FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(See section 10)
AN IMPROVED 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 process for the preparation of clevidipine intermediate-(butanoyloxy) methyl (2Z)-2-(2,3-dichiorobenzylidene)-3-oxobutanoate and its conversion to clevidipine.
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'-dichorophenyl)-5-methoxycarbonyl -3-pyridinecarboxyiic 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.
The commercially viable process for the preparation of (Butanoyloxy)methyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate (herein referred as Intermediate A) and methyl (2E)-3-aminobut-2-enoate (or) methyl 3-amino crotonate (herein referred as Intermediate - B) are not known which could lead to cost effective production of clevidipine at commercial scale.


(Butanoyloxy)methyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate
(Intermediate-A)

Methyl (2E)-3-aminobut-2-enoate
or
Methyl 3-amino crotonate (Intermediate - B)
Therefore, there is an unmet need to provide a process for the preparation of clevidipine intermediate as described above which could lead to cost effective commercial production of Clevidipine.
SUMMARY OF THE INVENTION
The main object of present invention is to provide novel process for the preparation of (Butanoyloxy) methyl (2Z)-2-(2,3-dich(orobenzylidene)-3-oxobutanoate (Intermediate A).
Another object of present invention is to provide cost effective process for the preparation of Clevidipine comprising the preparation of (Butanoyloxy) methyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate (Intermediate A).
Yet another object of the invention is to provide a process for the preparation of an improved, commercially scalable and economically viable process for the preparation of clevidipine.
Yet another object of the present invention is to provide a process for the preparation of clevidipine comprising reaction of (Butanoyloxy) methyl (2Z)-2-(2,3-dichiorobenzylidene)-3-oxobutanoate with commercially available alkyl acetoacetate.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of (butanoyloxy) methyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate (Intermediate A) and further converted to clevidipine. The process for preparing clevidipine is depicted as scheme 1.

In accordance with the present invention, the process for the preparation of. Intermediate A and its conversion to clevidipine comprising steps of:
(a) reacting tert-butyl acetoacetate of formula 2 and 2,3-dichlorobenzaldehyde In an organic solvent using a catalyst followed by filtering, washing and drying to provide tert-butyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate of formula 3, optionally purifying the product formed;
(b) reacting the 3-oxobutanoate of formula 3 with an acid to provide (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoic acid of formula 4;
(c) reacting the 3-oxobutanoic acid of formula 4 with chloromethyl butyrate of formula 5 in organic solvent using a base to provide (butanoyloxy) methyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate of formula 6;

(d) reacting the (butanoyloxy) methyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate of formula 6 with methyl-3-amino crotonate of formula 7 in an organic solvent to provide crude clevidipine
(e) the crude clevidipine is further purification to give pure clevidipine
In yet another embodiment, the present invention also provides the process for the preparation of (butanoyloxy) methyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate (Intermediate A of formula 6), which is further used to prepare clevidipine yielding high purity.
The solvent used in step-(a) is selected from the group comprising aromatic hydrocarbons such as toluene, benzene, xylene; cycloalkanes such as cyclohexane, C1 to C5 aliphatic alcohols such as methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, n-pentanol. The preferred solvent is 2-propanol, toluene, benzene, xylene; more preferably 2-propanol or toluene
The catalyst used in step -(a) comprises acetate salts of amines selected from the group comprising of piperidine or alkylpiperidine acetate, morpholine or alkylmorpholine acetate, piperazine or alkylpiperazine acetate, pyrrolidine or alkylpyrrolidine acetate and like. The catalyst used for in the present invention is preferably piperidine acetate. The alkyl radicals in the catalysts have preferably 1-4 carbon atoms. The catalyst used in step - (a) is in amount of 0.01 to 0.7 M per mole of 2,3-dichiorobenzaldehyde. While using aromatic hydrocarbons as solvents, the water formed during the reaction can be removed using Dean-Stark apparatus. Molecular sieve and dehydrating agents can be also successfully used. tert-Butyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate of formula 3 is optionally purified using alcohol or using mixture of alcohol and water.
The hydrolysis in step-(b) is carried out using organic and/or inorganic acid(s) in water and/or organic solvents. The suitable acid(s) is selected but not limited to hydrochloric acid, phosphoric acid, sulfuric acid, formic acid, alkyl or aryl sulfonic acid alone or in combination with each other. The acid is used in water and/or in various organic solvents such as esters, ketones, ethers and like. The reaction mass obtained in step - (b) is quenched in water. The obtained product (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoic acid of formula 4 is separated, stirred with water, filtered and optionally stirred with hexane or diisopropyl ether or cycloalkane preferably hexane and dried under vacuum. The product obtained is having HPLC purity >98 %.
The organic solvent(s) used in step-(c) is selected from the group consisting of aromatic hydrocarbons such as benzene, toluene, xylene; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers such as THF, 2-methyl THF, dioxane, diethyl ether, dipropyl ether, monoglyme, dibutyl ether; amide solvents such as N,N-dimethyl formamide, N-methyl 2-

pyrrolidone, N,N-dimethyl acetamide, 1,3-dimethyl ethylene urea, 1,3- dimethyl propylene urea, N,N,N',N'-tetramethyl urea; dimethyl sulfoxide, sulfolane, benzotrifluoride and like.
The base used in step-(c) is selected from the group comprising of carbonates and bicarbonates of alkali metal such as NaHCO3, KHC03, Na2C03, K2C03, Li2C03, Cs2C03; organic tertiary amines such as dimethyl aniline, diethyl aniline, trialkyl amines and like. The trialkyl amine is having C1 to C4 carbon atom in alkyl group. The iodide compounds such as Nal or Kl can be optionally added as catalyst to rapid the reaction.
On completion of the reaction in step - (c), the solvent is distilled and the mass is taken up In water-immiscible organic solvent, washed with water followed by separating the organic layer and the solvent is removed to provide (butanoyloxy)methyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate of formula 6 as an oil.
The solvent used in step-(d) is selected from the group comprising of C1 to C5 alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, tert. butanol, pentanol and fike. On completion of the reaction in step - (d), the solvent used in the reaction is evaporated to provide a thick oily mass which is further purified to provide pure clevidipine.
In another embodiment of the present invention, (butanoyloxy)methyl (2Z)-2-(2,3-dich!orobenzylidene)-3-oxobutanoate is converted to 2-(2,3-dichloro-benzylidene)-3-iminobutyricacid butryloxymethyl ester which can be reacted with methyl acetoacetate to provide clevidipine.

The invention is illustrated by the following non-limiting examples:
Example 1: Preparation of tert-butyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate
100 gm of 2,3-dichloro benzaldehyde, 117.2 gm of tert. Butyl acetoacetate, 4.85 gm of piperidine and 3.42 gm of acetic acid were taken together in isopropyl alcohol and stirred at 25-35°C. The reaction mass was cooled and stirred at low temperature for about 1 hour. The obtained mass was filtered, washed with chilled IPA : water and dried in vacuum oven at about 50°C temperature and 1-10mm/Hg pressure to give titfed compound. (Wt.= 140-155 gm)

Example 2: Purification of tert-butyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoata
tert-butyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate (100 gm) was dissolved in hot IPA and cooled up to 30°C. The reaction mass was diluted with water and stirred for an hour at ambient temperature. The reaction mass was filtered, washed with IPA:water mixture and dried in vacuum. (Wt. = 88-92 gm HPLC Purity >99%)
Example 3: Preparation of (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoic acid
tert-butyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate (100 gm) was added to a mixture of water (200 ml) and concentrated sulfuric acid and stirred at low temperature for about 1 hour. The reaction mass was poured into crushed ice and stirred at 0 to 10°C for about 15 minutes. The reaction mass was filtered and washed with water. The wet cake was stirred with water, filtered and washed with water. The obtained product was stirred with hexane, filtered and dried under vacuum. (Wt. = 80-83 gm, HPLC purity >98%)
Example 4: Preparation of (butanoyloxy) methyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate
(2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoic acid (50 gm) was added to dimethyl formamide (400 ml) and sodium bicarbonate (32.4 gm), heated gradually to 75-80°C and cooled at about 45°C. chloromethyl butyrate was added to the reaction mass and stirred at 45-50°C for about 3 hours. The solvent was distilled out at 60-70°C under vacuum, the oily mass was taken up in ethyl acetate and the organic layer was washed with water. The organic layer was dried and distilled to give titled product as thick oily mass. (Wt.= 58-62 gm)
Example 5: Preparation of Clevidipine
(Butanoyloxy) methyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate (60 gm), pyridine (1.75 gm), Methyl 3-amino crotonate (15.43 gm) and 2-propano! (240 ml) were mixed and stirred at about 45-50°C for 24 hours. The solvent was removed from the reaction mass under vacuum at 45-50°C. Crude clevidipine was obtained as thick oil. (Wt. = 48-52 gm).
Example 6: Purification of Clevidipine.
The crude clevidipine was purified by column chromatography using Ethyl acetate: hexane (1:9) as mobile phase to give pure clevidipine. (Wt. = 25-30 gm HPLC Purity = 99.7%)

We claim :
1 A process for the preparation of clevidipine comprising steps:
(a) reacting tert-butyl acetoacetate of formula 2 and 2,3-dichlorobenzaldehyde in an organic solvent using a catalyst followed by filtering, washing and drying to provide tert-butyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate of formula 3, optionally purifying the product;
(b) reacting the tert-butyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate of formula 3 with an acid to provide (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoic acid of formula 4;
(c) reacting the (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoic acid of formula 4 with chloromethyl butyrate of formula 5 in organic solvent using a base to provide (butanoyloxy) methyl (2Z)-2-(2,3-dich!orobenzylidene)-3-oxobutanoate of formula 6;
(d) reacting the (butanoyloxy) methyl (2Z)-2-(2,3-dichlorobenzylidene)-3-oxobutanoate of formula 6 with methyl-3-amino crotonate of formula 7 in organic solvent to provide crude clevidipine
(e) the crude on chromatographic purification yielding pure clevidipine.
2 The process as claimed in claim 1, wherein the solvent used in step-(a) is selected from the group comprising of aromatic hydrocarbons such as toluene, benzene, xylene; cycloalkanes such as cyclohexane, C1 to C5 aliphatic alcohols such as methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, n-pentanol.
3. The process as claimed in claim 1, wherein the catalyst used in step-(a) is selected from acetate salts of amines selected from the group comprising of piperidine or alkylpiperidine acetate, morphoiine or alkylmorpholine acetate, piperazine or alkylpiperazine acetate, pyrrolidine or alkylpyrrolidine acetate and like.
4 The process of claim 4, wherein the catalyst used in step - (a), is in amount of 0.01 to 0.7 M per mole of 2,3-dichlorobenzaldehyde.
5 The process as claimed in claim 1, wherein the product formed in step-(a) is optionally purified using alcohol or using mixture of alcohol and water.
6 The process as claimed in claim 1, wherein the acid used in step-(b) is selected from hydrochloric acid, phosphoric acid, sulfuric acid, formic acid, alkyl or aryl sulfonic acid or mixtures thereof.
7 The process of claim 7, wherein the preferred acid is sulfuric acid; more preferably the reaction of step-(b) is carried out in aqueous sulfuric acid.

8 The process as claimed in claim 1, wherein the solvent used in step-(c) is selected from (i) aromatic hydrocarbons such as benzene, toluene, xylene; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers such as THF, 2-methyl THF, dioxane, diethyl ether, dipropyl ether, monoglyme, dibutyi ether; amide solvents such as N,N-dimethyl formamide, N-methyl 2-pyrrolidone, N,N-dimethyl acetamide, 1,3-dimethy! ethylene urea, 1,3- dimethyl propylene urea, N,N,N',N'-tetramethyl urea; dimethyl sulfoxide, sulfolane, benzotrifluoride , preferably amide group of solvents described hereinabove and (ii) the base is selected from the group comprising of carbonates and bicarbonates of alkali metal such as NaHC03, KHC03, Na2C03, K2C03, Li2C03, Cs2C03; organic tertiary amines such as dimethyl aniline, diethyl aniline, trialkyl amines..
9 The process as claimed in claim 1, wherein the organic solvent used in step-(d) is selected from C1 to C5 alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, sec-butanol, tert. butanol, pentanol; preferably 2-propanol.
10. The process as claimed in claim 1, wherein the purification of clevidipine in step (d) is carried out using Ethyl acetate: hexane (1:9 v/v).