DESC:
FORM 2

THE PATENT ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)

“AN IMPROVED PROCESS FOR THE PREPARATION OF
ETHYL (Z)-2-CHLORO-2-(2-(4-METHOXYPHENYL) HYDRAZINYLIDENE) ACETATE”

Hikal Limited, an Indian Company of 3A & 3B, International Biotech Park, Hinjewadi, Pune – 411 057, 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 an improved process for the preparation of ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate formula (I).

BACKGROUND OF THE INVENTION
Apixaban is a direct factor Xa (FXa) inhibitor and used as an anticoagulant for the treatment of venous thromboembolic events. Apixaban is marketed by Bristol-Myers Squibb under the brand name ELIQUIS®. Apixaban is chemically known as l-(4-methoxy-phenyl)-7-oxo-6- [4-(2- oxopiperidin-l-yl)-phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4c]-pyridine-3-carboxamide and represented by following structure:

The US Patent 6,967,208 discloses Apixaban, process for the preparation of Apixaban and its intermediates. The said patent further discloses a series of coagulation factor Xa inhibitors and is developed for oral administration in a variety of indications that require the use of an antithrombotic agent.

The US Patent Nos. 6,750,225; 6,989,391; 6,919,451; and 7,153,960 which are all hereby incorporated by reference, disclosed processes for the preparation of Apixaban and its intermediates.

The ethyl-(z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate is one of the key intermediates used in the preparation of apixaban and processes for its preparation are disclosed in the prior art. The processes disclosed in the prior art for the preparation of ethyl-(z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate involve the use of sodium acetate as a buffer during coupling of diazonium salt. The reaction medium of diazotization salt is highly acidic due to presence of excess hydrochloric acid, and this acidic environment leads to degradation of reaction mixture in coupling reaction. Thus, it is essential to neutralize the acidic environment of diazonium salt to proceed before coupling reaction. Many prior art documents disclose the use of sodium acetate to neutralize the acidic environment but does not succeed as it was unable to neutralize acidic environment completely and leading to degradation of reaction medium. Therefore, a need arises for an improved process for preparation of ethyl-(z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate which overcomes the disadvantages of prior art. The inventors of the present invention investigated the use of sodium dihydrogen phosphate as a buffer which overcomes limitation of prior arts. The inventors of the present invention found that the use of sodium dihydrogen phosphate having pH 5.8 to 8.0, neutralizes the acidic environment of the reaction medium and favors coupling of diazonium salt without degradation of reaction mixture. The invented process for preparation of ethyl-(z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate is efficient, environment friendly and industrially viable as it does not involve any additional reagent, critical reaction condition to neutralize the reaction medium.

SUMMARY OF THE INVENTION
A present invention provides a process for the preparation of ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I)

comprising the steps of:
a) reacting p-Anisidine of formula (II)

with sodium nitrite in the presence of hydrochloric acid and water to obtain diazonium salt of formula (III);

b) coupling the diazonium salt of formula (III) with ethyl chloroacetoacetate of formula (IV)

in presence of sodium dihydrogen phosphate and in an alcoholic solvent to obtain ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I);

c) purifying the ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I) in an alcoholic solvent to obtain pure ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements.

As used in the specification, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

In accordance with the objectives, the present invention provides an improved process for the preparation of ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I).

In an embodiment of the present invention, the step (a) is performed by using p-Anisidine (II), sodium nitrite, water and hydrochloric acid at temperature 0°C to 20°C to obtain diazonium salt of formula (III).

In another embodiment of the present invention, the step (b) is performed by reacting the diazonium salt with ethyl-2-chloroacetoacetate in presence of sodium dihydrogen phosphate in an alcoholic solvent at 0°C to 30°C to obtain ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I).

In another embodiment of the present invention, step (c) purification of ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate having purity greater than 95% is performed by using alcoholic solvent.

In another embodiment of the present invention, step (c) purification ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate is carried out by dissolving, the ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I) in an alcoholic solvent at 60°C to 80°C, maintaining at 60°C to 50°C and isolating by cooling at 0°C to 5°C to obtain pure ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I).

In another embodiment of the present invention, wherein alcoholic solvent is selected from methanol, ethanol, isopropyl alcohol, n-butanol, and the like; preferably isopropyl alcohol.

In another embodiment, the intermediate ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I) obtained by the process of the present invention has purity greater than 97%, preferably greater than 98% by HPLC.

The process of the present invention is illustrated in the following general synthetic scheme:

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXPERIMENTAL:
Example : Preparation of ethyl-(Z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I).
To a slurry of p-Anisidine (1.0 eq) in water (1-2 vol), conc. hydrochloric acid (2-3 eq) was added at 0°C to10°C. To this mixture aqueous sodium nitrite solution (1-1.5 eq in water) was added and stirred for 1 hr. at 0°C to10°C to obtain diazonium salt. To this reaction mixture ethyl-2-chloroacetoacetate (1-1.5eq) methanol (5-8 vol), and aqueous sodium dihydrogen phosphate solution (1.5-2 eq in water) were added. The reaction mixture was s stirred at 0°C to10°C for 2-4 hrs. and further stirred at room temperature for 6-8 hrs. The precipitated compound was filtered and washed with water to obtain crude compound having purity >95% by HPLC. The crude compound was purified using isopropyl alcohol (3-5 vol) by heating at 70°C to 80°C, gradually cooling to 50°C to 55°C for 2-3hrs and finally cooling to 0°C to 5°C for 1 hr. The precipitated pure compound was obtained by filtering and drying with purity > 98% with yield > 80%.
,CLAIMS:We claim:

1) A process for the preparation of ethyl-(z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I)

which comprises steps of:
a) reacting p-Anisidine of formula (II)

with sodium nitrite in the presence of hydrochloric acid and water to obtain diazonium salt of formula (III);

b) coupling the diazonium salt of formula (III) of step (a) with ethyl chloroacetoacetate of formula (IV)

in presence of sodium dihydrogen phosphate in an alcoholic solvent to obtain ethyl (z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I);
c) purifying the ethyl-(z)-2-chloro-2-(2-(4-methoxyphenyl)-hydrazinylidene) acetate of formula (I) in an alcoholic solvent to obtain pure ethyl-(z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate of formula (I).

2) A process as claimed in claim 1, wherein alcoholic solvent is selected from methanol, ethanol, isopropyl alcohol, and n-butanol.

3) A process as claimed in claim 1, wherein step (a) is performed at temperature 0°C to 20°C. and step (b) is performed at 0°C to 30°C.

4) A process as claimed in claim 1, wherein purification step (c) is performed at temperature 60°C to 80°C and isolation of pure ethyl-(z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazinylidene) acetate is performed at 0°C to 5°C.