FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION -
AN IMPROVED PROCESS FOR PREPARATION OF
APREPITANT
2. APPLICANT(S)
(a) NAME: MEHTA API PVT. LTD.
(b) NATIONALITY: An Indian Company
(c) ADDRESS: 203, Centre Point, J B Nagar, Andheri (East),
Mumbai 400059
3. PREAMBLE TO THE DESCRITION
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 Aprepitant of formula-(l). More particularly the present invention is directed to an improved process for preparation of Aprepitant of formula-(l) in higher yields and purity.
BACKGROUND OF THE INVENTION:
Aprepitant, 5- [ [(2R,3 S)-2- [(1R)-1- [3,5 -bis(trifluoromethyl)phenyl] ethoxy] -3 -(4-
fluorophenyl)-4-morpholinyl]methyl]-l,2-dihydro-3H-l,2,4-triazol-3-one of
formula-(l), belongs to a class of drugs called substance P antagonists (SPA). It mediates its effect by blocking the neurokinin 1 (NK.1) receptor. Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic drugs and postoperative nausea and vomiting by blocking SP landing on receptors in the brains neurons. Aprepitant is manufactured by Merck & Co. under the brand name Emend®.


US5719147 discloses aprepitant and process for its preparation as represented below:

As represented above, the process involves use of di-isopropylethylamine (DIPEA) as base for preparing compound of formula-(2), which is purified by column chromatography followed by cyclisation in xylene to give aprepitant which is also further isolated by column chromatography and the overall yield reported is 72.2% on theoretical basis. The column chromatography at two steps for a product makes a limitation for industrial production. Also, the purity profile of the final product is not disclosed.
WO2007044829 also discloses use of DIPEA as base for preparing compound of formula-(2) and futher cyclising in acetonitrile to give aprepitant. Overall yield reported is 65.5% on theoretical basis. Purity profile of the final product is not disclosed.

WO2003089429 discloses use of inorganic base as potassium carbonate for prepaing compound of formula-(2) and further cyclising in dimethyl sulfoxide (DMSO)/Toluene mixture followed by purification in Methanol/water mixture. The overall yield reported is 85.1%. No data for the purity profile of the final product is disclosed.
WO2013124823 also discloses use of potassium carbonate as base with overall yield of 79.0% and purity of 99.80% for final compound. However, the document is silent over single maximum impurity as obtained in the final product.
WO 1999001444, also disclose use of potassium carbonate as base with overall yield of 72.0% and purity of 99.50% for final compound. However, the document is silent over single maximum impurity as obtained in the final product.
According to International Council on Harmanisation (ICH) guidelines for controlling impurities in drug substances, it is generally required to control the single maximum unspecified impurity in drug substance below 0.10% for the product to be considered safe for human consumption.
Furthermore, according to the European Pharmacopeia (EP), as per the revised monograph of aprepitant, limit for total impurities in aprepitant is required to be not more than 0.20% and single maximum unspecified impurity below 0.10%.
As none of the prior-art above discloses aprepitant with impurity levels below those defined by EP and ICH guidelines, it is desired to have a process enabling to obtain aprepitant with purity profile complying in EP and ICH quality.
Furthermore, as disclosed above most of the prior-art employ use of potassium carbonate, as base for preparing compound of formula-(2) instead of using organic base as the later did not afford better yields and purity . However, use of inorganic base in non-aqueous reaction systems is not preferred owing to their low solubility

and mixing of heterogeneous reaction mass in organic solvents. A better process for affording aprepitant in high yield and purity is desired.
In view of the problems occurred in above methods, there remains a need for a better process for the preparation of Aprepitant or its pharmaceutically acceptable salts, which overcomes the drawbacks as disclosed in the prior art.
OBJECTS OF THE INVENTION:
It is an object of the present invention to provide an improved process for the preparation of Aprepitant of formula-(l).
It is another object of the present invention to provide an improved process for the preparation of Aprepitant of formula-(l), employing use of organic base in presence of a another suitable organic base for preparing compound of formula-
(2).
It is yet another object of the invention to provide an improved process for the
preparation of Aprepitant of formula-(l) enabling high yields and purity
complying for the monograph as published in pharmaeuropa and also to meet ICH
quality.
SUMMARY OF THE INVENTION:

with a compound of formula-(3) or its acid addition salt thereof.
According to an aspect of the present invention there is provided an improved
process for the preparation of Aprepitant of formula-(l) comprising the steps of:
a) coupling a compound of formula-(4)


characterized in using suitable organic base in suitable solvent in presence of another suitable organic base to obtain compound of formula-(2);

b) cyclising the compound of formula-(2) in suitable solvent to give the compound of formula-(l) which is optionally purified;


DETAILED DESCRIPTION OF THE INVENTION:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as xylene, toluene, n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, cycloheptane, pet ether, "polar-aprotic solvents" such as dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; "nitrile solvents" such as acetonitnle, propionitrile, butyronitrile, isobutyronitrile and like; "polar solvents" such as water and/or mixtures thereof.
As used herein the present invention the term "addition salts" refer to salts of organic or inorganic acid comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, suphonate, oxalic acid and the like.

with a compound of formula-(3) or its acid addition salt thereof.
The present invention relates to an improved process for synthesis of Aprepitant employing use of suitable organic base in presence of another suitable organic base to obtain compound of formula-(2). According to this aspect of the present invention there is provided a process for preparation of Aprepitant of formula-(l) or its pharmaceutically acceptable salts comprising the steps of: a) coupling a compound of formula-(4)


characterized in using suitable organic base in suitable solvent in presence of another suitable organic base to obtain compound of formula-(2);

wherein the another suitable organic base is selected from a group of bases comprising of 4-Dimethyl amino pyridine (4-DMAP), Di-isopropylethylamine (DIPEA), Triethylamine (TEA) and/or mixtures thereof. Preferably the another suitable organic base is (4-DMAP)
The present inventors have evaluated the reaction conditions employing use of organic base to afford aprepitant in better yields and ICH quality purity profile. While studying these conditions it was found that using mixtures of organic base as against using a single organic base, for preparing compound of formula-(2), affords aprepitant with yields and quality much better as compared to reported prior-art.

The present inventors have compared the results of prior-art reported and other with those obtained by present invention as detailed in Table-01 below.
Table-01

Sr. Reference Base Another suitable organic base Yield Purity
1 US5719147 DIPEA Absent 72.2% Not reported
2 WO2007044829 DIPEA Absent 65.5% Not reported
3 WO2003089429 Potassium Carbonate Absent 85.1% Not reported
4 WO2013124823 Potassium Carbonate Absent 79.0% 99.80%
5 WOl 999001444 Potassium Carbonate Absent 72.0% 99.50%
6 MehtaAPI Potassium Carbonate Absent 75%% 99.71%
7 MehtaAPI DIPEA Absent 64%% 99.65%
8 MehtaAPI DIPEA 4-DMAP 84.8% 99.93%
9 MehtaAPI DIPEA TEA 63% 99.59%
10 MehtaAPI TEA DIPEA 53% 99.55%
11 MehtaAPI DMAP Absent 45% 99.71%
12 MehtaAPI TEA DMAP 61% 99.72%
As is evident from the above tabulated results, the use of more than one base in step-a) results in an increased overall yield and better purity profile of the final product.
As the reported prior-art do not clearly specify the impurity profile, the process as followed by present invention becomes important in the backdrop of stringent pharmaeuropa and ICH guidelines for limit of impurities in drug substances.
Suitable base in step a) comprises of organic base selected from a group of diisopropylethyl amine (DIPEA), 4-Dimefhyl amino pyridine (4-DMAP), triethylamine (TEA), diisopropyl amine, diisobutylamine, tert.butyl amine, methyl amine and/or the mixtures thereof. Suitable base in step a) is preferably is diisopropylethyl amine.

Suitable solvent in step a) is preferably selected from a group of solvents comprising of dimethylsulfoxide, dimethylformamide, acetonitrile and mixtures thereof. More preferably the suitable solvent is dimethylsulfoxide.
The reaction in step a) may be preferably carried out at temperatures ranging from about but not limiting to 30°C to 60°C and preferably at 45°C to 50°C.
In an embodiment according to this aspect of the invention, after the reaction in step a) complies the reaction mass is partitioned between suitable organic solvent and water preferably at same temperature, followed by further back extractions from the aqueous phase after layer separation. The organic layer obtained is then given water wash and concentrated by distillation.
The distillation may be carried out under vacuum or at atmospheric pressure. Preferably the distillation is carried out under atmospheric.pressure at 140-160°C.
Suitable organic solvent according to this embodiment of the present invention is
xylene.
Further according to this embodiment of the present invention, the concentrated
organic layer is forwarded to the next stage. Optionally the organic layer may be
forwarded as such without concentration to the next stage.
b) cyclising the compound of formula-(2) in suitable solvent to give the compound of formula-(l)which is optionally purified;


Suitable solvent selected for cyclisation in step b) is preferably selected from a group of solvents comprising of xylene, toluene, dimethylsulfoxide, dimethylformamide and mixture thereof. More preferably the suitable solvent is xylene.
In an embodiment according to this step of the reaction, the cyclisation reaction is carried out at temperatures ranging from about but not limiting to 130°C to 165°C and preferably at 145°C to 150°C.
Further according to this embodiment of the present invention after the cyclisation reaction complies, the reaction mass is cooled and filtered to afford compound of formula-(l) with purity profile complying according to ICH standards. The compound of formula-(l) obtained may be optionally purified.
Thus the present invention provides an improved process for preparing the compound of formula-(l) in higher yields and purity complying in EP and ICH quality.
Examples:
Example 1
In a round bottom flask, (250 gms) HC1 salt of compound of formula 3 is charged under stirring to (750 ml) Dimethylsulfoxide, (180 ml)Di-isopropylethylamine, (6.5 gms) 4-Dimethyl amino pyridine and (89.3) compound of formula 4. The reaction mass is stirred at 45-50°G till the reaction complies. After the reaction complies, the reaction mass is added to a mixture of (1500 ml) xylene and (1000 ml) water at 45-50 °C. The aqueous layer is back extracted with (500 ml) xylene. The organic layers are combined and given (500 ml) water washing. The Organic layer is concentrated at 145-160°C partially. The concentrated reaction mass is then further stirred at 145-160°C till the reaction complies and filtered at 25-30°C. The residue is washed with xylene and dried at 50-55°C to obtain crude of title

compound of formula-(l) which is further purified in methanol-water mixture to
give pure compound of formula-(l)
Dry weight: 239 gms.
Yield: 84.8% on theoretical basis.
Purity: 99.93%
We claim:
1. An improved process for the preparation of Aprepitant of formula (1), comprising the steps of:

with a compound of formula-(3) or its acid addition salt thereof.
a) coupling a compound of formula-(4)

characterized in using suitable organic base in suitable solvent in presence of another suitable organic base to obtain compound of formula-(2);


b) cyclising the compound of formula-(2) in suitable solvent to give the compound of formula-(l) which is optionally purified;

2. An improved process for the preparation of Aprepitant of formula (1), as claimed in claim 1, wherein another suitable organic base is selected from a group of bases comprising of 4-Dimethyl amino pyridine, Di-isopropylethylamine, Triethylamine and/or mixtures thereof.
3. An improved process for the preparation of Aprepitant of formula (1), as claimed in claim 1, wherein the suitable base is selected from a group of bases comprising of diisopropylethyl amine, 4-Dimethyl amino pyridine, triethylamine, diisopropyl amine, diisobutylamine, tert.butyl- amine, methyl amine and/or the mixtures thereof.

4. An improved process for the preparation of Aprepitant of formula (1), as claimed in claim 1, wherein the suitable solvent is selected from a group of solvents comprising of dimethylsulfoxide, dimethylformamide, acetonitrile and mixtures thereof.
5. An improved process for the preparation of Aprepitant of formula (1), as claimed in claim 1, wherein the acid addition salt of compound of formula-(3) is hydrochloride salt.
6. An improved process for the preparation of Aprepitant of formula (1), as claimed in claim 1, wherein the reaction in step-a) is carried out at 30°C to 60°C and the reaction in step-b) is carried out at 130-165°C
7. An improved process for the preparation of Aprepitant of formula (1), as claimed in claim 1, wherein'after the reaction in step-a) complies the reaction mass is partitioned between xylene and water at 30°C to 60°C and preferably at 45°C to 50°C.
8. An. improved process for the preparation of Aprepitant of formula (1), as claimed in claim 1, wherein after the reaction in step-a) complies the reaction mass is forwarded to the next stage without isolating compound of formula-(2)
9. An improved process for the preparation of Aprepitant of formula (1), as claimed in claim 1, wherein after the reaction in step-a) complies the reaction mass is concentrated partially and forwarded to next stage.
10. An improved process for the preparation of Aprepitant of formula (1),
process for the preparation of Aprepitant of formula (1), comprising the steps
of:
a) coupling a compound of formula-(4)

with a hydrochloride salt of compound of formula-(3)


characterized in using suitable diisopropylethyl amine as base in dimethylsulfoxide as solvent in presence of 4-Dimethyl amino pyridine as another suitable base at 45°C to 50°C to obtain compound of formula-(2);

b) cyclising the compound of formula-(2) in xylene at 140-160°C to give the compound of formula-(l).