FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13) TITLE OF THE INVENTION
"An improved process for preparation of Aprepitant"
Emcure Pharmaceuticals Limited, an Indian company, registered under the Indian Company's Act 1957 and
having its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF 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 a key intermediate of Aprepitant and Fosaprepitant. Specifically, this method relates to the preparation of the intermediate of formula (IV), namely 2-[2-[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]-l-iminoethyl] hydrazinecarboxylic acid methyl ester, which, after cyclization, yields Aprepitant (I) conforming to regulatory specifications.
BACKGROUND OF THE INVENTION
Aprepitant of formula (I), chemically known as 5-([(2R,3S)-2-((R)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluorophenyl)morpholino]methyl)-1H-1,2,4-triazol-3(2H)-one is an anti-emetic compound which belongs to the class of substance P antagonists (SPA). It mediates its effect by blocking the signals given by Neurokinin 1(NK1) receptors and hence is also classified as NK1 antagonist. Aprepitant has been shown to inhibit both acute and delayed emesis induced by cytotoxic chemotherapeutic drugs and post-operative nausea and vomiting. Aprepitant was approved in the United States by the Food and Drug Administration (FDA) in 2003 for the treatment of acute and delayed nausea and vomiting.

Aprepitant (I) and the process for its preparation was first disclosed in US 5,719,147 wherein
(2R, 2a(R), 3a}-2-[l-[3, 5-bis (trifluoromethyl) phenyl] ethoxy-3-(4-Fluorophenyl) morpholine
was condensed with N-methylcarboxy-2-chloroacetamidrazone in presence of N,N-
diisopropylethylamine and acetonitrile as solvent. The resultant product, 2(R)-(1-(R) [3, 5-bis
(trifluoromethyl) phenyl] ethoxy-3-(s)-4-(fluorophenyl)-4-(2-(n-methylcarboxy-

acetamidrazone) morpholine was purified by flash chromatography and subsequently cyclized by refluxing in xylene and again subjected to flash chromatographic purification to obtain Aprepitant.
The process involves use of an organic base such as diisopropylethylamine and also requires chromatographic separation procedures at different stages of synthetic sequence to obtain the purified penultimate intermediate as well as the final product. Extensive use of such purification techniques, coupled with low yields render this process unviable on industrial scale.
PCT application WO03/089429 discloses a process comprising the condensation of (2R, 2a(R), 3S}-2-[l-[3, 5-bis (trifluoromethyl) phenyl] ethoxy-3-(4-fluorophenyl) -1,4-oxazine with amidrazone in presence of potassium carbonate and mixture of organic solvents such as toluene
and dimethyl sulfoxide and cyclization of the resulting intermediate to afford Aprepitant.
After a careflil study of the synthetic processes for Aprepitant as disclosed in prior art, it is clear that most of the processes are accompanied with formation of undesired isomers and associated impurities, which necessitates extensive purification processes, ultimately resulting in low yielding, industrially unviable, high-cost synthesis of Aprepitant.
Thus, there still exists a need for a convenient, easy-to-scale up process for synthesis of Aprepitant (I) which avoids extensive chromatographic purification methods for the intermediates and final product in the synthetic sequence and provides a practical, high-yielding method for the same.
The present inventors have developed a novel, practical process for synthesis of Aprepitant (I), wherein the aforementioned drawbacks from prior art methods are avoided and the required compound (I) having desired purify is obtained in good yield.
OBJECT OF THE INVENTION
An objective of the present invention is to provide Aprepitant of formula (I) having desired purity by a cost-effective and industrially viable process which avoids extensive purification procedures at various stages in the synthetic sequence.

Another object of the present invention is to provide a convenient, industrially applicable process for preparation of the intermediate 2-[2-[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]-l-iminoethyl] hydrazinecarboxylic acid methyl ester of formula (IV), which, when cyclized, gives Aprepitant (I).
SUMMARY OF THE INVENTION
The present invention relates to a process for preparation of Aprepitant (I) having desired purity.
An aspect of the invention relates to a process for preparation of Aprepitant (I) comprising the reaction of (2R, 2