FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(See section 10)
PROCESS FOR THE PREPARATION OF CLEVIDIPINE AND ITS
INTERMEDIATE
CADILA PHARMACEUTICALS LIMITED
"Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad-382210, Gujarat,
India
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a commercially viable process for the preparation of clevidipine and clevidipine intermediate-1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxycarbonyl -3-pyridinecarboxylic acid.
BACKGROUND OF THE INVENTION
Clevidipine is a 1,4-dihydropyridine calcium channel blocker and indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. It was approved by the United States Food and Drug Administration on August 1, 2008.
Clevidipine is chemically named as 4-(2',3'-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl (1-oxybutoxy)methyl ester and is depicted as formula-l:

US Patent No. 5856346 (herein referred to as US '346) discloses a method for the preparation of clevidipine by reacting 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxycarbonyl-3-pyridinecarboxylic acid with chloromethyl butyrate in presence of an alkaline medium. The process of example-3 in US '346 discloses the use of chromatographic purification for crude product using 45% ethyl acetate in isooctane, which is further recrystallized using diisopropyl ether to give clevidipine. The use of chromatographic purification on large scale is cumbersome, time consuming and economically not a viable operation.
WO 00/31035 describes synthesis of 1,4-dihydro-2,6-dimethyl-4-{2',3'-dichorophenyJ)-5-methoxycarbonyl -3-pyridinecarboxylic acid from 2-cyanoethyl methyl 4-(2'3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate by cleavage of 2-cyanoethyl group in presence of an alkaline medium.
There is an unmet need to provide a commercially viable process for the preparation of clevidipine. SUMMARY OF THE INVENTION
The main object of the invention is to provide a commercially viable process for the preparation of clevidipine.
Another object of the invention is to provide a process for the preparation of 1,4-dihydro-2,6-dimethyl-4-(2',3,-dichorophenyl)-5-methoxycarbonyl -3-pyridinecarboxylic acid, a useful intermediate for the preparation of clevidipine.

Yet another object of the invention is to provide a process for the removal of t-butyl group from t-butyl methyl 4-(2',3'-dichlorophenyl)-2,6-dimethy!-1,4-dihydropyridine-3,5-dicarboxylate to provide 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxycarbonyl-3-pyridinecarboxylic acid, which is further converted to clevidipine.
Yet another object of the invention is to provide a process for the purification of clevidipine, which results in cfevidipine having purity >99.5%.
Yet another object of the invention is to provide an improved, commercially scalable and economically viable process for the preparation of clevidipine, without using chromatographic purification at any stage of synthesis.
DESCRIPTION OF DRAWINGS:
Fig. 1 to 3 HPLC chromatogram of Clevidipine obtained by present invention
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of clevidipine and its intermediate, 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxycarbonyl-3-pyridinecarboxylic acid.

In accordance with the present invention, the process involves selective removal of t-butyl ester group from t-butyl methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-

dihydropyridine-3,5-dicarboxylate (Compound of formula 5) to produce 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxycarbonyl-3-pyridinecarboxylic acid (Compound of formula 6). The t-butyl ester group in compound of formula 5 is selectively hydrolyzed to acid without affecting methyl ester group to result compound of formula 6 which is then purified in organic solvent to provide monoacid compound 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxycarbonyl-3-pyridinecarboxylic acid of formula 6 which is substantially free of dicarboxylic acid impurity having formula 8. The dicarboxylic acid impurity is difficult to removal

The present invention provides 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxycarbonyl-3-pyridinecarboxylic acid of formula 6 having purity over 99%. The 3-pyridinecarboxylic acid compound of formula 6 is further reacting with chloromethyl butyrate of formula 7 using organic solvent and in presence of a base provides Clevidipine.
The selective hydrolysis is carried out using an organic and/or inorganic acid(s) in an organic solvent or mixture of organic solvents. The acid is selected from organic acid{s) such as acetic, benzenesulfonic, ethanesulfonic, formic, p-toluenesulfonic acid; inorganic acid(s) such as hydrochloric, sulfuric, halosulfuric, halosulfonic, alkyl or aryl sulfonic acid(s) alone or in combination with each other.
The acid is used along with an organic solvent or mixture of organic solvents selected from esters, ketones, ethers. The ester solvent is preferred and selected from ethyl acetate, propyl acetate, butyl acetate. The selective hydrolysis is carried out optionally in an aqueous organic solvent. The suitable acid(s) is not limited to hydrochloric acid, sulfuric acid, formic acid or mixtures of formic acid with a mineral acid. Advantageously, a mixture of sulfuric acid and ethyl acetate is employed for selective hydrolysis.
In yet another embodiment, the present invention also relates to provide 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxycarbonyl-3-pyridinecarboxylic acid as a key intermediate for the preparation of clevidipine as well as process of preparing of the same. 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxycarbonyl-3-pyridinecarboxylic acid as key intermediate for preparing clevidipine is having HPLC purity at least about 98%.

Preferably, the HPLC purity is at least about 99%. Advantageously the acid compound is having purity more than 99% which in turn results Clevidipine having purity more than 99%.
Solvents to be used for 'the purification of 1,4-dihydro-2,6-dimethyl-4-(2,,3'-dichorophenyl)-5- methoxycarbonyl -3-pyridinecarboxylic acid are not particularly limited to any specific solvents. The suitable solvents include organic solvents. The organic solvent is selected from ketones such as acetone, methyl ethyl ketone,2-pentanone,3-pentanone methyl isobutyl ketone; alcohols such as methanol, ethanol, 2-propanol; esters such as ethyl acetate, n-buty) acetate; amides such as DMF; DMSO; chlorinated solvent such as methylene chloride; hydrocarbons such as n-hexane, cyclohexane; ethers such as , diethylether, diisopropyl ether, methyethyl ether, methyl tert butyl ether and like. The preferred solvent used for the purification of 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5- methoxycarbonyl -3-pyridinecarboxylic is ketonic solvents more preferably acetone.
The present invention also provides the process for the preparation of crude clevidipine by reaction of 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxycarbonyl -3-pyridinecarboxylic acid with chloromethyl butyrate in presence of a base in an organic solvent. The base used for the reaction is selected from carbonates and bicarbonates of alkali and alkaline earth metal. The preferred base is bicarbonates wherein sodium bicarbonate or potassium bicarbonate is used. The organic solvent used for the esterification reaction is selected from ketones such as acetone, methyl ethyl ketone,2-pentanone,3-pentanone methyl isobutyl ketone; alcohols such as methanol, ethanol, 2-propanol; esters such as ethyl acetate, propyl acetate, butyl acetate; amides such as DMF; DMSO;. The preferred organic solvent is selected from DMF or DMSO.
The crude clevidipine is further purified by dissolving in a solvent and crystallizing the product using an anti-solvent. The admixing may be done in any order, for example, the anti-solvent may be added to the solution, or alternatively, the solution may be added to the anti-solvent. When the hot solution is added to the anti-solvent, the temperature difference causes the rapid crystallization. The solution may be added drop-wise or in one lot which may cause gradual cooling to allow the crystallization of pure Clevidipine.
The solvent is selected from the group consisting of chlorinated solvents such as dichloromethane; alcohols such as C1-4 alkyl alcohols; esters such as ethyl acetate, propyl acetate, butyl acetate; aromatic hydrocarbons such as benzene, toluene, xylene; ketones such as acetone, methyl ethyl ketone; hydrocarbons such as n-hexane, cyclohexane. Preferably the first solvent is selected from the group consisting of: chlorinated solvent or esters. Preferably, the first solvent is selected from dichloromethane and/or ethyl acetate.
The anti-solvent is selected from the group consisting of C3-6 ketones, C3-6 ethers, nitriles such as acetonitrile, C3-7 straight and cyclic hydrocarbons, C6-12 aromatic hydrocarbons. Preferably, the anti-solvent is selected from diisopropyl ether and/or n-

hexane. The pure clevidipine of the present invention has HPLC purity of at least about 98%. Preferably, the HPLC purity is at least about 99%, more preferably at least about 99.5% or >99.5%. The resulting clevidipine according to present invention is having HPLC purity 99.5% or more.
According to present invention, tert-butyl methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate of formula 5 is prepared by the process known in the art. The synthetic scheme for the preparation of compound of formula 5 is depicted in scheme 1. The invention is illustrated by the following non-limiting examples:
Example-1: Preparation of 1,4-dihydro-2,6-dimethyi-4-(2\3'-dichorophenyl)-5-methoxycarbonyl-3-pyridinecarboxylic acid
350 gm of tert-butyl methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was added to a cooled mixture of concentrated sulfuric acid in ethyl acetate at low temperature. The reaction mass was stirred and quenched in crushed ice and water. The reaction mass was filtered and washed with water. The wet cake was stirred with 300ml acetone at about 50°C for about 30 minutes. The reaction mass was cooled, filtered and washed with acetone. The wet cake was dried under pressure to provide title compound. (Wt=120 gm, Purity over 99% by HPLC)
Example-2: Preparation of 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichlorophenyl)-5-methoxycarbonyl3-pyridine carboxylic acid.
100 gm of tert-butyl-4-{2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was added to a cooled mixture of 400 ml con. Sulfuric acid in 300 ml ethyl acetate and reaction mass stirred at 10-15°C and quenched in crushed ice and water. The reaction mass was filtered and washed with water. The wet cake was stirred with 300 ml acetone at 45-50°C. The reaction mass was cooled, filtered and washed with acetone (50 ml), wet cake was dried under vacuum to provide title compound. (Wt=35 gm Purity > 99 %)
Example-3: Preparation of [1,4]-dibydro-2,6 dimethyl-4-(2',3'-dichlorophenyl)-5-methoxycarbonyl3-pyridine carboxylic acid.
350 gm of tert-butyl methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was added to a cooled mixture of concentrated sulfuric acid in ethyl acetate at 0°C. The reaction mass was stirred and quenched in crushed ice and water. The reaction mass was filtered and washed with water. The wet cake was purified by 500 ml ethylacetate and wet cake was dried under vacuum to provide title compound. Wt=42 gm

Example-4: Preparation of [1,4]-dihydro-2,6 dimethyl-4-(2',3'-dichlorophenyl)-5-methoxycarbonyl3-pyridine carboxylic acid.
100 gm of tert-butyl4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate was added to a cooled mixture of .400 ml conc. Sulfuric acid in ethyl acetate (200 ml) at 0-5°C and stirred for 1 hour. After completion of reaction, reaction mixture was quenched in crushed ice and water. The reaction mass was filtered and washed with water. The wet cake was stirred with 150 ml methanol at RT for about 30 minute. The reaction mass was filtered, washed with methanol (10 ml), if required the product is further purified to yield title compound in desired purity.
Example-5: Preparation of Clevidipine:
100 gm of 1,4-dihydro-2,6-dimethyl-4-(2',3,-dichorophenyl)-5-methoxycarbonyl-3-pyridinecarboxylic acid and 35.4 gm of Sodium bicarbonate is stirred in DMF under nitrogen atmosphere. 49.9 gm of Chloromethyl butyrate was added and reaction mixture was heated at about 80°C for 4 hrs. The solvent was distilled out and residue was treated with methylene chloride. The obtained reaction mass was washed with water and the methylene chloride layer was dried over sodium sulphate. Methylene chloride was distilled out under vacuum. Diisopropyl ether (800 ml) was added to the residual mass and stirred at 25-30°C for one hour. The reaction mass was filtered, the wet cake was washed with diisopropyl ether to give crude clevidipine (Wt. = 97.5 gms HPLC Purity > 99%).
Example-6: Preparation of Clevidipine
1,4-dihydro-2,6 dimethyl-4-(2',3'-dichlorophenyl)-5-methoxycarbonyl3-pyridine carboxylic acid (25 gm) and NaHC03(11.77 Gm) were stirred in N,N-dimethyl formamide(200 ml). Under nitrogen atmosphere chloromethyl butyrate(12.42 gm) was added and the reaction mixture was heated at 75-80°C for 4 hours. The solvent was distilled out and the residue was treated with dichloromethane. The obtained reaction mass was washed with water and dichloromethane layer was dried over sodium sulfate.The dichloromethane was distilled under vacuum. The crude material was purified in ethyl acetate:n-hexane (32 gm) and dried to yield title compound. Wt= 19.10 gm
Example-7: Preparation of Clevidipine
1,4-dihydro-2,6 dimethyl-4-(2',3'-dichlorophenyl)-5-methoxycarbonyl3-pyridine carboxylic acid (20 gm) and NaHCO3(9.40 Gm) were stirred in N,N-dimethyl formamide (160 ml). Under nitrogen atmosphere chloromethyl butyrate (9.96 gm) was added and the reaction mixture was heated at 50-55°C for15 hours. After completion of the reaction, the solvent was

distilled and the residue was treated with dichloromethane. The obtained reaction mass was washed with water and dichloromethane layer was dried over sodium sulfate and distilled under vacuum. The crude material was purified in toluene and dried to yield title compound. Wt=15.4gm
Example-8: Preparation of Clevidipine
1,4-dihydro-2,6 dimethyl-4-(2',3'-dichlorophenyl)-5-methoxycarbonyl3-pyridine carboxylic acid (20 gm) and NaHCO3(9.40 Gm) were stirred in N,N-dimethyl formamide (160 ml). Under nitrogen atmosphere chloromethyl butyrate (9.96 gm) was added and the reaction mixture was heated at 90-95°C for 4 hours. After completion of the reaction, the solvent was distilled and the residue was treated with dichloromethane. The obtained reaction mass was washed with water and dichloromethane layer was dried over sodium sulfate and distilled under vacuum. The crude material was purified in Dichloromethane.Diisopropyl ether (3 : 5) and dried to yield title compound. Wt= 19 gm
Example-9: Purification of crude Clevidipine:
100 gm of crude clevidipine was dissolved in 300 ml MDC at 25-32°C. 1500 ml of DIPE was added to this solution. The reaction mass is stirred for two hour. The product is filtered, washed with DIPE and then dried under vacuum to give pure clevidipine (Wt= 85 gm, HPLC purity more than 99.5 %)
Example-10: Purification of crude Clevidipine:
The crude clevidipine (85 gms) was dissolved in dicholoromethane at ambient temperature. The reaction mass is filtered through hyflow bed.. The residue is washed with dichloromethane followed by washing with DIPE. The wet cake is dried under vacuum to give pure clevidipine (Wt= 63 gm, HPLC purity over 99.8 %)
The pure clevidipine obtained according to the present invention has HPLC purity of at least about 98%. Preferably, the HPLC purity is at least about 99%, more preferably at least about 99.5% or >99.5%. The HPLC chromatogram of clevidipine obtained by above exemplified process of the invention is presented as figure 1 -3.

We claim,
1. A process for preparation of 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-
methoxy carbonyl-3-pyridinecarboxylic acid comprising:
a. reaction of tert-butyl methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-dicarboxylate with an acid in organic solvent;
b. treating the reaction mixture with water,
c. separating the 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxy
carbonyl-3-pyridinecarboxylic acid,
d. purifying the product to give pure 1,4-dihydro-2,6-dimethyl-4-(2',3'-
dichorophenyl)- 5-methoxycarbonyl 3-pyridinecarboxylic acid.
2. The process as claimed in claim 1, wherein the acid is selected from organic acid(s) such as acetic, benzenesulfonic, citric, ethanesulfonic, fumaric, formic, succinic, p-toluenesulfonic acid; inorganic acid(s) such as hydrohaloic, phosphoric, sulfuric, halosulfuric, halosulfonic, halophosphoric, polyphosphoric, sulfamicacid, alkyl or aryl sulfonic acid(s) alone or in combination with each other.
3. The process as claimed in claim 2, wherein the acid is sulfuric acid.
4. The process as claimed in claim 1, wherein the solvent is selected from esters, ketones, ethers or mixtures thereof.
5. The process as claimed in claim 4, wherein the organic solvent is selected esters such as ethyl acetate, propyl acetate, butyl acetate and like.
6. The process as claimed in claim 1, wherein the purification is carried out using ketonic solvent such as acetone, methylethyl ketone,2-pentanone,3-pentanone methyl isobutyl ketone, and like.
7. A process for preparing Clevidipine comprising:

(a) selective hydrolysis of tert-butyl methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate with acid to obtain 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)-5-methoxy carbonyl-3-pyridinecarboxylic acid; and
(b) reacting 1,4-dihydro-2,6-dimethyl-4(2,3'-dichorophenyl)-5-methoxy carbonyl-3-pyridinecarboxylic acid to Clevidipine

8. The process as claimed in claim 7 wherein crude clevidipine is further purified by dissolving in a solvent and crystallizing the product using an anti-solvent.
9. The process as claimed in claim 1 or 8 wherein 1,4-dihydro-2,6-dimethyl-4-(2',3'-dichorophenyl)- 5-methoxycarbonyl 3-pyridinecarboxylic acid is having purity over 99%.

10. The process as claimed in claim 8 which is resulting pure clevidipine having HPLC purity over 99.5%.