FIELD OF INVENTION

The present invention relates to a facile and cost-effective process for the preparation of an ester compound which is a key raw material in the preparation of a veterinary drug Pimobendane. In particular it relates to a process for the preparation of methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxo-butanoate.

BACKGROUND OF THE INVENTION

Pimobendane having chemical name (/tS)-6-[2-(4-methoxyphenyl)-l//-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2//)-one of formula I, is one of the new inotropic and vasodilating agents with phospho diesterase-inhibiting properties.

There are number of literatures available which describe the process for preparation of Pimobendane using methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxo-butanoate as starting material. US 4361563 describes a process for the preparation of pimobendane using methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxo-butanoate as given in the below scheme-1:

But the preparation of this key raw material, methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutanoate is very scarcely reported in the literature.

Thus there is a need to develop a facile and economical process which will give methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutanoate in high purity and high yield.

SUMMARY OF THE INVENTION

Accordingly, the main aspect of the invention is to provide a process for the preparation of methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutanoate of formula V comprising the steps of:

a) reacting 2-nitro acetanilide of formula IX with alkanoyi chloride to form N-^T-nitro-4'-propionylphenyI)acetamide of formula VIII;

b) reacting N-(2'-nitro-4'-propionylphenyl)acetamide with haloester or with a halonitrile to form 4-(4'-acetylamino-3'-nitro-phenyl)-3-methyl-4-oxobutyric acid ethylester of formula VII;

c) hydrolysing the ester of formula VII obtained in step (b) using an acidic reagent to form 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutyric acid of formula VI; and

d) esterifying the acid of formula VI using an alcoholic solvent to obtain methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutanoate of formula V.

The process of the present invention may be illustrated by the below scheme-2:
Scheme-2

Where R= COOEt or CN

Another aspect of the invention is to provide a process for the preparation of methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutanoate of formula V comprising the steps of:

a) reacting acetanilide of formula XI with an alkanoyl chloride to form iV-(4'-propionylphenyl)acetamide of formula X;

b) nitrating Ar-(4'-propionylphenyl)acetamide of formula X to form jV-(2'-nitro-4'-propionylphenyl)acetamide of formula VIII;

c) reacting A'-(2'-nitro-4'-propionylphenyI)acetamide with haloester or with halonitrile to form 4-(4'-acetylamino-3'-nitro-phenyl)-3-methyl-4-oxobutyric acid ethylester of formula VII;

d) hydrolysing the ester of formula VII obtained in step (c) to form 4-(4>-amino-3'-nitro-phenyl)-3-methyl-4-oxo-butyric acid of formula VI; and

e) esterifying 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxo-butyric acid of formula VI obtained in step (d) to form methyl 4-(4'-arnino-3'-nitro-phenyl)-3-methyl-4-oxobutanoate of formula V.

The process of the present invention may be illustrated by the below scheme-3:

Where R = COOEtorCN

Another aspect of the invention is to provide a process for the preparation of Pimobendane comprising the steps of:

i. condensing methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutyrate of
formula V with 4-methoxybenzoyl chloride to form compound of formula IV;

ii. reacting compound of formula IV with hydrazine hydrate to form compound of formula III;

iii. reducing compound of formula III to form compound of formula II; and

iv. cyclising the compound of formula II with an acid and a reagent to form Pimobendane of formula I;

DETAIL DESCRIPTION OF THE INVENTION

In an embodiment of the invention, the reaction in step (a) in both processes illustrated in scheme 2 and scheme 3, is carried out in presence of alkanoyl chloride preferably propanoyl chloride, reagent such as aluminum trihalide preferably aluminium trichloride and in presence of a solvent preferably halogenated solvent more preferably monochlorobenzene (MCB).

In another embodiment the nitration in step (b) of the scheme 3 is carried out in acetic acid medium in presence of a mixture of mineral acid and nitric acid, preferably concentrated sulphuric acid and nitric acid.

In yet another embodiment of the present invention, the compound of formula VIII is reacted with a haloester such as ethyl halo acetate selected from ethyl bromo acetate, ethyl chloro acetate or a halonitrile, preferably chloro acetonitrile, in presence of a base such as potassium hydroxide, sodium hydroxide preferably potassium hydroxide and an alcoholic solvent preferably methanol.

In another embodiment of the invention, the hydrolysis is carried out in presence of a proton source.

In another embodiment of the invention, esterification is carried out in presence of an alcoholic solvent selected from methanol, ethanol or propanol, preferably methanol and a proton source.

In yet another embodiment of the invention, the condensation in step (i) is carried out in presence of an aromatic organic compound such as benzene, toluene and monochlorobenzene preferably monochlorobenzene and preferably at reflux temperature.

In another embodiment of the invention, the reaction in step (ii) is carried out preferably in presence of hydrazine hydrate.

In another embodiment of the invention, the reduction in step (iii) is carried out using a reducing agent selected from Raney nickel, Palladium on carbon or Platinum, preferably Palladium on carbon.

In another embodiment of the invention, the step (iv) is carried out in presence of an acid, preferably organic acid, more preferably acetic acid.

The present invention is illustrated with the following non-limiting examples.

Example 1: Preparatiou of methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutanoate

A. A'-(2'-Nitro-4'-propionylpheayl)acetamide

300 ml of MCB was taken in an RBF. 222g of aluminium chloride was added slowly with stirring at room temperature. Reaction mixture was cooled to 0°C and 103 g of propionyl chloride was added. Subsequently reaction mixture was stirred for ten minutes. 100g of O-Nitroacetanilide in a solution of 500 ml of MCB was added over a period of one hour. After reaction completed reaction mixture was quenched into 1.4 1 of 15% HC1 at below 5°C. After quenching, temperature of the slurry was raised to room temperature and layers were separated. Aqueous layer was washed with 200 ml X 2 MDC. Combined organic layers were concentrated to 200ml and chilled get 105g of N-(2'-nitro-4'-propionylphenyl)acetamide.

B. 4-(4'-AcetyIamino-3'-nitro-phenyl)-3-methyl-4-oxobutyric acid ethylester

100g of N-(2'-nitro-4'-propionylphenyl)acetamide was dissolved in 300 ml of methanol. 25.76g of pottsssium hydroxide dissolved in 100 ml of methanol is added to N- (2'-nitro-4'-propionylphenyl)acetamide solution slowly at 10°C over one hour. The reaction mixture was stirred at 10°C for one hour more. To the above reaction mixture 76.82g of ethylbromoacetate dissolved in 100 ml of methanol was added dropwise at 10°C. Afterwards the reaction mixture was raised to a temperature of 30°C. Reaction mixture was further stirred at 30°C for two hours. After reaction completion, reaction was neutralized with 10% HC1 and methanol was evaporated. From the aqueous solution the product was extracted with 500 ml of MDC. MDC layer was evaporated to get sufficiently pure material which could be used in next stage.

C. 4-(4'-Amino-3'-nitro-phenyl)-3-methyl-4-oxobutyric acid

80g of ethyl 4-[4'-(acetylamino)-3'-nitrophenyl]-3-methyl-oxobutanoate was mixed with 200ml of 10% HC1 solution. The reaction mixture was refluxed for one hour. After the reaction is completed reaction mixture was neutralized with sodium hydroxide solution. Product was extracted with 200 ml X 2 MDC. The MDC layer was evaporated to get 4-(4'-amino-3'-nitrophenyl)-3-methyl-4-oxobutanoicacid

D. Methyl 4-(4'-amino-3'-nitro-phenyI)-3-methyI-4-oxobutanoate

A mixture of 30g of 4-(4'-amino-3'-nitrophenyl)-3-methyl-4-oxobutanoicacid and 50 ml of absolute methanol were taken in a round bottomed flask. 2.7 ml of concentrated sulphuric acid was added. The reaction mixture was boiled till reaction is completed (4 hours). After the reaction is complete, methanol was distilled off. Water was added to the residue and the product was extracted with MDC. MDC was washed with water and evaporated to get methyl 4-(4'amino-3'-nitrophenyl)-3-methyl-4-oxobutanoate.

Example 2. Preparation of methyl 4-(4'-amino-3'-nitro-phenyI)-3-methyI-4-oxobutanoate A. N-(4'-PropionyIphenyI)acetamide

300 ml of MCB was taken in an RBF. 217.34g of aluminium chloride was added slowly with stirring at room temperature. Reaction mixture was cooled to OoC and 75.31 g of propionyl chloride was added. Subsequently reaction mixture was stirred for ten minutes. 100g of acetanilide in a solution of 500 ml of MCB was added over a period of one hour. After reaction completed reaction mixture was quenched into 1.4 1 of 15% HC1 at below 5oC. After quenching, temperature of the slurry was raised to room temperature and layers were separated. Aqueous layer was washed with 200 ml X 2 MDC. Combined organic layers were concentrated to 200ml and chilled get 113g of N-(4'-propionylphenyl)acetamide.

B. N-(2'-Nitro-4'-propionyIphenyl)acetamide

100g of N-(4'-propionylphenyl)acetamide was taken in 100 ml of glacial acetic acid. Stir the reaction mixture for 30 minutes. Subsequently the reaction mixture was cooled to 5oC. 190 ml of nitrating mixture containing 150 ml of sulphuricacid and 40 ml of nitric acid was added dropwise. After the addition is over, reaction mixture brought to a temperature of 25oC and stirred there for 1 hour. Afterwards the reaction mixture was extracted with MDC. The organic layer was washed with water and evaporated to get N-(2'-nitro-4'-propionylphenyl)acetamide.

C. 4-(4'-Acetylamino-3'-nitro-phenyl)-3-methyl-4-oxobutyric acid ethylester

100g of N-(2'-nitro-4'-propionylphenyl)acetamide was dissolved in 300 ml of methanol. 25.76g of potassium hydroxide dissolved in 100ml of methanol is added to N-(2'-nitro-4'-propionylphenyl)acetamide solution slowly at 10°C over one hour. The reaction mixture was stirred at 10°C for one hour more. To the above reaction mixture 76.82g of ethylbromoacetate dissolved in 100 ml of methanol was added dropwise at 10°C. Afterwards the reaction mixture was raised to a temperature of 30°C. Reaction mixture was further stirred at 30°C for two hours. After reaction completion, reaction was neutralized with 10% HC1 and methanol was evaporated. From the aqueous solution the product was extracted with 500 ml of MDC. MDC layer was evaporated to get sufficiently pure material which could be used in next stage.

D. 4-(4'-Acetylamino-3'-nitro-phenyl)-3-methyl-4-oxobutyric acid

80g of ethyl 4-[4'-(acetylamino)-3'-nitrophenyl]-3-rnethyl-oxobutanoate was mixed with 200ml of 10% HC1 solution. The reaction mixture was refluxed for one hour. After the reaction is completed reaction mixture was neutralized with sodium hydroxide solution. Product was extracted with 200 ml X 2 MDC. The MDC layer was evaporated to get 4-(4'-amino-3'-nitrophenyl)-3-methyl-4-oxobutanoicacid.

E. Methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutanoate

A mixture of 30g of 4-(4'-amino-3'-nitrophenyl)-3-methyl-4-oxobutanoicacid and 50 ml of absolute methanol were taken in a round bottomed flask. 2.7 ml of concentrated sulphuric acid was added. The reaction mixture was boiled till reaction is completed (4 hours). After the reaction is complete, methanol was distilled off. Water was added to the residue and the product was extracted with MDC. MDC was washed with water and evaporated to get methyl 4-(4'amino-3'-nitrophenyl)-3-methyl-4-oxobutanoate.

We claim:

1. A process for the preparation of methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutanoate of formula V comprising the steps of:

a) reacting 2-nitro acetanilide of formula IX with alkanoyl chloride to form JV-(2'-nitro-4'-propionylphenyl)acetamide of formula VIII;

b) reacting //-(2'-nitro-4'-propionylphenyl)acetamide with haloester or with a halonitrile to form 4-(4'-acetylamino-3'-nitro-phenyl)-3-methyl-4-oxobutyric acid ethylester of formula VII;

Where R= COOEt or CN

c) hydrolysing the ester of formula VII obtained in step (b) using an acidic reagent to form 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutyric acid of formula VI; and

d) esterifying the acid of formula VI using an alcoholic solvent to obtain methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutanoate of formula V.

2. A process according to claim 1, wherein alkanoyl chloride is propanoyl chloride.

3. A process according to claim 1, wherein haloester is selected from ethyl bromo acetate, and ethyl chloro acetate and halo nitrile is chloro acetonitrile.

4. A process according to claim 1, wherein alcoholic solvent for esterification is selected from methanol, ethanol, or propanol.

5. A process for the preparation of methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutanoate of formula V comprising the steps of:

a) reacting acetanilide of formula XI with an alkanoyl chloride to form N-(4'-propionylphenyl)acetamide of formula X;

b) nitrating Ar-(4'-propionylphenyl)acetamide of formula X to form JV-^'-nitro-^-propionylphenyl)acetamide of formula VIII;

c) reacting A42'-nitro-4'-propionylphenyl)acetarnide with haloester or with halonitrile to form 4-(4'-acetylamino-3'-nitro-phenyl)-3-methyl-4-oxobutyric acid ethylester of formula VII;

Where R = COOEt or CN

d) hydrolysing the ester of formula VII obtained in step (c) to form 4-(4'-amino-3'-nitro-phenyi)-3-methyl-4-oxo-butyric acid of formula VI; and

e) esterifying 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxo-butyric acid of formula VI obtained in step (d) to form methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutanoate of formula V.

6. A process according to claim 5, wherein alkanoyl chloride is propanoyl chloride.

7. A process according to claim 5, wherein haloester is selected from ethyl bromo acetate, and ethyl chloro acetate and halo nitrile is chloro acetonitrile.

8. A process according to claim 5, wherein esterification in step (e) is carried out in presence of an alcoholic solvent selected from methanol, ethanol, or propanol.

9. A process for preparation of Pimobendane comprising the steps of:

a) condensing methyl 4-(4'-amino-3'-nitro-phenyl)-3-methyl-4-oxobutyrate of formula V with 4-methoxybenzoyl chloride to form compound of formula IV;

b) reacting compound of formula IV with hydrazine hydrate to form compound of formula III;

c) reducing compound of formula III to form compound of formula II; and

d) cyclising the compound of formula II with an acid and a reagent to form Pimobendane of formula I;

10. A process according to claim 9, wherein the reduction in step (c) is carried out using a reducing agent selected from Raney nickel, Palladium on carbon or Platinum, preferably Palladium on carbon and acid for cyclisation in step d is acetic acid.