WO2010092591A2 - Novel crystalline polymorphs of 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 process for preparation thereof - Google Patents

Novel crystalline polymorphs of 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 process for preparation thereof Download PDF

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WO2010092591A2
WO2010092591A2 PCT/IN2009/000370 IN2009000370W WO2010092591A2 WO 2010092591 A2 WO2010092591 A2 WO 2010092591A2 IN 2009000370 W IN2009000370 W IN 2009000370W WO 2010092591 A2 WO2010092591 A2 WO 2010092591A2
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aprepitant
solution
solvent
preparation
filtered
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WO2010092591A3 (en
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Dhananjay Govind Sathe
Nandu Baban Bhise
Kamlesh Digambar Sawant
Anand Vinod Shindikar
Sachin Shivaji Patil
Tushar Anil Naik
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Usv Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • the present invention relates to novel polymorph of 5-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]- 1 ,2- dihydro-3H-l ,2,4-triazol-3-one, commonly known as Aprepitant or pharmaceutically acceptable salts thereof and process for preparation thereof.
  • the present invention further relates to highly pure polymorph, Form II of Aprepitant.
  • the present invention further relates to improved process for preparation of Aprepitant.
  • Aprepitant 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 and represented by Formula IX.
  • 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-I) 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.
  • 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 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(trifluorornethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4- morpholinyl]methyl]-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.
  • WO 2007/044829 discloses process for preparation of Aprepitant and intermediates thereof.
  • WO'829 also describes process for purification of Aprepitant using different solvents to get pure Aprepitant.
  • 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 polymorph Form III of Aprepitant, process for its preparation and pharmaceutical compositions containing same.
  • 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, fiowability 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. Fiowability affects the ease with which the material is handled while processing a pharmaceutical product.
  • Crystal polymorphisms 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, ball mills, microfluidization and such other techniques known to person skilled in the art.
  • 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.
  • the present invention therefore provides novel crystalline form, Form IV and highly crystalline Form II of Aprepitant having chemical and polymorphic purity > 99%.
  • An object of the present invention is to provide novel polymorph of Aprepitant having inproved flow properties, angle of repose, solubility etc. and processes for preparation thereof.
  • Another object of the present invention is to provide highly crystalline form, Form II of
  • Yet another object of the present invention is to provides improved process for preparation of Aprepitant.
  • the present invention provides highly crystalline Form II of
  • the present invention provides pharmaceutical composition
  • pharmaceutical composition comprising highly crystalline form, Form II or Form IV of Aprepitant or mixtures thereof as an active ingredient and the use of the compound and its formulations in the treatment or prevention of disorders of the central nervous system, inflammatory diseases, pain or migraine, asthma, and emesis.
  • Another aspect of the present invention provides an improved process for preparation of
  • Another aspect of the present invention provides Apripitant having mean particle size less than 250 microns.
  • Another aspect of the present invention provides Apripitant having purity at least 99% and individual impurities NMT 0.15%
  • FIG. 1 is an X-ray powder diffraction pattern of highly crystalline Form II of Aprepitant according to the present invention.
  • FIG. 2 is an X-ray powder diffraction pattern of Form IV of Aprepitant according to the present invention. Detail description of the invention:
  • the present invention provides highly crystalline polymorphs, Form II and novel crystalline Form FV of Aprepitant.
  • the present invention further describes process for preparation of novel crystalline Form FV and highly crystalline Form II of Aprepitant.
  • novel polymorphic form of Aprepitant Form FV.
  • the XRPD of Form IV of Aprepitant is given in figure 2.
  • Form FV of Aprepitant is characterized by the following XRPD peaks,
  • the novel polymorphic form of Aprepitant according to the present invention has advantages of superior properties over the known form of Aprepitant in terms of stability and suitability for pharmaceutical formulations.
  • the present inventors had compared the flow property of novel Form IV and prior art form and surprisingly found that flow property data of Form IV is superior as compared to prior art form.
  • the present invention thus involves technical advancement as compared to the existing knowledge and economic significance that makes the invention not obvious to a person skilled in the art. Test for assessment of establishing the efficacy are under progress and we request leave to amend the specification under relevant provisions in the Act.
  • a process for preparation of Aprepitant Form IV which comprises the following steps, a) dissolving Aprepitant in solubilizing solvent; b) cooling the obtained solution; c) isolating the product.
  • Aprepitant used for preparation of Form IV is either Form I or Form II or any other polymorph of Aprepitant or mixture thereof.
  • the suitable solvent is selected from aliphatic nitriles or ethylacetate or ketones or mixtures thereof.
  • Said aliphatic nitriles is acetonitrile and ketones are acetone, 2- butanone, diethyl ketone preferably acetone.
  • the dissolution is carried out at temperature of 55-75°C and the clear solution is filtered to remove any undissolved solid.
  • the clear filtrate is cooled to about 25-35°C.
  • the solution/suspension is stirred for 1-3 hrs at the same temperature and the solid separated is isolated by filtration.
  • the present invention provides highly crystalline Form II of Aprepitant.
  • the highly crystalline Form II of Aprepitant is characterized by the following XRPD peaks ( Figure 1),
  • 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% of crystalline Form II.
  • 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 product.
  • Suitable solubilizing solvent is selected form aliphatic esters such as ethyl acetate, isopropyl acetate, methyl acetate and tert-butyl acetate.
  • the dissolution is carried out at temperature of 35-65°C preferably at 45°C.
  • Suitable anti-solvent is selected from aliphatic hydrocarbons such as pentane, hexane, heptane or aliphatic ethers such as diethyl ether, di isopropyl ether and methyl tert butyl ether or mixtures thereof.
  • 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 and dried to get Form II of Aprepitant.
  • the present invention provides improved process for preparation of highly crystalline form, Form II of Aprepitant 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 d) isolating the product
  • the solubilizing solvent is selected from group consisting of aliphatic alcohol such as ethanol, 1- propanol and 2-propanol (IPA); ketone such as acetone, 2-butanone and diethyl ketone; cyclic ethers such as tetrahydrofuran (THF) and 1 ,4-dioxane; polar aprotic solvents such as dimethyl formamide (DMF), di- methyl sulfoxide (DMSO), dimethyl acetamide and chlorinated hydrocarbons such as methylenedichloride (MDC) and chloroform or mixtures thereof.
  • aliphatic alcohol such as ethanol, 1- propanol and 2-propanol (IPA)
  • ketone such as acetone, 2-butanone and diethyl ketone
  • cyclic ethers such as tetrahydrofuran (THF) and 1 ,4-dioxane
  • polar aprotic solvents such as dimethyl
  • the criteria for selection of anti-solvent is their miscibility with the solubilizing solvent.
  • the anti-solvents are selected from a group of aliphatic hydrocarbons, ether and water. Suitable aliphatic hydrocarbons are selected from pentane or hexane or heptane. Suitable aliphatic ethers are selected from diethyl ether, diisopropyl ether and methyl tert- butyl ether.
  • the dissolution temperature is varied depending on the solubility of Aprepitant in the solubilizing solvent.
  • the temperature is varied from room temperature to reflux temperature of the solvent preferably 25-65°C.
  • the solution of Aprepitant in suitable solubilizing solvent is optionally filtered and to the obtained filtrate suitable antisolvent is added at room temperature or higher temperature followed by stirring at the same temperature for 2-5 hours.
  • the solution is optionally cooled at desired temperature to get the desired polymorph of Aprepitant .
  • the separated solid is isolated by filtration and dried below 60°C to get Form II of Aprepitant.
  • the polymorphic forms, Form II and Form IV of Aprepitant obtained by the process of the present invention has chemical purity > 99.9% and polymorphic purity > 99%.
  • Both the highly crystalline Form II and novel Form IV are micronized by conventional micronization techniques to have particle size distribution, ds>o is between about 5-50 ⁇ preferably about 5-25 ⁇ more preferably about 5-15 ⁇ .
  • a process for the preparation of Aprepitant which 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-mo ⁇ holinone (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-benzy
  • the first step of the process involves preparation of N-benzyl-(S)-(4-fluorophenyl) glycine (II) which comprises stirring a solution of (S)-(4-fluorophenyl) glycine, benzaldehyde in 1 N aqueous sodium hydroxide solution and methanol at room temperature for 1 hour.
  • the reaction mixture is cooled at 0 0 C and treated with sodium borohydride followed by addition of benzaldehyde and sodium borohydride again to the reaction mixture in the same manner.
  • the reaction mixture is stirred for 1.5 hours.
  • the reaction mixture is partitioned between methyl tertiary butyl ether and water and acidifying the separated aqueous layer using 2N aqueous hydrochloric acid solution to obtain pH 5.
  • the precipitated solid is filtered and dried.
  • the second step of the process involves preparation of 3-(S)-(4-fluorophenyl)-4-benzyl- 2-morpholinone (III) which comprises stirring a mixture of N-Benzyl-(S)-(4- fluorophenyl) glycine, N,N-diisopropylethylamine, 1,2-dibromoethane and N 5 N- dimethylformamide at 80°C for 17 hours. After the completion of reaction the reaction mixture is cooled and concentrated in vacuum. The obtained residue is partitioned between ethyl acetate and water. A solution of potassium hydrogen sulphate is added to the mixture to render it acidic.
  • III 3-(S)-(4-fluorophenyl)-4-benzyl- 2-morpholinone
  • the third step of the process involves preparation of 2-(R)-(3,5-bis (trifluoromethyl) benzoyloxy)-3-(S)-(4-fluorophenyl)-4-benzylmorpholine (IV) which comprises cooling a solution of 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone in dry THF to -70 0 C.
  • the cold solution is treated with L-selectride solution in tetrahydrofuran (THF) maintaining the internal temperature below -70 0 C.
  • THF tetrahydrofuran
  • the resulting solution is stirred at same temperature for about 2 hours and the reaction is charged with 3,5-bis-(trifiuoromethyl) benzoyl chloride followed by stirring for 6 hours till completion of reaction.
  • reaction mass is then quenched with acetic acid in THF and the temperature of the reaction mixture is raised to room temperature.
  • the reaction mixture was partitioned between hexane and water. The separated organic layer is washed with 10 % sodium carbonate solution, water, dried over anhydrous sodium sulphate and concentrated in vacuum. The residue obtained is then dissolved in n-propanol to get solid of compound (FV).
  • the fourth step of process involves treating a solution of titanocene dichloride in dry THF and toluene in the dark at 0 0 C with solution of methyl magnesium chloride in THF maintaining the internal temperature below 5 0 C for 2 hours and further at room temperature for 30 minutes. After the completion, the reaction mixture is quenched in ammonium chloride solution.
  • the obtained solution of dimethyl titanocene is mixed with 2-(R)-(3,5-bis (trifluoromethyl) benzoyloxy)-3-(S)-(4-fluorophenyl)-4-benzylmo ⁇ holine (IV) and concentrated in vacuum below 60 0 C till desired volume containing 20 % of dimethyl titanocene reagent content obtained.
  • This concentrated reaction mixture is heated to about 80 0 C for 6 to 7 hours in dark. After completion of reaction, the reaction mixture is filtered to remove titanocene residues.
  • reaction mixture is concentrated in vacuum and adding hexane, sodium bicarbonate, water and 30 % hydrogen peroxide to the concentrated reaction mass maintaining the temperature in the range of 5-1O 0 C with stirring overnight at room temperature to get (2R,3S)-4-Benzyl-2-( ⁇ l-[3,5-bis (trifluoromethyl) phenyl] ethenyl ⁇ oxy)-3-(4-fiuorophenyl) morpholine(V).
  • the fifth step of the process involves reducing compound (V) using 10 % Pd-C at 40-45 psi pressure at room temperature for 6-8 hours. After completion of reaction, the reaction mixture is concentrated under reduced pressure to obtain the residue of compound (VI). Step VI
  • the obtained residue of compound (FV) is subjected to chromatographic separation using NOVASEP to isolate the desired isomer (VII).
  • the sixth step of the process involves stirring a mixture of 2-chloroacetamidrazone, anhydrous potassium carbonate in dimethyl sulphoxide at room temperature for 3 hours to get compound (VIII).
  • the eighth step of the process comprises dissolving compound (VII) in xylene and the refluxing the mixture for 5-6 hours. After the completion of reaction, the reaction mixture is concentrated and acetonitrile is added. The obtained solid is filtered and dried. The crude product thus obtained is dissolved in methanol at 50 0 C and treated with activated carbon at 60-62 0 C for 1 hour. The hot reaction mixture is filtered, washed with hot methanol. The combined filtrate is cooled to room temperature followed by water with stirring the slurry. The separated solid is filtered, washed with 2:1 mixture of methanol-water and dried at 60° to get the pure Aprepitant (IX).
  • the process for preparation of Aprepitant comprises 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 or mixture thereof 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) as described in the above process to get the pure Aprepitant (IX).
  • process for the preparation of Aprepitant comprises cyclizing (2R,3S)- ⁇ (lR)-[3,5-(trifluoromethyl) phenyl] ethoxy ⁇ -3- (4-fluorophenyl)-4-[2-(N-methyIcarboxy) acetamidrazono] morpholine (VIII) under the influence of heat in alcoholic solvent to get Aprepitant or cyclizing compound VIII under influence of heat in alcoholic solvent in presence of strong base and isolating Aprepitant.
  • process for preparation of Aprepitant comprises dissolving compound (VIII) in suitable solvent and adding suitable base to it.
  • the reaction mixture is then heated for about 6 to 7 hrs.
  • the solvent is removed from the reaction mixture to obtain residue which is partitioned using 1-butanol and water.
  • the pH of the reaction mixture is adjusted to 6 to 7 using suitable acid.
  • the separated aqueous layer is extracted with solvent and the combined organic layer is washed with 10 % aqueous solution of ethylene diamine tetraacetic acid followed by twice with water.
  • the organic layer is removed to obtain residue which is stripped with toluene and then with acetonitrile.
  • the residue left after stripping is dissolved in acetonitrile (40 to 50 volumes) under refluxed.
  • the reaction is performed at 75 to 105 0 C for a period of 3 to 7 hours preferably at 85 to 95°C for a period of 6-7 hours.
  • the solvent used for cyclization of compound VIII is selected from alcohols such as 1-propanol, methanol, isopropyl alcohol, 1- butanol, tert- butanol or mixtures thereof. Preferably, mixture of 1-propanol and methanol is used.
  • the base used for cyclization is alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, potassium tertiary butoxide or sodium hydride or mixtures thereof used in molar excess with respect to compound VIII preferably sodium hydroxide.
  • the acid used is selected from organic or inorganic acid preferably aqueous hydrochloric acid. The process is represented in scheme 2 below,
  • Advantages of this process are, a) avoiding high temperature for cyclisation by not using high boiling solvent b) providing clean reaction to reduce impurity profile of the desired product c) using inorganic base i.e. sodium hydroxide instead of organic base i.e. diisopropyl ethylamine which requires higher temperature for removal and d) avoids use of tedious conventional column chromatography as used in the prior art.
  • inorganic base i.e. sodium hydroxide instead of organic base i.e. diisopropyl ethylamine which requires higher temperature for removal and d
  • highly pure in context to present invention relates to highly pure Form II of Aprepitant or pharmaceutically acceptable salt thereof having purity more than 99.5 %.
  • the starting Aprepitant used in the present invention may be any crystalline or other form of Aprepitant, including various solvates, hydrates and salts, known in the art and can be prepared by known techniques.
  • salts that may be used with the present invention include sodium, calcium, potassium, acetate, benzoate, fumarate, maleate, citrate, tartrate, hydrochloride and hydrobromide salts.
  • Suitable solvents include, but are not limited to, alcoholic solvents having from 1 to 12 carbon atoms, halogenated solvents, aromatic hydrocarbon solvents, non- aromatic hydrocarbon solvents and the like and mixtures thereof. >
  • Useful alcoholic solvents include methanol, ethanol, isopropanol, butanol and the like and mixtures thereof.
  • Useful halogenated solvents include dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride and the like and mixtures thereof.
  • Useful aromatic hydrocarbons include benzene, toluene, xylene and the like and mixtures thereof.
  • Useful non-aromatic hydrocarbons include hexane, heptane and the like and mixtures thereof.
  • compositions containing the novel polymorph Form IV of Aprepitant and/or highly crystalline form, Form II of Aprepitant as disclosed herein.
  • the pharmaceutical compositions may further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • Example 1 Preparation of N-Benzyl-(S)-(4-fluorophenyl) glycine (II) A solution of 500 gm (2.94 M) (S)-(4-fluorophenylglycine), 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 0 C and treated with 44.4 gm ( 1.17 M) of sodium borohydride.
  • Example 2 Preparation of 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone (III) A mixture of 550 gm of N-Benzyl-(S)-(4-fluorophenyl) glycine, 1100 ml of N,N- diisopropylethylamine, 1100 ml of 1,2-dibromoethane and 5.5 L. of N 5 N- dimethylformamide was stirred at 80 0 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.
  • III A mixture of 550 gm of N-Benzyl-(S)-(4-fluorophenyl) glycine, 1100 ml of N,N- diisopropylethylamine, 1100 ml of
  • 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 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 0 C for 2 hours and further at room temperature for 30 minutes. The 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.
  • Example 8 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 (351 ml) was added slowly to it with stirring at 4O 0 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.
  • Aprepitant 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 0 C and stirred at the same temperature for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form IV.
  • Aprepitant 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. 40ml n-hexane was added to the solution and stirred at the same temperature for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form IV.

Abstract

Disclosed herein is novel polymorph of 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, commonly known as Aprepitant or pharmaceutically acceptable salts thereof and process for preparation thereof. The present invention further relates to highly pure polymorph, Form II of Aprepitant. The present invention further relates to improved process for preparation of Aprepitant.

Description

Field of invention:
The present invention relates to novel polymorph of 5-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]- 1 ,2- dihydro-3H-l ,2,4-triazol-3-one, commonly known as Aprepitant or pharmaceutically acceptable salts thereof and process for preparation thereof. The present invention further relates to highly pure polymorph, Form II of Aprepitant. The present invention further relates to improved 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]-l,2- dihydro-3H-l ,2,4- triazol-3-one and represented by Formula IX.
Figure imgf000002_0001
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-I) 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 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(trifluorornethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4- morpholinyl]methyl]-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.
WO 2007/044829 discloses process for preparation of Aprepitant and intermediates thereof. WO'829 also describes process for purification of Aprepitant using different solvents to get pure Aprepitant.
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 polymorph Form III of Aprepitant, process for its preparation and pharmaceutical compositions containing same.
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, fiowability 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. Fiowability 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, ball mills, microfluidization and such other techniques known to person skilled in the art. 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. The present invention therefore provides novel crystalline form, Form IV and highly crystalline Form II of Aprepitant having chemical and polymorphic purity > 99%. Object of the present invention:
An object of the present invention is to provide novel polymorph of Aprepitant having inproved flow properties, angle of repose, solubility etc. and processes for preparation thereof.
Another object of the present invention is to provide highly crystalline form, Form II of
Aprepitant, and process for preparation thereof.
Yet another object of the present invention is to provides improved process for preparation of Aprepitant.
Summary of the invention:
According to an aspect the present invention there is provided novel crystalline form of
Aprepitant, Form IV and processes for preparation thereof.
According to another aspect, the present invention provides highly crystalline Form II of
Aprepitant and process for preparation thereof.
According to another aspect, the present invention provides pharmaceutical composition comprising highly crystalline form, Form II or Form IV of Aprepitant or mixtures thereof as an active ingredient and the use of the compound and its formulations in the treatment or prevention of disorders of the central nervous system, inflammatory diseases, pain or migraine, asthma, and emesis.
Another aspect of the present invention provides an improved process for preparation of
Aprepitant.
Another aspect of the present invention provides Apripitant having mean particle size less than 250 microns.
Another aspect of the present invention provides Apripitant having purity at least 99% and individual impurities NMT 0.15%
Brief description of the figures :
FIG. 1 is an X-ray powder diffraction pattern of highly crystalline Form II of Aprepitant according to the present invention.
FIG. 2 is an X-ray powder diffraction pattern of Form IV of Aprepitant according to the present invention. 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 crystallization of Aprepitant using different solvents or solvent combinations, the present invention provides highly crystalline polymorphs, Form II and novel crystalline Form FV of Aprepitant. The present invention further describes process for preparation of novel crystalline Form FV and highly crystalline Form II of Aprepitant.
According to one embodiment, there is provided novel polymorphic form of Aprepitant, Form FV. The XRPD of Form IV of Aprepitant is given in figure 2. Form FV of Aprepitant is characterized by the following XRPD peaks,
Figure imgf000006_0001
The novel polymorphic form of Aprepitant according to the present invention has advantages of superior properties over the known form of Aprepitant in terms of stability and suitability for pharmaceutical formulations. The present inventors had compared the flow property of novel Form IV and prior art form and surprisingly found that flow property data of Form IV is superior as compared to prior art form. The present invention thus involves technical advancement as compared to the existing knowledge and economic significance that makes the invention not obvious to a person skilled in the art. Test for assessment of establishing the efficacy are under progress and we request leave to amend the specification under relevant provisions in the Act.
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; b) cooling the obtained solution; c) isolating the product.
Aprepitant used for preparation of Form IV is either Form I or Form II or any other polymorph of Aprepitant or mixture thereof.
The suitable solvent is selected from aliphatic nitriles or ethylacetate or ketones or mixtures thereof. Said aliphatic nitriles is acetonitrile and ketones are acetone, 2- butanone, diethyl ketone preferably acetone. The dissolution is carried out at temperature of 55-75°C and the clear solution is filtered to remove any undissolved solid. The clear filtrate is cooled to about 25-35°C. The solution/suspension is stirred for 1-3 hrs at the same temperature and the solid separated is isolated by filtration.
According to another embodiment, the present invention provides highly crystalline Form II of Aprepitant. The highly crystalline Form II of Aprepitant is characterized by the following XRPD peaks (Figure 1),
Figure imgf000007_0001
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% of 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 product.
Suitable solubilizing solvent is selected form aliphatic esters such as ethyl acetate, isopropyl acetate, methyl acetate and tert-butyl acetate.
The dissolution is carried out at temperature of 35-65°C preferably at 45°C. Suitable anti-solvent is selected from aliphatic hydrocarbons such as pentane, hexane, heptane or aliphatic ethers such as diethyl ether, di isopropyl ether and methyl tert butyl ether or mixtures thereof. 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 and dried to get Form II of Aprepitant.
According to another embodiment, the present invention provides improved process for preparation of highly crystalline form, Form II of Aprepitant 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 d) isolating the product
The solubilizing solvent is selected from group consisting of aliphatic alcohol such as ethanol, 1- propanol and 2-propanol (IPA); ketone such as acetone, 2-butanone and diethyl ketone; cyclic ethers such as tetrahydrofuran (THF) and 1 ,4-dioxane; polar aprotic solvents such as dimethyl formamide (DMF), di- methyl sulfoxide (DMSO), dimethyl acetamide and chlorinated hydrocarbons such as methylenedichloride (MDC) and chloroform or mixtures thereof.
The criteria for selection of anti-solvent is their miscibility with the solubilizing solvent. The anti-solvents are selected from a group of aliphatic hydrocarbons, ether and water. Suitable aliphatic hydrocarbons are selected from pentane or hexane or heptane. Suitable aliphatic ethers are selected from diethyl ether, diisopropyl ether and methyl tert- butyl ether.
The dissolution temperature is varied depending on the solubility of Aprepitant in the solubilizing solvent. The temperature is varied from room temperature to reflux temperature of the solvent preferably 25-65°C. The solution of Aprepitant in suitable solubilizing solvent is optionally filtered and to the obtained filtrate suitable antisolvent is added at room temperature or higher temperature followed by stirring at the same temperature for 2-5 hours. The solution is optionally cooled at desired temperature to get the desired polymorph of Aprepitant . The separated solid is isolated by filtration and dried below 60°C to get Form II of Aprepitant. The polymorphic forms, Form II and Form IV of Aprepitant obtained by the process of the present invention has chemical purity > 99.9% and polymorphic purity > 99%. Both the highly crystalline Form II and novel Form IV are micronized by conventional micronization techniques to have particle size distribution, ds>o is between about 5-50μ preferably about 5-25μ more preferably about 5-15μ .
According to another embodiment of the present invention there is provided a process for the preparation of Aprepitant which 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-moφholinone (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 (IV); 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)-[3,5-(trifluoromethyl) phenyl] ethoxy}-3-(4- fluorophenyl) morpholine (VII) with N-methylcarboxyl-2-chloroacetarnidrazone to get (2R,3S)-{(lR)-[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) to get the desired product; i) optionally crystallizing the obtained product to get pure Aprepitant (IX). The process for preparation of Aprepitant in accordance with the present invention is represented in Scheme 1 below;
Figure imgf000011_0001
Step I
The first step of the process involves preparation of N-benzyl-(S)-(4-fluorophenyl) glycine (II) which comprises stirring a solution of (S)-(4-fluorophenyl) glycine, benzaldehyde in 1 N aqueous sodium hydroxide solution and methanol at room temperature for 1 hour. The reaction mixture is cooled at 00C and treated with sodium borohydride followed by addition of benzaldehyde and sodium borohydride again to the reaction mixture in the same manner. The reaction mixture is stirred for 1.5 hours. The reaction mixture is partitioned between methyl tertiary butyl ether and water and acidifying the separated aqueous layer using 2N aqueous hydrochloric acid solution to obtain pH 5. The precipitated solid is filtered and dried.
Step II
The second step of the process involves preparation of 3-(S)-(4-fluorophenyl)-4-benzyl- 2-morpholinone (III) which comprises stirring a mixture of N-Benzyl-(S)-(4- fluorophenyl) glycine, N,N-diisopropylethylamine, 1,2-dibromoethane and N5N- dimethylformamide at 80°C for 17 hours. After the completion of reaction the reaction mixture is cooled and concentrated in vacuum. The obtained residue is partitioned between ethyl acetate and water. A solution of potassium hydrogen sulphate is added to the mixture to render it acidic. The separated organic layer was washed with 10 % sodium carbonate solution followed by water and concentrated in vacuum to obtain the residue. The obtained residue is dissolved in isopropyl acetate and ethanolic HCl and methyl tertiary butyl ether is added to precipitate the HCl salt. The obtained hydrochloride salt is neutralized to get compound (III).
Step III
The third step of the process involves preparation of 2-(R)-(3,5-bis (trifluoromethyl) benzoyloxy)-3-(S)-(4-fluorophenyl)-4-benzylmorpholine (IV) which comprises cooling a solution of 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone in dry THF to -700C. The cold solution is treated with L-selectride solution in tetrahydrofuran (THF) maintaining the internal temperature below -700C. The resulting solution is stirred at same temperature for about 2 hours and the reaction is charged with 3,5-bis-(trifiuoromethyl) benzoyl chloride followed by stirring for 6 hours till completion of reaction. The reaction mass is then quenched with acetic acid in THF and the temperature of the reaction mixture is raised to room temperature. The reaction mixture was partitioned between hexane and water. The separated organic layer is washed with 10 % sodium carbonate solution, water, dried over anhydrous sodium sulphate and concentrated in vacuum. The residue obtained is then dissolved in n-propanol to get solid of compound (FV).
Step IV
The fourth step of process involves treating a solution of titanocene dichloride in dry THF and toluene in the dark at 00C with solution of methyl magnesium chloride in THF maintaining the internal temperature below 50C for 2 hours and further at room temperature for 30 minutes. After the completion, the reaction mixture is quenched in ammonium chloride solution.
The obtained solution of dimethyl titanocene is mixed with 2-(R)-(3,5-bis (trifluoromethyl) benzoyloxy)-3-(S)-(4-fluorophenyl)-4-benzylmoφholine (IV) and concentrated in vacuum below 600C till desired volume containing 20 % of dimethyl titanocene reagent content obtained. This concentrated reaction mixture is heated to about 800C for 6 to 7 hours in dark. After completion of reaction, the reaction mixture is filtered to remove titanocene residues. The reaction mixture is concentrated in vacuum and adding hexane, sodium bicarbonate, water and 30 % hydrogen peroxide to the concentrated reaction mass maintaining the temperature in the range of 5-1O0C with stirring overnight at room temperature to get (2R,3S)-4-Benzyl-2-({l-[3,5-bis (trifluoromethyl) phenyl] ethenyl}oxy)-3-(4-fiuorophenyl) morpholine(V).
Step V
The fifth step of the process involves reducing compound (V) using 10 % Pd-C at 40-45 psi pressure at room temperature for 6-8 hours. After completion of reaction, the reaction mixture is concentrated under reduced pressure to obtain the residue of compound (VI). Step VI
The obtained residue of compound (FV) is subjected to chromatographic separation using NOVASEP to isolate the desired isomer (VII). The condition of chromatographic method for isolating the compound (VII) are, Column: silica gel-60, 15-40 μ, Dimension: LD .= 110 mm, length = 25 cm , Flow rate: 250 ml / min, λmax = 263 run Solvent ratio: hexane: isopropyl acetate : 60: 40.
Step VII
The sixth step of the process involves stirring a mixture of 2-chloroacetamidrazone, anhydrous potassium carbonate in dimethyl sulphoxide at room temperature for 3 hours to get compound (VIII).
Step VIII
The eighth step of the process comprises dissolving compound (VII) in xylene and the refluxing the mixture for 5-6 hours. After the completion of reaction, the reaction mixture is concentrated and acetonitrile is added. The obtained solid is filtered and dried. The crude product thus obtained is dissolved in methanol at 500C and treated with activated carbon at 60-620C for 1 hour. The hot reaction mixture is filtered, washed with hot methanol. The combined filtrate is cooled to room temperature followed by water with stirring the slurry. The separated solid is filtered, washed with 2:1 mixture of methanol-water and dried at 60° to get the pure Aprepitant (IX).
Alternatively , the process for preparation of Aprepitant comprises 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 or mixture thereof 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) as described in the above process to get the pure Aprepitant (IX). According to another embodiment of the present invention process for the preparation of Aprepitant comprises cyclizing (2R,3S)-{(lR)-[3,5-(trifluoromethyl) phenyl] ethoxy}-3- (4-fluorophenyl)-4-[2-(N-methyIcarboxy) acetamidrazono] morpholine (VIII) under the influence of heat in alcoholic solvent to get Aprepitant or cyclizing compound VIII under influence of heat in alcoholic solvent in presence of strong base and isolating Aprepitant.
Preferably, process for preparation of Aprepitant comprises dissolving compound (VIII) in suitable solvent and adding suitable base to it. The reaction mixture is then heated for about 6 to 7 hrs. After completion of the reaction the solvent is removed from the reaction mixture to obtain residue which is partitioned using 1-butanol and water. The pH of the reaction mixture is adjusted to 6 to 7 using suitable acid. The separated aqueous layer is extracted with solvent and the combined organic layer is washed with 10 % aqueous solution of ethylene diamine tetraacetic acid followed by twice with water. The organic layer is removed to obtain residue which is stripped with toluene and then with acetonitrile. The residue left after stripping is dissolved in acetonitrile (40 to 50 volumes) under refluxed. Activated neutral alumina (1-2 times w/w) is added to the solution and reaction mixture is stirred for 2-3 hours, filtered and the filtrate is concentrated. The concentrated reaction mass is stirred at room temperature for 10-12 hours to get crystalline Aprepitant. The Aprepitant thus obtained is further crystallized from acetonitrile to get highly pure compound (IX).
The reaction is performed at 75 to 1050C for a period of 3 to 7 hours preferably at 85 to 95°C for a period of 6-7 hours. The solvent used for cyclization of compound VIII is selected from alcohols such as 1-propanol, methanol, isopropyl alcohol, 1- butanol, tert- butanol or mixtures thereof. Preferably, mixture of 1-propanol and methanol is used. The base used for cyclization is alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, potassium tertiary butoxide or sodium hydride or mixtures thereof used in molar excess with respect to compound VIII preferably sodium hydroxide. The acid used is selected from organic or inorganic acid preferably aqueous hydrochloric acid. The process is represented in scheme 2 below,
Figure imgf000016_0001
Advantages of this process are, a) avoiding high temperature for cyclisation by not using high boiling solvent b) providing clean reaction to reduce impurity profile of the desired product c) using inorganic base i.e. sodium hydroxide instead of organic base i.e. diisopropyl ethylamine which requires higher temperature for removal and d) avoids use of tedious conventional column chromatography as used in the prior art.
The novel polymorph of Aprepitant in accordance with the present invention are characterized by Xpert'PRO, Panalytical, diffractometer equipped with accelerator detector using Copper Ka (λ =1.5406 A) radiation with scanning range between 4-50 θat scanning speed of 2°/min.
The Organic solvent' used are known to a person of ordinary skills in art through several literature references.
The term "highly pure" in context to present invention relates to highly pure Form II of Aprepitant or pharmaceutically acceptable salt thereof having purity more than 99.5 %.
It is well known that the physicochemical characteristics of pharmaceutical compositions for example bulk density, flow properties, Carr index, Hausner ratio, aspect ratio, compressibility of particles aid processability and result in desired physicochemical properties of compositions and dosage forms like hardness, friability, solubility properties and bioavailability. These and other physicochemical properties of the pharmaceutical compositions of Aprepitant, either alone or in combination with any of the other embodiments described above are all within the scope of this invention without limitation. Any modifications required to be made to these physicochemical properties to improve further processing are also within the scope of this invention. Other improved physicochemical characteristics of novel polymorph of Aprepitant, Form IV which help in the effective delivery of Aprepitant are all within the scope of this invention without limitation.
The starting Aprepitant used in the present invention may be any crystalline or other form of Aprepitant, including various solvates, hydrates and salts, known in the art and can be prepared by known techniques. Examples of salts that may be used with the present invention include sodium, calcium, potassium, acetate, benzoate, fumarate, maleate, citrate, tartrate, hydrochloride and hydrobromide salts. With crystallization processes, the crystalline form of the starting material does not usually affect the final result since the original crystalline form is lost once a material goes into solution.
Suitable solvents include, but are not limited to, alcoholic solvents having from 1 to 12 carbon atoms, halogenated solvents, aromatic hydrocarbon solvents, non- aromatic hydrocarbon solvents and the like and mixtures thereof. >
Useful alcoholic solvents include methanol, ethanol, isopropanol, butanol and the like and mixtures thereof. Useful halogenated solvents include dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride and the like and mixtures thereof. Useful aromatic hydrocarbons include benzene, toluene, xylene and the like and mixtures thereof. Useful non-aromatic hydrocarbons include hexane, heptane and the like and mixtures thereof.
Another embodiment of the present invention is directed to the pharmaceutical compositions containing the novel polymorph Form IV of Aprepitant and/or highly crystalline form, Form II of Aprepitant as disclosed herein. The pharmaceutical compositions may further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1: Preparation of N-Benzyl-(S)-(4-fluorophenyl) glycine (II) A solution of 500 gm (2.94 M) (S)-(4-fluorophenylglycine), 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 00C 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 = 550 gm (71 %)
Example 2: Preparation of 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone (III) A mixture of 550 gm of N-Benzyl-(S)-(4-fluorophenyl) glycine, 1100 ml of N,N- diisopropylethylamine, 1100 ml of 1,2-dibromoethane and 5.5 L. of N5N- dimethylformamide was stirred at 800C 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 vacuum to obtain the residue. The residue obtained was dissolved in 860 ml of isopropyl acetate and 302 ml of ethanolic HCl and 942 ml of methyl tertiary butyl ether was added to precipitate the HCl 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 (III). 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 -700C. The cold solution was treated with IL. of L-selectride solution in THF maintaining the internal temperature below -700C. The resulting solution was stirred at same temperature for 2 hours and the reaction was charged with 250 ml of 3,5- 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 (trifluoromethyl) phenyl] ethenyl}oxy)-3-(4-fluorophenyl) morpholine (V)
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 00C 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 50C for 2 hours and further at room temperature for 30 minutes. The 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 vacuum 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 800C 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 500C 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 5-100C 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).
The obtained residue was subjected to chromatographic separation to isolate the desired isomer (VII). Yield = 124 gm
The condition of chromatographic method for isolating the compound (VII) are,
Column: silica gel-60, 15-40 μ, Dimension: LD. = 110 mm, length = 25 cm, Flow rate: 250 ml / min, λmax = 263 run 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 vacuum to get compound (VIII). Yield - 154.2 gm (96%).
Compound (VIII) (154.2 g) 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 450 ml of acetonitrile was added. The solid obtained was filtered off, washed with acetonitrile (450 ml) and dried to get the residue of crude Aprepitant (59.8 g). The crude product thus obtained was dissolved in 490 ml of methanol at 500C and treated with 6 g activated carbon at 60-620C for 1 hour. Then the hot reaction mixture was filtered, washed with hot methanol. The combined filtrate was cooled to room temperature and 250 ml 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) having form II. Yield = 40.25 g (28 %).
Example 7:
A mixture of 124 g of 2-(R)-(I (R)-[3,5-bis-(trifluoromethyl) phenyl] ethoxy}-3-(S)-(4- fluorophenyl) morpholine (VII), 70.45 g of 2-chloroacetamidrazone, 78 g 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 (2.25 L) 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 g (96%).
The obtained 154.2 g of compound (VIII) was dissolved in 2.5 L of 1-propanol and to it was added 158 ml of methanol and 19.75 g of sodium hydroxide. Reaction mixture was heated at 85 to 95°C. After completion of reaction, 1-propanol was removed by distillation, water was added and pH of the mixture was adjusted to 6 to 7 using hydrochloric acid. The mixture was partitioned between 2.0 L of water and 2.0 L of 1- butanol. The layers were separated and the aqueous layer was extracted with 270 ml of 1- butanol. Butanol layers were combined and then washed with 2.2 L of 10 % aqueous solution of ethylene diamine tetraacettic acid followed by washing with 2.0 L of 0.5 N HCl. The butanol layer was further washed with 2 x 2.5 L of water and then dried over anhydrous sodium sulphate. 1 -butanol was removed by flash distillation. The mixture was stripped with 1.25 L of toluene followed by stripping with 1.25 L of acetonitrile. The residue obtained was crude aprepitant Yield = 118 g (81.2 %). Purification of Aprepitant:
This crude aprepitant (118 g) was dissolved in 4.2 L of acetonitrile under reflux. The mixture was filtered through hyflo and was stirred at room temperature when aprepitant crystallized out. Crystals were filtered, washed with acetonitrile and dried at 80 to 950C. Aprepitant (83 g) thus obtained was dissolved in 3.3 L of acetonitrile under reflux and to it was added 83 g of neutral alumina. The mixture was stirred at same temperature for half an hour and then filtered through hyflo. The filtrate was stirred at room temperature. Solid crystallized out was pure Aprepitant (IX) having Form IV Yield = 68. O g (81.9 %).
Example 8: 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 (351 ml) was added slowly to it with stirring at 4O0C. 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 500C to get the p- toluenesulphonate salt of compound (VI). Yield = 174 g ( 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 was1 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 400C. 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 500C to get the desired pure p- toluenesulphonate salt of compound (VII).Yield = 125 g (71.8 %).
Example 9:
Preparation 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-triazol-3-one (IX) (Aprepitant):
A solution of N-methylcarboxyl-2-chloroacetamidrazone (36.5g ) in dimethyl sulphoxide (500 ml) was added to a stirred mixture of (2R,3S)-2-{(R)-l-[3,5-bis(trifluoromethyl) phenyl] ethoxy}-3-(4-fluorophenyl) morpholine-4-methylbenzenesulphonate (125g), powdered potassium carbonate (101g ) in dimethyl sulphoxide (500 ml) at room temperature and continued the stirring for 1 hour. The reaction mixture was then quenched with water (700 ml) 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 (110 g) 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 (IX). The crude product thus obtained was dissolved in 617 ml of methanol at 500C and treated with activated carbon at 60-620C 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 600C to get the pure compound (IX). Yield = 3O g (21.0%)
Example 10
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 25-300C for 15-20 min. The solution was further cooled to 0-50C for 2 hrs. The separated solid was filtered and dried at 600C 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 25-300C. To this clear solution 40 ml n-hexane was added and the solution was stirred at 25-300C for 4-5 hrs. The separated solid was filtered and dried at 6O0C 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 25-300C. To this clear solution 40 ml water was added and the solution was stirred at 25-300C for 4-5 hrs. The separated solid was filtered and dried at 600C to get Aprepitant Form II.
Example 13
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 25-300C. To this clear solution 40 ml diisopropylether (DIPE) was added and the solution was stirred at 25-3O0C for 4-5hrs. The separated solid was filtered and dried at 600C to get Aprepitant Form II. Example 14
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 600C to get Aprepitant Form II.
Example IS
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 16
1 g Aprepitant was dissolved in 15 ml ethanol at 50-600C. 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 17
1 g Aprepitant was dissolved in 15 ml tetrahydrofuran (THF) at 50-600C. The solution was filtered and to this filtrate 30 ml water was added and the solution was stirred at 25- 300C for 4-5hrs. The separated solid was filtered and dried at 600C to get Aprepitant Form II.
Example 18
1 g Aprepitant was dissolved in 15 ml THF at 50-600C. The solution was filtered and to this clear filtrate 30 ml hexane was added and the solution was stirred at 25-300C for 4- 5hrs. The separated solid was filtered and dried at 600C to get Aprepitant Form II.
Example 19
1 g Aprepitant was dissolved in 15 ml THF at 50-600C. The solution was filtered and to this clear filtrate 30 ml DIPE was added and the solution was stirred at 25-300C for 4- 5hrs. The separated solid was filtered and dried at 600C to get Aprepitant Form II. Example 20
1 g Aprepitant was dissolved in 15 ml 1,4-dioxane at 50-600C. 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 6O0C to get Aprepitant Form II.
Example 21
1 g Aprepitant was dissolved in 15 ml 1,4-dioxane at 50-600C. The solution was filtered and to this clear filtrate 30 ml hexane was added and the solution was stirred at 25-300C for 4-5hrs. The separated solid was filtered and dried at 600C to get Aprepitant Form II.
Example 22
1 g Aprepitant was dissolved in 15 ml 1,4-dioxane at 50-600C. The solution was filtered and to this clear filtrate 30 ml DIPE was added and the solution was stirred at 25-300C for 4-5hrs. The separated solid was filtered and dried at 600C to get Aprepitant Form II.
Example 23
1 g Aprepitant was dissolved in 15 ml methylenedichloride (MDC) at 50-600C. The solution was filtered and 30 ml hexane was added to the obtained clear filtrate and the solution was stirred at 25-300C for 4-5hrs. The separated solid was filtered and dried at 600C to get Aprepitant Form II.
Example 24
1 g Aprepitant was dissolved in 15 ml MDC at 50-600C. The solution was filtered and 30 ml DIPE was added to the obtained clear filtrate and the solution was stirred at 25-300C for 4-5hrs. The separated solid was filtered and dried at 600C to get Aprepitant Form II.
Example 25
1 g Aprepitant was dissolved in 5 ml dimethylformamide (DMF) at 25-300C. The solution was filtered and 30 ml water was added to the obtained clear filtrate and the solution was stirred at 25-300C for 4-5hrs. The separated solid was filtered and dried at 600C to get Aprepitant Form II. Example 26
1 g Aprepitant was dissolved in 5 ml dimethylsulfoxide (DMSO) at 25-30°C. The solution was filtered and 30 ml water was added to the obtained clear 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.
Process for preparation of Aprepitant 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 25-300C and stirred at the same temperature for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form IV.
Example 28
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. 40ml n-hexane was added to the solution and stirred at the same temperature for 4-5hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form IV.
Example 29
1 g Aprepitant was dissolved in 15 ml ethyl acetate at 70-75°C. The solution is maintained at 70° for 30 min to ensure complete dissolution. The obtained hot solution was filtered and the filtrate was cooled to 25-300C followed by stirring at the same temperature for 2-3hrs. The separated solid was filtered and dried at 600C to get Aprepitant Form IV.
Example 30
1 g Aprepitant was dissolved in 15 ml ethyl acetate at 70-750C. The solution is maintained at 70° for 30 min to ensure complete dissolution. The obtained hot solution was filtered and the filtrate was cooled to 25-300C followed by stirring at the same temperature for 24 hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form IV.
Example 31
1 g Aprepitant was dissolved in 15 ml ethyl acetate at 70-75 °C. The solution is maintained at 70° for 30 min to ensure complete dissolution. The obtained hot solution was filtered and the filtrate was cooled to 0-5°C followed by stirring at the same temperature for 2hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form IV.
Example 32
1 g Aprepitant was dissolved in 15 ml acetone at 60-65 °C. The solution is maintained at 65° for 30 min to ensure complete dissolution. The obtained hot solution was filtered and the filtrate was cooled to 0-50C followed by stirring at the same temperature for 2hrs. The separated solid was filtered and dried at 60°C to get Aprepitant Form FV.

Claims

We claim,
1. Aprepitant having at least one characteristic X-ray diffraction peak at 2Θ values selected from the group consisting of: about 12.41, 20.14, 23.69, 24.03, 24.89, 25.43, 25.82, 27.70, 29.09 and 29.39 degrees.
2. Aprepitant as claimed in claim 1 further characterized by X-ray diffraction peaks at 2Θ values ; about 4.22, 8.29, 15.44, 17.28, 17.73, 18.83, 19.58, 20.71, 22.07, 31.55, 33.65, 35.56, 37.671, 39.46, 42.02, 45.99, 47.57, 47.98.
3. A process for preparation of Aprepitant having at least one characteristic X-ray diffraction peak at 2Θ values selected from the group consisting of: about 12.41, 20.14, 25.82, 27.70, 29.09 and 29.39 degrees two theta comprising the steps of; a) dissolving Aprepitant in solubilizing solvent; b) cooling the obtained solution; c) isolating the separated product.
4. The process as claimed in claim 3 wherein said solubilizing solvent is selected from aliphatic nitriles or ethylacetate or ketones or mixtures thereof .
5. The process as claimed in 4 wherein said aliphatic nitriles is acetonitrile and ketones are acetone, 2-butanone, diethyl ketone preferably acetone.
6. The process as claimed in claim 3 wherein said dissolution is carried out at temperature of 55-75°C and said cooling is performed at temperature 25-35°C.
7. Aprepitant having particle size distribution, d% less than about 50μ .
8. A pharmaceutical composition comprising Form IV of Aprepitant and one or more suitable excipients/additives.
9. Highly crystalline Aprepitant Form II with X-ray diffraction peaks at 2Θ values : about 4.16, 8.31, 12.44, 12.73, 13.63, 14.57, 16.29, 16.90, 17.31, 18.20, 20.28, 20.81, 21.24, 23.04, 24.07, 25.00, 26.78, 27.27, 27.80, 29.24, 30.69, 31.70, 35.71, 37.83, 38.85, 42.23, 44.04 having chemical and polymorphic purity more than 99%.
10. A process for preparation of highly crystalline Form II of Aprepitant which comprises the following steps, a) dissolving Aprepitant in solubilizing solvent; b) adding antisolvent selected from aliphatic ether aliphatic hydrocarbon to the obtained solution of step (a); c) optionally cooling the solution of step (b) and d) isolating the separated product
11. The process as claimed in claim 10 wherein said solubilizing solvent is selected from group consisting of aliphatic esters, aliphatic alcohol, ketone, cyclic ether, polar aprotic solvent and chlorinated hydrocarbon.
12. The process as claimed in claim 10 wherein said ester is selected from ethyl acetate, isopropyl acetate, methyl acetate and tert-butyl acetate, alcohol is selected from ethanol, 1- propanol and 2-propanol (TPA), ketone is selected from acetone, 2-butanone and diethyl ketone, chlorinated hydrocarbon is selected from methylenedichloride (MDC), chloroform , the aliphatic cyclic ether is selected from tetrahydrofuran (THF), 1,4-dioxane and polar aprotic solvent is selected from dimethyl formamide (DMF), di- methyl sulfoxide (DMSO), dimethyl acetamide.
13. The process as claimed in claim 10 wherein said anti-solvent is selected from a group consisting of aliphatic ether selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether and aliphatic hydrocarbon selected from pentane, hexane and heptane.
14. The process as claimed in claim 10 wherein said dissolution is carried out at temperature between room temperature to reflux temperature of the solvent and said cooling is performed at 25-3O0C.
15. A pharmaceutical composition comprising highly crystalline Form II of Aprepitant as claimed in claim 9.
16. A process for the preparation of Aprepitant comprising cyclizing (2R,3S)-{(1R)- [3,5-(trifluoromethyl) phenyl] ethoxy}-3-(4-fluorophenyl)-4-[2-(N- methylcarboxy) acetamidrazono] morpholine (VIII) under the influence of heat in alcoholic solvent to get Aprepitant or cyclizing compound VIII under influence of heat in alcoholic solvent in presence of strong base and isolating Aprepitant.
17. The process as claimed in claim 16, wherein said solvent used is selected from 1- propanol, methanol, isopropyl alcohol, tert.- butanol or mixtures thereof..
18. The process as claimed in claim 16, wherein said base is selected from sodium hydroxide, potassium hydroxide, potassium tertiary butoxide, sodium hydride or mixtures thereof used in molar excess with respect to compound VIIL.
19. The process as claimed in claim 16, wherein said reaction is carried out at 75 to 105°C for a period of 3 to 5 hours.
20. The process as claimed in claim 16, wherein said isolation comprises extracting the reaction mixture / residue using alcohol preferably 1-butanol.
21. Aprepitant polymorph, Form IV and highly crystalline Form II and process for preparation thereof as claimed in any of the preceding claims 1 to 20 substantially as described herein with reference to foregoing examples 1 to 32.
PCT/IN2009/000370 2008-06-30 2009-06-29 Novel crystalline polymorphs of 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 process for preparation thereof WO2010092591A2 (en)

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US20130109853A1 (en) * 2010-05-24 2013-05-02 Jianxin Ji Preparation method of 5-[[2(r)-[1(r)-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3(s)-4-fluorophenyl-4-morpholinyl]methyl]-1,2-dihydro-3h-1,2,4-triazole-3-one
CN103193725A (en) * 2013-04-12 2013-07-10 上海医药工业研究院 Preparation method of (2R, 3R)-2-((1R)-1-(3, 5-bis (trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl) morpholine
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CN104119325A (en) * 2014-07-15 2014-10-29 中山奕安泰医药科技有限公司 Preparation method of aprepitant polymorphic substance
CZ304982B6 (en) * 2012-04-30 2015-03-11 Zentiva, K.S. Process for preparing and purifying novel polymorphs of fosaprepitant intermediate
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CN104119325A (en) * 2014-07-15 2014-10-29 中山奕安泰医药科技有限公司 Preparation method of aprepitant polymorphic substance
CN104119325B (en) * 2014-07-15 2017-03-22 中山奕安泰医药科技有限公司 Preparation method of aprepitant polymorphic substance
CN110776502A (en) * 2019-12-06 2020-02-11 广州白云山汉方现代药业有限公司 Refining method of aprepitant

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