PROCESS FOR PREPARING APREPITANT
INTRODUCTION TO THE INVENTION The present invention relates to a process for the preparation of aprepitant. Aprepitant is chemically known as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one and has the structure shown as Formula I.
Aprepitant is asuusiaiiuts r ineuruMiiui-1; rcucpiur anuayunist useful in the treatment of chemotherapy-induced nausea and vomiting, and is commercially available in the market under the brand name EMEND™ as 80 mg or 125 mg capsules.
U.S. Patent No. 5,719,147 discloses the preparation of aprepitant, its pharmaceutical^ acceptable salts, pharmaceutical composition and methods of treatment. Aprepitant is the cis-isomer of 5-[2-[1-(3,5-Bis-trifluoromethyl-phenyl)-ethoxy]-3-(4-fluorophenyl)-morpholin-4-ylmethyl]-2,4-dihydro-[1,2,4]triazol-3-one.
International Application Publication No. WO 03/089429 A1 discloses a preparation of aprepitant which involves condensation of the hydrochloride salt of (2R,2-a-R,3S)-2-[1-[3,54)is(trifluorom
oxazine with amidrazone to give an intermediate which on cyclization gives aprepitant. The application also describes the preparation of racemic aprepitant by condensation of the hydrochloride salt of 2-[1-(3,5-bistrifluoromethylphenyl) ethoxy] morpholine with amidrazone in presence of potassium carbonate and the organic solvents toluene and dimethylsulfoxide to give an intermediate which is further cyclized at 140 °C to provide the desired compound.
International Application Publication No. WO 01/96315 A1 discloses a preparation of aprepitant by condensation of 3-chloromethyl-1,2,4-triazolin-5-one with2-(R)-(1-(R)-(3,5-bistrifluoromethyl)phenyl)ethoxy)3-(SH4-

fluorophenyl)morpholine(R)-camphorsulfonic acid salt in the presence of potassium carbonate and N,N-dimethyformamide.
Alternatively, aprepitant was prepared by condensation of 3-chloromethyl-1,2,4-triazolin-5-one with 2-(RH1-(RH3,5-bistrifluoromethyl)phenyl)ethoxy)3-(S)-(4-fluorophenyl)morpholine paratoluenesulfonic acid salt in the presence of bases N,N-diisopropylethylamine and N,N-dimethyformamide.
Alternatively, aprepitant was prepared by condensation of 3-chloromethyI-1,2,4-triazolin-5-onewith2-(R)-(1-(R)-(3^
fluorophenyl)morpholine paratoluenesulfonic acid salt at 21-23° C in presence of bases potassium carbonate and N,N-dimethyformamide.
U.S. Patent Nos. 5,719,147 and 5,637,699 discloses a process for the preparation of aprepitant which involves condensation of 2(R)-(1-(R)-3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluoro)phenylmorpholine with N-methylcarboxy-2-chloroacetami-drazone in presence of a base N,N-diisopropylethylamine and solvent acetonitrile. Subsequent processing by flash chromatography using methylene chloride / methanol / ammonium hydroxide as eluant in a ratio of 50:1:0.1 provided 2(R)-(1-(R)-3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(N-ethylcarboxyacetamidrazono)morpholine, which was further refluxed in xylene and purified by flash chromatography using methylene chloride/methanol/ammonium hydroxide as an eluant in a ratio of 50:1:0.1, to afford aprepitant.
The preparation of aprepitant by condensation of 3-chloromethyl-1,2,4-triazolin-5-onewith2-(R)-(1-(RH3,5-bistrifluoromethyl)phenyl)ethoxy)3-(SH4-fluorophenyl) morpholine paratoluenesulfonic acid salt at 0 °C in the presence of potassium carbonate or N,N-diisopropylethylamine and N,N-dimethylformamide with 1% water has also been described (Cameron J. Cowden et al., Tetrahedron Letters Vol. 41 (2000), pages 8661-8664).
Joseph F. Payach et al., Organic Process Research & Development, Vol. 8, 2004, pages 256-259 describes the preparation of aprepitant by reaction of 3,5-bis-trifluoromethylbenzoicacid-4-benzyl-3(S)-(4-fluorophenyl)morpholin-2-ylesterwith dimethyltitanocene to give 4-benzyl-2-[1-(3,5-bistirfluoromethylphenyl)-vinyloxy]-3-(4-fluorophenyl) morpholine.
U.S. Patent No. 6,395,898 discloses the preparation of optically pure intermediate compound 2-(R)-(1-(R)-(3,5-bistrifluoromethyl) phenyl) ethoxy) 3-(S)-(4-

fluorophenyl) morpholine of Formula lib of the present invention, which features a highly stereoselective Lewis acid catalysed transacetalization of (R)-3,5-bistrifluoromethyl-phenyl ethanol with trichloroacetamidate, followed by inversion of the adjacent chiral center on the morpholine ring. The process for the preparation of the chiral alcohol (R)-3,5-bistrifluoromethylphenyl ethanol employs (1S, 2R)-cis-1-aminoindan-2-ol and dichloro (p-cymene) Ru (II) dimer as a metal source. This route is industrially and economically infeasible because as expensive raw materials such as dichloro (p-cymene) Ru (II) dimer were involved.
The processes for the preparation of aprepitant and intermediate 2-(R)-(1-(R)-(3,5-bistrifluoromethyl) phenyl) ethoxy) 3-(S)-(4-fluorophenyl) morpholine of Formula (lib) described above involve either the use of expensive chiral intermediates or industrially unacceptable reagents such as dimethyltitanocene, or (1S, 2R)-cis-1-aminoindan-2»ol, dichloro (p-cymene) Ru (II) dimer. Further, the selective substitution reactions disclosed in the art are governed by the thermodynamic stability of the intermediates and are highly sensitive to minor process variations such as temperature, moisture, time, rate of addition, solvent, etc. and thus the processes are practically found to be inconsistent in producing the desired stereochemistry.
There remains a need for a simple, industrially feasible, cost effective, scaleable and safe-to-handle process for the synthesis of aprepitant.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of aprepitant.
In one aspect, the present invention provides a process for preparing aprepitant, which comprises of:
i) reacting the compound (-)-trans-morpholinol of Formula VIII with the compound 3,5-Bis(trifluoromethyl)-bromoethylbenzene of Formula VII

to afford the compound of Formula Vlb in the presence of a suitable base;

rormuiaHID v) converting the compound of Formula lllb to the compound of Formula lib; and

Formula lib vi) reacting the compound of Formula lib with compound of Formula II in the presence of a suitable base to afford aprepitant of Formula I.
LI

In another aspect, the present invention provides an alternative process for the preparation of compound of Formula lib, which comprises of:
a) reacting the compound of Formula VIII with trichloroacetonitrile, followed by reaction with the compound of Formula Vila in the presence of suitable base

butoxide, N,N-diethylamine, N,N-triethylamine, N,N-diisopropylethylamine, triethanolamine and the like; and inorganic bases such as sodium hydride sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and the like.
Suitable solvents include, but are not limited to: aprotic solvents such as dimethylsulfoxide (DMSO), N,N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP) and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; ethers such THF, diethyl ether, methyl tert-butyl ether and the like; hydrocarbons such as toluene, xylene, cyclohexane and the like; alcohols such as methanol, ethanol, isopropanol; and mixtures thereof or their combinations with water in various proportions.
Suitable temperatures for conducting the reaction range from about 35 °C to about 75 °C, or from about 25 °C to about 65 °C.
Step ii) involves reaction of the compound of Formula VIb with a suitable reducing agent in the presence of a suitable organic solvent under suitable conditions to afford the compound of Formula Vb.
Suitable reducing agents include but are not limited to palladium catalysts such as palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium hydroxide on carbon, and the like. Optionally, the compound of Formula VIb is contacted with a strong inorganic or organic acid prior to hydrogenation. Useful acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, formic acid, acetic acid and the like; and organic acids such as oxalic acid, tartaric acid, camphorsulphonic acid, diparatoluoyl tartaric acid, benzene sulfonic acid, para-toluenesulfonic acid, and the like.
Suitable solvents include, but are not limited to: alcohols such as methanol, ethanol, isopropanol and the like; hydrocarbons such as toluene, xylene, cyclohexane and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; and mixtures thereof or combinations with water in various proportions.
Suitable temperatures for conducting the reaction range from about 10 °C to about 50 °C, or from about 20 °C to about 40 °C.

Step iii) involves reaction of the compound of Formula Vb with a suitable dehydrogenating agent in the presence of a suitable organic solvent under suitable conditions to afford the compound of Formula IVb.
Suitable dehydrogenating agents include but are not limited to 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU), N-chlorosuccinimide (NCS), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and the like.
Suitable organic solvents include but are not limited to: aprotic polar solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N-methylpyrrolidinone (NMP) and the like; ethers such as tetrahydrofuran (THF), diethylether, methyl tertiary butyl ether and the like; esters such as ethyl acetate, isopropyl acetate, n-propyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; hydrocarbons such as toluene, cyclohexane, heptane, xylene and the like; and mixtures thereof or their combinations with water in various proportions.
Suitable temperatures for conducting the reaction range from about 25 °C to about 50 °C, or from about 20 °C to about 40 °C.
Step iv) involves reaction of the compound of Formula IVb with a suitable reducing agent in the presence of a suitable organic solvent under suitable conditions to afford the compound of Formula 1Mb.
Suitable reducing agents include but are not limited to palladium catalysts such as palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium hydroxide on carbon, and the like.
Alternatively, the reduction of the compound of Formula IVb to give the compound of Formula 11 lb can be accomplished using chemical reducing agents such as sodium borohydride, potassium borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate (Vitride), sodium cyanoborohydride, sodium triacetoxyborohydride, and the like in the presence of a suitable organic solvent such as: alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutyl alcohol, tertiary-butyl alcohol, and the like; hydrocarbons such as toluene, xylene, cyclohexane and the like; esters such as ethyl acetate, isopropyl acetate, n-butyl acetate, tertiary butyl acetate and the like; and mixtures thereof or their combinations with water in various proportions.

Typically, using a reducing agent such as sodium borohydride for conversion of the compound of Formula IVb to the compound of Formula lllb enhances the high purity and yield of the final compound.
Suitable solvents include but are not limited to: alcohols such as methanol, ethanol, isopropylalcohol, n-propanol, n-butanol, tertiary-butyl alcohol and the like; hydrocarbons such as toluene, xylene, cyclohexane and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; and mixtures thereof or their combinations with water in various proportions.
Suitable temperatures for conducting the reaction range from about 25 °C to about 50 °C, or from about 20 °C to about 40 °C.
Step v) involves diastereomeric crystallization of the compound of Formula lllb using a suitable organic solvent under suitable conditions to afford the compound of Formula lib.
Suitable organic solvents include but are not limited to: ethers such as tetrahydrofuran (THF), diethyl ether, methyl tertiary-butyl ether (MTBE) and the like; esters such as ethyl acetate, isopropyl acetate, n-propyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; hydrocarbons such as toluene, cyclohexane, heptane, xylene and the like; and mixtures thereof or their combinations with water in various proportions.
Suitable temperatures for conducting the reaction range from about 25 °C to about 40 °C, or from about 20 °C to about 35 °C.
Step vi) involves reaction of the compound of Formula lib with the compound of Formula II in the presence of a suitable base and a suitable organic solvent to afford aprepitant of Formula I.
Suitable bases include but are not limited to: organic bases such as N,N-diethylamine, triethylamine (TEA), N,N-diisopropylethylamine (DIPE), triethanolamine and the like; and inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
Suitable organic solvents include but are not limited to: aprotic polar solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N-methylpyrrolidinone (NMP) and the like; ethers such as tetrahydrofuran (THF), diethyl ether, methyl tertiary-butyl ether and the like; esters such as ethyl acetate,

isopropyl acetate, n-propyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; hydrocarbons such as toluene, cyclohexane, heptane, xylene and the like; and mixtures thereof or their combinations with water in various proportions.
Suitable temperatures for conducting the reaction range from about 10 °C to about 50 °C, or from about 20 °C to about 40 °C.
In another aspect, the present invention provides an alternative process for the preparation of compound of Formula lib, which comprises of:
a) reacting the compound of Formula VIII with trichloroacetonitrile, followed by reaction with the compound of Formula Vila in the presence of suitable base


Formula Va
c) dehydrogenating the compound of Formula Va using a suitable
dehydrogenating agent to afford the compound of Formula IVa

Formula Ilia
d) converting the compound of Formula Ilia to the compound of Formula Mb.
The compound of Formula lib is then converted to aprepitant compound of
Formula I.
Step a) involves reaction of the compound of Formula VIII with trichloroacetonitrile followed by condensation with the compound of Formula Vila to give the compound of Formula Via, in the presence of a suitable base and suitable organic solvent under suitable conditions.
Suitable bases which can be used include but are not limited to: organic bases such as N,N-diethylamine, triethylamine, N,N-diisopropylethylamine, triethanolamine and the like; and inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

Suitable organic solvents which can be used include but are not limited to: aprotic polar solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N-methylpyrrolidinone (NMP) and the like; ethers such as tetrahydrofuran (THF), diethyl ether, methyl tertiary-butyl ether and the like; esters such as ethyl acetate, isopropyl acetate, n-propyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; hydrocarbons such as toluene, cyclohexane, heptane, xylene and the like; and mixtures thereof or their combinations with water in various proportions.
Suitable temperatures for conducting the reaction range from about 35°C to about 75 °C, or from about 25 °C to about 65 °C.
Step b) involves debenzylation of the compound of Formula Via using a suitable reducing agent in the presence of a suitable organic solvent under suitable conditions.
Suitable reducing agents which can be used include but are not limited to: palladium catalysts such as palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate and palladium hydroxide on carbon and the like.
Optionally, the compound of Formula Via is contacted with a strong inorganic or organic acid prior to hydrogenation. The acids include but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, formic acid, acetic acid and the like; and organic acids such as oxalic acid, tartaric acid, camphorsulphonic acid, diparatolouyl tartaric acid benzene sulfonic acid, paratoluenesulfonic acid and the like.
Suitable organic solvents which can used include but are not limited to: alcohols such as methanol, ethanol, isopropylalcohol and the like; hydrocarbons such as toluene, xylene, cyclohexane and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; and mixtures thereof or their combinations with water in various proportions.
Step c) involves dehydrogenation of the compound of Formula Va using a suitable dehydrogenating agent to afford the compound of Formula IVa
Suitable dehydrogenating agents include but are not limited to 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU), N-chlorosuccinimide (NCS), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

Suitable organic solvents which can used include but are not limited to: alcohols such as methanol, ethanol, isopropylalcohol and the like; hydrocarbons such as toluene, xylene, cyclohexane and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; and mixtures thereof or their combinations with water in various proportions.
Suitable temperatures for conducting the reaction range from about 35 °C to about 75 °C, or from about 25 °C to about 55 °C.
Step d) involves reduction of the imine compound of Formula IVa to afford the amine compound of Formula Ilia using a suitable reducing agent in the presence of a suitable organic solvent under suitable conditions.
Suitable reducing agents which can be used include but are not limited to palladium catalysts such as palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium hydroxide on carbon and the like.
Alternatively, the reduction of the compound of Formula IVa to give the compound of Formula Ilia can be accomplished using chemical reducing agents such as sodium borohydride, potassium borohydride, sodium dihydro-bis-(2-methoxyethoxy)aluminate(Vitride), sodium cyanoborohydride, sodium triacetoxyborohydride, and the like in the presence of a suitable organic solvent such as: alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutyl alcohol, tertiary-butyl alcohol, and the like; hydrocarbons such as toluene, xylene, cyclohexane and the like; esters such as ethyl acetate, isopropyl acetate, n-butyl acetate, tertiary butyl acetate and the like; and mixtures thereof or their combinations with water in various proportions.
Typically, using a reducing agent such as sodium borohydride for conversion of the compound of Formula IVa to the compound of Formula Ilia enhances the high purity and yield of the final compound.
Suitable organic solvents which can be used include but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol and the like; hydrocarbons such as toluene, xylene, cyclohexane and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; and mixtures thereof or their combinations with water in various proportions.

Suitable temperatures for conducting the reaction range from about 10 °C to about 50 °C, or from about 20 °C to about 40 °C.
Step e) involves diastereomeric crystallization of the amine compound of Formula Ilia using a suitable organic solvent to afford the compound of Formula lib.
Suitable organic solvents which can be used include but are not limited to: ethers such as tetrahydrofuran (THF), diethyl ether, methyl tertiary-butyl ether and the like; esters such as ethyl acetate, isopropyl acetate, n-propyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; hydrocarbons such as toluene, cyclohexane, heptane, xylene and the like; and mixtures thereof or their combinations with water in various proportions.
Suitable temperatures for conducting the reaction range from about 10 °C to about 50 °C, or from about 20 °C to about 40 °C.
The compound of Formula lib is then converted to aprepitant compound of Formula I.
The aprepitant of Formula I produced by the above processes is substantially free from impurities, including process, structural, and isomeric impurities. Typically the aprepitant is of high purity, such as at least about 99.5 wt %, or at least about 99.9 wt % purity. Correspondingly, the level of impurities may be less than about 0.5 wt %, or about 0.1 wt %, as determined by high performance liquid chromatography (HPLC).
Similarly, the aprepitant of Formula I produced by the above processes is substantially free from residual solvents such as solvents used in making the aprepitant. The residual solvent content may be less than about 10 wt %, or less than about 2 wt %, or less than about 1 wt %, about 0.5 wt %, or about 0.1 wt %, as determined by gas chromatography (HPLC).
The process of the present invention is simple, cost effective, eco-friendly, commercially suitable, and reproducible on an industrial scale.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES EXAMPLE 1 PREPARATION OF frans-4-BENZYL-2-[2-(3,5-BIS-TRIFLUORO METHYL PHENYL)-ETHOXY]-3-(4-FLUOROPHENYL) MORPHOLINE (FORMULA Vlb)
500 g of the compound of Formula VIM and 2.5 L of N,N-dimethylformamide were charged into a clean and dry round bottom flask followed by stirring for about 5 minutes. 70 g of sodium hydroxide and 560 g of the compound of Formula VII were charged under stirring followed by heating to about 65° C. The resultant reaction mixture was stirred at about 65° C for about 3 hours. After the completion of the reaction, reaction mass was cooled to about 30° C followed by quenching the reaction mass by the addition of 5 liters of water. The reaction mass was stirred for about 20 minutes followed by charging of 2.5 liters of ethyl acetate. Organic and aqueous layers were separated followed by extraction of aqueous layer with 2x1250 ml of ethyl acetate. Organic and aqueous layers were separated followed by combining of organic layers and the total organic layer was washed with 3x1250 ml of water. Organic and aqueous layers were separated followed by drying the organic layer over 100 g of anhydrous sodium sulphate. Organic layer was distilled completely at about 55 ° C to afford 600 g of the title compound in the form of syrup.
EXAMPLE 2 PREPARATION OF frans-2-[1-(3,5-BIS-TRIFLUORO METHYL PHENYL)ETHOXY]-3-(4-FLUOROPHENYL)-MORPHOLINE (FORMULA Vb)
500 g of frans-4-benzyl-2-[2-(3,5-bis-trifluoro methyl phenyl)-ethoxy]-3-(4-fluorophenyl) morpholine of Formula Vlb, 180 g of para-toluenesulfonic acid dissolved in 2 liters of toluene, 250 g of (5%) palladium on carbon and 1 liter of methanol were charged into a clean and dry autoclave vessel followed by applying 3.5 kg/cm2 anhydrous hydrogen gas pressure to the reaction suspension at about 30 °C for about 3 hours under agitation. After the completion of the reaction, the suspension was filtered through celite and the celite was washed with 1 liter of methanol, followed by distillation of filtrate completely at about 55° C under vacuum in a Buchi Rotavapor to afford a residue. The residue was dissolved in 2.5 liters of toluene followed by washing the toluene layer with 2x100 ml of 10% aqueous sodium carbonate solution. Organic and aqueous layers were separated followed by washing the organic layer with 3x1 liters of water followed by separation of organic

and aqueous layers. The organic layer was distilled at about 60° C to afford 260 g of the title compound in the form of a syrup.
EXAMPLE 3 PREPARATION OF THE COMPOUND OF FORMULA IVb
120 g of the compound of Formula Vb and 720 ml of N,N-dimethylformamide (DMF) were charged into a clean and dry round bottom flask followed by stirring for about 15 minutes. 15 g of potassium carbonate was charged followed by cooling to about 0° C and 47.6 g of N-chlorosuccinamide was added in small portions over about 30 minutes. The resultant reaction mixture was stirred further for about 30 minutes followed by the dropwise addition of 55.5 g of dibromouricil over about 30 minutes. The reaction mixture was cooled to about 30° C followed by stirring for about 6 hours. After the completion of the reaction, the reaction mass was quenched by charging of 1200 ml of water followed by charging of 1200 ml of toluene under stirring. Organic and aqueous layers were separated followed by extraction of the aqueous layer with 2x600 ml of toluene. Organic and aqueous layers were separated and the organic layers were combined followed by washing with 3*600 ml of water. Organic and aqueous layers were separated and the organic layer was distilled completely at about 60° C under reduced pressure of about 600-650 mm Hg to afford 96 g of the title compound.
EXAMPLE 4 PREPARATION OF 2-[1-(3,5-BIS-TRIFLUORO METHYL PHENYL) ETHOXY]-3-(4-FLUOROPHENYL)-MORPHOLINE (FORMULA lllb)
50 g of the compound of Formula IVb, 50 g of palladium-carbon (5% Pd) and 500 ml of methanol were charged into a clean and dry stainless steel hydrogenation vessel followed by applying 3 kg/cm2 anhydrous hydrogen gas pressure to the reaction suspension at about 30° C for about 3 hours under agitation. After the completion of the reaction, the suspension was filtered through celite and the celite was washed with 150 ml of methanol. The resultant filtrate was distilled completely at about 50° C under reduced pressure of about 600-650 mm Hg to afford 48 g of the title compound in the form of syrup.

EXAMPLE 5 PREPARATION OF (2R, 3S)-2-{(1R)-1-[3,5-BIS-TRIFLUORO METHYL PHENYL] ETHOXY}-3-(4-FLUOROPHENYL) MORPHOLINE (FORMULA lib)
40 g of 2-[1 -(3,5-bis-trifluoro methyl phenyl) ethoxy]-3-(4-fluorophenyl)-morpholine of Formula 1Mb and 400 ml of toluene were charged into a clean and dry round bottom flask followed by stirring for about 10 minutes. 17.5 g of para-toluene sulfonic acid monohydrate was charged followed by stirring at about 30 °C for about 30 minutes. Solvent from the reaction mixture distilled completely at about 60° C under vacuum. 40 ml of toluene was charged to the residue followed by stirring for about 10 minutes. 160 ml of petroleum ether was charged followed by stirring for about 4 hours. Separated solid was filtered and the solid was washed with 80 ml of petroleum ether followed by charging of the solid into a clean and dry round bottom flask. 100 ml of toluene was charged to the solid followed by stirring for about 10 minutes. 200 ml of water was charged followed by stirring for about 30 minutes. pH of the resultant reaction suspension was adjusted to about 9 by the addition of 14 ml of caustic lye under stirring over about 30 minutes. Organic and aqueous layers were separated and the aqueous layer was extracted with 2x50 ml of toluene followed by separation of organic and aqueous layers. Both the organic layers were combined and the total organic layer was washed with 3x50 ml of water followed by separation of organic and aqueous layers. Organic layer was distilled completely at about 60° C under reduced pressure of about 600-650 mm Hg to afford 13 g of the title compound in the form of syrup.
EXAMPLE 6 PREPARATION OF APREPITANT (FORMULA I)
5 g of (2R, 3S)-2-{(1R)-1-[3,5-bis-trifluoro methyl phenyl] ethoxy}-3-(4-fluorophenyl) morpholine of Formula lib and 15 ml of N, N-dimethylformamide (DMF) were charged into a clean and dry round bottom flask followed by stirring for about 10 minutes. The resultant reaction solution was cooled to about 0° C followed by charging 1.8 g of potassium carbonate and 0.5 ml of water. 1.9 g of 3-chloromethyl-1,2,4-triazolin-5-one in 5 ml of N,N-dimethylformamide was added over about 15 minutes followed by stirring for about 3 hours. After the completion of the reaction, the reaction mass was quenched by the charging of 50 ml of water followed by charging 50 ml of ethyl acetate under stirring. Organic and aqueous layers were separated and the aqueous layer was extracted with 2x50 ml of ethyl acetate

followed by separation and combining of all the organic layers. Total organic layer was washed with 2x50 ml of water followed by separation of organic and aqueous layers. Organic layer was dried over 5 g of anhydrous sodium sulphate, followed by distillation of solvent completely at about 50° C under reduced pressure of about 600-650 mm Hg to afford a crude solid of the title compound. 50 ml of acetonitrile was charged to the crude solid followed by stirring for about 30 minutes followed by filtration of separated solid, and the solid was washed with 10 ml of acetonitrile. Solid obtained was dried at about 60° C under vacuum of about 600-650 mm Hg over about 5 hours to afford 3.8 g of the title compound in pure form. Purity by chiral HPLC of 99.9%.
EXAMPLE 7 PREPARATION OF frans-4-BENZYL-2-[2-(3,5-BIS-TRIFLUORO METHYL PHENYL)-ETHOXY]-3-(4-FLUOROPHENYL) MORPHOLINE (FORMULA Via)
500 g of the compound of Formula VIM and 2.5 liters of toluene were charged into a clean and dry round bottom flask followed by stirring for about 10 minutes. 240 g of potassium carbonate and 380 g of trichloroacetonitrile were charged followed by stirring for about 6 hours. Separated solid was filtered and the solid was washed with 500 ml of toluene. The resultant filtrate was taken into a Buchi Rotavapor and the solvent was distilled completely at about 50° C under vacuum of about 600-650 mm Hg to afford an intermediate compound in the form of syrup.
The above obtained syrup, 450 g of the compound of Formula Vila and 5 liters of tetrahydrofuran (THF) were charged into a clean and dry round bottom flask followed by cooling to about -15° C. 30 g of borontriflouride ethylrate was added over about 30 minutes followed by stirring for about 2 hours. The resultant reaction mass was quenched with a solution of 500 g of sodium carbonate and 500 g of sodium chloride in 1 liter of water over about 15 minutes. Organic and aqueous layers were separated and the organic layer was distilled completely at about 50° C under vacuum of about 600-650 mm Hg to afford 350 g of the title compound in the form of syrup.
EXAMPLE 8 PREPARATION OF frans-2-[1-(3,5-BIS-TRIFLUORO METHYL PHENYL)ETHOXY]-3-(4-FLUOROPHENYL)-MORPHOLINE (FORMULA Va)
350 g of frans-4-benzyl-2-[2-(3,5-bis-trifluoro methyl phenyl )-ethoxy]-3-(4-fluorophenyl) morpholine of Formula Via obtained in the above example and 1260 g

of para-toluenesulfonic acid dissolved in 1400 ml of toluene were charged into a clean and dry autoclave vessel followed by charging of 175 g of palladium on carbon and 700 ml of methanol. 3.5 kg/cm2 of anhydrous hydrogen gas pressure was applied to the reaction suspension at about 30 °C for a period of 3 hours. After the completion of the reaction, the reaction suspension was filtered through celite and the celite was washed with 700 ml of methanol followed by distillation of the filtrate completely at about 60° C under reduced pressure of about 600-650 mmHg to afford the residue. The above-obtained residue was dissolved in 2 liters of toluene followed by washing the toluene layer with 2x750 ml of aqueous 10% sodium carbonate solution. Separated the organic and aqueous layers followed by washing the organic layer with 3x750 ml of water. Organic and aqueous layers were separated and the organic layer was distilled at about 60° C under vacuum of about 600-650 mmHg to afford 230 g of an intermediate compound in the form of syrup.
120 g of the intermediate compound and 720 ml of N,N-dimethylformamide were charged into a clean and dry round bottom flask followed by stirring for about 10 minutes. 15 g of potassium carbonate was charged followed by cooling to about 0° C and 47.6 g of N-chlorosuccinamide was added in small portions under stirring over about 30 minutes. The resultant reaction mixture was stirred for about 30 minutes followed by drop wise addition of 55.5 g of dibromouracil (DBU) over about 30 minutes. The reaction mixture to attain the temperature of about 30° C followed by stirring for about 3 hours. After the completion of the reaction, the reaction mass was quenched by the addition of 1200 ml of water under stirring followed by charging of 1200 ml of toluene. Organic and aqueous layers were separated and the aqueous layer was extracted with 2x600 ml of toluene. Organic layers were combined and the total organic layer was washed with 3x600 ml of water followed by separation of organic and aqueous layers. Organic layer was dried over 100 g of anhydrous sodium sulphate followed by distillation of organic layer completely at about 60° C under vacuum of about 600-650 mm Hg to afford 98.5 g of the title compound in the form of a solid.
EXAMPLE 9 PREPARATION OF (2R, 3S)-2-{(1R)-1-[3,5-BIS-TRIFLUOROMETHYL PHENYL] ETHOXY}-3-(4-FLUOROPHENYL) MORPHOLINE (FORMULA IVa)
50 g of frans-2-[1-(3,5-bis-trifluoro methyl phenyl)ethoxy]-3-(4-fluorophenyl)-morpholine of Formula Va, 50 g of (5%) palladium on carbon and 500 ml of methanol

were charged into a clean and dry hydrogenation vessel followed by applying 3 kg/cm2 dry hydrogen gas pressure under agitation for about 3 hours. After the completion of the reaction, the suspension was filtered through celite and the celite was washed with 150 ml of methanol. The resultant filtrate was distilled completely at about 50° C under vacuum to afford 46 g of the title compound in the form of syrup.
EXAMPLE 10 PREPARATION OF (2R, 3S)-2-{(1R)-1-[3,5-BIS-TRIFLUOROMETHYL PHENYL] ETHOXY}-3-(4-FLUOROPHENYL) MORPHOLINE (FORMULA lib)
40 g of (2R, 3S)-2-{(1R)-1-[3,5-bis-trifluoromethyl phenyl] ethoxy}-3-(4-fluorophenyl) morpholine of Formula IVa and 400 ml of toluene were charged into a clean and dry round bottom flask followed by stirring for about 10 minutes. 17.5 g of para-toluenesulfonic acid monohydrate was charged and the resultant reaction mixture was stirred for about 45 minutes. The reaction solution was distilled at about 60° C under vacuum of about 600-650 mm Hg followed by cooling to about 30° C and charging of 40 ml of toluene and 160 ml of petroleum ether to the residue and stirring for about 3 hours. Separated solid was filtered and the solid was washed with 80 ml of petroleum ether. The solid obtained and 100 ml of toluene were charged into a clean and dry round bottom flask followed by stirring for about 15 minutes. 200 ml of water was charged and the pH of the resultant reaction suspension was adjusted to about 9.5 by the addition of 14 ml of caustic lye under stirring. Organic and aqueous layers were separated and the aqueous layer was extracted with 2x50 ml of toluene followed by separation of organic and aqueous layers. Total organic layer was washed with 3*50 ml of water followed by separation of organic and aqueous layers and the organic layer was distilled at about 60° C under vacuum of about 600-650 mm Hg to afford 12.2 g of the title compound in the form of syrup.
EXAMPLE 11 PREPARATION OF APREPITANT (FORMULA I)
5 g of (2RI3S)«2-{(1R)-1-[3,5-bis-trifluoromethyl phenyl] ethoxy}-3-(4-fluorophenyl) morpholine of Formula lib and 15 ml of N,N-dimethylformamide (DMF) were charged into a clean and dry round bottom flask followed by stirring for about 5 minutes. The resultant reaction solution was cooled to about 0° C followed by charging 1.8 g of potassium carbonate and 0.5 ml of water. 1.9 g of 3-chIoromethyl-1,2,4-triazolin-5-one in 5 ml of N,N-dimethylformamide (DMF) was added over about

15 minutes followed by stirring at about 30 °C for about 3 hours. After the completion of the reaction, the reaction mass was quenched by the addition of 50 ml of water followed by charging 50 ml of ethyl acetate under stirring. Organic and aqueous layers were separated and the aqueous layer was extracted with 2x50 ml of ethyl acetate followed by separation and combining of all the organic layers. Total organic layer was washed with 2x50 ml of water followed by separation of organic and aqueous layers. The organic layer was dried over 5 g of anhydrous sodium sulphate, followed by distillation of solvent completely at about 50° C under vacuum to afford a crude solid of the title compound. 50 ml of acetonitrile was charged to the crude solid followed by stirring for about 30 minutes and separation of solid by filtration, and the solid was washed with 10 ml of acetonitrile. Solid obtained was dried at about 60° C under vacuum of about 600-650 mm Hg for about 5 hours to afford 3.7 g of the title compound in a pure form with purity by chiral HPLC of 99.95%.

We Claim:
1. A process for preparing aprepitant, comprising reducing a compound having
Formula IVb,

using a reducing agent, to form a compound having Formula 1Mb,

and recovering a compound having Formula lib from a diastereomeric crystallization.

I
F
2. The process of claim 1 where in the reducing agent comprises palladium, sodium borohydride, potassium borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate(Vitride), sodium cyanoborohydride, sodium triacetoxyborohydride.
3. A process for preparing aprepitant, comprising recovering.a compound having Formula lib,
r

from a diastereomeric crystallization of an isomeric mixture having Formula Ilia.

4. The process of either of claims 1 or 3, wherein diastereomeric crystallization comprises reacting with p-toluenesulfonic acid.
5. The process of any one of claims 1-4, further comprising reacting a compound having Formula lib

F with a compound having Formula II, in the presence of a base.

6. The process of claim 1 wherein the compound of Formula IVb is obtained by
a process comprising
a) reacting the _ compound (-)-trans-morpholinol of Formula VIII with the

com
to afford the compound of Formula Vlb in the presence of a suitable base;

1
b) debenzylating the compound of Formula Vlb with a suitable reducing agent
to afford the compound of Formula Vb; and

c) reacting the compound of Formula Vb with a suitable dehydrogenating
agent.
7. The process of claim 3 wherein the compound of Formula Ilia is obtained by a process comprising:
a) reacting the compound of Formula VIII with trichloroacetonitrile, followed by reaction with the compound of Formula Vila in the presence of suitable base
F F3C ^3
Formula VIII Formula Vila
to afford the compound of Formula Via;
/
Formula Via
b) debenzylating the compound of Formula Via using a suitable reducing
agent to afford the compound of Formula Va

c) dehydrogenating the compound of Formula Va using a suitable
dehydrogenating agent to afford the compound of Formula IVa

d) treating the compound of Formula IVa using a suitable reducing agent.
8. The process of either of claims 6 or 7 where in the reaction step a) occurs in
the presence of base selected from organic or inorganic base.
9. The process of either of claims 6 or 7 where in the reaction step b) occurs in
the presence of hydrogen with a palladium catalyst as reducing agent,
10. The process of either of claims 6 or 7 where in the reaction step c) occurs in
the presence of a dehydrogenating agent selected from 1,8-Diazabicyclo [5.4.0]
undec-7-ene (DBU), N-chlorosuccinimide (NCS), 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ).