Indian Patents. 279324:AN IMPROVED PROCESS FOR THE PREPARATION OF APREPITANT

Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF APREPITANT
Abstract	The present invention relates to an improved process for the preparation of Aprepitant compound of formula-1 through a novel oxalate salt of 2(R)-[l-(R)-3,5-bis-(trifluoromethyl)phenyl)ethoxy]-3(S)"(4-fluoro phenyl) morpholine compound of formula-VII.

Full Text	AN IMPROVED PROCESS FOR THE PREPARATION OF APREPITANT Field of the Invention: The present invention relates to process for the preparation of Aprepitant. The present invention provides an improved process for the preparation of Aprepitant, which is chemically known as 5-[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy] -3-(4-fluorophenyl)-4-morpholinyl]methyl]-l,2-dihydrO-3H-l,2,4-triazol-3-one, having structural formula-I. Aprepitant is a useful therapeutic agent, specifically as a P (neurokinin-1) receptor antagonist useful in the treatment of chemotherapy-induced nausea and vomiting. It is T\>l commercially available in the market under the brand name EMEND TM as 80 mg or 125 mg capsules. Background of the Invention: Aprepitant and the process for its preparation is disclosed in US patent number 5719147, The disclosed process involves the condensation of 2(R)-( 1 -(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl morpholine with N-methyl carboxy-2-chloroacetamidrazone in the presence of the base N,N-diisopropylethylamine and the solvent acetonitrile. Subsequent processing by flash chromatography using methylene chloride/methanol/ammonium hydroxide as eluant in a ratio of 50:1:0.1 to provide 2(R)-(l-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(N-methylcarboxyacetamidrazono)morpholine which was cyclised by refluxing in xylene and purified by flash chromatography using methylene chloride/methanol/ammonium hydroxide as eluant in a ratio of 50:1:0.1 to provide aprepitant. International publication number WO 01/96315 discloses the preparation of aprepitant by the condensation of the 3-chloromethyl-l,2,4-triazolin"5-one with 2(R)-(1-(R)-(3,5-bis (trifluoromethyl) phenyl) ethoxy) -3-(S)-(4-fluoro) phenyl morpholine. The general processes disclosed in the above patents result in relatively low and inconsistent yields of the desired products. Also separation of enantiomers formed and isolating the products by chromatographic techniques is difficult. And therefore it is not an ideal technique. U.S. Patent number 6,395,898 discloses the preparation of optically pure intermediate compound 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl morpholine which features a highly stereo selective Lewis acid catalyzed transacetylization of (R)-3,5-bis(trifluoromethyl) phenyl ethanol with trichlroacetamidate 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 (lS,2R)-cis-l-aminoindan-2-ol and dichloro (p-cymene)Ru(II) dimer as a metal source. This route is industrially and economically not feasible because expensive raw materials such as dichloro(p-cymene)Ru(II) dimer are involved. Further, the selective substitution reactions are governed by the thermodynamic stability of the intermediates 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro)-phenyl morpholine prepared by reaction of 3,5-bis(trifluoromethyl)benzyl alcohol and 2,6-di-tert-butyl-4-methylpyridine in the presence of carbon tetrachloride which is further treated with trifluoromethanesulfonic anhydride to afford 3,5-Bis(trifluoromethyl)benzyl alcohol, trifluromethanesulfonate ester. N-benzyl-3-(S)-phenylmorpholin-2-one was treated with lithium tri(sec-butyl)-borohydride (L-SelectrideTM) in THF at -75°C, then above obtained 3,5"bis(trifluoro methyl) benzyl alcohol, trifluromethanesulfonate ester was added, after completion of reaction it was extracted with ethyl acetate and concentrated in vacuum to afford residue. The residue was purified by flash chromatography to afford pure 4-Benzyl-2-(S)-(3,5-bis (trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro)phenylmorpholine. The above obtained 4-Benzyl-2-(S)-(3,5-bis (trifluoromethyl) benzyloxy)-3-(S)-(4-fluoro) phenylmorpholine was reduced by Pd/C. The resultant residue was purified by flash chromatography to give pure 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro)phenyl-morpholine which are highly sensitive to minor process variations such as temperature, moisture, time, and rate of addition, solvent and thus the processes are practically found to be inconsistent in producing the desired stereochemistry.(R)-(3,5-bis(trifluoromethyl)phenyl) ethanol is reacted with tricholoroimidate in toluene at below -20°C,then quenched via addition of a mixture of 10% brine to provide trans-glycoside International publication number WO 03/089429 discloses the preparation of aprepitant of Formula I which involves condensation of the hydrochloride salt of (2R,2-α-R,3S)-2-[l"(3,5-bis(trifluoromethyl)pheny)ethoxy]-3-(4-fluorophenyl)-l,4-oxazine with amidrazone in presence of potassium carbonate and the organic solvents toluene and dimethylsulfoxide to give an intermediate, which on cyclization at 140°C affords aprepitant. In summary, some of the disadvantages of the foregoing processes include; i) the purity of the isolated aprepitant is low, thereby requiring additional steps like flash chromatography, which is industrially not feasible, to obtain a pharmaceutically acceptable substance; ii) the chemical yield of aprepitant is low; iii) high temperature reactions are involved iv) a lengthy time cycle is required ; and v) expensive reagents are used. As such there is a need for a process for the preparation of aprepitant that is cost effective and utilizes readily available reagents In contrast to previously known processes, the present invention provides a more efficient, practical and economical method for preparing the aprepitant in relatively high yield and purity. Brief description of the Invention: The present invention relates to an improved process for the preparation of aprepitant. Aprepitant is chemically known as 5-[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoro-methyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, represented as a compound of formula-I. Accordingly the main feature of the present invention is to provide an improved process for the preparation of aprepitant of formula-1, which comprises of the following steps; a) alkylation of (S)-2-(benzyl amino)-2-(4-Fluorophenyl) acetic acid (formula-II) with 1,2-dihaloethane, followed by treatment with an acid gives an acid addition salt of the compound of formula-Ill, b) reducing the compound of formula-Ill or its salt thereof, with an active hydride reducing agent, and subsequently reacting this mixture with substituted benzoyl halide compound of formula-IV provides compound of formula-V. c) conversion of Formula-V using "Titanium ylide" to provide an enol ether of Formula-VI, d) reduction and debenzylation of the compound of formula-VI with suitable reducing agents and treating the compound formed with oxalic acid to provide an oxalate salt of the compound of formula-VII, e) reacting the oxalate salt of formula-VII with N-methylcarboxyI-2-chloroacetamidrazone in presence of suitable base and suitable organic solvents to obtain a compound of formula VIII, f) cyclising the compound of Formula-VIII, to get aprepitant (formula-I), g) purifying the aprepitant formed in step f) to provide pure aprepitant. Brief Description of the Drawings: Figure-1: Illustrates the powder X-ray powder diffractogram of aprepitant. Figure-2: Illustrates the photographs of aprepitant recorded on a microscope. Detailed Description of the Invention: The present invention relates to a novel process for the preparation of Aprepitant. Aprepitant, chemically known as 5-[[(2R,3S)-2-[l(lR)-l-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-Dihydro-3H-1,2,4-triazol-3-one represented as a compound of formula-I Accordingly the main feature of the present invention is to provide a novel process for the preparation of Aprepitant compound of formula-1, which comprises of the following steps; a) The alkylation of (S)-2-(benzylamino)-2-(4-fluorophenyl) acetic acid compound of formula II, with 1,2 dihaloethane in presence of suitable base in an organic solvent, gives a compound of formula-Ill, which on treatment with an acid provided the acid addhion salt of the compound of formula-Ill, b) reducing the above compound of formula-Ill or its salt thereof, with active hydride reducing agent in presence of suitable organic solvents, reacting this mixture with substituted benzoyl halide compound of formula-IV, to obtain compound of Formula-V, c) conversion of Formula-V using "Titanium ylide" in presence of organic solvents to produce an enol-ether of Formula-VI, Formula-VI d) reduction and debenzylation of the compound of formula VI with a suitable reducing agent in presence of suitable organic solvent, to give the free base of compound of formula-VII, which on subsequent treatment with oxalic acid to provide an oxalate salt of Formula-VII, e) reacting the oxalate salt of Formula-VII with N-methylcarboxyl-2-chloro-acetamidrazone in presence of suitable bases and suitable organic solvents to obtain a compound of formula-VIII, which has been isolated as a solid with the usage of suitable organic solvent, g) purifying the aprepitant formed in step f) to provide pure aprepitant. In the step a) compound of formula-II is alkylated with 1,2-dibromoethane in the presence of diisopropylethylamine to provide the morpolin-2-one derivative(formula-III). The reaction is carried out in toluene solvent, which improved the yield, purity and also facilitated the formation of crystalline acid addition salt of the morpholin-2-one by the addition of an acid. The acid is selected from group consisting of hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, hydrogenbromide, hydrogen iodide, trifluoromethane sulfonic acid, camphor sulfonic acid, sulfuric acid, phosphoric acid, benzene sulphonic acid, p-toluene sulfonic acid and p-chlorobenzene sulfonic acid. In the step b) the compound of formula-Ill is contacted with active hydride reagent, lithium tri(sec-butyl)-borohydride (L-selectride®) at low temperature around -78°C in toluene solvent, and the resulting intermediate is reacted with 3,5-bis (trifluoromethyl)benzoyl chloride (formula-IV) to provide 2,3-cis substituted product of formula-V. In the step c) the compound of formula-V is converted to its enol ether compound of formula-VI, using "titanium ylide" generated with dimethyl titanonocene (Petasis,N.A,, Bzowej,E.I., Journal of the American Chemical Society, 112, 6392 (1990)). The solvents used for the reaction are tetrahydrofuran and toluene. In the step d) the compound of formula-VI is treated with 5% Pd/C/Ha in methanol, in conditions which assisted in simultaneous reduction of the double bond and to remove the N-benzyl group on the morpholine nitrogen as well, to provide the compound of formula-VII. The processes in the prior art utilized two different reducing agents, first to reduce the double bond and second to remove the N-benzyl group on the morpholine nitrogen. Hence the present invention has been able to reduce the number reagents used in this stage. Also the use of 5% Pd/C for the reduction of the double bond provided greater yield of the required isomer. Compound of formula-VII was converted into its oxalate salt by adding oxalic acid to yield the crystalline acid addition salt with high purity. The p-toluene sulfonic acid salt of compound of formula-VII was also prepared. It has been observed that the inorganic acid salt of formula-VII were found to be hygroscopic in nature, hence were not suitable for getting high pure compound of formula-VII. The oxalate salt was found to be manifest with more salient properties like purity, crystalline nature and non hygroscopic in nature etc. when compared with p-toluene sulfonic acid salt. In the step e) the oxalate salt of Formula-VII was treated with N-methylcarboxyl-2-chloro acetamidrazone in presence of potassium carbonate and dimethyl sulfoxide solvent to obtain a compound of formula-VIII, which was isolated as a solid using cyclohexane solvent. In the processes disclosed in prior art the compound of formula-VIII was reported as a foamy substance which was obtained as a residue on dry distillation. Isolation of the above compound by filtration from the solvent provided highly pure intermediate, which on subsequent cyclisation provided aprepitant of high purity. In the step f) the compound of Formula-VIII was taken in xylene and heated to 130°C in the presence of diisopropylethylamine to provide aprepitant of formula (I) which was isolated using a mixture of methanol and water to provide aprepitant. In the step g) the aprepitant formed in step f) is crystallized using methanol, water or a mixture thereof to provide aprepitant of high purity. The present invention provides aprepitant with particles having irregular flake morphology as illustrated in photographs of microscopic aprepitant in figure-2, which could be further micronised or milled to provide highly crystalline aprepitant. Analysis of particle size distribution of aprepitant: A Malvern laser diffraction instrument was used to characterize the particle size distribution of aprepitant. Instrument model: Malvern Mastersizer 2000 Technique used: Wet method Instrument parameters: i) Material RI: 1,500 ii) Dispersant RI: 1.330 iii) Dispersant: water iv) Sensitivity: Normal v) Particle shape : Irregular The present invention is schematically represented by the following scheme-L The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. EXAMPLES Example-1: Preparation of (S) -3-(4-fluorophenyI)- 4-benzyl -morphoIin-2-one hydrochloric acid. (Formula-Ill) To a solution compound of formula II (25 grams) in toluene (500 ml), added 1,2 dibromoethane (179.85 grams) and diisopropylethyl amine (50 ml). Reaction mixture was heated to reflux and stirred for 20-24 hrs. Quenched the reaction mixture with water and extracted the aqueous layer with toluene. The organic layer was washed with sodium bicarbonate solution followed by sodium chloride solution. The organic solvent was distilled off under reduced pressure and the residue was converted into hydrochloride salt using ethyl acetate hydrochloride at 0-5°C. Solid formed was filtered and dried to get the title compound. Yield: 18 grams Example-2: Preparation of (2R,3S)-4-benzyl-3-(4-fluorophenyI)morpholin-2-yl-3,5-bis(trifluoromethyl)benzoate (Formula-V). To the compound of formula-Ill (23 grams) was converted in to its free base using water and sodium carbonate. Extracted the reaction mixture with toluene and distilled the toluene to get the crude free base of formula-Ill. Dissolved the free base in tetrahydofuran and added L-selectride at -70 to -75°C. Stirred the reaction mixture for 15-30 min at the same temperature and then added 3,5-bis(trifluoromethyl)benzoyl chloride (25.19 grams). Maintained the reaction mixture for 15-30 min at -70 to -75°C, quenched the reaction mixture using mixture of acetic acid and tetrahydrofuran, then distilled the reaction mixture below 40°C. Added water to the reaction mixture and extracted it using n-hexane. The n-hexane layer was washed using a solution of 10 % sodium carbonate. The organic layer was distilled off completely; the solid formed was isolated and re-crystallized using isopropyl alcohol solvent to get the title compound. Yield: 16 gm. Example-3: Preparation of (2R,3S)-2-[[l-[3,5-bis(trifluoromethyI)phenyl] ethenyI]oxy]-3-(4-fluorophenyl)-4-benzyI morpholine (Formula-VI), Methyl magnesium chloride (119.3 ml) was added to the solution of titonocene dichloride in toluene (360 ml). The reaction mixture was stirred for 60-90 min at 0-5°C and the complete formation of Dimethyl titanocene was confirmed by HPLC analysis. Quenched the reaction mixture using 12% ammonium chloride solution at 0-5°C the layers then separated, added formula-V compound (20 grams) and concentrated the organic layer volume to 70-80 ml below 35°C. Heated to SO-SS^'C and maintained for 5-6 hrs at 80-85°C and concentrated the reaction mixture to 30-40 ml below 40°C then slowly added n-Heptane (100 ml) during 10-15 min to the reaction mixture. Filtered the reaction mixture for the elimination of byproduct and concentrated the reaction mixture to 20-25 ml below 40°C then added sodium carbonate (3.5 grams), methanol (48 ml) and water (2.5 ml), heated the reaction mixture to 40-45°C then maintained for 12 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, filtered the mixture and washed with toluene (32 ml) then distilled off the solvent completely under reduced pressure. Co-distilled the reaction mixture using 32 ml of methanol and added 80 ml of methanol to the crude compound and heated the reaction mixture to 50°C, then added 50% aqueous methanol at 25-30°C. Solid precipitated was filtered and dried to get the title compound. Yield: 14 grams. Example-4: Preparation of 2(R)-[l-(R)-3,5-bis-(trifluoromethyl)phenyI)ethoxy]-3(S)-(4-fluorophenyl) morpholine oxalate (Formula-VII). A mixture of compound of formula-VI (10 grams), methanol (50 ml), ethyl acetate (50 ml) and 5% palladium carbon was taken in an autoclave vessel. Reaction mixture was hydrogenated at ambient temperature by applying 3-4 Kg's of hydrogen pressure. The reaction mixture was filtered to remove the palladium carbon and the filtrate was distilled off completely under reduced pressure. Oxalic acid in methanol was added to the reaction mixture. The precipitated compound was filtered and dried to get the title compound. Yield: 7 grams. M.R: 102-110° C, Purity by HPLC is >99%. Example-5: Preparation of 2-(R)-[l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxyl -3- (S)-(4-fluoro)phenyl-4-(2-(N-methylcarboxyacetamidrazono)morpholine (Formula-VIII): The compound of formula VII (15 grams) was converted in to its free base by treating it with 10% sodium hydroxide solution. The free base was extracted into dichloromethane (150 ml) then the solvent distilled off to get the free base of formula-VII. The free base was dissolved in DMSO (75 ml) and added potassium carbonate (9.6 grams). To the above mixture a solution of N-mehylcarboxy-2- chloroacetamidrazone dissolved in DMSO (45 ml) was added. The reaction mixture was stirred for 30-60 min and then quenched with water (75 ml). The reaction mixture was extracted with dichloromethane (75 ml and 45 ml) and the combined organic layer was washed using saturated sodium carbonate solution (25 ml), followed by saturated sodium chloride solution (25 ml). The organic layer was distilled off and the solid formed was slurried in cyclohexane (15 ml). The solid obtained was filtered and dried to get the title compound. Yield: 13.5 grams. Example-6: Preparation of Aprepitant (Formula-I): Compound of formula-VIII (10 grams) was taken in a mixture of xylene (55.5 ml) and NjN-diisopropylethyl amine (34.4 ml) and then refluxed for 4-6 hrs then cooled the reaction mixture. Filtered the precipitated compound and washed with xylene (5 ml) to get the crude Aprepitant. The crude compound was crystallized from a mixture of methanol and water to get Aprepitant. Yield: 6.5 grams. Example-7: Purification of Aprepitant (Formula-I): The crude aprepitant obtained in example-6 (65 grams) was dissolved in methanol (650 ml) by heating the reaction mixture to reflux temperature. Carbon was added and stirred for 5-10 min at reflux temperature. The reaction mixture was filtered through hyflow-bed and washed with methanol (65 ml). The reaction mixture was cooled and added water (585 ml) slowly in 45-60 min and stirred for 30-45 min at 25-30°C. Filtered the compound, washed with water (65 ml), and dried to get a pure compound of formula (I); Aprepitant. Yield: 60.6 grams Particle size distribution: D(0.1):9.206 ; D (0.5):27.373 ; D(0.9):73.182 ; D(l.OO): 198.04. We Claim: 1. A process for the preparation of Aprepitant compound of formula-1, which comprises of the following steps; a) The alkylation of (S)-2-(benzyl amino)-2-(4-fluorophenyl) acetic acid compound of formula II, Formula (II) with 1,2-dibromoethane in presence of suitable base like diisopropylethyl amine in a suitable organic solvent, to provide a compound of formula-Ill, which on treatment with hydrochloric acid provided the hydrochloride salt of the compound of formula-Ill, b) reducing the above compound of formula-III or its salt thereof, with lithium tri (sec-butyl)-borohydride (L-selectride®) at low temperature around -78°C in toluene solvent, and reacting this mixture with substituted benzoyl halide compound of formula-IV, to obtain compound of Formula-V, c) conversion of Formula-V using "Titanium ylide" in presence of tetrahydrofuran and toluene, to produce an enol-ether of Formula-VI, h) reduction and debenzylation of the compound of formula VI with a suitable reducing agent in presence of suitable organic solvent, to give the free base of compound of formula-VII, which on subsequent treatment with oxalic acid in a suitable solvent to provide an oxalate salt of Formula-VII, d) reacting the oxalate salt of Formula-VII with N-methylcarboxyl-2-chloroacet- amidrazone in presence of potassium carbonate and dimethylsulfoxide solvent to obtain a compound of formula-VIII, isolated as a solid using cyclohexane solvent, e) cyclising the compound of Formula-VIII, by refluxing it in xylene in the presence of a N,N-diisopropyl amine, followed by isolation from a mixture of methanol and water to obtain aprepitant of formula (I), f) purifying the aprepitant formed in step f) recrystallizing it using methanol, water or a mixture thereof to provide pure aprepitant. 2. A process of claim-1, wherein the solvent used in step a) for alkylation of compound of formula-II, is toluene. 3. A process of claim-1, wherein salt of compound of formula-VII is an oxalate salt. 4. A process of claim-1, wherein the compound of formula-VIII is isolated as a solid. 5. Aprepitant obtained as per the process of claim-1, having a mean particle size in the range of 30-60 \|im and D (v 0.9) in the range of 60-90 µm. 6. A process for the preparation of the oxalate salt of compound of formula-VII, which comprises of: a) Reduction of double bond and debenzylation of Formula-VI using hydrogen and 5% palladium on carbon, b) treating the resulting free base of compound of formula-VII, with a solution of oxalic acid in methanol to precipitate the oxalate salt of compound of formula-VII followed by optionally purifying the obtained solid in a suitable solvent to provide highly pure oxalate compound of formula-VII. 7. The process of claim 6, in step b) wherein the solvent used for purification is selected from methanol, ethanol, isopropyl alcohol, n-butanol and ethyl acetate. 8. A compound of 2(R)-[l-(R)-3,5-bis-(trifluoromethyl)phenyl)ethoxy]-3(S)-(4-fluoro phenyl) morpholine oxalate having the following structure. 9. A process for the preparation of the compound of formula-VIII as a solid, which comprises of treating the free base of compound of formula-VII or its salt with N- methylcarboxy-2-chloroacetamidrazone in presence of potassium carbonate and dimethylsulfoxide, followed by isolation using cyclohexane solvent. 10. Aprepitant with particles having the shape of irregular flakes when photographed with a microscope.

Full Text

AN IMPROVED PROCESS FOR THE PREPARATION OF
APREPITANT
Field of the Invention:
The present invention relates to process for the preparation of Aprepitant. The present invention provides an improved process for the preparation of Aprepitant, which is chemically known as 5-[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy] -3-(4-fluorophenyl)-4-morpholinyl]methyl]-l,2-dihydrO-3H-l,2,4-triazol-3-one, having structural formula-I.
Aprepitant is a useful therapeutic agent, specifically as a P (neurokinin-1) receptor antagonist useful in the treatment of chemotherapy-induced nausea and vomiting. It is
T\>l
commercially available in the market under the brand name EMEND TM as 80 mg or 125 mg capsules.
Background of the Invention:
Aprepitant and the process for its preparation is disclosed in US patent number 5719147, The disclosed process involves the condensation of 2(R)-( 1 -(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl morpholine with N-methyl carboxy-2-chloroacetamidrazone in the presence of the base N,N-diisopropylethylamine and the solvent acetonitrile. Subsequent processing by flash chromatography using methylene chloride/methanol/ammonium hydroxide as eluant in a ratio of 50:1:0.1 to provide 2(R)-(l-(R)-3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(N-methylcarboxyacetamidrazono)morpholine which was cyclised by refluxing in xylene and purified by flash chromatography using methylene chloride/methanol/ammonium hydroxide as eluant in a ratio of 50:1:0.1 to provide aprepitant.

International publication number WO 01/96315 discloses the preparation of aprepitant by the condensation of the 3-chloromethyl-l,2,4-triazolin"5-one with 2(R)-(1-(R)-(3,5-bis (trifluoromethyl) phenyl) ethoxy) -3-(S)-(4-fluoro) phenyl morpholine.
The general processes disclosed in the above patents result in relatively low and inconsistent yields of the desired products. Also separation of enantiomers formed and isolating the products by chromatographic techniques is difficult. And therefore it is not an ideal technique.
U.S. Patent number 6,395,898 discloses the preparation of optically pure intermediate compound 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl morpholine which features a highly stereo selective Lewis acid catalyzed transacetylization of (R)-3,5-bis(trifluoromethyl) phenyl ethanol with trichlroacetamidate 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 (lS,2R)-cis-l-aminoindan-2-ol and dichloro (p-cymene)Ru(II) dimer as a metal source. This route is industrially and economically not feasible because expensive raw materials such as dichloro(p-cymene)Ru(II) dimer are involved.
Further, the selective substitution reactions are governed by the thermodynamic stability of the intermediates 2-(S)-(3,5-Bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro)-phenyl morpholine prepared by reaction of 3,5-bis(trifluoromethyl)benzyl alcohol and 2,6-di-tert-butyl-4-methylpyridine in the presence of carbon tetrachloride which is further treated with trifluoromethanesulfonic anhydride to afford 3,5-Bis(trifluoromethyl)benzyl alcohol, trifluromethanesulfonate ester.
N-benzyl-3-(S)-phenylmorpholin-2-one was treated with lithium tri(sec-butyl)-borohydride (L-SelectrideTM) in THF at -75°C, then above obtained 3,5"bis(trifluoro methyl) benzyl alcohol, trifluromethanesulfonate ester was added, after completion of reaction it was extracted with ethyl acetate and concentrated in vacuum to afford residue. The residue was purified by flash chromatography to afford pure 4-Benzyl-2-(S)-(3,5-bis (trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro)phenylmorpholine.

The above obtained 4-Benzyl-2-(S)-(3,5-bis (trifluoromethyl) benzyloxy)-3-(S)-(4-fluoro) phenylmorpholine was reduced by Pd/C. The resultant residue was purified by flash chromatography to give pure 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro)phenyl-morpholine which are highly sensitive to minor process variations such as temperature, moisture, time, and rate of addition, solvent and thus the processes are practically found to be inconsistent in producing the desired stereochemistry.(R)-(3,5-bis(trifluoromethyl)phenyl) ethanol is reacted with tricholoroimidate in toluene at below -20°C,then quenched via addition of a mixture of 10% brine to provide trans-glycoside
International publication number WO 03/089429 discloses the preparation of aprepitant of Formula I which involves condensation of the hydrochloride salt of (2R,2-α-R,3S)-2-[l"(3,5-bis(trifluoromethyl)pheny)ethoxy]-3-(4-fluorophenyl)-l,4-oxazine with amidrazone in presence of potassium carbonate and the organic solvents toluene and dimethylsulfoxide to give an intermediate, which on cyclization at 140°C affords aprepitant.
In summary, some of the disadvantages of the foregoing processes include;
i) the purity of the isolated aprepitant is low, thereby requiring additional steps like
flash chromatography, which is industrially not feasible, to obtain a pharmaceutically
acceptable substance; ii) the chemical yield of aprepitant is low; iii) high temperature reactions are involved iv) a lengthy time cycle is required ; and v) expensive reagents are used.
As such there is a need for a process for the preparation of aprepitant that is cost effective and utilizes readily available reagents
In contrast to previously known processes, the present invention provides a more efficient, practical and economical method for preparing the aprepitant in relatively high yield and purity.

Brief description of the Invention:
The present invention relates to an improved process for the preparation of aprepitant. Aprepitant is chemically known as 5-[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoro-methyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, represented as a compound of formula-I.

Accordingly the main feature of the present invention is to provide an improved process for the preparation of aprepitant of formula-1, which comprises of the following steps;
a) alkylation of (S)-2-(benzyl amino)-2-(4-Fluorophenyl) acetic acid (formula-II) with 1,2-dihaloethane, followed by treatment with an acid gives an acid addition salt of the compound of formula-Ill,
b) reducing the compound of formula-Ill or its salt thereof, with an active hydride reducing agent, and subsequently reacting this mixture with substituted benzoyl halide compound of formula-IV provides compound of formula-V.
c) conversion of Formula-V using "Titanium ylide" to provide an enol ether of Formula-VI,
d) reduction and debenzylation of the compound of formula-VI with suitable reducing agents and treating the compound formed with oxalic acid to provide an oxalate salt of the compound of formula-VII,
e) reacting the oxalate salt of formula-VII with N-methylcarboxyI-2-chloroacetamidrazone in presence of suitable base and suitable organic solvents to obtain a compound of formula VIII,
f) cyclising the compound of Formula-VIII, to get aprepitant (formula-I),
g) purifying the aprepitant formed in step f) to provide pure aprepitant.

Brief Description of the Drawings:
Figure-1: Illustrates the powder X-ray powder diffractogram of aprepitant. Figure-2: Illustrates the photographs of aprepitant recorded on a microscope.
Detailed Description of the Invention:
The present invention relates to a novel process for the preparation of Aprepitant. Aprepitant, chemically known as 5-[[(2R,3S)-2-[l(lR)-l-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-Dihydro-3H-1,2,4-triazol-3-one represented as a compound of formula-I

Accordingly the main feature of the present invention is to provide a novel process for the preparation of Aprepitant compound of formula-1, which comprises of the following steps;
a) The alkylation of (S)-2-(benzylamino)-2-(4-fluorophenyl) acetic acid compound
of formula II,
with 1,2 dihaloethane in presence of suitable base in an organic solvent, gives a compound of formula-Ill, which on treatment with an acid provided the acid addhion salt of the compound of formula-Ill,

b) reducing the above compound of formula-Ill or its salt thereof, with active
hydride reducing agent in presence of suitable organic solvents, reacting this
mixture with substituted benzoyl halide compound of formula-IV,

to obtain compound of Formula-V,

c) conversion of Formula-V using "Titanium ylide" in presence of organic solvents
to produce an enol-ether of Formula-VI,

Formula-VI
d) reduction and debenzylation of the compound of formula VI with a suitable
reducing agent in presence of suitable organic solvent, to give the free base of

compound of formula-VII, which on subsequent treatment with oxalic acid to provide an oxalate salt of Formula-VII,

e) reacting the oxalate salt of Formula-VII with N-methylcarboxyl-2-chloro-acetamidrazone in presence of suitable bases and suitable organic solvents to obtain a compound of formula-VIII, which has been isolated as a solid with the usage of suitable organic solvent,

g) purifying the aprepitant formed in step f) to provide pure aprepitant.
In the step a) compound of formula-II is alkylated with 1,2-dibromoethane in the presence of diisopropylethylamine to provide the morpolin-2-one derivative(formula-III). The reaction is carried out in toluene solvent, which improved the yield, purity and also facilitated the formation of crystalline acid addition salt of the morpholin-2-one by the

addition of an acid. The acid is selected from group consisting of hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, hydrogenbromide, hydrogen iodide, trifluoromethane sulfonic acid, camphor sulfonic acid, sulfuric acid, phosphoric acid, benzene sulphonic acid, p-toluene sulfonic acid and p-chlorobenzene sulfonic acid.
In the step b) the compound of formula-Ill is contacted with active hydride reagent, lithium tri(sec-butyl)-borohydride (L-selectride®) at low temperature around -78°C in toluene solvent, and the resulting intermediate is reacted with 3,5-bis (trifluoromethyl)benzoyl chloride (formula-IV) to provide 2,3-cis substituted product of formula-V.
In the step c) the compound of formula-V is converted to its enol ether compound of formula-VI, using "titanium ylide" generated with dimethyl titanonocene (Petasis,N.A,, Bzowej,E.I., Journal of the American Chemical Society, 112, 6392 (1990)). The solvents used for the reaction are tetrahydrofuran and toluene.
In the step d) the compound of formula-VI is treated with 5% Pd/C/Ha in methanol, in conditions which assisted in simultaneous reduction of the double bond and to remove the N-benzyl group on the morpholine nitrogen as well, to provide the compound of formula-VII. The processes in the prior art utilized two different reducing agents, first to reduce the double bond and second to remove the N-benzyl group on the morpholine nitrogen. Hence the present invention has been able to reduce the number reagents used in this stage. Also the use of 5% Pd/C for the reduction of the double bond provided greater yield of the required isomer. Compound of formula-VII was converted into its oxalate salt by adding oxalic acid to yield the crystalline acid addition salt with high purity. The p-toluene sulfonic acid salt of compound of formula-VII was also prepared. It has been observed that the inorganic acid salt of formula-VII were found to be hygroscopic in nature, hence were not suitable for getting high pure compound of formula-VII. The oxalate salt was found to be manifest with more salient properties like purity, crystalline nature and non hygroscopic in nature etc. when compared with p-toluene sulfonic acid salt.

In the step e) the oxalate salt of Formula-VII was treated with N-methylcarboxyl-2-chloro acetamidrazone in presence of potassium carbonate and dimethyl sulfoxide solvent to obtain a compound of formula-VIII, which was isolated as a solid using cyclohexane solvent. In the processes disclosed in prior art the compound of formula-VIII was reported as a foamy substance which was obtained as a residue on dry distillation. Isolation of the above compound by filtration from the solvent provided highly pure intermediate, which on subsequent cyclisation provided aprepitant of high purity.
In the step f) the compound of Formula-VIII was taken in xylene and heated to 130°C in the presence of diisopropylethylamine to provide aprepitant of formula (I) which was isolated using a mixture of methanol and water to provide aprepitant.
In the step g) the aprepitant formed in step f) is crystallized using methanol, water or a mixture thereof to provide aprepitant of high purity.
The present invention provides aprepitant with particles having irregular flake morphology as illustrated in photographs of microscopic aprepitant in figure-2, which could be further micronised or milled to provide highly crystalline aprepitant.
Analysis of particle size distribution of aprepitant: A Malvern laser diffraction instrument was used to characterize the particle size distribution of aprepitant. Instrument model: Malvern Mastersizer 2000 Technique used: Wet method Instrument parameters:
i) Material RI: 1,500
ii) Dispersant RI: 1.330
iii) Dispersant: water
iv) Sensitivity: Normal
v) Particle shape : Irregular The present invention is schematically represented by the following scheme-L

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
EXAMPLES
Example-1: Preparation of (S) -3-(4-fluorophenyI)- 4-benzyl -morphoIin-2-one
hydrochloric acid. (Formula-Ill)
To a solution compound of formula II (25 grams) in toluene (500 ml), added 1,2 dibromoethane (179.85 grams) and diisopropylethyl amine (50 ml). Reaction mixture was heated to reflux and stirred for 20-24 hrs. Quenched the reaction mixture with water and extracted the aqueous layer with toluene. The organic layer was washed with sodium bicarbonate solution followed by sodium chloride solution. The organic solvent was distilled off under reduced pressure and the residue was converted into hydrochloride salt using ethyl acetate hydrochloride at 0-5°C. Solid formed was filtered and dried to get the title compound. Yield: 18 grams
Example-2: Preparation of (2R,3S)-4-benzyl-3-(4-fluorophenyI)morpholin-2-yl-3,5-bis(trifluoromethyl)benzoate (Formula-V).
To the compound of formula-Ill (23 grams) was converted in to its free base using water and sodium carbonate. Extracted the reaction mixture with toluene and distilled the toluene to get the crude free base of formula-Ill. Dissolved the free base in tetrahydofuran and added L-selectride at -70 to -75°C. Stirred the reaction mixture for 15-30 min at the same temperature and then added 3,5-bis(trifluoromethyl)benzoyl chloride (25.19 grams). Maintained the reaction mixture for 15-30 min at -70 to -75°C, quenched the reaction mixture using mixture of acetic acid and tetrahydrofuran, then distilled the reaction mixture below 40°C. Added water to the reaction mixture and extracted it using n-hexane. The n-hexane layer was washed using a solution of 10 % sodium carbonate. The organic layer was distilled off completely; the solid formed was isolated and re-crystallized using isopropyl alcohol solvent to get the title compound. Yield: 16 gm.

Example-3: Preparation of (2R,3S)-2-[[l-[3,5-bis(trifluoromethyI)phenyl] ethenyI]oxy]-3-(4-fluorophenyl)-4-benzyI morpholine (Formula-VI),
Methyl magnesium chloride (119.3 ml) was added to the solution of titonocene dichloride in toluene (360 ml). The reaction mixture was stirred for 60-90 min at 0-5°C and the complete formation of Dimethyl titanocene was confirmed by HPLC analysis. Quenched the reaction mixture using 12% ammonium chloride solution at 0-5°C the layers then separated, added formula-V compound (20 grams) and concentrated the organic layer volume to 70-80 ml below 35°C. Heated to SO-SS^'C and maintained for 5-6 hrs at 80-85°C and concentrated the reaction mixture to 30-40 ml below 40°C then slowly added n-Heptane (100 ml) during 10-15 min to the reaction mixture. Filtered the reaction mixture for the elimination of byproduct and concentrated the reaction mixture to 20-25 ml below 40°C then added sodium carbonate (3.5 grams), methanol (48 ml) and water (2.5 ml), heated the reaction mixture to 40-45°C then maintained for 12 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, filtered the mixture and washed with toluene (32 ml) then distilled off the solvent completely under reduced pressure. Co-distilled the reaction mixture using 32 ml of methanol and added 80 ml of methanol to the crude compound and heated the reaction mixture to 50°C, then added 50% aqueous methanol at 25-30°C. Solid precipitated was filtered and dried to get the title compound. Yield: 14 grams.
Example-4: Preparation of 2(R)-[l-(R)-3,5-bis-(trifluoromethyl)phenyI)ethoxy]-3(S)-(4-fluorophenyl) morpholine oxalate (Formula-VII).
A mixture of compound of formula-VI (10 grams), methanol (50 ml), ethyl acetate (50 ml) and 5% palladium carbon was taken in an autoclave vessel. Reaction mixture was hydrogenated at ambient temperature by applying 3-4 Kg's of hydrogen pressure. The reaction mixture was filtered to remove the palladium carbon and the filtrate was distilled off completely under reduced pressure. Oxalic acid in methanol was added to the reaction mixture. The precipitated compound was filtered and dried to get the title compound. Yield: 7 grams.

M.R: 102-110° C, Purity by HPLC is >99%.
Example-5: Preparation of 2-(R)-[l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxyl -3-
(S)-(4-fluoro)phenyl-4-(2-(N-methylcarboxyacetamidrazono)morpholine (Formula-VIII):
The compound of formula VII (15 grams) was converted in to its free base by
treating it with 10% sodium hydroxide solution. The free base was extracted into
dichloromethane (150 ml) then the solvent distilled off to get the free base of
formula-VII. The free base was dissolved in DMSO (75 ml) and added potassium
carbonate (9.6 grams). To the above mixture a solution of N-mehylcarboxy-2-
chloroacetamidrazone dissolved in DMSO (45 ml) was added. The reaction mixture was
stirred for 30-60 min and then quenched with water (75 ml). The reaction mixture was
extracted with dichloromethane (75 ml and 45 ml) and the combined organic layer was
washed using saturated sodium carbonate solution (25 ml), followed by saturated sodium
chloride solution (25 ml). The organic layer was distilled off and the solid formed was
slurried in cyclohexane (15 ml). The solid obtained was filtered and dried to get the title
compound.
Yield: 13.5 grams.
Example-6: Preparation of Aprepitant (Formula-I):
Compound of formula-VIII (10 grams) was taken in a mixture of xylene (55.5 ml) and NjN-diisopropylethyl amine (34.4 ml) and then refluxed for 4-6 hrs then cooled the reaction mixture. Filtered the precipitated compound and washed with xylene (5 ml) to get the crude Aprepitant. The crude compound was crystallized from a mixture of methanol and water to get Aprepitant. Yield: 6.5 grams.
Example-7: Purification of Aprepitant (Formula-I):
The crude aprepitant obtained in example-6 (65 grams) was dissolved in methanol (650 ml) by heating the reaction mixture to reflux temperature. Carbon was added and stirred for 5-10 min at reflux temperature. The reaction mixture was filtered through

hyflow-bed and washed with methanol (65 ml). The reaction mixture was cooled and
added water (585 ml) slowly in 45-60 min and stirred for 30-45 min at 25-30°C. Filtered
the compound, washed with water (65 ml), and dried to get a pure compound of
formula (I); Aprepitant.
Yield: 60.6 grams
Particle size distribution: D(0.1):9.206 ; D (0.5):27.373 ; D(0.9):73.182 ; D(l.OO): 198.04.

We Claim:
1. A process for the preparation of Aprepitant compound of formula-1, which comprises of the following steps;
a) The alkylation of (S)-2-(benzyl amino)-2-(4-fluorophenyl) acetic acid compound
of formula II,
Formula (II) with 1,2-dibromoethane in presence of suitable base like diisopropylethyl amine in a suitable organic solvent, to provide a compound of formula-Ill, which on treatment with hydrochloric acid provided the hydrochloride salt of the compound of formula-Ill,

b) reducing the above compound of formula-III or its salt thereof, with lithium tri
(sec-butyl)-borohydride (L-selectride®) at low temperature around -78°C in
toluene solvent, and reacting this mixture with substituted benzoyl halide
compound of formula-IV,
to obtain compound of Formula-V,

c) conversion of Formula-V using "Titanium ylide" in presence of tetrahydrofuran
and toluene, to produce an enol-ether of Formula-VI,

h) reduction and debenzylation of the compound of formula VI with a suitable reducing agent in presence of suitable organic solvent, to give the free base of compound of formula-VII, which on subsequent treatment with oxalic acid in a suitable solvent to provide an oxalate salt of Formula-VII,

d) reacting the oxalate salt of Formula-VII with N-methylcarboxyl-2-chloroacet-
amidrazone in presence of potassium carbonate and dimethylsulfoxide solvent to
obtain a compound of formula-VIII, isolated as a solid using cyclohexane solvent,

e) cyclising the compound of Formula-VIII, by refluxing it in xylene in the presence
of a N,N-diisopropyl amine, followed by isolation from a mixture of methanol
and water to obtain aprepitant of formula (I),

f) purifying the aprepitant formed in step f) recrystallizing it using methanol, water
or a mixture thereof to provide pure aprepitant.
2. A process of claim-1, wherein the solvent used in step a) for alkylation of compound of formula-II, is toluene.
3. A process of claim-1, wherein salt of compound of formula-VII is an oxalate salt.
4. A process of claim-1, wherein the compound of formula-VIII is isolated as a solid.
5. Aprepitant obtained as per the process of claim-1, having a mean particle size in the range of 30-60 |im and D (v 0.9) in the range of 60-90 µm.
6. A process for the preparation of the oxalate salt of compound of formula-VII, which comprises of:

a) Reduction of double bond and debenzylation of Formula-VI using hydrogen and
5% palladium on carbon,

b) treating the resulting free base of compound of formula-VII, with a solution of
oxalic acid in methanol to precipitate the oxalate salt of compound of
formula-VII followed by optionally purifying the obtained solid in a suitable
solvent to provide highly pure oxalate compound of formula-VII.

7. The process of claim 6, in step b) wherein the solvent used for purification is selected from methanol, ethanol, isopropyl alcohol, n-butanol and ethyl acetate.
8. A compound of 2(R)-[l-(R)-3,5-bis-(trifluoromethyl)phenyl)ethoxy]-3(S)-(4-fluoro phenyl) morpholine oxalate having the following structure.

9. A process for the preparation of the compound of formula-VIII as a solid, which
comprises of treating the free base of compound of formula-VII or its salt with N-
methylcarboxy-2-chloroacetamidrazone in presence of potassium carbonate and
dimethylsulfoxide, followed by isolation using cyclohexane solvent.
10. Aprepitant with particles having the shape of irregular flakes when photographed
with a microscope.

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Patent Number

279324

Indian Patent Application Number

526/CHE/2008

PG Journal Number

03/2017

Publication Date

20-Jan-2017

Grant Date

18-Jan-2017

Date of Filing

03-Mar-2008

Name of Patentee

MSN LABORATORIES LIMITED

Applicant Address

MSN LABORATORIES LTD., FACTORY : SY. NO: 317 & 323, RUDRARAM (VIL), PATANCHERU(MDL), MEDAK (DIST), ANDRA PRADESH - 502 329.

Inventors:

#	Inventor's Name	Inventor's Address
1	MANNE SATYANARAYANA REDDY	MSN LABORATORIES LTD., FACTORY : SY. NO: 317 & 323, RUDRARAM (VIL), PATANCHERU(MDL), MEDAK (DIST), ANDRA PRADESH - 502 329.
2	SAJJA ESWARAIAH	MSN LABORATORIES LTD., FACTORY : SY. NO: 317 & 323, RUDRARAM (VIL), PATANCHERU(MDL), MEDAK (DIST), ANDRA PRADESH - 502 329.
3	VENKATESH MUMMADI	MSN LABORATORIES LTD., FACTORY : SY. NO: 317 & 323, RUDRARAM (VIL), PATANCHERU(MDL), MEDAK (DIST), ANDRA PRADESH - 502 329.

PCT International Classification Number

A61K31/4196

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA