 ml) dried over sodium sulfate and concentrated to get 12 gms of 1,5 diketo compound of formula C. HPLC purity : 98%
Method II:
To the stirred solution of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (15 gm, 0.0393 mol) in isopropanol ( 50 ml), diethyl amine (8.7 g, 0.11811 mol) was added at ambient temperature. The reaction mass was then refluxed for 5 hrs and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (9.8 gm, 0.0393 mol) was added to the reaction mass in one lot at reflux temperature. It was then refluxed for 18 hr and organic layer was evaporated to obtain oil. It was then cooled to room temperature and quenched with 2N hydrochloride acid solution (250 ml). The reaction Mass was stirred for 30 min and extracted thrice with dichloromethane (75 ml). Combined extract was washed twice with
9

water (50 ml), dried over sodium sulfate and concentrated to get 20 gm of 1,5 diketo compound of formula C HPLC purity : 98%.
Method III:
To a cleaned and thoroughly dried flask was charged freshly prepared l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) ( 25 gm, 0.0656 mol) with diglyme (100 ml) under inert atmosphere at ambient temperature. The reaction mass was stirred for 10 min at same temperature and freshly prepared fused Potassium fluoride (30 gm, 0.516 mol) was charged to the reaction mass at same temperature. Stirred the reaction mass at room temperature for 2 hrs and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (16.33 gm, 0.0656 mol) was charged portion wise in 5 to 6 hrs under stirring. The reaction mass was then stirred for 18 hrs and it was then quenched with saturated ammonium chloride solution (500 ml) below 10°C .Extracted the reaction mass thrice with dichloromethane (200ml ). Combined all organic layer and washed six times with water (100 ml). Dried organic layer over sodium sulphate and evaporated to obtain 35 gms of 1,5 diketo compound of formula C HPLC purity : 98%
Example 3
To a 15 % methanolic ammonia solution (150 ml) was charged 1,5 diketo compound of formula C (25 gm, 0.03968 mol) at ambient temperature and stirred for 18 hrs at to get complete conversion. The methanolic layer was concentrated under reduced pressure and obtained residue was quenched in chilled IN Hydrochloride acid . It was then stirred for 15 min at 20-25°C and extracted thrice with methylene dichloride (50 ml). Combined extract was then washed with water and concentrated to obtain oil. This oil was then dissolved in methyl isobutyl ketone (200 ml) at 50°C and cooled gradually to ambient temperature till complete precipitation of solid. The resulting solid was filtered and washed with methyl isobutyl ketone (50 ml) and dried under vacuum at 50°C to get 20 g of Methyl 1,1,N-trimethylN-(3,3-diphenyl-propyl)-2-aminoethyll,4-dihydro-2,6-dimethyl-4-(3nitrophenyl) -pyridine-,3,5-dicarboxylate HPLC Purity: 99.5%.
10

Example 4
Synthesis of 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester (D)
Method I:
2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (10 gm, 0.40 mol) was suspended in methanol (100 ml) at ambient temperature . To this solution 33% aqueous ammonia solution was added ( 30 ml) below 35°C. The reaction mass was then stirred as such for 24 hrs and quenched with water (200 ml). The resulting solid was filtered and washed with waterand dried to get 9 gm of the titled compound (D). Yield : 90%, HPLC purity : 99% +
Method II :
To the solution of 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (25 gm, 0.10 mol) and methanol ( 100 ml ) ammonium Carbonate (50 gm, 0.52 mol) was added and reaction mass was warmed to 40-50°C. The reaction mass was then kept at same temperature for 6 hrs. Additional amount of ammonium carbonate (50 gm, 0.52 mol) was added and it was kept at same temperature for 18 hrs. Cooled to room temperature and quenched with water (250ml) below 25°C. The resulting solid was filtered washed with water and dried to get 18 gm of compound D. HPLC purity : 98% +
Example 5
3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester (D) (15 gm, 0.0604 mol) andl,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (20.5 gm, 0.059 mol) was stirred in isopropanol at ambient temperature. The reaction mass was then refluxed for 48 hrs and organic layer was evaporated to obtain a brown sticky residue. This residue was stirred with IN Hydrochloric acid solution (200 ml) for 30 min at ambient temperature. It was then extracted thrice with methylene dichloride (250 ml). Combined extract was then washed with water and concentrated to obtain oil. This oil was then dissolved in methyl
11

isobutyl ketone (250 ml) at 50°C and cooled gradually to ambient temperature. It was then stirred for 2 days to get Precipitation of solid. It was then filtered and washed with methyl isobutyl ketone ( 25 ml), weight of Lercanidipine Hydrochloride ( 28 gm ), HPLC Purity: 99.5%.
12

We claim,
1. A process for preparation of lercarnidipine hydrochloride of formula II

N^,

Lercariidipine Hydrochloride (II)
comprising the steps of :-
a) reacting compound of formula A

(A)
b) with compound of formula B to obtain 1, 5 diketo compound of formula C;

OMe
,NOj

c) cyclizing the compound of formula C in presence of an ammonia source
d) quenching the reaction mass with hydrochloric acid; and
e) precipitating lercarnidipine hydrochloride using methyl isobutyl ketone.

2. The process as claimed in claim 1, wherein the said reaction is carried out at a temperature of 25-30°C to reflux temperature of the solvent used.
3. The process as claimed in claim 1, wherein the said reaction is carried out in organic solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ter.butanol or ethers such as diglyme.
13

4. The process as claimed in claim 1, wherein said base is selected from the group comprising inorganic bases such as sodium and potassium alkoxides and organic bases such as diethyl amine, triethyl amine, diisopropyl amine, di-n-propyl amine and piperidine.
5. The process as claimed in claim 1, wherein said ammonia source is selected from the group consisting of alcoholic ammonia, aqueous ammonia, ammonium carbonate, ammonium chloride and ammonium acetate.
6. A process for preparation of lercarnipidine hydrochloride comprising the steps of:
a) reacting the compound of B using ammonia source in an alcoholic solvent at a
temperature of 40-60°C to obtain imine ester of formula D;

OMe (D)
b) cyclizing the compound of formula D with active methylene group of compound of formula A in an alcoholic solvent in presence of catalytic amount of acid source to obtain lercarnidipine hydrochloride.
7. The process as claimed in claim 6, wherein said ammonia source is selected from aqueous ammonia, alcoholic ammonia, ammonium carbonate, ammonium chloride and ammonium acetate.
8. The process as claimed in claim 6, wherein said alcoholic solvent is selected from the group consisiting of methanol, ethanol or isopropanol.
9. The process as claimed in claim 6, wherein said reaction is carried out at temperature of 25-30°C to reflux temperature of the solvent used.
10. The process as claimed in claim 6, wherein said acid source is selected from the group consisting of mineral acids or organic acids.
11. A process for preparation of compound of formula A comprising the steps of:
14

a. reacting N-methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol with 5-
Acetyl-2,2-dimethyl-[l,3]dioxane-4,6-dione in toluene at reflux temperature
for 2-4 hrs;
b. extracting the reaction mass with hydrochloric acid, and discarding the
organic layer
c. extracting the aqueous layer with dichloromethane and concentrating to
isolate compound of formula A.
12. The process for preparation of lercamidipine hydrochloride is substantially as described herein with reference to the description and forgoing examples 1 to 5.
Dated this 23rd day of January 2007

15

ABSTRACT:
Disclosed herein is a simple and efficient process for the synthesis of lercanidipine hydrochloride, wherein 1,1 ,N-trimethyl-N-(3,3 -diphenylpropyl)-2-aminoethylacetoacetate and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester are subjected to a simple Michael addition under mild reaction conditions to obtain 1,5 diketo compound of formula C, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercamidipine in good yield and high purity. The invention further discloses an alternate process for the synthesis of lercanidipine hydrochloride wherein, 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester is converted into 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester by reacting with an ammonia source. 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester undergoes cyclisation with the active methylene group of compound (A) in presence of catalytic amount of acid source to give lercamidipine hydrochloride.
16
COMPETE AFTER PROVISIONAL
LEFT ON 23 JAN 2007
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"An Improved process for the synthesis of 1,4 dihydropyridine 3,5 dicarboxylic
acid derivatives"
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956 (c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be formed.

Technical field of the Invention
The present invention relates to an improved process for the synthesis of 1,4-dihydropyridine-3,5- dicarboxylic acid derivatives like lacidipine, isradipine and more particularly for the synthesis of lercanidipine hydrochloride.
Background of the invention
Dihydropyridine derivatives are well established for prophylaxis and treatment of various cardiovascular diseases. The asymmetrical diesters of l,4-dihydropyridines-3,5-dicarboxylic acid of the general formula I wherein R1,R2,R3 are as defined in the table, were found to be effective as very short-acting, potent and vasoselective antihypertensive agents, useful for intravenous as well as oral administration. Diesters of l,4-dihydropyridines-3,5 dicarboxylic acid of the general formula I are known to be synthesised using Hantzsch synthesis as shown in Scheme-I
o R1 o

Table

Rl R2 R3
p*8 CH3 ^y^^N^&^A C2H5 C2H5

N—0 CH3 (CH3)2CH
Scheme I

-R/R'

Various processes for the synthesis of l,4-dihydropyridine-3,5-dicarboxylic acid derivatives are disclosed in the prior art they are all associated with numerous disadvantages. As the technology evolves, need for an efficient and economical process arises. The present invention provides a simple and efficient process for the synthesis of 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives like lacidipine, isradipine and more particularly for the synthesis of lercanidipine hydrochloride.
3

ij
Lercanidipine Hydrochloride (II)
Lercanidipine Hydrochloride (l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate) of the formula (II) which is a calcium-channel blocker used for the treatment of mild to moderate hypertension. Lercanidipine slows the movement of calcium through cells, which has two results. It decreases the rate at which the heart beats and also has a widening effect on blood vessels. This combination causes blood pressure to be reduced. Lercanidipine causes fewer vasodilatory adverse effects than other calcium-channel blockers. It is also being promoted for the treatment of isolated systolic hypertension (ISH) in elderly patients.
Lercanidipine was first disclosed in patent US4705797, it describes the synthesis as in Scheme-II wherein the aminoalcohol (1) is esterified with diketene to form the corresponding acetoacetate (2), which is further coupled with 3-nitrobenzaldehyde to give l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl -a-acetyl 3-nitrocinnamate (3),which is further cyclised with methyl 3-aminocrotonate.

Lercanidipine Hydrochloride

Scheme-II

4

The process disclosed in the patent has several disadvantages. It employs use of hazardous
material like diketene. The process leads to several by-products in the final step, which
requires cumbersome purification technique like column chromatography. The process
results in Lercanidipine hydrochloride hemihydrate, which is hygroscopic in nature. The
overall yield of the process is 23%. These disadvantages make the process not suitable for
industrial scale up.
Hence there is a need for an industrially suitable process that avoids the use of the hazardous
reagent also eliminates the need for column purification.
WO 9635668 discloses an alternate process (Scheme-Ill) for the synthesis of lercanidipine
hydrochloride

H,COOC
COOH
Lercanidipine Hydrochloride

(4)

(D

Scheme-Ill
which comprises converting (4) to its acid chloride derivative and further reacting it with (1) in aprotic solvent leading to anhydrous lercanidipine hydrochloride which has low hygroscopicity. The disadvantage of this process is that it employs the use of a monocarboxylic acid (4) as a starting material which is not commercially available and the synthesis of this intermediate is difficult, it is prepared by hydrolysis of its diester which also lead to dicarboxylic acid derivative as an impurity and further purification is required to isolate the intermediate (4).
Solution of these problems associated with prior art becomes the objects of the present invention. Hence, the present invention provides industrially viable and economically feasible process thereby eliminating the all the above-mentioned shortcomings.
Summary of the Invention
The present invention provides a simple and efficient process for the synthesis of lercanidipine hydrochloride is described in Scheme-A, wherein the compound of formula A
5

and compound of formula B are subjected to a simple Michael addition reaction leading to a 1,5 diketo compound of formula C, the reaction conditions employed are mild which results in lesser impurity formation and gives a product with high purity. The resulting diketo compound, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercanidipine in good yield and high purity. Lercamidipine is isolated as hydrochloride salt by quenching the residue with chilled hydrochloric acid and precipitated from a ketonic solvent; preferably methyl isobutyl ketone. Scheme A

OMe
Michael Addition Reaction

lj OMe
+ (A)

Lercanidipine Hydrochloride (II)

Scheme- A

The reaction is carried out at a temperature of ambient to reflux temperature of the solvent used. The solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ter.butanol or ethers such as diglyme.
The base is selected from the group comprising inorganic bases such as sodium and potassium alkoxides and organic bases such as diethyl amine, triethyl amine diisopropyl amine, di-n-propyl amine and piperidine.
The ammonia source is selected from the group consisting of alcoholic ammonia, aqueous ammonia, ammonium carbonate ammonium chloride and ammonium acetate.
In another aspect the present invention provides an alternate process for the synthesis of lercanidipine hydrochloride of formula (II) (Scheme A) wherein, the compound of formula (B) is converted to an imine ester of formula (D) in an alcoholic solvent at a temperature of 40-60°C by reacting it with an ammonia source. Compound (D) undergoes cyclisation with the active methylene group of compound (A) in an alcoholic solvent, in presence of catalytic amount of acid source to give Lercanidipine
The ammonia source is selected from aqueous ammonia, alcoholic ammonia, ammonium
carbonate ammonium chloride and ammonium acetate.
The alcoholic solvent is selected from the group consisiting of methanol, ethanol or
isopropanol.
The said reaction is carried out at ambient temperature to reflux temperature of the solvent
used.
As used herein the word 'ambient temperature' means to refer a temperature of 25-30°C.
The acid source is selected from the group consisting of mineral acids or organic acids.
Compound of formula (A) can be prepared following the teaching of US4705797 as shown
below
7

\ //

OH

(A)
Compound of formula A can also be synthesized by using a diketene acetone adduct as
disclosed in the application WO2005107374.
Alternatively compound of formula A can also be prepared using acyl meldrums acid as
shown below
wherein the tert. alcohol (N-methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol) is reacted
with easily available non hazardous acyl meldrums acid (5-Acetyl-2,2-dimethyl-
[l,3]dioxane-4,6-dione) in toluene at reflux temperature to get compound of formula A,
thereby providing a cost effective safe and non hazardous process.

0

Acyl Meldrums Acid

(A)

The following specific examples presented to illustrate the best mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious set forth in the description.
Example 1
5-Acetyl-2,2-dimethyl-[l,3]dioxane-4,6-dione (15 gm, 0.0806 mol) was reacted with N-
methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol (26.4 gm., 0.088 mol ) in toluene (150
8

ml ) at reflux temperature for 2-3 hrs. The reaction mass was then cooled to ambient temperature and extracted twice with IN HC1 (100 ml). The organic layer was discarded and the combined aqueous layer was extracted thrice with dichloromethane (75 ml). Combined organic layer was washed with water (50 ml) and dried over sodium sulphate it was further concentrated to obtain l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) as an brown yellowish oil (30 gm.) having HPLC Purity : 98 %
Example 2 Method I:
To the stirred solution of sodium methoxide (2.12g, 0.04 mol ) in methanol ( 75 ml) kept under stirring was added 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (8.12 gm, 0.033 mol) at ambient temperature under argon atmosphere. Stirred the reaction mass for 10 min and a solution of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (10 gm, 0.0262 mol) prepared in methanol ( 25ml) was charged drop wise in 10 min. Refluxed the reaction mass for 3 hrs and organic layer was evaporated under reduced pressure. The obtained residue was quenched with chilled water (150 ml) below 10°C and extracted thrice with dichloromethane (100ml). Combined organic layer was washed with water (50 ml) dried over sodium sulfate and concentrated to get 12 gms of 1,5 diketo compound of formula C. HPLC purity : 98%
Method II:
To the stirred solution of l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (15 gm, 0.0393 mol) in isopropanol ( 50 ml), diethyl amine (8.7 g, 0.11811 mol) was added at ambient temperature. The reaction mass was then refluxed for 5 hrs and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (9.8 gm, 0.0393 mol) was added to the reaction mass in one lot at reflux temperature. It was then refluxed for 18 hr and organic layer was evaporated to obtain oil. It was then cooled to room temperature and quenched with 2N hydrochloride acid solution (250 ml). The reaction Mass was stirred for 30 min and extracted thrice with dichloromethane (75 ml). Combined extract was washed twice with
9

water (50 ml), dried over sodium sulfate and concentrated to get 20 gm of 1,5 diketo compound of formula C HPLC purity : 98%.
Method III:
To a cleaned and thoroughly dried flask was charged freshly prepared l,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) ( 25 gm, 0.0656 mol) with diglyme (100 ml) under inert atmosphere at ambient temperature. The reaction mass was stirred for 10 min at same temperature and freshly prepared fused Potassium fluoride (30 gm, 0.516 mol) was charged to the reaction mass at same temperature. Stirred the reaction mass at room temperature for 2 hrs and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (16.33 gm, 0.0656 mol) was charged portion wise in 5 to 6 hrs under stirring. The reaction mass was then stirred for 18 hrs and it was then quenched with saturated ammonium chloride solution (500 ml) below 10°C .Extracted the reaction mass thrice with dichloromethane (200ml ). Combined all organic layer and washed six times with water (100 ml). Dried organic layer over sodium sulphate and evaporated to obtain 35 gms of 1,5 diketo compound of formula C HPLC purity : 98%
Example 3
To a 15 % methanolic ammonia solution (150 ml) was charged 1,5 diketo compound of formula C (25 gm, 0.03968 mol) at ambient temperature and stirred for 18 hrs at to get complete conversion. The methanolic layer was concentrated under reduced pressure and obtained residue was quenched in chilled IN Hydrochloride acid . It was then stirred for 15 min at 20-25°C and extracted thrice with methylene dichloride (50 ml). Combined extract was then washed with water and concentrated to obtain oil. This oil was then dissolved in methyl isobutyl ketone (200 ml) at 50°C and cooled gradually to ambient temperature till complete precipitation of solid. The resulting solid was filtered and washed with methyl isobutyl ketone (50 ml) and dried under vacuum at 50°C to get 20 g of Methyl 1,1,N-trimethylN-(3,3-diphenyl-propyl)-2-aminoethyll,4-dihydro-2,6-dimethyl-4-(3nitrophenyl) -pyridine-,3,5-dicarboxylate HPLC Purity: 99.5%.
10

Example 4
Synthesis of 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester (D)
Method I:
2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (10 gm, 0.40 mol) was suspended in methanol (100 ml) at ambient temperature . To this solution 33% aqueous ammonia solution was added ( 30 ml) below 35°C. The reaction mass was then stirred as such for 24 hrs and quenched with water (200 ml). The resulting solid was filtered and washed with waterand dried to get 9 gm of the titled compound (D). Yield : 90%, HPLC purity : 99% +
Method II :
To the solution of 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester (B) (25 gm, 0.10 mol) and methanol ( 100 ml ) ammonium Carbonate (50 gm, 0.52 mol) was added and reaction mass was warmed to 40-50°C. The reaction mass was then kept at same temperature for 6 hrs. Additional amount of ammonium carbonate (50 gm, 0.52 mol) was added and it was kept at same temperature for 18 hrs. Cooled to room temperature and quenched with water (250ml) below 25°C. The resulting solid was filtered washed with water and dried to get 18 gm of compound D. HPLC purity : 98% +
Example 5
3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester (D) (15 gm, 0.0604 mol) andl,l,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethylacetoacetate (A) (20.5 gm, 0.059 mol) was stirred in isopropanol at ambient temperature. The reaction mass was then refluxed for 48 hrs and organic layer was evaporated to obtain a brown sticky residue. This residue was stirred with IN Hydrochloric acid solution (200 ml) for 30 min at ambient temperature. It was then extracted thrice with methylene dichloride (250 ml). Combined extract was then washed with water and concentrated to obtain oil. This oil was then dissolved in methyl
11

isobutyl ketone (250 ml) at 50°C and cooled gradually to ambient temperature. It was then stirred for 2 days to get Precipitation of solid. It was then filtered and washed with methyl isobutyl ketone ( 25 ml), weight of Lercanidipine Hydrochloride ( 28 gm ), HPLC Purity: 99.5%.
12

We claim,
1. A process for preparation of lercarnidipine hydrochloride of formula II

N^,

Lercariidipine Hydrochloride (II)
comprising the steps of :-
a) reacting compound of formula A

(A)
b) with compound of formula B to obtain 1, 5 diketo compound of formula C;

OMe
,NOj

c) cyclizing the compound of formula C in presence of an ammonia source
d) quenching the reaction mass with hydrochloric acid; and
e) precipitating lercarnidipine hydrochloride using methyl isobutyl ketone.

2. The process as claimed in claim 1, wherein the said reaction is carried out at a temperature of 25-30°C to reflux temperature of the solvent used.
3. The process as claimed in claim 1, wherein the said reaction is carried out in organic solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ter.butanol or ethers such as diglyme.
13

4. The process as claimed in claim 1, wherein said base is selected from the group comprising inorganic bases such as sodium and potassium alkoxides and organic bases such as diethyl amine, triethyl amine, diisopropyl amine, di-n-propyl amine and piperidine.
5. The process as claimed in claim 1, wherein said ammonia source is selected from the group consisting of alcoholic ammonia, aqueous ammonia, ammonium carbonate, ammonium chloride and ammonium acetate.
6. A process for preparation of lercarnipidine hydrochloride comprising the steps of:
a) reacting the compound of B using ammonia source in an alcoholic solvent at a
temperature of 40-60°C to obtain imine ester of formula D;

OMe (D)
b) cyclizing the compound of formula D with active methylene group of compound of formula A in an alcoholic solvent in presence of catalytic amount of acid source to obtain lercarnidipine hydrochloride.
7. The process as claimed in claim 6, wherein said ammonia source is selected from aqueous ammonia, alcoholic ammonia, ammonium carbonate, ammonium chloride and ammonium acetate.
8. The process as claimed in claim 6, wherein said alcoholic solvent is selected from the group consisiting of methanol, ethanol or isopropanol.
9. The process as claimed in claim 6, wherein said reaction is carried out at temperature of 25-30°C to reflux temperature of the solvent used.
10. The process as claimed in claim 6, wherein said acid source is selected from the group consisting of mineral acids or organic acids.
11. A process for preparation of compound of formula A comprising the steps of:
14

a. reacting N-methyl-N-(3,3-diphenylpropyl)-l-amino-2-propanol with 5-
Acetyl-2,2-dimethyl-[l,3]dioxane-4,6-dione in toluene at reflux temperature
for 2-4 hrs;
b. extracting the reaction mass with hydrochloric acid, and discarding the
organic layer
c. extracting the aqueous layer with dichloromethane and concentrating to
isolate compound of formula A.
12. The process for preparation of lercamidipine hydrochloride is substantially as described herein with reference to the description and forgoing examples 1 to 5.
Dated this 23rd day of January 2007

15

ABSTRACT:
Disclosed herein is a simple and efficient process for the synthesis of lercanidipine hydrochloride, wherein 1,1 ,N-trimethyl-N-(3,3 -diphenylpropyl)-2-aminoethylacetoacetate and 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester are subjected to a simple Michael addition under mild reaction conditions to obtain 1,5 diketo compound of formula C, which can optionally be isolated, undergoes a simple cyclisation reaction in presence of an ammonia source to give lercamidipine in good yield and high purity. The invention further discloses an alternate process for the synthesis of lercanidipine hydrochloride wherein, 2-(3-Nitrobenzylidene)-3-oxo-butyric acid methyl ester is converted into 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester by reacting with an ammonia source. 3-Imino-2-(3-nitro-benzylidene)-butyric acid methyl ester undergoes cyclisation with the active methylene group of compound (A) in presence of catalytic amount of acid source to give lercamidipine hydrochloride.
16

Documents:

117-mum-2006-abstract (complete).doc

117-mum-2006-abstract (complete).pdf

117-MUM-2006-ABSTRACT(22-11-2012).pdf

117-mum-2006-claims (complete).doc

117-mum-2006-claims (complete).pdf

117-MUM-2006-CLAIMS(AMENDED)-(22-11-2012).pdf

117-MUM-2006-CORRESPONDENCE(1-10-2009).pdf

117-mum-2006-correspondence-received-ver-020207.pdf

117-mum-2006-correspondence-received-ver-200106.pdf

117-mum-2006-correspondence-received-ver-230107.pdf

117-mum-2006-correspondence-received.pdf

117-mum-2006-description (complete).pdf

117-mum-2006-description (provisional).pdf

117-MUM-2006-FORM 1(13-2-2006).pdf

117-MUM-2006-FORM 18(1-10-2009).pdf

117-MUM-2006-FORM 2(TITLE PAGE)-(COMPLETE)-(23-1-2007).pdf

117-MUM-2006-FORM 2(TITLE PAGE)-(PROVISIONAL)-(24-1-2006).pdf

117-MUM-2006-FORM 5(23-1-2007).pdf

117-mum-2006-form-1.pdf

117-mum-2006-form-2 (complete).doc

117-mum-2006-form-2 (complete).pdf

117-mum-2006-form-2 (provisional).pdf

117-mum-2006-form-26.pdf

117-mum-2006-form-3.pdf

117-mum-2006-form-5.pdf

117-MUM-2006-MARKED COPY(22-11-2012).pdf

117-MUM-2006-REPLY TO EXAMINATION REPORT(22-11-2012).pdf

117-MUM-2006-SPECIFICATION(AMENDED)-(22-11-2012).pdf

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Patent Number

256168

Indian Patent Application Number

117/MUM/2006

PG Journal Number

20/2013

Publication Date

17-May-2013

Grant Date

10-May-2013

Date of Filing

24-Jan-2006

Name of Patentee

CIPLA LIMITED

Applicant Address

289, BELLASIS ROAD, MUMBAI CENTRAL, MUMBAI 400 008

Inventors:

#	Inventor's Name	Inventor's Address
1	KANKAN, RAJENDRA NARAYANRAO	A-3/5, N.B.D.SOCIETY, N.S.S ROAD, GHATKOPAR, MUMBAI 400 084
2	RAO, DHARMARAJ RAMACHANDRA	4/403, GARDEN ENCLAVE, POKHARAN ROAD 2, THANE (W) 400 601
3	CHIKHALIKAR, SANDIP VASANT	A-16, 3RD FLOOR, SAMPADA CHS, TELLI-GALLI CROSS LANE, S.N.MARG, S.N.NAGAR, ANDHERI (EAST), MUMBAI 400 069

PCT International Classification Number

C07D211/90

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA