WO2019016828A1 - Nouveaux procédés pour la préparation de chlorhydrate de trans-n-{4-[2-[4-(2,3-dichlorophényl)pipérazine-1-yl]éthyl] cyclohexyl}-n',n'-diméthyl urée et polymorphes de celui-ci - Google Patents

Nouveaux procédés pour la préparation de chlorhydrate de trans-n-{4-[2-[4-(2,3-dichlorophényl)pipérazine-1-yl]éthyl] cyclohexyl}-n',n'-diméthyl urée et polymorphes de celui-ci Download PDF

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WO2019016828A1
WO2019016828A1 PCT/IN2018/050460 IN2018050460W WO2019016828A1 WO 2019016828 A1 WO2019016828 A1 WO 2019016828A1 IN 2018050460 W IN2018050460 W IN 2018050460W WO 2019016828 A1 WO2019016828 A1 WO 2019016828A1
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formula
compound
acid
solvents
trans
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Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Venkat Reddy Ghojala
Rajeshwar Reddy Sagyam
Adilakshmi Singavarapu
Srinivasulu Rangineni
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Msn Laboratories Private Limited, R&D Center
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention provides novel processes for the preparation of trans-N- ⁇ 4-[2- [4-(2,3-dichlorophenyl)piperazine-l-yl]ethyl]cyclohexyl ⁇ -N',N'-dimethylurea hydrochloride represented by the following structural formula- la and polymorphs thereof.
  • the present invention also provides novel intermediate compounds which are useful for the preparation of compound of formula- la.
  • Cariprazine HC1 is an atypical antipsychotic drug indicated for the treatment of schizophrenia and also for the acute treatment of manic or mixed episodes associated with bipolar I disorder.
  • Cariprazine HC1 is developed by Richter Gedeon. This drug was approved by United States Food and Drug administration (USFDA) on Sep 17, 2015 and European Medicines Agency on July 13, 2017 and it is marketed under the brand name VRAYLAR in USA and Reagila in Europe.
  • the present inventors have developed novel processes for the preparation of trans-N- ⁇ 4-[2-[4-(2,3-dichlorophenyl)piperazine-l-yl]ethyl]cyclohexyl ⁇ -N',N' -dimethylurea hydrochloride, which proceeds through novel intermediate compounds.
  • US7943621B2 describes crystalline form-I of trans-N- ⁇ 4-[2-[4-(2,3- dichlorophenyl)piperazine- 1 -yl] ethyl] cyclohexyl ⁇ -N' , ⁇ ' -dimethylurea hydrochloride.
  • US7829569B2 describes crystalline form-Ill as well as formic acid solvate of trans- N- ⁇ 4-[2-[4-(2,3-dichlorophenyl)piperazine-l-yl]ethyl]cyclohexyl ⁇ -N',N'-dimethylurea hydrochloride.
  • US8912197B2 describes fumaric acid co-crystal of trans-N- ⁇ 4-[2-[4-(2,3- dichlorophenyl)piperazine- 1 -yl] ethyl] cyclohexyl ⁇ -N' , ⁇ ' -dimethylurea hydrochloride.
  • CN106543105A describes crystalline form-IV of trans-N- ⁇ 4-[2-[4-(2,3- dichlorophenyl)piperazine- 1 -yl] ethyl] cyclohexyl ⁇ -N' , ⁇ ' -dimethylurea hydrochloride.
  • the first aspect of the present invention is to provide a novel process for the preparation of trans-N- ⁇ 4-[2-[4-(2,3-dichlorophenyl)piperazine-l-yl]ethyl]cyclohexyl ⁇ - ⁇ ', ⁇ ' -dimethylurea compound of formula- 1 and its pharmaceutically acceptable salts.
  • the second aspect of the present invention is to provide a novel intermediate compound of formula- 11 which is useful for the preparation of compound of formula- 1 and its salts.
  • the third aspect of the present invention is to provide a process for the preparation of trans 2-(4-(3,3-dimethylureido)cyclohexyl)-N-methoxy-N-methylacetamide compound of formula- 11.
  • the fourth aspect of the preset invention is to provide a process for the preparation of trans l, l-dimethyl-3-(4-(2-oxoethyl)cyclohexyl)urea compound of formula- 12.
  • the fifth aspect of the present invention is to provide pure amorphous form of trans- N- ⁇ 4-[2-[4-(2,3-dichlorophenyl)piperazine- 1 -yl]ethyl]cyclohexyl ⁇ -N' , ⁇ ' -dimethylurea hydrochloride compound of formula- 1 a.
  • the sixth aspect of the present invention is to provide a process for the preparation of pure amorphous form of compound of formula- 1 a.
  • the seventh aspect of the present invention is to provide amorphous solid dispersion comprising compound of formula- la and at least one pharmaceutically acceptable excipient.
  • the eighth aspect of the present invention is to provide a process for the preparation of amorphous solid dispersion comprising compound of formula- la and at least one pharmaceutically acceptable excipient.
  • the ninth aspect of the present invention is to provide a novel process for the preparation of compound of formula- 1 and its pharmaceutically acceptable salts.
  • the tenth aspect of the present invention is to provide a process for the preparation of trans-2-(4-aminocyclohexyl)-N-methoxy-N-methyl acetamide compound of formula- 16.
  • the eleventh aspect of the present invention is to provide a crystalline polymorph of compound of formula- la.
  • the twelfth aspect of the present invention is to provide a crystalline solid dispersion comprising compound of formula- la and MCC (microcrystalline cellulose).
  • the thirteenth aspect of the present invention is to provide a crystalline polymorph of compound of formula- 1.
  • the fourteenth aspect of the present invention is to provide a process for the preparation of compound of formula- 1 and its pharmaceutically acceptable salts.
  • the fifteenth aspect of the present invention is to provide novel solvated forms of compound of formula- 1.
  • the sixteenth aspect of the present invention is to provide a process for the preparation of novel solvated form of compound of formula- 1 with a suitable acid.
  • the seventeenth aspect of the present invention is to provide novel solvated forms of compound of formula- 1 a.
  • the eighteenth aspect of the present invention is to provide a process for the preparation of novel solvated form of compound of formula- 1 a with a suitable acid.
  • the nineteenth aspect of the present invention is to provide novel acid-addition salts of compound of formula- 1.
  • the twentieth aspect of the present invention is to provide a process for the preparation of novel acid-addition salt of compound of formula- 1.
  • Figure-1 Illustrates the PXRD pattern of pure amorphous form of compound of formula- la
  • Figure-2 Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula- 1 a and PVP K-30
  • Figure-3 Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula- 1 a and HPC
  • Figure-4 Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula- la and HPMC
  • Figure-5 Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula- 1 a and crospovidone
  • Figure-6 Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula- 1 a and copovidone
  • Figure-7 Illustrates the PXRD pattern of compound of formula- la obtained according to example- 18.
  • Figure-8 Illustrates the PXRD pattern of compound of formula- la obtained according to example- 19.
  • Figure-9 Illustrates the PXRD pattern of compound of formula- la obtained according to example-20.
  • Figure-10 Illustrates the PXRD pattern of a crystalline solid dispersion comprising compound of formula- la and MCC-102 obtained according to example-21.
  • Figure-11 Illustrates the PXRD pattern of compound of formula- 1.
  • Figure-12 Illustrates the PXRD pattern of trans 2-(4-(3,3-dimethylureido)cyclohexyl)acetic acid (Formula- 10)
  • Figure-13 Illustrates the PXRD pattern of trans 2-(4-(3,3-dimethylureido)cyclohexyl)-N- methoxy-N-methylacetamide (Formula- 11)
  • Figure-14 Illustrates the PXRD pattern of formic acid solvate of compound of formula- 1
  • Figure-15 Illustrates the PXRD pattern of acetic acid solvate of compound of formula- 1
  • Figure-16 Illustrates the PXRD pattern of propanoic acid solvate of compound of formula- 1
  • Figure-17 Illustrates the PXRD pattern of propanoic acid solvate of compound of formula- 1 a
  • Figure-18 Illustrates the PXRD pattern of octanoic acid/propanoic acid mixed solvate of compound of formula- 1 a
  • Figure-19 Illustrates the PXRD pattern of 4-hydroxy benzoic acid salt of compound of formula- 1.
  • Figure-20 Illustrates the PXRD pattern of oxalic acid salt of compound of formula- 1. Detailed description of the Invention:
  • suitable solvent used in the present invention can be selected from but not limited to "hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethyls
  • the “suitable base” used in the present invention can be selected from but not limited to “inorganic bases” selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide and the like; ammonia; “organic bases” like “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium
  • suitable acid used in the present invention can be selected from but not limited to "inorganic acids” such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and “organic acids” such as formic acid, acetic acid, propionic acid (propanoic acid), butyric acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, citric acid, tartaric acid, benzoic acid, 4-hydroxy benzoic acid, octanoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, naphthalenesulfonic acid and the like.
  • inorganic acids such as hydrochloric acid, hydro
  • the "suitable coupling agent" used in the present invention can be selected from but not limited to ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '-diisopropyl carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), ⁇ , ⁇ ' -carbonyl diimidazole (CDI), 1 -[bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU), lH-benzotriazolium l-[bis(dimethylamino)methylene]- 5chloro-hexa
  • the suitable "amine protecting group” or “N-protecting group” 'PG' can be selected from but not limited to alkoxycarbonyl such methoxycarbonyl (Moc), ethoxycarbonyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxy benzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxy carbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), tosyl (Ts), trifluoroacetyl (TFA), trichloroethoxy carbonyl (Troc), pivaloyl (Piv), triphenylmethyl (trityl or Trt
  • the suitable amine protecting agent can be selected such that it is capable of protecting the nitrogen atom with any of the above mentioned amine protecting groups.
  • Suitable amine protecting agent can be selected from but not limited to di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fluorenylmethyloxy carbonyl chloride (Fmoc chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzoic anhydride, benzyl halides, alkyl haloformates such as methyl chloroformate, ethyl chloroformate, isopropyl chloroformate and the like, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, trifluoroacetyl chloride, trichloroethoxycarbonyl chloride, pivaloyl chloride, triphenylmethyl
  • the "suitable deprotecting agent” can be selected based on the protecting group employed.
  • the “suitable deprotecting agent” can be selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; acetyl chloride in combination with alcohols; BF 3 -OEt 2 , trimethylsilyl halides, TMSOTf, TiCl 4 , SnCl 4 , A1C1 3 , Sn(OTf) 2 and ZnBr 2 and the like; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates
  • the first aspect of the present invention provides a novel process for the preparation of trans-N- ⁇ 4- [2- [4-(2, 3-dichlorophenyl)piperazine- 1 -yl] ethyl] cyclohexyl ⁇ -N' , ⁇ ' -dimethyl urea compound of formula- 1 and its pharmaceutically acceptable salts, comprising of;
  • groups 'Ri', 'R 2 ' and 3 ⁇ 4' can be same or different and independently selected from Ci-C 6 straight chain or branched chain alkyl;
  • 'X' represents halogen such as F, CI, Br and I;
  • step-a) purifying the acid-addition salt from a suitable solvent to provide the pure compound.
  • the suitable base is selected from inorganic bases, organic bases, organolithium bases, organosilicon bases or mixture thereof;
  • the hydrogenation step can be carried out with H 2 in presence of a suitable metal catalyst selected from but not limited to Pd, Pt, Ni, Rh and Ru or in presence of Pt0 2 .
  • a suitable metal catalyst selected from but not limited to Pd, Pt, Ni, Rh and Ru or in presence of Pt0 2 .
  • Ammonium formate can also be used instead of hydrogen gas for the hydrogenation step;
  • step-b) the suitable acid is selected from inorganic acids and the suitable base is selected from inorganic bases;
  • step-d) the suitable deprotecting agent is selected based on the protecting group employed.
  • the deprotecting agent is as defined above;
  • step-f) the suitable coupling agent is selected from the above;
  • the suitable reducing agent is selected from but not limited to diisobutylaluminium hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminumhydride (vitride or Red-Al), sodium triacetoxy borohydride (NaBH(OAc)3), sodium cyanoborohydride (NaCNBH 3 ), LiAlH 4 and the like;
  • the suitable reducing agent is selected from but not limited to sodium triacetoxy borohydride (NaBH(OAc) 3 ), sodium cyanoborohydride (NaCNBH 3 ), vitride, diisobutylaluminium hydride (DIBAL), LiAlH 4 , NaBH 4 and the like;
  • the suitable acid is selected from inorganic acids and organic acids.
  • the acid is preferably hydrochloric acid;
  • the suitable solvent wherever necessary is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or any of the mixtures thereof.
  • the compound of general formula-2, compound of general formula-3, compound of general formula-9 and l-(2,3-dichlorophenyl)piperazine compound of formula- 13 or its hydrochloride salt utilized in the above described process can be obtained from any commercial sources available or they can be synthesized by any of the known processes.
  • a preferred embodiment of the present invention provides a process for the preparation of trans-N- ⁇ 4-[2-[4-(2,3-dichlorophenyl)piperazine-l-yl]ethyl]cyclohexyl ⁇ - ⁇ ', ⁇ '-dimethylurea hydrochloride salt compound of formula- la, comprising of;
  • the process developed by the present inventors is simple, safe, eco-friendly and commercially viable and involves the usage of simple and commercially available raw materials, reagents and solvents.
  • the second aspect of the present invention provides a novel intermediate compound which is useful for the preparation of compound of formula- 1 and its salts.
  • the said novel intermediate compound is represented by the following structural formula.
  • An embodiment of the present invention provides the use of novel intermediate compound of formula-11 for the preparation of compound of formula- 1 and its pharmaceutically acceptable salts.
  • the other embodiment of the present invention provides compound of formula- 11 as a crystalline solid.
  • Another embodiment of the present invention provides crystalline polymorph of compound of formula-11, characterized by its PXRD pattern having peaks at 8.2, 14.3, 16.5, 17.1, 18.4, 19.4, 20.4, 23.9, 29.1 ⁇ 0.2° of 2-theta values.
  • the said crystalline polymorph is characterized by its PXRD pattern as shown in figure- 13.
  • the third aspect of the present invention provides a process for the preparation of trans 2-(4-(3,3-dimethylureido)cyclohexyl)-N-methoxy-N-methylacetamide compound of formula-11, comprising of reacting the trans 2-(4-(3,3-dimethylureido)cyclohexyl)acetic acid compound of formula- 10 with ⁇ , ⁇ -dimethylhydroxylamine or its hydrochloride salt in a suitable solvent optionally in presence of a suitable coupling agent and/or a suitable base to provide compound of formula- 11.
  • the suitable coupling agent, suitable base and the suitable solvent are same as defined in step-f) of the first aspect of the present invention.
  • a preferred embodiment of the present invention provides a process for the preparation of compound of formula-11, comprising of reacting the compound of formula- 10 with ⁇ , ⁇ -dimethylhydroxylamine hydrochloride in presence of ⁇ , ⁇ '-carbonyldiimidazole in dichloromethane to provide compound of formula- 11.
  • An embodiment of the present invention provides compound of formula- 10 as a crystalline solid.
  • Another embodiment of the present invention provides crystalline polymorph of compound of formula-10, characterized by its PXRD pattern having peaks at 10.7, 14.4, 16.6, 18.0, 19.2, 21.0, 21.6, 23.7, 26.6 ⁇ 0.2° of 2-theta values.
  • the said crystalline polymorph is characterized by its PXRD pattern as shown in figure- 12.
  • the fourth aspect of the preset invention provides a process for the preparation of trans l, l-dimethyl-3-(4-(2-oxoethyl)cyclohexyl)urea compound of formula-12, comprising of reduction of trans 2-(4-(3,3-dimethylureido)cyclohexyl)-N-methoxy-N-methylacetamide compound of formula- 11 with a suitable reducing agent in a suitable solvent to provide compound of formula-12.
  • the suitable reducing agent is selected from but not limited to diisobutylaluminium hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminumhydride (vitride or Red-Al), sodium triacetoxy borohydride (NaBH(OAc) 3 ), sodium cyanoborohydride (NaCNBH 3 ), LiAlH 4 and the like;
  • the suitable solvent is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or mixtures thereof.
  • a preferred embodiment of the present invention provides a process for the preparation of compound of formula- 12, comprising of reduction of compound of formula- 11 with Red-Al in dichloromethane to provide compound of formula- 12.
  • the fifth aspect of the present invention provides pure amorphous form of trans-N- ⁇ 4-[2-[4-(2,3-dichlorophenyl)piperazine-l-yl]ethyl]cyclohexyl ⁇ -N',N'-dimethylurea hydrochloride compound of formula- la.
  • the said pure amorphous form is characterized by its PXRD pattern as shown in figure- 1.
  • the pure amorphous form of compound of formula- la of the present invention is useful for the preparation of various pharmaceutical formulations.
  • An embodiment of the present invention provides use of pure amorphous form of compound of formula- la for the preparation of various pharmaceutical formulations.
  • the other embodiment of the present invention provides pharmaceutical composition comprising pure amorphous form of compound of formula- la and at least one pharmaceutically acceptable excipient.
  • the sixth aspect of the present invention provides a process for the preparation of pure amorphous form of trans-N- ⁇ 4-[2-[4-(2,3-dichlorophenyl)piperazine-l-yl]ethyl] cyclohexyl ⁇ -N',N'-dimethylurea hydrochloride compound of formula- la, comprising of; a) Providing a solution of compound of formula- la in a suitable solvent,
  • the suitable solvent is selected from but not limited to alcohol solvents, polar-aprotic solvents, polar solvents, chloro solvents, acetic acid, hydrocarbon solvents or mixtures thereof.
  • providing a solution of compound of formula- la in a suitable solvent or mixture of solvents can be done by dissolving the compound of formula- la in any of the above described solvents or their mixtures at a suitable temperature, wherein the suitable temperature generally ranges between 20°C to reflux temperature of the solvent used.
  • the solution of step-a) can also be obtained directly from the synthetic procedure in which the compound of formula- la was prepared.
  • the seventh aspect of the present invention provides amorphous solid dispersion comprising trans-N- ⁇ 4-[2-[4-(2,3-dichlorophenyl)piperazine-l-yl]ethyl]cyclohexyl ⁇ -N',N'- dimethylurea hydrochloride compound of formula- la and at least one pharmaceutically acceptable excipient.
  • solid dispersion means any solid composition having at least two components.
  • a solid dispersion as disclosed herein includes an active ingredient (compound of formula- la) dispersed among at least one other component, for example an excipient.
  • the excipient is selected from but not limited to polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K- 90 and K-120 may be used), copovidone, polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), Eudragit, polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl cellulose
  • the excipient is preferably selected from PVP, HPC, HPMC, crospovidone and copovidone.
  • the pure amorphous form as well as amorphous solid dispersion of compound of formula- la of the present invention are having purity of greater than 98%, preferably greater than 99% by HPLC and is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- la is present in the composition in particular polymorphic form mentioned.
  • Such pharmaceutical compositions may comprise compound of formula- la present in the composition in a range of between 0.005% and 100% (wt/wt), with the balance of the pharmaceutical composition comprising additional substances such as excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.
  • additional substances such as excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.
  • the eighth aspect of the present invention provides a process for the preparation of amorphous solid dispersion comprising trans-N- ⁇ 4-[2-[4-(2,3-dichlorophenyl)piperazine-l- yl]ethyl]cyclohexyl ⁇ -N',N'-dimethylurea hydrochloride compound of formula-la and at least one pharmaceutically acceptable excipient, comprising of;
  • step-a) the excipient is same as defined above in the seventh aspect of the present invention; and the suitable solvent is same as defined in step-a) of the sixth aspect of the present invention.
  • providing a solution of compound of formula- la and at least one excipient in a suitable solvent or mixture of solvents can be done by dissolving the compound of formula- la and the excipient in any of the above described solvents at a suitable temperature ranges between 20°C to reflux temperature of the solvent used.
  • the solution provided in step-a) of the sixth aspect or step-a) of the eighth aspect of the present invention may optionally be treated with charcoal or any other suitable material to remove color and/or to clarify the solution and the solution may optionally be filtered to make it particle free.
  • filtering the reaction mixture/solution to make it particle free can be carried out by passing through paper, cloth, glass fiber or other membrane material or a bed of a clarifying agent such as Celite® or hyflow.
  • a clarifying agent such as Celite® or hyflow.
  • the filtration apparatus may need to be preheated to avoid premature crystallization.
  • the suitable techniques which may be used for the removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction mixture or by any other suitable techniques known in the art.
  • a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction mixture
  • the suitable anti-solvent is selected from but not limited to ether solvents, chloro solvents, hydrocarbon solvents, ketone solvents, ester solvents, nitrile solvents and the like or their mixtures.
  • the solvent may be removed optionally under reduced pressures, at temperatures less than about 200°C, less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C or less than about -60°C.
  • the ratio of the amount by weight of compound of formula- la within the solid dispersion to the amount by weight of the excipient therein ranges from but not limited to about 1 :0.05 to about 1 : 5.
  • the compound of formula- la which is used as input for the preparation of pure amorphous form as well as amorphous solid dispersion of compound of formula- la can be prepared by any of the processes known in the art or it can be prepared by the processes described in the preset invention.
  • the pure amorphous form of compound of formula- la of the present invention can be utilized as input for the preparation of any known polymorphic form of compound of formula- la and it can also be used in the preparation of novel polymorphic forms of compound of formula- la.
  • the ninth aspect of the present invention provides a novel process for the preparation of trans-N- ⁇ 4- [2- [4-(2, 3-dichlorophenyl)piperazine- 1 -yl] ethyl] cyclohexyl ⁇ -N' , ⁇ ' -dimethyl urea compound of formula- 1 and its pharmaceutically acceptable salts, comprising of;
  • 'X' represents halogen such as F, CI, Br and I;
  • step-a) treating the compound of formula- 1 with a suitable acid in a suitable solvent to provide corresponding acid-addition salt.
  • the suitable coupling agent is selected from the coupling agents defined above;
  • the suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures;
  • the suitable reducing agent is selected from but not limited to metals such as Pd, Pt, Rh, Raney Ni, Platinum oxide, (NH 4 ) 2 S or any combination thereof optionally under hydrogen gas pressure; the metal is optionally supported on activated charcoal;
  • the suitable reducing agent is selected from diisobutylaluminium hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminumhydride (vitride or Red-Al), sodium triacetoxy borohydride (NaBH(OAc)3), sodium cyanoborohydnde (NaCNBH 3 ), LiAlH 4 and the like;
  • the suitable reducing agent is selected from sodium triacetoxy borohydride (NaBH(OAc) 3 ), sodium cyanoborohydride (NaCNBH 3 ), vitride, DIBAL, LiAlH 4 , NaBH 4 and the like;
  • the suitable acid is selected from organic acids, inorganic acids as described above;
  • the suitable solvent wherever necessary is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or their mixtures.
  • step-b) of the above process can be carried out in a two-step procedure.
  • the first step involves the reduction of nitro group to amine with a suitable reducing agent selected from metals such as Pd, Pt, Rh, Raney Ni, Fe or Zn or Sn optionally in presence of acidic media such as HC1, acetic acid, NH 4 C1, stannous chloride (SnCl 2 ), Pt0 2 , NaBH 4 , Lithium borohydride, LiAlH 4 , sodium aluminium hydride, diborane, hydrazine hydrate, sodiumdithionate, sodium sulfide, ammonium sulfide, sodium amalgam and the like optionally in presence of H 2 .
  • a suitable reducing agent selected from metals such as Pd, Pt, Rh, Raney Ni, Fe or Zn or Sn optionally in presence of acidic media such as HC1, acetic acid, NH 4 C1, stannous chloride (SnCl 2 ), Pt0 2 , NaBH 4 , Lithium borohydride, LiA
  • the second step involves the reduction of benzene ring to cyclohexane ring with a suitable reducing agent selected from metals such as Pd, Pt, Rh, Raney Ni, Platinum oxide, (NH4) 2 S or any combination thereof optionally under hydrogen gas pressure.
  • a suitable reducing agent selected from metals such as Pd, Pt, Rh, Raney Ni, Platinum oxide, (NH4) 2 S or any combination thereof optionally under hydrogen gas pressure.
  • the metals used in the present invention can be optionally supported on activated charcoal.
  • An embodiment of the present invention provides an alternate process for the preparation of trans-2-(4-aminocyclohexyl)-N-methoxy-N-methyl acetamide compound of formula- 16, comprising of;
  • step-a) the suitable reducing agent and the suitable solvent are same as defined in step-b) of the ninth aspect of the present invention.
  • step-b) the suitable coupling agent, suitable base and the suitable solvent are same as defined in step-a) of the ninth aspect of the present invention.
  • the reduction of compound of formula- 14 to compound of formula-8 can be carried out in a two-step procedure.
  • the first step involves the reduction of nitro group to amine with a suitable reducing agent selected from metals such as Pd, Pt, Rh, Raney Ni, Fe or Zn or Sn optionally in presence of acidic media such as HCl, acetic acid, NH 4 C1, stannous chloride (SnCl 2 ), Pt0 2 , NaBH 4 , Lithium borohydride, LiAlH 4 , sodium aluminium hydride, diborane, hydrazine hydrate, sodiumdithionate, sodium sulfide, ammonium sulfide, sodium amalgam and the like optionally in presence of 3 ⁇ 4.
  • a suitable reducing agent selected from metals such as Pd, Pt, Rh, Raney Ni, Fe or Zn or Sn optionally in presence of acidic media such as HCl, acetic acid, NH 4 C1, stannous chloride (SnCl 2 ), Pt0 2 , NaBH 4 , Lithium borohydride, Li
  • the second step involves the reduction of benzene ring to cyclohexane ring with a suitable reducing agent selected from metals such as Pd, Pt, Rh, Raney Ni, Platinum oxide, (NH 4 )2S or any combination thereof optionally under hydrogen gas pressure.
  • a suitable reducing agent selected from metals such as Pd, Pt, Rh, Raney Ni, Platinum oxide, (NH 4 )2S or any combination thereof optionally under hydrogen gas pressure.
  • trans-2-(4-aminocyclohexyl)-N-methoxy-N-methyl acetamide compound of formula- 16 obtained by the above process is a novel compound.
  • the said compound is very useful for the preparation of compound of formula- 1 of the present invention and its pharmaceutically acceptable salts, for example hydrochloride salt.
  • An embodiment of the present invention provides novel intermediate compound of formula- 16.
  • the other embodiment of the present invention provides the use of said novel intermediate compound of formula- 16 for the preparation of compound of formula- 1 and its pharmaceutically acceptable salts.
  • the 2-(4-nitrophenyl)acetic acid compound of formula- 14 utilized in step-a) of the above process is a well-known and commercially available raw material. It can be procured from any commercial sources available or can be synthesized by any of the known processes.
  • the tenth aspect of the present invention provides a process for the preparation of trans-2-(4-aminocyclohexyl)-N-methoxy-N-methyl acetamide compound of formula- 16, comprising of;
  • 'PG' represents 'N-protecting group' or 'amine protecting group'
  • the suitable reducing agent is selected from but not limited to metals such as Pd, Pt, Rh, Raney Ni, Platinum oxide, (NH4) 2 S or any combination thereof optionally under hydrogen gas pressure; the metal is optionally supported on activated charcoal;
  • step-b) the suitable amine protecting agent is same as defined above;
  • the suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures; and the suitable coupling agent is selected from the coupling agents defined above;
  • step-d) the suitable deprotecting agent is same as defined above;
  • the suitable solvent wherever necessary is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or their mixtures.
  • the compound of formula- 16 obtained in the above process can be converted into compound of formula- 1 and its pharmaceutically acceptable acid-addition salts according to the procedure described above.
  • the 2-(4-nitrophenyl)acetic acid compound of formula- 14 which is used in the above process can be prepared by any of the processes known in the art or it can be procured from any commercial sources.
  • the amine protecting group 'PG' represents tert-butyloxycarbonyl (Boc).
  • the amine group protection can be carried out using di-tert.butyl dicarbonate (DIBOC) optionally in presence of a suitable base selected from inorganic bases, organic bases or their mixtures.
  • DIBOC di-tert.butyl dicarbonate
  • the deprotection step can be carried out by using acids such as hydrochloric acid, hydrobromic acid, formic acid, acetic acid, trifluoroacetic acid (TFA), substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; acetyl chloride in combination with alcohols; trialkylsilyl halide, tetrabutylammonium fluoride, eerie ammonium nitrate and the like.
  • acids such as hydrochloric acid, hydrobromic acid, formic acid, acetic acid, trifluoroacetic acid (TFA), substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-
  • Boc deprotection can also be done by treating the protected compound with a suitable HC1 source such as conc.HCl, aq.HCl, HC1 gas, ethyl acetate-HCl, isopropyl acetate-HCl, methanol-HCl, ethanol-HCl, isopropanol-HCl, HC1 in dioxane and the like.
  • a suitable HC1 source such as conc.HCl, aq.HCl, HC1 gas, ethyl acetate-HCl, isopropyl acetate-HCl, methanol-HCl, ethanol-HCl, isopropanol-HCl, HC1 in dioxane and the like.
  • the eleventh aspect of the present invention provides a crystalline polymorph of compound of formula- la.
  • the said crystalline polymorph is characterized by its PXRD pattern as shown in figure- 7 or figure- 8.
  • An embodiment of the present invention provides a process for the preparation of crystalline polymorph of compound of formula- la, comprising of;
  • the suitable solvent is selected from but not limited to alcohol solvents, hydrocarbon solvents or mixtures thereof;
  • step-b) the suitable temperature ranges from 35°C to reflux temperature of the solvent used;
  • the suitable second solvent is selected from but not limited to ether solvents or mixture of ether solvents; and suitable temperature ranges from -70°C to 70°C.
  • the other embodiment of the present invention provides a process for the preparation of crystalline polymorph of compound of formula- la, comprising of;
  • the suitable solvent is selected from chloro solvents or mixture of chloro solvents.
  • step-b) the suitable temperature ranges from 25 °C to reflux temperature of the solvent used; and in step-c) the suitable temperature ranges from -40°C to 20°C.
  • Another embodiment of the present invention provides a process for the preparation of crystalline polymorph of compound of formula- la having PXRD pattern as shown in figure-9, comprising of;
  • step-b) filtering the solid and drying to provide crystalline polymorph of compound of formula- la having PXRD pattern as shown in figure-9.
  • the suitable temperature ranges from 25°C to 90°C;
  • step-c) the suitable temperature ranges from 20°C to -20°C.
  • the twelfth aspect of the present invention provides a crystalline solid dispersion comprising compound of formula- la and MCC (microcrystalline cellulose).
  • the said crystalline solid dispersion is characterized by its PXRD pattern as illustrated in figure- 10.
  • An embodiment of the present invention provides a process for the preparation of a crystalline solid dispersion comprising compound of formula- la and MCC, comprising of; a) providing a mixture of compound of formula- la, MCC and a suitable solvent, b) stirring the reaction mixture at a suitable temperature,
  • the suitable solvent is selected from but not limited to alcohol solvents, polar-aprotic solvents, polar solvents, chloro solvents, acetic acid, hydrocarbon solvents or mixtures thereof.
  • step-b) the suitable temperature ranges from 25 °C to reflux temperature of the solvent used;
  • the suitable techniques which may be used for the removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction mixture or by any other suitable techniques known in the art.
  • a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of the precipitated solid, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction mixture
  • the suitable anti-solvent is selected from but not limited to ether solvents, chloro solvents, hydrocarbon solvents, ketone solvents, ester solvents, nitrile solvents and the like or their mixtures.
  • Compound of formula- la which is used as input in the present invention can be prepared by any of the processes known in the prior-art.
  • the thirteenth aspect of the present invention provides a crystalline polymorph of compound of formula- 1.
  • the said crystalline polymorph is characterized by its PXRD pattern having peaks at 5.6, 11.3, 14.4, 17.0, 18.3, 18.7 and 22.4 ⁇ 0.2° of 2-theta and further characterized by its PXRD pattern as illustrated in figure-11.
  • An embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising of;
  • the suitable acid in the acid-addition salt is selected from inorganic acids and organic acids described above; and the suitable solvent is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or their mixtures.
  • the suitable temperature ranges from -70°C to reflux temperature of the solvent used.
  • step providing a solution of acid-addition salt of compound of formula- 1 in a suitable solvent can be done by dissolving the acid-addition salt in a suitable solvent or mixture of solvents described above or the said solution can be obtained directly from the synthetic procedure in which the said acid-addition salt is prepared.
  • suitable base is selected from inorganic bases, organic bases or mixture thereof; suitable temperature ranges from -70 °C to reflux temperature of solvent used.
  • the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or their mixtures.
  • the suitable temperature ranges from -50°C to reflux temperature of the solvent used.
  • An embodiment of the present invention provides the use of crystalline polymorphs of compound of formula- la of the present invention for the preparation of various pharmaceutical formulations.
  • the other embodiment of the present invention provides a pharmaceutical composition comprising any of the crystalline polymorphs of compound of formula- la of the present invention and at least one pharmaceutically acceptable excipient.
  • the other embodiment of the present invention provides the use of crystalline polymorph of compound of formula- 1 of the present invention for the preparation of acid-addition salts of compound of formula- 1 , preferably for the preparation of its HC1 salt.
  • the fourteenth aspect of the present invention provides a process for the preparation of compound of formula- 1 and its pharmaceutically acceptable salts, comprising of;
  • step-a) purifying the acid-addition salt from a suitable solvent or mixture of solvents to provide the pure compound.
  • the suitable base is selected from organic bases, inorganic bases or mixtures thereof; and the suitable coupling agent is selected from the coupling agents as defined above;
  • the suitable reducing agent is selected from but not limited to NaBH 4 optionally in combination with BF 3 .etherate, NaAlH 4 , LiBH 4 , lithium aluminium hydride (LiAlH 4 ), Aluminium hydride (A1H 3 ), diisobutylaluminium hydride (DIBAL), NaAlH(0-t- Bu) 3 , Na(AcO) 3 BH, sodium cyanoborohydride (NaCNBH 3 ), B 2 H 6 , sodium bis(2- methoxyethoxy)aluminumhydride (Red-Al or Vitride), borane-DMS, borane-THF, hydrogenation in presence of Pd, Pt, Ni, Rh, Ru or Pt0 2 and the like. Ammonium formate can also be used instead of H 2 gas for hydrogenation step;
  • the suitable acid is selected from inorganic acids or organic acids.
  • the acid is preferably hydrochloric acid;
  • the suitable solvent wherever necessary is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or any of the mixtures thereof.
  • the compound of formula- 10 which is used as input in the above process can be prepared by the process described in the present invention or it can be prepared by the processes known in the art.
  • the fifteenth aspect of the present invention provides novel solvated forms of compound of formula- 1.
  • the solvated forms include formic acid solvate, acetic acid solvate and propanoic acid solvate.
  • An embodiment of the present invention provides a crystalline polymorph of formic acid solvate of compound of formula- 1, characterized by its PXRD pattern having peaks at 5.7, 8.1, 11.4, 15.7, 18.2, 18.6, 19.5, 21.5, 21.8, 24.4, 24.8, 25.1 ⁇ 0.2° of 2-theta values.
  • the said polymorph is further characterized by its PXRD pattern as shown in figure- 14.
  • the other embodiment of the present invention provides a crystalline polymorph of acetic acid solvate form of compound of formula- 1, characterized by its PXRD pattern having peaks at 10.7, 13.6, 17.6, 18.7, 19.9, 21.4, 21.7, 23.1 ⁇ 0.2° of 2-theta values.
  • the said polymorph is further characterized by its PXRD pattern as shown in figure- 15.
  • Another embodiment of the present invention provides a crystalline polymorph of propanoic acid solvate form of compound of formula- 1, characterized by its PXRD pattern having peaks at 4.4, 9.0, 12.5, 13.5, 16.9, 19.0, 20.0, 23.2, 25.8 ⁇ 0.2° of 2-theta values.
  • the said polymorph is further characterized by its PXRD pattern as shown in figure- 16.
  • the sixteenth aspect of the present invention provides a process for the preparation of novel solvated form of compound of formula- 1 with a suitable acid.
  • the said process comprising of;
  • the suitable acid is selected from formic acid, acetic acid and propanoic acid; and the suitable temperature ranges from -30°C to 90°C.
  • the suitable anti-solvent is selected from but not limited to ether solvents, chloro solvents, hydrocarbon solvents, ketone solvents, ester solvents, nitrile solvents and the like or their mixtures; and the suitable temperature ranges from -30°C to 30°C.
  • One embodiment of the present invention provides use of solvate forms of compound of formula- 1 of the present invention for the preparation of compound of formula- la.
  • An embodiment of the present invention provides a process for the preparation of compound of formula- 1 a, comprising of treating the solvate form of compound of formula- 1 of the present invention with a suitable HC1 source optionally in presence of a suitable solvent at a suitable temperature to provide compound of formula- 1 a.
  • the solvate form is selected from formic acid solvate, acetic acid solvate, propanoic acid solvate.
  • the suitable HCl source is selected from conc.HCl, aqueous HCl, HCl gas, ethyl acetate-HCl, isopropyl acetate-HCl, methanol-HCl, ethanol-HCl, isopropanol-HCl, HCl in dioxane and the like.
  • the suitable temperature ranges from -30°C to 70°C.
  • the seventeenth aspect of the present invention provides novel solvated forms of compound of formula- 1 a.
  • the solvated forms include propanoic acid solvate, octanoic acid/propanoic acid mixed solvate.
  • An embodiment of the present invention provides the use of above solvate forms of compound of formula- 1 a for the preparation of pharmaceutical composition.
  • An embodiment of the present invention provides a crystalline polymorph of propanoic acid solvate form of compound of formula- la.
  • the said crystalline polymorph is characterized by its PXRD pattern as shown in figure- 17.
  • the other embodiment of the present invention provides a crystalline polymorph of octanoic acid/propanoic acid mixed solvate form of compound of formula- la.
  • the said polymorph is characterized by its PXRD pattern as shown in figure- 18.
  • the eighteenth aspect of the present invention provides a process for the preparation of solvate form of compound of formula- la with a suitable acid, comprising of;
  • the suitable acid is selected from propanoic acid, octanoic acid/propanoic acid mixture; and the suitable temperature ranges from -30°C to 90°C.
  • the suitable anti-solvent is selected from but not limited to ether solvents, chloro solvents, hydrocarbon solvents, ketone solvents, ester solvents, nitrile solvents and the like or their mixtures; and the suitable temperature ranges from -30°C to 30°C.
  • the nineteenth aspect of the present invention provides novel acid-addition salts of compound of formula- 1.
  • the acid in the acid-addition salt is selected from 4-hydroxy benzoic acid and oxalic acid.
  • An embodiment of the present invention provides a crystalline polymorph of 4-hydroxy benzoic acid salt of compound of formula- 1, characterized by its PXRD pattern having peaks at 5.0, 7.9, 10.8, 13.8, 15.2, 16.5, 18.3, 19.2, 19.6, 20.1, 21.6, 23.6 ⁇ 0.2° of 2-theta values.
  • the said crystalline polymorph is further characterized by its PXRD pattern as shown in figure- 19.
  • the other embodiment of the present invention provides a crystalline polymorph of oxalic acid salt of compound of formula- 1 , characterized by its PXRD pattern having peaks at 6.2, 7.4, 9.5, 10.4, 12.4, 14.8, 16.4, 16.7, 17.7, 18.6, 21.0, 22.3, 22.9, 24.2, 25.5, 28.8 ⁇ 0.2° of 2-theta values.
  • the said crystalline polymorph is further characterized by its PXRD pattern as shown in figure-20.
  • the twentieth aspect of the present invention provides a process for the preparation of novel acid-addition salts of compound of formula- 1.
  • the said process comprising of;
  • the suitable acid is selected from 4-hydroxy benzoic acid and oxalic acid
  • the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or any of the mixtures thereof
  • the suitable temperature ranges from 30°C to reflux temperature of the solvent used.
  • step-b) the suitable temperature ranges from -30°C to 30°C.
  • novel acid-addition salts of compound of formula- 1 of the present invention are useful for the preparation of pure compound of formula- 1 and also useful for the preparation of compound of formula- la.
  • An embodiment of the present invention provides the use of novel acid-addition salts of compound of formula- 1 of the present invention for the preparation of pure compound of formula- 1 and compound of formula- 1 a.
  • the compound of formula- 1 a produced by various processes of the present invention is having purity of greater than 99%, preferably greater than 99.5%, more preferably greater than 99.7%, most preferably greater than 99.8% by HPLC.
  • trans-N- ⁇ 4- [2- [4-(2, 3 -dichlorophenyl)piperazine- 1 -yl] ethyl] cyclohexyl ⁇ -N' , ⁇ ' - dimethylurea hydrochloride compound of formula- la produced by the process of the present invention was analyzed by HPLC under the following conditions;
  • Apparatus A liquid chromatographic system equipped with variable wavelength UV detector; Column: Durashell C18(L) 150 X 4.6mm, 3.5 ⁇ (or) equivalent; Wavelength: 215 nm; Column temperature: 45°C; Injection volume: 5 ⁇ ⁇ ; Diluent: Methanol; Elution: Gradient; Buffer: Accurately transfer 1000 mL of milli-Q-water into a suitable clean and dry beaker. Transfer 1.0 mL of orthophosphoric acid (85%) into 1000 mL of milli-Q-water and mix well. Filter this solution through Poly vinylidene fluoride membrane filter paper; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Buffer (70:30 v/v).
  • the PXRD analysis of compounds of the present invention was carried out by using BRUKER/D8 ADVANCE X-Ray diffractometer using CuKa radiation of wavelength 1.5406A 0 and at a continuous scan speed of 0.03°/min.
  • the compound of formula- la produced by the process of the present invention is having particle size distribution of D90 less than 500 ⁇ , preferably less than 250 ⁇ , more preferably less than 100 ⁇ .
  • An embodiment of the present invention provides compound of formula- la with particle size distribution of D90 less than 50 ⁇ , preferably less than 20 ⁇ , more preferably less than 15 ⁇ .
  • the compound of formula- 1 and the compound of formula- la produced by the processes of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product.
  • Particle size distribution (PSD) method of analysis Particle size distribution (PSD) method of analysis:
  • the particle size distribution analysis was carried out by using Malvern Mastersizer 3000 instrument.
  • the present invention is schematically represented as follows;
  • 'PG' represents 'N-protecting group' or 'amine protecting group' ;
  • 'Ri', 'R 2 ' and 'R 3 ' can be same or different and can be independently selected from Ci-C 6 straight chain or branched chain alkyl groups;
  • 'Ac' represents acetyl group
  • 'X' represents halogen such as F, Cl, Br or I.
  • 'PG' represents N-protecting group or amine protecting group
  • 'X' represents halogen such as CI, Br & I.
  • Example-2 Preparation of trans 2-(4-(3,3-dimethylureido)cyclohexyl)acetic acid (Formula-10)
  • 2-Methoxy ethanol (750 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Heated the reaction mixture to 75-80°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 15 min at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred for 2 hr at the same temperature. Filtered the solid, washed with 2-methoxy ethanol and dried the material to get the title compound.
  • N,N'-Carbonyldiimidazole (127.8 gm) was slowly added to a mixture of trans 2-(4- (3,3-dimethylureido)cyclohexyl)acetic acid compound of formula-10 (150 gm) and dichloromethane (1050 ml) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 2 hr at the same temperature.
  • ⁇ , ⁇ -dimethylhydroxylamine hydrochloride (76.8 gm) was added to the reaction mixture at 25-30°C and stirred the reaction mixture for 4 hr at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 20 min at the same temperature.
  • Methyl tert.butyl ether (10 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 1 hr at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and dried the material to get the title compound.
  • a mixture of compound of formula-1 (100 gm), methanol (200 ml) and water (800 ml) was heated to 65-70°C and stirred the reaction mixture for 15 min at the same temperature.
  • Aqueous hydrochloric acid solution (27 ml of hydrochloric acid in 22 ml of water) was slowly added to the reaction mixture at 65-70°C and stirred the reaction mixture for 15 min at the same temperature. Filtered the reaction mixture to make it particle free. Cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Further cooled the reaction mixture to 0-5 °C and stirred for 3 hr at the same temperature. Filtered the solid, washed with water and dried the material to get the title compound.
  • Amine impurity Not detected; Dichloro piperazine impurity: 0.03%; Highest individual unspecified impurity: 0.06%.
  • Example-10 Preparation of amorphous solid dispersion comprising compound of formula-la and PVP K-30
  • PVP K-30 (0.5 gm) was added to a mixture of compound of formula- la (0.5 gm) and methanol (15 ml) at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure to get the title compound.
  • the PXRD pattern of the obtained compound is shown in figure-2. Yield: 0.9 gm.
  • Example-11 Preparation of amorphous solid dispersion comprising compound of formula-la and HPC
  • Example-12 Preparation of amorphous solid dispersion comprising compound of formula-la and HPMC
  • Example-14 Preparation of amorphous solid dispersion comprising compound of formula-la and copovidone
  • Part-II Sodium carbonate (29.25 gm) was dissolved in water (50 ml) at 25-30°C in another RBF and stirred the reaction mixture for 15 min at the same temperature.
  • ⁇ , ⁇ -dimethyl hydroxylamine hydrochloride (16.15 gm) was added to the reaction mixture at 25-30°C and cooled the reaction mixture to 0-5 °C.
  • the solution obtained in part-I was slowly added to the reaction mixture at 0-5 °C and stirred the reaction mixture for 90 min at the same temperature.
  • Dichloromethane was added to the reaction mixture and separated the organic layer and aqueous layer. Extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.
  • Rhodium (1.5 gm) was added to a mixture of N-methoxy-N-methyl-2-(4- nitrophenyl) acetamide compound of formula-15 (5 gm) and water (50 ml) at 25-30°C in an autoclave vessel and stirred the reaction mixture for 15 min at the same temperature. Heated the reaction mixture to 45-50°C, H 2 gas pressure (4.5 kg) was applied to it and stirred for 7 hr at the same temperature. 5% Rhodium (1.5 gm) was added to the reaction mixture, heated to 55-60°C and stirred for 70 hr at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with water. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methanol to get the title compound.
  • Triethylamine (11.36 gm) was slowly added to a mixture of trans-2-(4-amino cyclohexyl)-N-methoxy-N-methyl acetamide compound of formula- 16 (7.5 gm) and dichloromethane (75 ml) at 25-30°C and stirred the reaction mixture for 10 min at the same temperature.
  • Dimethylcarbamic chloride (3.78 ml) was slowly added to the reaction mixture at 25-30°C and stirred the reaction mixture for 12 hr at the same temperature. Saturated sodium chloride solution was added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and distilled off the solvent completely under reduced pressure. The obtained compound was purified by column chromatography to get the title compound. Yield: 3.5 gm.
  • Example-18 Preparation of crystalline polymorph of compound of formula-la
  • Example-20 Preparation of crystalline polymorph of compound of formula-la
  • Example-21 Preparation of solid dispersion comprising compound of formula-la and MCC-102
  • N-Methylmorpholine (12.8 ml) was slowly added to a pre-cooled mixture of trans 2-(4-(tert-butoxycarbonylamino)cyclohexyl)acetic acid compound of formula-7b (15 gm) and dichloromethane (150 ml) at -20°C to -15°C.
  • ⁇ , ⁇ -dimethylhydroxylamine hydrochloride 5.4 gm
  • l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.4 gm) were added to the reaction mixture at -20°C to -15°C and stirred for 4 hr at the same temperature.
  • Triethylamine (13.1 ml) was slowly added to a mixture of trans 2-(4-amino cyclohexyl)-N-methoxy-N-methylacetamide hydrochloride compound of formula- 16a (7.5 gm) and dichloromethane (75 ml) at 25-30°C and stirred the reaction mixture for 10 min at the same temperature.
  • ⁇ , ⁇ -Dimethylaminocarbonyl chloride compound of formula-9a (3.2 ml) was slowly added to the reaction mixture at 25-30°C and stirred the reaction mixture for 12 hr at the same temperature.
  • Aqueous sodium chloride solution was added to the reaction mixture at 25-30°C and stirred for 5 min at the same temperature.
  • Lithium aluminium hydride (7.36 ml) was slowly added to a pre-cooled mixture of trans 2-(4-(3,3-dimethylureido)cyclohexyl)-N-methoxy-N-methylacetamide compound of formula-11 (5 gm) and tetrahydrofuran (25 ml) at -78°C under nitrogen atmosphere and stirred the reaction mixture for 15 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 min at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 4 hrs at the same temperature.
  • Ethyl 2-(diethoxyphosphoryl)acetate compound of formula-3a (43.3 gm) was added to a pre-cooled mixture of tetrahydrofuran (500 ml) and potassium tert-butoxide (23.5 gm) at 0-5°C and stirred the reaction mixture for 90 min at the same temperature.
  • N-(4-oxo cyclohexyl)acetamide compound of formula-2a 25 gm was slowly added to the reaction mixture at 0-5 °C and stirred the reaction mixture for 15 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hr at the same temperature.
  • Lithium hydroxide hydrate (53.2 gm) was added to a mixture of ethyl 2-(4-acetamido cyclohexyl) acetate compound of formula-5a (143 gm) and tetrahydrofuran (1430 ml) at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Heated the reaction mixture to 45-50°C and stirred for 6 hr at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Cooled the obtained compound to 0-5 °C, 10% aqueous hydrochloric acid solution was slowly added to it and stirred the reaction mixture for 90 min at the same temperature. Filtered the solid, washed with water and dried the material to get the title compound. Yield: 100 gm.
  • Potassium hydroxide (40.05 gm) was added to a mixture of trans 2-(4-acetamido cyclohexyl) acetic acid compound of formula-7a (20 gm) and n-butanol (240 ml) at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Heated the reaction mixture to 115-120°C and stirred for 24 hr at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Cooled the obtained compound to 25-30°C, dichloromethane (100 ml) was added to it and further cooled the reaction mixture to 0-5°C.
  • Dimethylcarbamic chloride (17.27 gm) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 16 hr at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure and co-distilled with water. Cooled the obtained compound to 0-5 °C, aqueous hydrochloric acid solution was slowly added to it and stirred the reaction mixture for 90 min at the same temperature. Filtered the solid, washed with water and dried the material to get the title compound. Yield: 18.0 gm.
  • Example-35 Preparation of trans 3-(4-(2-(4-(2,3-dichlorophenyl)piperazin-l-yl)-2- oxoethyl)cyclohexyl)-l,l-dimethylurea (Formula-19)
  • the PXRD pattern of the obtained compound is similar to the PXRD pattern of crystalline form-I of compound of formula-la described in US7943621B2.
  • the PXRD pattern of the obtained compound is similar to the PXRD pattern of crystalline form-I of compound of formula-la described in US7943621B2.
  • the PXRD pattern of the obtained compound is similar to the PXRD pattern of crystalline form-I of compound of formula-la described in US7943621B2.
  • a mixture of compound of formula- la (2 gm) and octanoic acid (20 ml) was slowly heated to 75-80°C and stirred the reaction mixture for 30 min at the same temperature.
  • Propanoic acid (20 ml) was added to the reaction mixture at 75-80°C and stirred for 15 min at the same temperature.
  • the obtained solution was added to n-heptane (200 ml) at 25-30°C and stirred the reaction mixture for 30 min at the same temperature. Filtered the solid, washed with n-heptane and dried the material to get the title compound.
  • Oxalic acid (0.3 gm) was added to a mixture of compound of formula-1 (1 gm) and dichloromethane (25 ml) at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 2 hr at the same temperature. Half of the solvent was distilled off from the reaction mixture. Filtered the solid, washed with dichloromethane and dried the material to get the title compound.
  • the PXRD pattern of the obtained compound is shown in figure-20.

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Abstract

La présente invention concerne un nouveau procédé de préparation du chlorhydrate de trans- N-{4-[2- [4-(2,3-dichloro phényl) pipérazine-1-yl] éthyl] cyclohexyl} -N',N'-diméthyl urée représenté par la formule structurale suivante 1a et des polymorphes de celui-ci. La présente invention concerne également de nouveaux composés intermédiaires qui sont utiles pour la préparation d'un composé de formule 1a.
PCT/IN2018/050460 2017-07-15 2018-07-15 Nouveaux procédés pour la préparation de chlorhydrate de trans-n-{4-[2-[4-(2,3-dichlorophényl)pipérazine-1-yl]éthyl] cyclohexyl}-n',n'-diméthyl urée et polymorphes de celui-ci WO2019016828A1 (fr)

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IN201741035999 2017-10-10
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CN113527227A (zh) * 2020-04-15 2021-10-22 成都弘达药业有限公司 一种卡利拉嗪的制备方法
CN114539185A (zh) * 2020-11-24 2022-05-27 上海博志研新药物技术有限公司 一种卡利拉嗪及其中间体的制备方法

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CN114539185A (zh) * 2020-11-24 2022-05-27 上海博志研新药物技术有限公司 一种卡利拉嗪及其中间体的制备方法

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