FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
THE PATENTS RULES, 2003
PROVISIONAL SPECIFICATION
[See section 10 ; rule 13]
1. TITLE OF THE INVENTION
"Novel Crystalline polymorphs of 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"
2. APPLICANT


a) NAME: USV LIMITED
b) NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention


Field of invention:
The present invention relates to polymorphs of 5-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyI]-l,2- dihydro-3H-l ,2,4-triazoI-3-one, commonly known as Aprepitant and process for preparation thereof The present invention further relates to process for preparation of Aprepitant.
Background of invention:
Aprepitant is chemically known as 5-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-U2- dihydro-3H-l ,2,4-triazol-3-one and represented by Formula IX.

Formula (DC)
Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NKi) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine and corticosteroid receptors, which are the targets of some therapies for chemotherapy-induced nausea and vomiting (CINV). The neuropeptide receptors for substance neurokinin-1 (NK-1) are widely distributed throughout the mammalian nervous system. It is naturally occurring undecapeptide belonging to the tachykinin family of peptide and is involved in controlling various bioprocess, which includes vision, pain, movement control, gastric motility, vasodilation, salivation. Evidence has proved the usefulness of tachykinin receptor antagonist in pain, headache, migraine, Alzheimer, multiple sclerosis, cardiovascular changes, and other respiratory disease. It is commercially available in the market under the brand name EMEND(TM) as 80 mg or 125 mg capsules. Aprepitant in combination with other antiemetic agents is indicated for the prevention of acute and delayed
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nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.
US5719147 discloses various morpholine and thiomorpholine compounds in particular 5-[[(2R,
3S)-2-[(lR)-l-[3,5- bis(trifluoromethyI) phenyl]ethoxy]-3-(4-fhiorophenyl)-4-
morpholinyl]methyI]-l,2- dihydro-3H-l ,2,4-triazol-3-one (Aprepitant) and process for preparation of Aprepitant.
US6096742 discloses crystalline Form I of Aprepitant and process for preparation thereof. US 742 also disclosed that crystalline Form I of Aprepitant has superior property over the crystalline Form II, Aprepitant Form I is thermodynamically more stable, non- hygroscopic and solubility is less as compared to Form II in 2/1 (v/v) methanol / water. Both Form I and Form II of Aprepitant are distinguished by XRPD but DSC shows no significant difference in their thermal behaviour. Both phases produced thermograms with a single melting endotherm at the same temperature.
WO2007/088483 discloses amorphous form of Aprepitant, mixture of Form I and Form II of Aprepitant and process for preparation thereof.
WO2007/112457 discloses intimate mixtures of crystalline polymorphic Form I and Form II of Aprepitant, processes for their preparation, compositions containing them, and their methods of use.
WO2008026216 describes process for preparation of crystalline Form II of Aprepitant which comprises; a) distilling off the solvent from a solution of Aprepitant in a solvent selected from methanol, ethanol, isopropyl alcohol and tert-butyl alcohol at least until precipitation of Aprepitant occurs; b) separating the solid Aprepitant, if necessary; c) slurrying the solid Aprepitant in water; and d) separating crystalline Form II of Aprepitant from the contents..
WO2008044102 discloses a novel stable polymorph of Aprepitant, designated polymorph Form III, process for its preparation and pharmaceutical compositions containing same.
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Polymorphism is the ability of the compound to exhibit more than one orientation or conformation of molecule within the crystal lattice. Many organic compounds including active pharmaceutical ingredient (API) exhibit polymorphisms. Drug substance existing in various polymorphic forms, differ from each other in terms of stability, solubility, compressibility, flowability and spectroscopic properties thus affecting dissolution, bioavailability and handling characteristics of the substance. Rate of dissolution of an API in patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally administrated API can reach the patient bloodstream. Flowability affects the ease with which the material is handled while processing a pharmaceutical product.
Knowledge of existence of different crystal phases and their overall physical and chemical behaviour is required for selection of polymorphic form to be used in the preparation of final dosage form. Towards this end, investigation of crystal polymorphisms is an essential step in pharmaceutical research due to the influence of solid-state properties on dosage form. The rate of dissolution can be improved especially for water insoluble drug substance such as Aprepitant and a stable dissolution profile can be obtained by small particle size. The particle size reduction of Aprepitant can improve the dissolution profile and hence the bioavailability. The conventional method of micronization of solid involves jet or fluid energy mills and ball mills. The basic principal in all these techniques involve application of force on the particle in the form of collision which will act at the imperfection in crystal surface, initiating crack propagation through the particle.
A crystalline form can undergo phase transformation to amorphous form during grinding or micronization. A mixture of polymorph may lead to complicated situation during formulation, as there is possibility that mixture of forms may transform to thermodynamically most stable form thus affecting the solubility and hence the bioavailability. Ideally purity of the polymorphic form, selected for developing formulation is very important, the present inventors thus developed the solid state characteristic properties, especially particle size of Aprepitant without affecting its chemical activity as well as physical appearance. The present invention therefore provides highly crystalline Form II and novel crystalline form, Form IV having chemical and polymorphic purity > 99%.
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Object of the present invention:
The object of the present invention is to provide novel polymorph of Aprepitant, Form IV and process for preparation thereof.
Another object of the present invention is to provide highly crystalline form of Aprepitant, Form II and process for preparation thereof.
Summary of the invention:
The present invention discloses process for preparation of Aprepitant, crystalline forms of Aprepitant and process for preparation thereof.
According to one aspect, the present invention provides highly crystalline Form II of Aprepitant and process for preparation thereof.
According to second aspect, the present invention provides novel crystalline form of Aprepitant, Form IV and process for preparation thereof.'
According to third aspect, the present invention provides pharmaceutical composition comprising highly crystalline form of Aprepitant, Form II or Form IV or mixtures thereof.
Brief description of the figures :
FIG. 1 is an X-ray powder diffraction pattern of Form II of Aprepitant. FIG. 2 is an X-ray powder diffraction pattern of Form IV of Aprepitant.
Detail description of the invention:
Considering the solvent combination tried in the prior art processes, it is likely that Aprepitant can exist in different polymorphic forms. A same solvent or different solvent or solvent combination with/without changes in process parameter can lead to novel and pure polymorphic forms. In line of crystallisation of Aprepitant using different solvents or solvent combinations, the present invention provides highly crystalline polymorphs, Form II and novel crystalline Form IV of Aprepitant.
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The present invention describes highly crystalline Form II of Aprepitant, novel crystalline Form IV of Aprepitant and process for preparation thereof.
The process for the preparation of Aprepitant comprises the following steps ;
a) protecting amino group of (S)-(4-fluorophenyl) glycine (I) to get N-Benzyl-(S)-(4-fluorophenyl) glycine (II);
b) condensing N-Benzyl-(S)-(4-fluorophenyl) glycine (II) with 1,2-dibromoethane in presence of base to get 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone (III);
c) reducing 4-benzyl-3-(S)-(4-fluorophenyl)- 2-morpholinone (III) followed by reaction with acid chloride to get 2-(R)-(3,5-bis (trifluoromethyl) benzoyloxy)-3-(S)-(4-fluorophenyl)-4-benzyl morpholine (TV);
d) reaction of 2-(R)-(3,5-bis-(trifluoromethyl) benzoyloxy)-3-(S)-(4-fluorophenyl)-4-benzyl morpholine (IV) with dimethyl titanocene to get (2R,3S)-4-Benzyl-2-({l-[3,5-bis (trifluoromethyl) phenyl] ethenyl}oxy)-3-(4-fluorophenyl) morpholine (V);
e) hydrogenating compound (V) to get (2R, 3S)-2-{l-[3,5-bis (trifluoromethyl) phenyl] ethoxy}-3-(4-fluorophenyl) morpholine (VI);
f) isolating the desired isomer (2R,3S)-{l(R)-[3,5-(trifluoromethyl) phenyl] ethoxy}-3-(4-fluorophenyl) morpholine (VII) using column chromatography;
g) condensing (2R,3S)-{l(R)-[3J5-(trifluoromethyl) phenyl] ethoxy}-3-(4-fluorophenyl) morpholine (VII) with N-methylcarboxyl-2-chloroacetamidrazone to get (2R,3S)-{(1R)-[3,5-(trifluoromethyl) phenyl] ethoxy}-3-(4-fluorophenyl)-4-[2(N-methylcarboxy) acetamidrazono] morpholine (VIII);
h) cyclizing (2R,3S)-{(lR)-[3,5-(trifluoromethyl) phenyl] ethoxy}-3-(4-fluorophenyl)-4-[2(N-methylcarboxy) acetamidrazono] morpholine (VIII) under the influence of heat to get the crude Aprepitant and
i) crystallizing the obtained crude Aprepitant to get pure Aprepitant (IX).
The process for preparation of Aprepitant is represented in Scheme 1 below;
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Scheme 1

Alternatively reacting the compound (VI) with p-toluene sulphonic acid to get p-toluene sulphonate salts of compound (VI). The p-toluene sulphonate salts of compound (VI) is subjected to basification with suitable base followed by purification using methyl tertiary butyl ether and hexane to get the p-toluene sulphonate salts of compound (VII). The reaction is further proceeded as per the step g), step h) and step i) to get the pure Aprepitant (IX).
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According to one embodiment, the present invention provides highly crystalline Form II of
Aprepitant. The XRPD of highly crystalline Form II of Aprepitant as in Figure 1, Form II of Aprepitant is characterized by the following XRPD peaks,

Pos. [°2Th.l Rel. Int. [%1
4.1679 2.42
8.3158 7.45
12.4438 5.87
12.7300 11.09
13.6319 3.29
14.5758 4.77
16.2966 19.78
16.9008 15.72
17.3145 27.47
18.2002 14.68
20.2840 39.60
20.8100 47.92
21.2460 46.75
23.0410 50.03
24.0753 35.61
25.0004 100.00
26.7839 20.44
27.2732 5.61
27.8081 15.04
29.2439 6.58
30.6928 8.42
31.7062 3.45
35.7110 7.76
37.8363 7.29
38.8510 8.74
42.2319 8.98
44.0430 1.49
As used herein, the term " highly crystalline" refers to Aprepitant From II of at least 80% of crystalline Form II, preferably at least 90% crystalline form II, more preferably at least 95% crystalline Form II.
According to another embodiment, the present invention provides process for preparation of highly crystalline Form II of Aprepitant which comprises following steps,
a) dissolving Aprepitant in solubilizing solvent;
b) adding anti-solvent to the obtained solution of step (a);
c) isolating the separated product and drying the isolated product.
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The solubilizing solvent may be selected from aliphatic ester. The aliphatic ester may be selected form ethyl acetate, iso propyl acetate, methyl acetate, tert-butyl acetate.
The dissolution is carried out at temperature of 35-65°C preferably at 45°C. The anti-solvent may be selected from aliphatic hydrocarbon and aliphatic ether.
Aliphatic hydrocarbon may be selected from pentane, hexane and heptane. The aliphatic ether may be selected from diethyl ether, di isopropyl ether and methyl tert butyl ether. The solution is cooled to 25-30°C for few hours followed by further cooling to 0-5°C and maintaining for several hours. The separated solid is isolated by filtration process followed by drying to get Form II of Aprepitant.
Another embodiment of the present invention provides improved process for preparation of Aprepitant Form II which comprises the following steps,
a) dissolving Aprepitant in solubilizing solvent;
b) adding antisolvent to the obtained solution of step (a);
c) cooling the solution of step (b) and isolating the separated product and
d) drying the isolated product.
The solubilizing solvent may be selected from group comprising of aliphatic alcohol, ketone, cyclic ether, polar aprotic solvent and chlorinated hydrocarbon. The alcohol may be selected from ethanol, 1- propanol and 2-propanol (IPA). Ketone may be selected from acetone, 2-butanon and diethyl ketone, chlorinated hydrocarbon may be selected from methylenedichloride (MDC), chloroform and the aliphatic cyclic ether may be selected from tetrahydrofiiran (THF) and 1,4-dioxane. The polar aprotic solvent may be selected from dimethyl formamide (DMF), di- methyl sulfoxide (DMSO), dimethyl acetamide.
The criteria for selection of anti-solvent is their miscibility with the solubilizing solvent. The antisolvents are selected from a group of aliphatic hydrocarbons, ether and water. The said aliphatic ethers are selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether preferably DIPE. The aliphatic hydrocarbon can be selected from pentane, hexane and heptane. The dissolution temperature is varied depending on the solubility of Aprepitant in the solublizing solvent. The temperature is varied from room temperature to reflux temperature of the solvent
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preferably 30-60°C. The antisolvent is added at room temperature. The solution is cooled to 25-30°C to get the solid. The separated solid is isolated by filtration process followed by drying below 60°C to get Form II of Aprepitant.
According to another embodiment, the present invention provides novel polymorphic form of Aprepitant, Form IV. The XRPD of Form IV of Aprepitant is given in figure 2. Form IV of Aprepitant is characterized by the following XRPD peaks,

Pos. [°2Th.l Rel. Int. r%l
4.2229 0.83
8.2976 3.03
12.4180 3.26
15.4421 2.92
17.2890 1.83
17.7391 1.42
18.8365 1.09
19.5844 0.81
20.1445 3.44
20.7190 20.77
22.0764 2.29
23.6913 10.84
24.0324 4.42
24.8928 100.00
25.8277 4.94
27.7092 2.52
29.0928 5.70
29.3970 5.63
31.5595 1.40
33.6591 2.55
35.5623 3.43
7.67173 7.73
39.4678 2.96
42.0235 9.89
45.9940 0.72
47.5768 0.64
47.9823 1.38
According to yet another embodiment of the present invention there is provided a process for preparation of Aprepitant Form IV which comprises the following steps, a) dissolving Aprepitant in solubilizing solvent;
a) cooling the obtained solution;
b) stirring the suspension for several hours and
c) isolating the separated product and drying
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Aprepitant used for preparation of Form IV is either Form I or Form II of Aprepitant or mixture thereof. The solubilizing solvent may be selected from aliphatic nitriles such as acetonitrile. Dissolution is carried out at temperature of 55-65°C and the clear solution is filtered to remove any undissolved solid. The clear filtrate is cooled to 25-30"C. The solution is stirred for 1-3 hrs at the same temperature and the solid separated is isolated by filtration.
The polymorphic Form II and Form IV of Aprepitant obtained by the process of the present invention has chemical purity > 99.9 and polymorphic parity > 99. Both the highly crystalline Form II and novel Form IV are micronized by conventional micronization techniques to have particle size distribution, d90 is between 5-50p preferably 5-25p more preferably 5-15p.
Methods for preparing Aprepitant and its polymorphic forms of this invention are illustrated in the following Examples. The following examples are given for the purpose of illustrating the present invention and shall not be construed as being limitations on the scope or spirit of the instant
Example 1: Preparation of N-Benzyl-(S)-(4-fluorophenyl) glycine (II)
A solution of 500 gm (2.94 M) (S)-(4-fluorophenyIglycine), 300 ml of benzaldehyde in 3L of 1 N aqueous sodium hydroxide solution and 3L of methanol was stirred at room temperature for 1 hour. The reaction mixture was cooled at 0°C and treated with 44.4 gm ( 1.17 M) of sodium borohydride. The cooling bath was removed and the resulting mixture was stirred at room temperature for 30 minutes 300 ml benzaldehyde and 44,4 gm sodium borohydride was added again to the reaction mixture in same manner and the mixture was stirred for 1.5 hours. The reaction mixture was partitioned between 5L of methyl tertiary butyl ether and 4L of water and the layers were separated. The separated aqueous layer was acidified to pH 5 with 2N aqueous hydrochloric acid solution and the precipitated solid was filtered, rinsed with water, then with diisopropyl ether and dried. Yield = 550gm(71%)
Example 2: Preparation of 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone (III)
A mixture of 550 gm of N-BenzyI-(S)-(4-fluorophenyl) glycine, 1100 ml of N,N-
diisopropylethylamine, 1100 ml of 1,2-dibromoethane and 5.5 L. of N,N-dimethylformamide was
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stirred at 80°C for 17 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between 4.4 L of ethyl acetate and 3.85 L of water. A solution of potassium hydrogen sulphate was added to the mixture to render it acidic. The separated organic layer was washed with 2 x 2.75 lit. of 10 % sodium carbonate solution, 3 x 5.5 L water, dried over anhydrous sodium sulphate and concentrated in vacuo to obtain the residue. The residue obtained was dissolved in 860 ml of isopropyl acetate and 302 ml of ethanolic HC1 and 942 ml of methyl tertiary butyl ether was added to precipitate the HO salt. The obtained hydrochloride salt was neutralized by 1.6 L of aqueous sodium carbonate solution. The reaction mass was extracted with 5.5L ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulphate and concentrated in vacuo to get compound (IH). Yield = 302 gm (50 %)
Example 3: Preparation of 2-(R)-(3,5-bis (trifluoromethyl) benzoyloxy)-3-(S)-(4-fluorophenyl)-4-benzylmorpholine (IV)
A solution of 302 gm 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone in 2.72 L of dry THF was cooled to -70°C. The cold solution was treated with 1L. of L-selectride solution in THF maintaining the internal temperature below -70°C. The resulting solution was stirred at same temperature for 2 hours and the reaction was charged with 250 ml of 3s5-bis-(trifluoromethyl) benzoyl chloride. The resulting mixture was stirred for 6 hours till completion of reaction. The reaction mass was quenched with 32 ml of acetic acid in 160 ml of THF and the temperature of the reaction mixture was raised to room temperature. The reaction mixture was partitioned between 2.4L of hexane and 2.4L of water. The separated organic layer was washed with of 10 % sodium carbonate solution (2 x 1.2 L), water (3 x 1.8 L), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue obtained was dissolved in 2.3L n-propanol. Solid obtained was filtered and washed with cold n-propanol and dried under vacuum. Yield = 352 gm (63%)
Example 4: Preparation of (2R,3S)-4-Benzyl-2-({l-[3,5-bis (trifluorornethyl) phenyl] ethenyl}oxy)-3-(4-fluorophenyl) morpholine (V)
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Part A: A solution of 452 gm ( 1.81 M) of titanocene dichloride in 2.5 lit. of dry THF and 2.5L of toluene in the dark at 0°C was treated with 2.1L of solution of methyl magnesium chloride in THF maintaining the internal temperature below 5°C. The resulting yellow orange mixture was stirred below 5°C for 2 hours and further at room temperature for 30 minutes. Completion of reaction was monitored by HPLC. After the completion, the reaction mixture was quenched in 3L of ammonium chloride solution and stirred. The separated organic layer was washed with 2 x 2 L of water and dried over anhydrous sodium sulphate.
The obtained solution of dimethyl titanocene was then mixed with 352 gm of 2-(R)-(3,5-bis (trifluoromethyl) benzoyloxy)-3-(S)-(4-fluorophenyl)-4-benzylmorpholine (IV) and concentrated in vacuo below 60°C till desired volume containing 20 % of dimethyl titanocene reagent content was obtained.
Part B: The concentrated reaction mixture (obtained from Part A) was heated to about 80°C for 6 to 7 hours in dark. After completion of reaction, 84 gm of sodium bicarbonate, 65 ml of water and 445 ml of ethanol were added at 50°C and the mixture stirred at 50 -55°C for 12 hours. The reaction mixture was then filtered to remove titanocene residues and then concentrated in vacuo. 2.3 L of hexane, 235 gm of sodium bicarbonate, 2.3 L of water and 410 ml of 30 % hydrogen peroxide was added maintaining the temperature in the range of 5-10°C to the concentrated reaction mass and the mixture was stirred overnight at room temperature. The separated organic layer was washed with water (3 x 1.5 L), dried over anhydrous sodium sulphate and concentrated in vacuo to get the compound (V). Yield = 234 gm (66.73 %)
Example 5: Preparation of 2-(R)-(l-(3,5-bis-(trifluoromethyl) phenyl) ethoxy)-3-(S)-(4-fluorophenyl) morpholine (VI)
A solution of (2R,3S)-4-Benzyl-2-({l-[3,5-bis (trifluoromethyl) phenyl] ethenyl}oxy)-3-(4-fluorophenyl) morpholine (V) (234 gm) in 1:1 ethyl acetate: absolute alcohol (2.5L) was mixed with 35 gm of 10 % Pd-C and the resulting mixture was hydrogenated with hydrogen at 40-45 psi pressure at room temperature for 6-8 hours. After completion of reaction, the reaction mixture was filtered and the catalyst was washed twice with ethyl acetate. The combined filtrate was concentrated under reduced pressure to obtain the residue of compound (VI).
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The obtained residue was subjected to chromatographic separation to isolate the desired isomer
(VII).Yield=124gm
The condition of chromatographic method for isolating the compound (VII) are,
Column: silica gel-60,15-40 u, Dimension: I.D.= 110 mm, length = 25 cm ,
Flow rate: 250 ml / min, Xmax = 263 ran
Solvent ratio: hexane: isopropyl acetate : 60: 40
Example 6: Preparation of 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 (IX) (Aprepitant) A mixture of 124 gm of 2-(R)-{l(R)-[3,5-bis-(trifluoromethyl) phenyl] ethoxy}-3-(S)-(4-fluorophenyl) morpholine (VII), 70.45 gm of 2-chloroacetamidrazone, 78 gm of anhydrous potassium carbonate in 1.4 L of dimethyl sulphoxide was stirred at room temperature for 3 hours and water (3.4 L) and methyl tert-butyl ether (2.25L) were added to the reaction mixture. The separated aqueous layer was extracted with 2 x 700 ml of methyl tert-butyl ether. The combined organic layer was washed with 3 x 2.25 L of water, dried over anhydrous sodium sulphate and the solvent was evaporated in vacuo to get compound (VIII). Yield- 154.2 gm (96%) The obtained 154.2 gm of compound (VIII) was dissolved in 2.3 L of xylene and the mixture was refluxed for 5-6 hours. After the completion of reaction, the reaction mixture was concentrated and 451 ml of acetonitrile was added. The solid obtained was filtered off, washed with acetonitrile (451ml) and dried to get the residue of crude Aprepitant (103g). The crude product thus obtained was dissolved in 864ml of methanol at 50°C and treated with l0g activated carbon at 60-62°C for 1 hour. Then the hot reaction mixture was filtered, washed with hot methanol. The combined filtrate was cooled to room temperature and 432ml water was added slowly followed by stirring the slurry. The separated solid was filtered, washed with 2:1 mixture of methanol-water and dried at 60° to get the pure compound (IX). Yield = 68.87 gm (47.3 %)
Example 7: Preparation of (2R,3S)-2-{(lR)-[3,5-bis(trifluoromethyl) phenyl] ethoxy}-3-(4-
fluorophenyl)morpholine-4-methylbenzenesulphonate.
Part A: 195 gm of the residue obtained in example 5 was dissolved in 351 ml of methyl tert. butyl
ether and a solution of p-toluenesulphonic acid monohydrate (82.7 gm) in methyl tert. butyl ether
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(351 ml) was added slowly to it with stirring at 40°C. 2.1 L of hexane was added to the reaction mixture and the resulting slurry was stirred at room temperature for 2 hours. The separated solid was filtered, washed twice with mixture of methyl tert. butyl ether: hexane (235 ml) (1:3) and dried at 50°C to get the p-toluenesulphonate salt of compound (VI). Yield = 174 gm ( 62.16 %).
Part B: (2R,3S)-2-{(lR)-[3,5-bis(trifluoromethyl) phenyl] ethoxy}-3-(4-fluorophenyl)
morpholine-4-methylbenzenesulphonate ( 174 gm ) was treated with a mixture of 10 % aqueous sodium carbonate solution ( 870 ml). The layers were separated and the organic layer was washed twice with water (435 ml ). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get a residue. The residue was dissolved in methyl tert. butyl ether (300 ml) and a solution of p-toluene sulphonic acid monohydrate ( 51.5 gm ) in methyl tert. butyl ether ( 300 ml ) was added slowly with stirring at 40°C. Hexane ( 600 ml ) was slowly added and the resulting slurry was stirred at room temperature for 2 hours. The solid obtained was filtered, washed twice with 1:3 mixture of methyl tert. butyl ether- hexane and dried at 50°C to get the desired pure p-toluenesulphonate salt of compound (VII). Yield = 125 gm (71.8%).
Example 8: Preparation of 5-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-moipholinyI]methyl]-l,2- dihydro-3H-l ,2,4-triazol-3-one (IX) (Aprepitant) A solution of N-methylcarboxyl-2-chloroacetamidrazone (36.5 gm ) in dimethyl sulphoxide ( 500 ml ) was added to a stirred mixture of (2R,3S)-2-{(R)-l-[3,5-bis(trifluoromethyI) phenyl] ethoxy}-3-(4-fluorophenyl) morpholine-4-methylbenzenesuIphonate (125 gm), powdered potassium carbonate (101 gm ) in dimethyl sulphoxide (500 ml ) at room temperature and continued the stirring for 1 hour. The reaction mixture was then quenched with water (700ml) and extracted with methyl tert. butyl ether (2 x 700 ml). The separated organic layer was washed twice with water, dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure to get the viscous residue. The residue (llOg) thus obtained was dissolved in xylene (1.65 L) and the mixture was refluxed for 5-6 hours. After the completion of reaction, mixture was concentrated and acetonitrile (250 ml) was added to the obtained reaction mass and the separated solid was filtered, washed with acetonitrile and dried to get compound (VIII) (73.5g). The crude product thus obtained was dissolved in 617 ml of methanol at 50°C and treated
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with activated carbon at 60-62°C for 1 hour. The reaction mixture was filtered, washed with hot methanol and the combined filtrate was cooled to room temperature and 308ml of water was added slowly followed by stirring the slurry. The solid obtained was filtered, washed with 2:1 mixture of methanol-water and dried at 60° to get the pure compound (IX).
Yield = 49.5 gm (47.6%)
Example 9
1 g Aprepitant was dissolved in 20 ml ethyl acetate at 65°C temperature. The hot solution was filtered and the filtrate was cooled to 25-30°C. To this clear solution, 40 ml of n-hexane was added and the solution was stirred at 25-30°C for 15-20 min. The solution was further cooled to 0-5°C for 2 hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 10
1 g Aprepitant was dissolved in 10 ml acetone at reflux temperature. The solution was refluxed to get clear solution. The hot solution was filtered and cooled to 25-30°C. To this clear solution 40 ml n-hexane was added and the solution was stirred at 25-30°C for 4-5 hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 11
1 g Aprepitant was dissolved in 10 ml acetone at reflux temperature. The solution was refluxed to get clear solution. The hot solution was filtered and cooled to 25-30°C. To this clear solution 40 ml water was added and the solution was stirred at 25-30°C for 4-5 hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 12
1 g Aprepitant was dissolved in 10 ml acetone at reflux temperature. The solution was refluxed to get clear solution. The hot solution was filtered and cooled,to 25-30°C. To this clear solution 40 ml diisopropylether (DIPE) was added and the solution was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
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Example 13
1 g Aprepitant was dissolved in 15 ml ethanol at 50-60°C. The solution was filtered and 30 ml of
water was added to the obtained filtrate. The solution was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 14
1 g Aprepitant was dissolved in 15 ml ethanol at 50-60°C. The solution was filtered, 30 ml of
hexane was added to the filtrate and the solution was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 15
1 g Aprepitant was dissolved in 15 ml ethanol at 50-60°C. The solution was filtered, of 30 ml DIPE was added to the filtrate and the solution was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 16
1 g Aprepitant was dissolved in 15 ml tetrahydrofuran (THF) at 50-60°C. The solution was filtered and to this filtrate 30 ml water was added and the solution was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 17
1 g Aprepitant was dissolved in 15 ml THF at 50-60°C. The solution was filtered and to this clear filtrate 30 ml hexane was added and the solution was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 18
1 g Aprepitant was dissolved in 15 ml THF at 50-60°C. The solution was filtered and to this clear filtrate 30 ml DIPE was added and the solution was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 19
1 g Aprepitant was dissolved in 15 ml 1,4-dioxane at 50-60°C. The solution was filtered and to this clear filtrate 30 ml water was added and the solution was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
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Example 20
1 g Aprepitant was dissolved in 15 ml 1,4-dioxane at 50-60°C. The solution was filtered and to this clear filtrate 30 ml hexane was added and the solutioA was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 21
1 g Aprepitant was dissolved in 15 ml 1,4-dioxane at 50'60°C. The solution was filtered and to this clear filtrate 30 ml DIPE was added and the solution was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 22
1 g Aprepitant was dissolved in 15 ml methylenedichlorkte (MDC) at 50-60°C. The solution was filtered and to this clear filtrate 30 ml hexane was added and the solution was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 23
1 g Aprepitant was dissolved in 15 ml MDC at 50-60°C. The solution was filtered and to this clear filtrate 30 ml DIPE was added and the solution was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 24
1 g Aprepitant was dissolved in 5 ml dimethylformamide (DMF) at 25-30°C. The solution was filtered and to this clear filtrate 30 ml water was added and the solution was stined at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
Example 25
1 g Aprepitant was dissolved in 5 ml dimethylsulfoxide (DMSO) at 25-30°C. The solution was filtered and to this clear filtrate 30 ml water was added 2nd the solution was stirred at 25-30°C for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form II.
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Process for preparation of Aprepitant Form IV:
Example 26
1 g Aprepitant was dissolved in 20 ml acetonitrile at 50-60°C. The solution is maintained at 60° for 30 min to ensure complete dissolution. The hot solution was filtered and the filtrate was cooled to 25-30°C and stirred at the same temperature for 4-5hrs. The separated solid was filtered and drted at 60°C to g,et Aptepitot Form IV.
Example 27
1 g Aprepitant was dissolved in 20 ml acetonitrile at 50-60°C. The solution is maintained at 60° for 30 min. to ensure complete dissolution The hot solution was filtered and the filtrate was cooled to 25-30°C. To this solution 40ml n-hexane was added and stirred at the same temperature for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form IV.
Dated this the 27th day of June 2008
Dr. K.C.liajendran USV Limited Applicant
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