WO2013111161A2 - Process for the preparation of 3-aryl-2-methyl-propanamine derivatives and polymorphs thereof - Google Patents

Process for the preparation of 3-aryl-2-methyl-propanamine derivatives and polymorphs thereof Download PDF

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WO2013111161A2
WO2013111161A2 PCT/IN2013/000017 IN2013000017W WO2013111161A2 WO 2013111161 A2 WO2013111161 A2 WO 2013111161A2 IN 2013000017 W IN2013000017 W IN 2013000017W WO 2013111161 A2 WO2013111161 A2 WO 2013111161A2
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solvents
compound
formula
acid
tapentadol
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PCT/IN2013/000017
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French (fr)
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WO2013111161A3 (en
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Gogulapati Venkata Panakala Rao
Peri SEETHA RAMA SHARMA
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Msn Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/72—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • 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
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a novel process for the preparation of 3-[(1R,2R)- 3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol represented by the structural formula- 1 and its hydrochloride salt represented by the structural formula-1a.
  • the present invention also provides novel intermediates which are useful in the preparation of 3- [(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1.
  • the present invention also relates to a stable and pure crystalline form-B of 3- [(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride and process for its preparation.
  • the present invention also provides highly pure 3-[(1R,2R)-3-
  • the main drawback of the above said process is the usage of trimethyl chlorosilane in the diastereomeric separation, which is hazardous and highly flammable, hence not advisable to use in the industrial scale.
  • the other drawback of this process is resolution of enantiomers by chiral HPLC, which is cost-effective, not amenable for commercial synthesis on industrial scale and thereby making the process commercially unfeasible.
  • the usage of reducing agents in the above process, such as zinc borohydride which is hazardous substance and poses considerable fire when used on the large-scale, hence it is not advisable to use on large scale.
  • the disclosed process involves the reaction of l-(3-methoxyphenyl)propan-l-one, dimethylamine and formaldehyde provides 3 -(dimethylamino)- 1 -(3 -methoxyphenyl)-2-methylpropan- 1 -one, which on resolution by treating with L-(-)-DBTA provides (2S)-3-(dimethylamino)-l-(3- methoxyphenyl)-2-methylpropan-1-one and the obtained compound is further treated with ethyl magnesium halide.
  • U.S. Patent US7649114 disclosed a resolution method for the separation of the two enantiomers from the enantiomeric pair, (2R,3R)/(2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol, with the aid of a chiral acid, such as (+)-di-O,O'-p- toluoyltartaric acid, (-)-di-0,0'-p-toluoyltartaric acid and D-(-)-tartaric acid, in the presence of a suitable solvent such as 2-butanone.
  • a suitable solvent such as 2-butanone.
  • PCT publication WO2011 107876 disclosed a resolution method for the separation of the two enantiomers from the enantiomeric pair, (2S,3R)/(2R,3S)-1-dimethylamino-3 ⁇ (3-methoxyphenyl)-2-methylpentan-3-ol, with the aid of chiral auxiliary, such as (S)- naproxen.
  • the said publication also disclosed a resolution method for the separation of enantiomers from the enantiomeric pair, (2R,3R)/(2S,3S)-3-(3-methoxyphenyl)-N,N,2- trimethylpentan-1 -amine using an optically active acid, such as di-p-toluoyl-L-tartaric acid and di-benzoyl-L-tartaric acid.
  • an optically active acid such as di-p-toluoyl-L-tartaric acid and di-benzoyl-L-tartaric acid.
  • the main objective of the present invention is to provide a novel process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula- 1 and its hydrochloride salt compound of formula-1a.
  • Other objective of the present invention is to provide pure and stable crystalline form-B of Tapentadol hydrochloride compound of formula- la and its process for the preparation.
  • the first aspect of the present invention is to provide novel intermediate compounds which are useful in the synthesis of 3-[(li?,2i?)-3-(dimethylamino)-1-ethyl-2- methylpropyl] phenol compound of formula- 1 as well as its hydrochloride salt compound of formula-1a.
  • the second aspect of the present invention is to provide a novel process for the preparation of (2 S)- 1 -(3 -methoxyphenyl)-2-methyl-3 -(N-substituted-N-( 1 -phenylethyl) amino) propan-1-one compound of general formula-4, comprising of reacting the l-(3- methoxyphenyl)propan-1-one compound of formula-2 with 1-phenylethylamine derivative compound of general formula-3 with formaldehyde in presence of an acid in a suitable solvent, followed by hydrolysis provides compound of general formula-4.
  • the third aspect of the present invention is to provide a process for preparation of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l-(N-substitUted-N-(l-phenylethyl)amino) pentan-3-ol compound of general formula-5, comprising of reacting the (2S)-1-(3- methoxyphenyl)-2-methyl-3-(N-substituted-N-(l-phenylethyl)amino)propan-l-one compound of general formula-4 with ethyl magnesium halide in a suitable solvent to provide compound of general formula-5.
  • the fourth aspect of the present invention is to provide a process for preparation of (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N-substituted-N-(l-phenylethyl)amino) pent-1-en-3-ol compound of general formula- 10, comprising of reacting the (2S)-1-(3- methoxyphenyl)-2-methyl-3-(N-substituted-N-( 1 -phenylethyl)amino)propan- 1 -one compound of general formula-4 with vinyl magnesium halide in a suitable solvent to provide compound of general formula- 10.
  • the fifth aspect of the present invention is to provide a process for the preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine compound of formula- 8, comprising of N-methylating (2R,3R)-3-(3-methoxyphenyl)-2-methyl-N-substituted- pentan-1 -amine compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide compound of formula-8.
  • the sixth aspect of the present invention is to provide a novel process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol compound of formula- 1, comprising of acylation of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-1-(-- substiruted-N-(l-phenylethyl)amino)pentan-3-ol compound of general formula-5, followed by catalytic hydrogenation, N-methylation and O-demethylation to provide compound of formula-1.
  • the seventh aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of dehydration of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l- (N-substituted-N-(l-phenylethyl)amino)pentan-3-ol compound of general formula-5, followed by catalytic hydrogenation, N-methylation and O-demethylation provides compound of formula-1.
  • the eighth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of acylation of (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N- substituted-N-(l-phenylethyl)amino)pent-l-en-3-ol compound of general formula- 10, followed by catalytic hydrogenation, N-methylation and O-demethylation provides compound of formula-1.
  • the ninth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl]phenol compound of formula- 1, comprising of catalytic hydrogenation of (3R,4S)-3-(3-methoxyphenyl)-4- methyl-5-(N-substituted-N-(l-phenylethyl)amino)pent-l-en-3-ol compound of general formula- 10, followed by dehydration, catalytic hydrogenation, N-methylation and O- demethylation provides compound of formula- 1.
  • the tenth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl]phenol compound of formula- 1, comprising of catalytic hydrogenation of (3R,4S)-3-(3-methoxypheriyl)-4- methyl-5-(N-substituted-N-(l-phenylethyl)amino)pent-l-en-3-ol compound of general formula- 10, followed by acylation, catalytic hydrogenation, N-methylation and O- demethylation provides compound of formula- 1.
  • the eleventh aspect of the present invention is to provide a process for the preparation of crystalline form-B of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl ]phenol hydrochloride compound of formula- la.
  • the twelfth aspect of the present invention is to provide (3R,4S)-5- (dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15, which is an useful intermediate in the synthesis of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl- 2-methylpropyl] phenol compound of formula- 1 and its hydrochloride salt compound of formula- la, and process for its preparation.
  • the thirteenth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula- 1, comprising of catalytic hydrogenation of (3R,4S)-5-(dimethylamino)-3-(3- methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15, followed by dehydration, reduction and O-demethylation provides compound of formula- 1.
  • the fourteenth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula- 1, comprising of acylation of (3R,4S)-5-(dimethylamino)-3-(3- methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula- 15, followed by catalytic hydrogenation, and O-demethylation provides compound of formula-1.
  • the fifteenth aspect of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
  • the sixteenth aspect of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
  • the seventeenth aspect of the present invention is to provide a process for the preparation of pure Tapentadol hydrochloride compound of formula- la, comprising the following steps of:
  • step-(b) isolating the compound with a suitable solvent, c) converting the compound obtained in step-(b) into its hydrochloride salt compound of formula- la by the process disclosed in the fifteenth and sixteenth aspects of the present invention.
  • the eighteenth aspect of the present invention is to provide one pot process for the preparation of pure Tapentadol hydrochloride compound of formula- la, comprising the following steps of:
  • step-(a) converting the obtained compound in step-(a) into its hydrochloride salt compound of formula- la by the process disclosed in fifteenth and sixteenth aspects of the present invention.
  • the nineteenth aspect of the present invention is to provide a process for the preparation of crystalline modification-B of Tapentadol free base, comprising the following steps of:
  • Figure-1 Illustrates the powder X-ray diffractogram of crystalline form-B of Tapentadol hydrochloride.
  • Figure-2 Illustrates the powder X-ray diffractogram of crystalline modification-B of Tapentadol free base.
  • suitable solvent used in the present invention is selected from, but are not limited to "ester solvents” such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, 1,2-dimethoxyethane, diisopropyl ether and the like; “hydrocarbon solvents” such as toluene, hexane, heptane and cyclohexane and the like; “polar aprotic solvents” such as dimethyl acetamide, dimethylformamide, dimethyl sulfoxide, acetonitrile and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl
  • the "base” is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert- butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; and ammonia; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine, piperidine, pyridine, tributyl amine, 4-dimethylaminopyridine, N-methyl morpholine and the like.
  • inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert- butoxide, potassium tert-butoxid
  • suitable acylating agent used in the present invention is selected from, but are not limited to anhydrides and halides of acetic acid, phenyl acetic acid, chloro acetic acid, trifluoro acetic acid, dichloro acetic acid, trichloro acetic acid, benzoic acid, chlorobenzoic acid, terephthalic acid, phthalic acid, succinic acid, mono C 1 -C 4 alkyl esters of succinic acid, oxalic acid, mono C 1 -C 4 alkyl esters of oxalic acid such as ethyl oxalyl chloride and methyl oxalyl chloride, and mixed anhydride of formic acid such as ethylchloroformate, methylchloroformate and acetylsalicyloyl chloride.
  • the "suitable metal catalyst” used for hydrogenation in the present invention is selected from, but are not limited to Pd, Pt, Ru, Rh catalysts such as Pd, Pd-C, Pd(OH) 2 , Pd(OAc) 2 , PdCl 2 , Pd(PPh3) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd 2 (dba) 3 [tris(dibenzylidene acetone) dipalladium], palladium thipmethyl phenylglutaramide, palladium on metal oxide, palladium on zeolites, Pt, Pt-C, PtO 2 , Ru-C, Rh-C, rhodium on alumina; and Raney-Ni.
  • Pd, Pt, Ru, Rh catalysts such as Pd, Pd-C, Pd(OH) 2 , Pd(OAc) 2 , PdCl 2 , Pd(PPh3) 4 , Pd(PPh 3 )
  • suitable methylating agent herein the present invention refers, but not limited to dimethyl sulfate, methyl iodide, dimethyl carbonate, methyl methane sulfonate, methyl triflate, trimethyl oxonium tetrafluoroborate, N-methyl methane sulfonamide, formaldehyde/formic acid and formaldehyde/sodium borohydride.
  • suitable demethylaying agent herein the present invention is selected from, but are not limited to hydrobromic acid with or without carboxylic acid such as formic acid, acetic acid; methane sulfonic acid, methionine, diisobutyl aluminium hydride, pyridine chloride, lewis acids like aluminium chloride, boron tribromide and mixtures thereof.
  • suitable dehydrating agent used in the present invention is selected from, but are not limited to inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like; and organic acid such as formic acid and methane sulfonic acid; acid anhydrides such as trifluoroacetic anhydride and acetic anhydride; phosphorous pentoxide; phosphoryl chloride; phosphoric acid; and dicyclohexylcarbodiimide.
  • inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like
  • organic acid such as formic acid and methane sulfonic acid
  • acid anhydrides such as trifluoroacetic anhydride and acetic anhydride
  • phosphorous pentoxide phosphoryl chloride
  • phosphoric acid and dicyclohexylcarbodiimide.
  • Ci.C4 alkyl refers to alkyl group having 1 to 4 carbon atoms.
  • Examples of Ci. C 4 alkyl groups include, without limitation, methyl, ethyl, n- propyl, is -propyl, n-butyl, sec-butyl, iso-butyl and t-butyl.
  • C6-Q0 aryl refers to aromatic ring having 6 to 10 carbon atoms.
  • Examples of C 6 -Ci 0 aryl groups includes, without limitation phenyl, naphthyl and pyridine.
  • cycloalkyl refers to saturated monocyclic and bicyclic hydrocarbon rings, generally having a specified number of carbon atoms that comprise the ring.
  • a "C 3 -C 7 cycloalkyl” refers to cycloalkyl group having 3 to 7 carbon atoms. Examples of monocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • hydrochloric acid source used herein the present invention is selected from hydrochloric acid gas, aqueous hydrochloric acid, ethyl acetate-hydrochloric acid, isopropanol-hydrochloric acid, diisopropyl ether-hydrochloric acid, diethylether- hydrochloric acid, and trimethylchlorosilane.
  • the "lower aliphatic acid” used herein the present invention is selected from formic acid, acetic acid, propanoic acid and the like.
  • alkyl formate used herein the present invention is selected from methyl formate, ethyl formate and isopropyl formate.
  • the first aspect of the present invention is to provide novel compounds represented by following structural formulae:
  • acyl represents CH 3 -CO-, CF 3 -CO-, CH 2 C1-C0-, CHC1 2 -C0-, CCI 3 -CO-,
  • R represents -H, -CH 3 , -CH 2 Ph in which Ph is optionally substituted with d-C 4 alkyl, halogen, C 6 -C 10 aryl, C 3 -C 7 cycloalkyl, -OH, -O-C1-C4 alkyl and the like; and "R 1 " represents -H;
  • the second aspect of the present invention is to provide a novel process for the preparation of (2S)- l-(3-methoxyphenyl)-2-methyl-3-(N-substituted-N-(l-phenylethyl) amino)propan-l-one compound of general formula-4, comprising of reacting the l-(3- methoxyphenyl)propan-l-one compound of formula-2 with 1 -phenyl ethylamine derivative compound of general formula-3 with formaldehyde in presence of an acid in a suitable solvent, followed by hydrolysis provides compound of general formula-4.
  • the "suitable solvent” is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar aprotic solvents, hydrocarbon solvents and alcoholic solvents; and the “acid” refers to inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid.
  • the third aspect of the present invention is to provide a process for preparation of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-1-(N-substituted-N-(l-phenylethyl)amino) pentan-3-ol compound of general formula-5, comprising of reacting (2S)-1-(3- methoxyphenyl)-2-methyl-3-(N-substituted-N-( 1 -phenyl ethyl)amino)propan- 1 -one compound of general formula-4 with ethyl magnesium halide in a suitable solvent to provide compound of general formula-5.
  • the "suitable solvent” is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and hydrocarbon solvents; and the "ethyl magnesium halide” used is selected from ethyl magnesium bromide and ethyl magnesium chloride.
  • the fourth aspect of the present invention is to provide a process for preparation of (3R,4S)-3 -(3 -methoxyphenyl)-4-methyl-5-(N-substituted-N-(l -phenyl ethyl)amino) pent-1-en-3-ol compound of general formula- 10, comprising of reacting (2S)-1-(3- methoxyphenyl)-2-methyl-3-(N-substituted-N-(l-phenylethyl)amino)propan-1-one compound of general formula-4 with vinyl magnesium halide in a suitable solvent to provide compound of general formula- 10.
  • the "suitable solvent” is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and hydrocarbon solvents; and the "vinyl magnesium halide” used is selected from vinyl magnesium bromide and vinyl magnesium chloride.
  • the fifth aspect of the present invention is to provide a process for the preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l -amine compound of formula- 8, comprising of N-methylating the (2R,3R)-3-(3-methoxyphenyl)-2-methyl-N- substituted-pentan-1 -amine compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent provides compound of formula-8.
  • the "suitable solvent” is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof; and the "suitable methylating agent” is selected from dimethylsulfate, methyl iodide, dimethylcarbonate, methyl methane sulfonate, methyl triflate, trimethyl oxonium tetrafluoroborate, N-methyl methane sulfonamide, formaldehyde/formic acid and formaldehyde/sodium borohydride.
  • the sixth aspect of the present invention is to provide a novel process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of the following steps:
  • the "suitable acylating agent" is selected from anhydrides and halides of acetic acid, phenyl acetic acid, chloro acetic acid, trifluoro acetic acid, dichloro acetic acid, trichloro acetic acid, benzoic acid, chlorobenzoic acid, terephthalic acid, phthalic acid, succinic acid, mono C 1 -C 4 alkyl esters of succinic acid, oxalic acid, mono C 1 -C 4 alkyl esters of oxalic acid such as ethyl oxalyl chloride and methyl oxalyl chloride, and mixed anhydride of formic acid such as ethylchloroformate, methylchloroformate and acetylsalicyloyl chloride; and the "base" is inorganic or organic base;
  • the "suitable metal catalyst” is selected from Pd, Pt, Ru and Rh catalysts such as Pd, Pd-C, Pd(OH) 2 , Pd(OAc) 2 , PdCl 2 , Pt, PtO 2 , Ru-C and Rh-C; and Raney-Ni;
  • step-c) the "suitable methylating agent” and “suitable solvent” are same as defined in fifth aspect of the present invention.
  • the "suitable demethylating agent” is selected from hydrobromic acid, optionally in combination with carboxylic acid such as formic acid, acetic acid; methane sulfonic acid, methionine, diisobutyl aluminium hydride, pyridine chloride, lewis acids such as aluminium chloride, boron tribromide and mixtures thereof;
  • the "suitable solvent” used in step-(a) and step-(b) is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably alcoholic solvents and ether solvents; and
  • the "suitable solvent” used in step-(d) is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents polar solvents, chloro solvents and/or mixtures thereof, preferably polar solvents and chloro solvents.
  • the seventh aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl] phenol compound of formula- 1, comprising of the following steps:
  • the "suitable dehydrating agent” is selected from inorganic acids, organic acids, acid anhydrides, phosphorous pentoxide; phosphoryl chloride; phosphoric acid; dicyclohexyl carbodiimide; and the "suitable solvent” used is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents; and
  • the eighth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl]phenol compound of formula- 1, comprising of the following steps:
  • suitable acylating agent used in step-(a), step-(b), step-(c) & step-(d) are same as defined in step-(a), step-(b), step-(c) & step-(d) of sixth aspect of the present invention respectively;
  • the ninth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyljphenol compound of formula- 1, comprising of the following steps:
  • suitable metal catalyst used in step-(a), step-(c), step-(d) & step-(e) are same as defined in step-(b), step-(c) & step-(d) of sixth aspect of the present invention respectively;
  • suitable dehydrating agent and “suitable solvent” used in step-(b) are same as defined in step-(a) of seventh aspect of the present invention.
  • (2R)-3-(3-methoxyphenyl)-2-methyl-N-substituted- pent-3 -en- 1 -amine compound of general formula-14 in the above aspect undergoes methylation, followed by catalytic hydro genation and then demethylation to provide 3- [(l/?,2 ?)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1.
  • the tenth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methyl propyl]phenol compound of formula-1, comprising of the following steps:
  • suitable methylating agent used in step-(a), step-(b), step-(c), step-(d) & step-(e) are same as defined in step-(a), step-(b), step-(c) & step-(d) of sixth aspect of the present invention respectively;
  • the compound of general formula- 13 in the above aspect undergoes methylation, followed by catalytic reduction and then demethylation to provide 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol compound of formula- 1.
  • the compounds of general formula- 13 and 14 of the present invention undergoes methylation and demethylation, followed by catalytic reduction provides 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula- 1.
  • the eleventh aspect of the present invention is to provide a process for the preparation of crystalline form-B of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyljphenol hydrochloride compound of formula- la, comprising of:
  • the compound of general formula- 14 is commercially available and can be prepared by any of the known methods.
  • compounds of general formula-5, 10, 12 and compound of formula- 15 are undergoes tosylation or mesylation to provide its corresponding tosylated or mesylated derivatives.
  • the obtained compound further hydrogenated in presence of suitable metal catalyst under hydrogen pressure to provide (2R,3R)-3-(3- methoxyphenyl)-2-methyl-N-substituted-pentan-1-amine compound of general formula- 7.
  • the starting materials used in the present invention are commercially available and can be also prepared by the known methods.
  • All the intermediate compounds of the present invention are converted into their acid addition salts like hydrochloride, hydrobromide and hydrogen sulfate salts.
  • the twelfth aspect of the present invention is to provide novel compounds represented by structural formulae
  • the twelfth aspect of the present invention also provides a process for the preparation of (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula- 15, comprising of reacting the (S)-3-(dimethylamino)-l-(3- methoxyphenyl)-2-methylpropan-l-one compound of formula- 14 with vinyl magnesium halide in a suitable solvent to provide compound of formula- 15.
  • the term "vinyl magnesium halide” is selected from vinyl magnesium chloride and vinyl magnesium bromide; and the "suitable solvent” is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and hydrocarbon solvents.
  • the thirteenth aspect of the present invention provides a process for preparation of 3 -[(lR,2R)-3-(dimethyl amino)- 1 -ethyl-2-methylpropyl]phenol compound of formula- 1, comprising of:
  • the "suitable metal catalyst” is selected from Pd, Pt, Ru and Rh catalysts such as Pd, Pd-C, Pd(OH) 2 , Pd(OAc) 2 , PdCl 2 , Pt, PtO 2 , Pt-C, Ru-C and Rh-C; and Raney-Ni; and the "suitable solvent” is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and alcoholic solvents;
  • the "suitable dehydrating agent” is selected from inorganic acids, organic acids, acid anhydrides, phosphorous pentoxide; phosphoryl chloride; phosphoric acid; and dicyclohexyl carbodiimide; and the "suitable solvent” is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents;
  • the "suitable reducing agent” is selected from Ru, Rh metal catalysts such as Ru-C and Rh-C in presence of hydrogen; and Raney-Ni in presence of hydrogen; sodium borohydride; and Pd, Pt, Ru, Rh and Re catalysts such as Pd, Pd-C, Pd(OH) 2 , PdCl 2 , Pd(OAC) 2 , Pt, Pt-C, Pt0 2 , Ru-C, Rh-C, ReIO 2 (PPh 3 ) 2 , ReOCl 3 (PPh 3 ) 2 , ReOCl 3 (dppm), and Re 2 O 7 in presence of hydrogen source such as silane and sodium borohydride;
  • the "silane” is selected from dimethylphenyl silane, phenyl silane, triethyl silane, triphenyl silane and poly methylhydrosiloxane; and the
  • suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof; preferably hydrocarbon solvents, alcoholic solvents, chloro solvents and polar aprotic solvents; and
  • the "suitable demethylating agent” is selected from hydrobromic acid optionally in combination with carboxylic acid such as formic acid, acetic acid; methane sulfonic acid, methionine, diisobutyl aluminium hydride, pyridine chloride, lewis acid such as aluminium chloride, boron tribromide and mixtures thereof; and the "suitable solvent” is selected from is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents and chloro solvents.
  • carboxylic acid such as formic acid, acetic acid
  • methane sulfonic acid methionine
  • diisobutyl aluminium hydride pyridine chloride
  • lewis acid such as aluminium chloride, boron tribromide and mixtures thereof
  • the "suitable solvent” is selected from is selected from ester solvents
  • the fourteenth aspect of the present invention provides a process for preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula- 1, comprising of:
  • the "suitable acylating agent” is selected from anhydrides and halides of acetic acid, phenyl acetic acid, chloro acetic acid, trifluoro acetic acid, dichloro acetic acid, trichloro acetic acid, benzoic acid, chlorobenzoic acid, terephthalic acid, phthalic acid, succinic acid, mono C 1 -C 4 alkyl esters of succinic acid, oxalic acid, mono C 1 -C 4 alkyl esters of oxalic acid such as ethyl oxalyl chloride and methyl oxalyl chloride, and mixed anhydride of formic acid such as ethyl chloroformate, methyl chloroformate and acetyl salicyloyl chloride;
  • the "base” is inorganic or organic base; and the "suitable solvent” is selected from ester solvents, ether solvents, hydrocarbon solvents
  • step-(b) and step-(c) are same as defined in step-(a) and step-(d) of thirteenth aspect of the present invention respectively.
  • 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula- 1 obtained by the present invention is further converted into its hydrochloride salt compound of formula-1a by treating it with a suitable HC1 source such as HC1, aq.HCl, ethyl acetate-HCl, isopropanol-HCl, diethyl ether-HCl and diisopropyl ether- HC1.
  • a suitable HC1 source such as HC1, aq.HCl, ethyl acetate-HCl, isopropanol-HCl, diethyl ether-HCl and diisopropyl ether- HC1.
  • Another object of the present invention is to provide pure and stable crystalline form-B of Tapentadol hydrochloride compound of formula-1a and its process for the preparation.
  • All the prior art processes for the preparation of Tapentadol hydrochloride involves the usage of ethyl acetate-hydrochloric acid, isopropanol-hydrochloric acid in various solvents. All the processes leading to the formation of crystalline form-A, mixture of crystalline form-A and form-B and unstable crystalline form-B of Tapentadol hydrochloride.
  • Tapentadol hydrochloride compound of formula- la from Tapentadol free base compound of formula- 1, by salt formation technique using hydrochloric acid source in various solvents as mentioned below:
  • the fifteenth aspect of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
  • the lower aliphatic carboxylic acid is selected from formic acid and acetic acid
  • hydrochloric acid source is selected from hydrochloric acid gas, ethyl acetate- hydrochloric acid, isopropanol-hydrochloric acid, diisopropyl ether-hydrochloric acid and diethylether-hydrochloric acid
  • the suitable solvent is selected from ester solvent such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and tertiary butyl acetate.
  • a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride comprising the following steps of:
  • In another preferred embodiment of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of: a) Adding ethyl acetate to Tapentadol free base,
  • the sixteenth aspect of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
  • the suitable hydrochloric acid source is same as defined in fifteenth aspect; alkyl formate is selected from methyl formate, ethyl formate and isopropyl formate; and the suitable solvent is selected from ester solvent such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and tertiary butyl acetate.
  • a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride comprising the following steps of:
  • In another preferred embodiment of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of: a) Adding ethyl formate to Tapentadol free base in ethyl acetate, b) cooling the reaction mixture,
  • the seventeenth aspect of the present invention is to provide a process for the preparation of pure Tapentadoi hydrochloride compound of formula- la, comprising the following steps of:
  • step-(b) converting the compound obtained in step-(b) to its hydrochloride salt compound of formula- la by the process disclosed in fifteenth and sixteenth aspects of the present invention.
  • the suitable base is selected from inorganic bases like alkali metal alkoxides, hydroxides, carbonates and bicarbonates;
  • the water immiscible solvent used in step-(a) is selected from ester solvents; and in step-(b) is selected from hydrocarbon solvents.
  • step-(b) converting the compound obtained in step-(b) to its hydrochloride salt compound of formula- la by the process disclosed in fifteenth and sixteenth aspects of the present invention.
  • Tapentadoi hydrochloride obtained by the prior art process such as USRE39593 does not able to meet the desired ICH purity.
  • a suitable solvent like cyclohexane and then converting it into its hydrochloride salt results in the formation of highly pure Tapentadol hydrochloride compound of formula- la.
  • the eighteenth aspect of the present invention is to provide one pot process for the preparation of pure Tapentadol hydrochloride compound of formula-1a, comprising the following steps of:
  • step-(a) converting the obtained compound in step-(a) into its hydrochloride salt compound of formula- la from the fifteenth and sixteenth aspects of the present invention.
  • the suitable base is selected from inorganic base and the suitable solvents is selected from ester solvents, ether solvents, hydrocarbon solvents, . polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents.
  • the nineteenth aspect of the present invention is to provide a novel process for the preparation of crystalline modification B of Tapentadol free base, comprising the following steps of:
  • the Tapentadol free base used in step-(a) is obtained from the step-(a) of seventeenth aspect of the present invention.
  • Stable crystalline form-B of Tapentadol hydrochloride compound of formula- la of the present invention indicates that the crystalline form-B never converts into crystalline form-A as like crystalline form-B obtained as per the prior known methods.
  • the crystalline form-B of compound of formula- la obtained by the present invention is stable during storage for a longer period of time.
  • the stable crystalline form-B of Tapentadol hydrochloride obtained as per the present invention is stable under the following conditions:
  • 3-[(li?,2i?)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride compound of formula- la of the present invention can be further micronized or milled to get the desire particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • Apparatus A liquid chromatograph equipped with variable wavelength UV detector; Column: Symmetry C18, 250 x 4.6mm, 5 ⁇ m or equivalent; Flow rate: 1.0 ml/min; Wavelength: 220 nm; Column temperature: 45°C; Injection volume: 5 ⁇ L.; Run time: 55 min; Diluent: acetonitrile:methanol (50:50)v/v; Mobile phase-A: Buffer; Mobile phase-B: Buffer: Acetonitrile:methanol (30:20:50)v/v.
  • the present invention is schematically represented by following schemes:
  • Example-1 Preparation of crystalline form-B of 3-[(lR,2R)-3-(dimethylamino)-1- ethyI-2-methylpropyl]phenol hydrochloride (Formula-la)
  • Example-8 Preparation of Tapentadol free base (Formula-1) from Tapentadol hydrochloride
  • a mixture of Tapentadol hydrochloride compound of formula- la (1000 gms), ethyl acetate (6000 ml) and water (4000 ml) was cooled to 0-5°C. Basify the reaction mixture with a solution of sodium carbonate (453 gms) and water (4500 ml) at 0-5°C. The temperature of the reaction mixture was raised to 20-25°C and then both organic and aqueous layers were separated. The organic layer was dried with sodium sulfate and then distilled off the solvent completely under reduced pressure to obtain a residue. The obtained residue was cooled to 35-40°C and cyclohexane (1000 ml) was added to the residue and stirred for 2 hours at 25-30°C. The reaction mixture was cooled to 10-15°C and stirred for 60 minutes. Filtered the solid and then dried to get title compound.
  • Example-9 Preparation of stable crystalline form-B of Tapentadol hydrochloride (Formula-1a) in the presence of ethyl formate
  • D(0.1) is 94.43 ⁇ m
  • D(0.5) is 174.37 ⁇ m
  • D(0.9) is 299.94 ⁇ m
  • D(4,3) is 186.42 ⁇ m.
  • Example-10 Process for the preparation of Tapentadol hydrochloride (Formula-la) Step-a) Preparation of Tapentadol Free base (Formula-1)
  • step-(a) To the compound obtained in step-(a) ethyl formate (100 ml) and ethyl acetate (100 ml) were added under nitrogen atmosphere and the reaction mixture was cooled to -5 to 0°C. A pre-cooled solution of ethyl acetate-hydrochloric acid (83 ml) was added to the reaction mixture. The precipitated product was isolated and then dried to get Tapentadol hydrochloride compound of formula-la. Yield: 18.3 gms; Purity by HPLC: 99.75%; Impurity at 1.77 RRT: 0.09%. Particle size distribution: D(0.1) is 94.43 ⁇ m; D(0.5) is 174.37 ⁇ m; D(0.9) is 299.94 ⁇ m, D(4,3) is 186.42 ⁇ m.
  • Example-11 Preparation of stable crystalline form-B of Tapentadol hydrochloride (Formula-la) in the presence of formic acid.
  • D(0.1) is 94.43 ⁇ m
  • D(0.5) is 174.37 ⁇ m
  • D(0.9) is 299.94 ⁇ m
  • D(4,3) is 186.42 ⁇ m.
  • Example-12 Preparation of stable crystalline form-B of Tapentadol hydrochloride
  • D(0.1) is 94.43 ⁇ m
  • D(0.5) is 174.37 ⁇ m
  • D(0.9) is 299.94 ⁇ m
  • D(4,3) is 186.42 ⁇ m.
  • Example-13 Preparation of stable crystalline form-B of Tapentadol hydrochloride (Formula-la) in the presence of ethyl formate
  • Tapentadol free base compound of formula-1 350 gms
  • ethyl formate 3500 ml
  • Ethyl acetate-hydrochloric acid 38.1 ml
  • assay was added to the reaction mixture for about 2 hours at the same temperature. Filtered the precipitated product and then dried to get title compound.
  • D(0.1) is 94.43 ⁇ m
  • D(0.5) is 174.37 ⁇ m
  • D(0.9) is 299.94 ⁇ m
  • D(4,3) is 186.42 ⁇ m.
  • Example-14 Preparation of stable crystalline form-B of Tapentadol hydrochloride (Formula-la) in the presence of formic acid.
  • D(0.1) is 94.43 ⁇ m
  • D(0.5) is 174.37 ⁇ m
  • D(0.9) is 299.94 ⁇ m
  • D(4,3) is 186.42 ⁇ m.

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Abstract

The present invention relates to novel process for the preparation of 3-[(lR,2R)-3- (dimethylamino)-l-ethyl-2-methylpropyl]phenol and its pharmaceutically acceptable salts.

Description

Process for the preparation of 3-aryl-2-methyI-propanamine derivatives and polymorphs thereof
Related Applications:
This application claims the benefit of priority of our Indian patent application numbers 97/CHE/2012 filed on 10th Jan. 2012 and 3403/CHE/2012 filed on 17th Aug. 2012 which are incorporated herein by reference.
Field of the Invention:
The present invention relates to a novel process for the preparation of 3-[(1R,2R)- 3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol represented by the structural formula- 1 and its hydrochloride salt represented by the structural formula-1a. The present invention also provides novel intermediates which are useful in the preparation of 3- [(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1.
Figure imgf000003_0001
The present invention also relates to a stable and pure crystalline form-B of 3- [(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride and process for its preparation.
Further, the present invention also provides highly pure 3-[(1R,2R)-3-
(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride represented by structural formula-1a by converting hydrochloride salt compound of formula- la into free base 3- [(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol represented by structural formula-1, followed by converting the free base to hydrochloride salt compound of formula-1a.
3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride is developed by Grunenthal in conjunction with Johnson & Johnson Pharmaceutical Reasearch and development and is marketed under the trade names Nucynta, Palexia, Zyntap. "3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol" is commonly known as Tapentadol. It is a centrally acting analgesic with dual mode of action as an agonist of μ-opioid receptor and norepinephrine reuptake inhibitor. Background of the invention:
3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride and its process for the preparation was first disclosed in US RE39593. The disclosed process starts from the reaction of 3-bromoanisole with 1-dimethylamino-2-methylpentane-3-one to form diastereomeric mixture of 1-dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol. The separation of the diastereomeric isomers, i.e., the two enantiomeric pairs is carried out by precipitating as hydrochloride salt with trimethylchloro silane/water in 2-butanone. The resolution of the racemic mixture of the two enantiomers of (2S,3S) and (2R,3R) isomers is carried out by separation on a chiral HPLC column to provide (2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2- methylpentan-3-ol. The resolved intermediate is then converted into its corresponding chloro compound, followed by reduction with Zinc borohydride and finally demethylated using HBr.
The main drawback of the above said process is the usage of trimethyl chlorosilane in the diastereomeric separation, which is hazardous and highly flammable, hence not advisable to use in the industrial scale. The other drawback of this process is resolution of enantiomers by chiral HPLC, which is cost-effective, not amenable for commercial synthesis on industrial scale and thereby making the process commercially unfeasible. The usage of reducing agents in the above process, such as zinc borohydride which is hazardous substance and poses considerable fire when used on the large-scale, hence it is not advisable to use on large scale.
PCT publications WO 2008012283, WO2008012047 and WO 2008012046 were disclosed a process for the preparation of (2S,3R)-l-(dimethylamino)-3-(3-methoxy phenyl)-2-methylpentan-3-ol, which is a key intermediate in the synthesis of 3-[(lR,2R)- 3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride. The disclosed process involves the reaction of l-(3-methoxyphenyl)propan-l-one, dimethylamine and formaldehyde provides 3 -(dimethylamino)- 1 -(3 -methoxyphenyl)-2-methylpropan- 1 -one, which on resolution by treating with L-(-)-DBTA provides (2S)-3-(dimethylamino)-l-(3- methoxyphenyl)-2-methylpropan-1-one and the obtained compound is further treated with ethyl magnesium halide.
U.S. Patent US7649114 disclosed a resolution method for the separation of the two enantiomers from the enantiomeric pair, (2R,3R)/(2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol, with the aid of a chiral acid, such as (+)-di-O,O'-p- toluoyltartaric acid, (-)-di-0,0'-p-toluoyltartaric acid and D-(-)-tartaric acid, in the presence of a suitable solvent such as 2-butanone.
PCT publication WO2011 107876 disclosed a resolution method for the separation of the two enantiomers from the enantiomeric pair, (2S,3R)/(2R,3S)-1-dimethylamino-3~ (3-methoxyphenyl)-2-methylpentan-3-ol, with the aid of chiral auxiliary, such as (S)- naproxen. The said publication also disclosed a resolution method for the separation of enantiomers from the enantiomeric pair, (2R,3R)/(2S,3S)-3-(3-methoxyphenyl)-N,N,2- trimethylpentan-1 -amine using an optically active acid, such as di-p-toluoyl-L-tartaric acid and di-benzoyl-L-tartaric acid.
The main drawback of the above mentioned methods for the preparation of 3-
[(li?,2i?)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride is that all the processes are leading to the enantiomeric separation of its intermediates, which increases the total number of steps of the reaction resulting the usage of additional solvents and reagents making the process expensive.
Therefore, there is an obvious need for the development of a cost-effective and industrially viable process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-
2-methylpropyl]phenol hydrochloride and that do not involve the chiral chromatographic technique.
The crystalline form of Tapentadol hydrochloride obtained by the process disclosed in US RE39593 was later characterized as crystalline form-B in US2009186947.
All the prior art processes for the preparation of Tapentadol hydrochloride involves the usage of ethyl acetate-hydrochloric acid, isopropanol-hydrochloric acid in various solvents. All the processes are leading to the formation of crystalline form-A, mixture of crystalline form-A and form-B and unstable crystalline form-B of Tapentadol hydrochloride. Hence there is a need in the art to develop a stable crystalline form-B of Tapentadol hydrochloride.
The crystalline modification-B of Tapentadol free base was first disclosed in US8134032. However as on date, there is no alternative processes were reported in the literature for preparing the said crystalline modification-B of Tapentadol free base. Henceforth, there is a need to develop an alternative process for the preparation of said crystalline polymorph.
Brief description of the invention:
The main objective of the present invention is to provide a novel process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula- 1 and its hydrochloride salt compound of formula-1a. Other objective of the present invention is to provide pure and stable crystalline form-B of Tapentadol hydrochloride compound of formula- la and its process for the preparation. The first aspect of the present invention is to provide novel intermediate compounds which are useful in the synthesis of 3-[(li?,2i?)-3-(dimethylamino)-1-ethyl-2- methylpropyl] phenol compound of formula- 1 as well as its hydrochloride salt compound of formula-1a. The second aspect of the present invention is to provide a novel process for the preparation of (2 S)- 1 -(3 -methoxyphenyl)-2-methyl-3 -(N-substituted-N-( 1 -phenylethyl) amino) propan-1-one compound of general formula-4, comprising of reacting the l-(3- methoxyphenyl)propan-1-one compound of formula-2 with 1-phenylethylamine derivative compound of general formula-3 with formaldehyde in presence of an acid in a suitable solvent, followed by hydrolysis provides compound of general formula-4.
The third aspect of the present invention is to provide a process for preparation of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l-(N-substitUted-N-(l-phenylethyl)amino) pentan-3-ol compound of general formula-5, comprising of reacting the (2S)-1-(3- methoxyphenyl)-2-methyl-3-(N-substituted-N-(l-phenylethyl)amino)propan-l-one compound of general formula-4 with ethyl magnesium halide in a suitable solvent to provide compound of general formula-5. The fourth aspect of the present invention is to provide a process for preparation of (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N-substituted-N-(l-phenylethyl)amino) pent-1-en-3-ol compound of general formula- 10, comprising of reacting the (2S)-1-(3- methoxyphenyl)-2-methyl-3-(N-substituted-N-( 1 -phenylethyl)amino)propan- 1 -one compound of general formula-4 with vinyl magnesium halide in a suitable solvent to provide compound of general formula- 10.
The fifth aspect of the present invention is to provide a process for the preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine compound of formula- 8, comprising of N-methylating (2R,3R)-3-(3-methoxyphenyl)-2-methyl-N-substituted- pentan-1 -amine compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide compound of formula-8.
The sixth aspect of the present invention is to provide a novel process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol compound of formula- 1, comprising of acylation of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-1-(-- substiruted-N-(l-phenylethyl)amino)pentan-3-ol compound of general formula-5, followed by catalytic hydrogenation, N-methylation and O-demethylation to provide compound of formula-1.
The seventh aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of dehydration of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l- (N-substituted-N-(l-phenylethyl)amino)pentan-3-ol compound of general formula-5, followed by catalytic hydrogenation, N-methylation and O-demethylation provides compound of formula-1.
The eighth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of acylation of (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N- substituted-N-(l-phenylethyl)amino)pent-l-en-3-ol compound of general formula- 10, followed by catalytic hydrogenation, N-methylation and O-demethylation provides compound of formula-1. The ninth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl]phenol compound of formula- 1, comprising of catalytic hydrogenation of (3R,4S)-3-(3-methoxyphenyl)-4- methyl-5-(N-substituted-N-(l-phenylethyl)amino)pent-l-en-3-ol compound of general formula- 10, followed by dehydration, catalytic hydrogenation, N-methylation and O- demethylation provides compound of formula- 1.
The tenth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl]phenol compound of formula- 1, comprising of catalytic hydrogenation of (3R,4S)-3-(3-methoxypheriyl)-4- methyl-5-(N-substituted-N-(l-phenylethyl)amino)pent-l-en-3-ol compound of general formula- 10, followed by acylation, catalytic hydrogenation, N-methylation and O- demethylation provides compound of formula- 1. The eleventh aspect of the present invention is to provide a process for the preparation of crystalline form-B of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl ]phenol hydrochloride compound of formula- la.
The twelfth aspect of the present invention is to provide (3R,4S)-5- (dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15, which is an useful intermediate in the synthesis of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl- 2-methylpropyl] phenol compound of formula- 1 and its hydrochloride salt compound of formula- la, and process for its preparation. The thirteenth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula- 1, comprising of catalytic hydrogenation of (3R,4S)-5-(dimethylamino)-3-(3- methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula-15, followed by dehydration, reduction and O-demethylation provides compound of formula- 1.
The fourteenth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula- 1, comprising of acylation of (3R,4S)-5-(dimethylamino)-3-(3- methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula- 15, followed by catalytic hydrogenation, and O-demethylation provides compound of formula-1.
The fifteenth aspect of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
a) Adding a suitable solvent to Tapentadol free base,
b) cooling the reaction mixture,
c) adding a lower aliphatic carboxylic acid to the reaction mixture,
d) adding a hydrochloric acid source to the reaction mixture,
e) filtering the precipitated solid and then dried to get crystalline form-B of Tapentadol hydrochloride.
The sixteenth aspect of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
a) Adding an alkyl formate to Tapentadol free base in the presence or absence of a suitable solvent,
b) cooling the reaction mixture,
c) adding a hydrochloric acid source to the reaction mixture,
d) filtering the precipitated solid and then dried to get crystalline form-B of Tapentadol hydrochloride.
The seventeenth aspect of the present invention is to provide a process for the preparation of pure Tapentadol hydrochloride compound of formula- la, comprising the following steps of:
a) Treating the Tapentadol hydrochloride with an aqueous base in a water immiscible solvent, followed by concentrating the organic layer to provide Tapentadol free base as a residue,
b) isolating the compound with a suitable solvent, c) converting the compound obtained in step-(b) into its hydrochloride salt compound of formula- la by the process disclosed in the fifteenth and sixteenth aspects of the present invention.
The eighteenth aspect of the present invention is to provide one pot process for the preparation of pure Tapentadol hydrochloride compound of formula- la, comprising the following steps of:
a) Reacting (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan- 1 -amine compound of formula-2 with hydrobromic acid in presence or absence of a suitable solvent, followed by treating with a suitable base to provide Tapentadol free base compound of formula- 1 ,
b) converting the obtained compound in step-(a) into its hydrochloride salt compound of formula- la by the process disclosed in fifteenth and sixteenth aspects of the present invention.
The nineteenth aspect of the present invention is to provide a process for the preparation of crystalline modification-B of Tapentadol free base, comprising the following steps of:
a) Adding cyclohexane to residue of Tapentadol free base at 35-40°C,
b) cooling the reaction mixture to 25-30°C and stirring the reaction mixture, c) cooling the reaction mixture to 10- 15°C and stirring the reaction mixture, d) filtering the solid and then dried to get crystalline modification-B of Tapentadol free base.
Advantages of the present invention:
• Produces 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol in shorter reaction time.
• Avoids chiral chromatographic separation techniques as well as avoids the additional resolution step using chiral reagents, which in turn avoids the usage of additional reagents and solvents.
• Avoids trimethylchlorosilane in the diastereomeric separation, which is highly flammable liquid and hazardous and also avoids the usage of zinc borohydride which is hazardous and poses considerable fire. • Provides stable crystalline form-B of Tapentadol hydrochloride compound of formula- la.
• Provides simple process for the preparation of crystalline form-B of Tapentadol hydrochloride compound of formula-1a and also provides a novel process for the preparation of crystalline modification-B of Tapentadol free base compound of formula- 1.
• Provides commercially viable and cost-effecetive and environmental friendly process for the preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyljphenol.
• Provides (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent- 1 -en-3- ol, which is useful in the synthesis of Tapentadol and its hydrochloride salt.
Brief description of the Figures:
Figure-1: Illustrates the powder X-ray diffractogram of crystalline form-B of Tapentadol hydrochloride.
Figure-2: Illustrates the powder X-ray diffractogram of crystalline modification-B of Tapentadol free base.
Detailed description of the invention:
The "suitable solvent" used in the present invention is selected from, but are not limited to "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "ether solvents" such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane, 1,2-dimethoxyethane, diisopropyl ether and the like; "hydrocarbon solvents" such as toluene, hexane, heptane and cyclohexane and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethylformamide, dimethyl sulfoxide, acetonitrile and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; and "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert- butanol and the like; "chloro solvents" such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; polar solvents such as water; and also mixtures thereof. As used herein the "base" is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert- butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; and ammonia; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine, piperidine, pyridine, tributyl amine, 4-dimethylaminopyridine, N-methyl morpholine and the like.
The "suitable acylating agent" used in the present invention is selected from, but are not limited to anhydrides and halides of acetic acid, phenyl acetic acid, chloro acetic acid, trifluoro acetic acid, dichloro acetic acid, trichloro acetic acid, benzoic acid, chlorobenzoic acid, terephthalic acid, phthalic acid, succinic acid, mono C1-C4 alkyl esters of succinic acid, oxalic acid, mono C1-C4 alkyl esters of oxalic acid such as ethyl oxalyl chloride and methyl oxalyl chloride, and mixed anhydride of formic acid such as ethylchloroformate, methylchloroformate and acetylsalicyloyl chloride.
The "suitable metal catalyst" used for hydrogenation in the present invention is selected from, but are not limited to Pd, Pt, Ru, Rh catalysts such as Pd, Pd-C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3 [tris(dibenzylidene acetone) dipalladium], palladium thipmethyl phenylglutaramide, palladium on metal oxide, palladium on zeolites, Pt, Pt-C, PtO2, Ru-C, Rh-C, rhodium on alumina; and Raney-Ni.
The "suitable methylating agent" herein the present invention refers, but not limited to dimethyl sulfate, methyl iodide, dimethyl carbonate, methyl methane sulfonate, methyl triflate, trimethyl oxonium tetrafluoroborate, N-methyl methane sulfonamide, formaldehyde/formic acid and formaldehyde/sodium borohydride.
The "suitable demethylaying agent" herein the present invention is selected from, but are not limited to hydrobromic acid with or without carboxylic acid such as formic acid, acetic acid; methane sulfonic acid, methionine, diisobutyl aluminium hydride, pyridine chloride, lewis acids like aluminium chloride, boron tribromide and mixtures thereof. The "suitable dehydrating agent" used in the present invention is selected from, but are not limited to inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like; and organic acid such as formic acid and methane sulfonic acid; acid anhydrides such as trifluoroacetic anhydride and acetic anhydride; phosphorous pentoxide; phosphoryl chloride; phosphoric acid; and dicyclohexylcarbodiimide.
As used herein, the term "Ci.C4 alkyl" refers to alkyl group having 1 to 4 carbon atoms. Examples of Ci. C4 alkyl groups include, without limitation, methyl, ethyl, n- propyl, is -propyl, n-butyl, sec-butyl, iso-butyl and t-butyl.
As used herein the term "C6-Q0 aryl" refers to aromatic ring having 6 to 10 carbon atoms. Examples of C6-Ci0 aryl groups includes, without limitation phenyl, naphthyl and pyridine.
As used herein, the term "cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon rings, generally having a specified number of carbon atoms that comprise the ring. A "C3-C7 cycloalkyl" refers to cycloalkyl group having 3 to 7 carbon atoms. Examples of monocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The "hydrochloric acid source" used herein the present invention is selected from hydrochloric acid gas, aqueous hydrochloric acid, ethyl acetate-hydrochloric acid, isopropanol-hydrochloric acid, diisopropyl ether-hydrochloric acid, diethylether- hydrochloric acid, and trimethylchlorosilane.
The "lower aliphatic acid" used herein the present invention is selected from formic acid, acetic acid, propanoic acid and the like.
The "alkyl formate" used herein the present invention is selected from methyl formate, ethyl formate and isopropyl formate.
The first aspect of the present invention is to provide novel compounds represented by following structural formulae:
Figure imgf000014_0001
Wherein,
"acyl" represents CH3-CO-, CF3-CO-, CH2C1-C0-, CHC12-C0-, CCI3-CO-,
CH3O-CO-, CH3CH20-CO-, CH3O-CO-CO, CH3CH20-CO-CO-, phenyl-CO-, or meta- CH3COO-phenyl-CO- , Cl-phenyl-CO-, HOOC-CH2-CH2-CO-, (Ci-C4alkyl)-OOC-CH2- CH2-CO, ortho-HOOC-Phenyl-CO, ortho-(Ci-C4alkyl)-phenyl-CO-, para-HOOC-Phenyl- CO, para-(CrC4alkyl)-phenyl-CO- and the like;
"R" represents -H, -CH3, -CH2Ph in which Ph is optionally substituted with d-C4 alkyl, halogen, C6-C10 aryl, C3-C7 cycloalkyl, -OH, -O-C1-C4 alkyl and the like; and "R1" represents -H;
which are useful intermediates in the synthesis of 3-[(li?,2i?)-3-(dimethylamino)- l-ethyl-2-methylpropyl]phenol compound of formula- 1 as well as its hydrochloride salt compound of formula- 1 a.
The second aspect of the present invention is to provide a novel process for the preparation of (2S)- l-(3-methoxyphenyl)-2-methyl-3-(N-substituted-N-(l-phenylethyl) amino)propan-l-one compound of general formula-4, comprising of reacting the l-(3- methoxyphenyl)propan-l-one compound of formula-2 with 1 -phenyl ethylamine derivative compound of general formula-3 with formaldehyde in presence of an acid in a suitable solvent, followed by hydrolysis provides compound of general formula-4.
Wherein, the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar aprotic solvents, hydrocarbon solvents and alcoholic solvents; and the "acid" refers to inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid.
The third aspect of the present invention is to provide a process for preparation of (2S,3R)-3-(3-methoxyphenyl)-2-methyl-1-(N-substituted-N-(l-phenylethyl)amino) pentan-3-ol compound of general formula-5, comprising of reacting (2S)-1-(3- methoxyphenyl)-2-methyl-3-(N-substituted-N-( 1 -phenyl ethyl)amino)propan- 1 -one compound of general formula-4 with ethyl magnesium halide in a suitable solvent to provide compound of general formula-5.
Wherein, the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and hydrocarbon solvents; and the "ethyl magnesium halide" used is selected from ethyl magnesium bromide and ethyl magnesium chloride.
The fourth aspect of the present invention is to provide a process for preparation of (3R,4S)-3 -(3 -methoxyphenyl)-4-methyl-5-(N-substituted-N-(l -phenyl ethyl)amino) pent-1-en-3-ol compound of general formula- 10, comprising of reacting (2S)-1-(3- methoxyphenyl)-2-methyl-3-(N-substituted-N-(l-phenylethyl)amino)propan-1-one compound of general formula-4 with vinyl magnesium halide in a suitable solvent to provide compound of general formula- 10.
Wherein, the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and hydrocarbon solvents; and the "vinyl magnesium halide" used is selected from vinyl magnesium bromide and vinyl magnesium chloride.
The fifth aspect of the present invention is to provide a process for the preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l -amine compound of formula- 8, comprising of N-methylating the (2R,3R)-3-(3-methoxyphenyl)-2-methyl-N- substituted-pentan-1 -amine compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent provides compound of formula-8. Wherein, the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof; and the "suitable methylating agent" is selected from dimethylsulfate, methyl iodide, dimethylcarbonate, methyl methane sulfonate, methyl triflate, trimethyl oxonium tetrafluoroborate, N-methyl methane sulfonamide, formaldehyde/formic acid and formaldehyde/sodium borohydride.
The sixth aspect of the present invention is to provide a novel process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1, comprising of the following steps:
a) Acylating the (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l-(N-substituted-N-(l- phenyl ethyl)amino)pentan-3-ol compound of general formula-5 with a suitable acylating agent in presence or absence of a base in a suitable solvent to provide its corresponding acyl derivative compound of general formula-6,
b) hydrogenating the compound of general formula-6 in presence of a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2R,3R)-3-(3- methoxyphenyl)-2-methyl-N-substituted-pentan-l -amine compound of general formula-7,
c) N-methylating the compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide (2R,3R)-3-(3- methoxyphenyl)-N,N,2-trimethylpentan-l -amine compound of formula-8, d) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide 3-[(lR,2R)-3- (dimethylamino)-l-ethyl-2-methylpropyl] phenol compound of formula-1.
Wherein,
In step-a) the "suitable acylating agent" is selected from anhydrides and halides of acetic acid, phenyl acetic acid, chloro acetic acid, trifluoro acetic acid, dichloro acetic acid, trichloro acetic acid, benzoic acid, chlorobenzoic acid, terephthalic acid, phthalic acid, succinic acid, mono C1-C4 alkyl esters of succinic acid, oxalic acid, mono C1-C4 alkyl esters of oxalic acid such as ethyl oxalyl chloride and methyl oxalyl chloride, and mixed anhydride of formic acid such as ethylchloroformate, methylchloroformate and acetylsalicyloyl chloride; and the "base" is inorganic or organic base;
In step-b) the "suitable metal catalyst" is selected from Pd, Pt, Ru and Rh catalysts such as Pd, Pd-C, Pd(OH)2, Pd(OAc)2, PdCl2, Pt, PtO2, Ru-C and Rh-C; and Raney-Ni;
In step-c) the "suitable methylating agent" and "suitable solvent" are same as defined in fifth aspect of the present invention;
In step-d) the "suitable demethylating agent" is selected from hydrobromic acid, optionally in combination with carboxylic acid such as formic acid, acetic acid; methane sulfonic acid, methionine, diisobutyl aluminium hydride, pyridine chloride, lewis acids such as aluminium chloride, boron tribromide and mixtures thereof;
the "suitable solvent" used in step-(a) and step-(b) is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably alcoholic solvents and ether solvents; and
the "suitable solvent" used in step-(d) is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents polar solvents, chloro solvents and/or mixtures thereof, preferably polar solvents and chloro solvents.
The seventh aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl] phenol compound of formula- 1, comprising of the following steps:
a) Dehydrating the (2S,3R)-3-(3-methoxyphenyl)-2-methyl-1-(N-substituted-N-(l- phenylethyl)amino)pentan-3-ol compound of general formula-5 with a suitable dehydrating agent in a suitable solvent to provide (2R)-3-(3-methoxyphenyl)-2- methyl-N-substituted-N-(l-phenylethyl)pent-3 -en- 1 -amine compound of general formula-9,
b) hydrogenating the compound of general formula-9 in presence of a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2R,3R)-3-(3- methoxyphenyl)-2-methyl-N-substituted-pentan-1 -amine compound of general formula-7,
c) N-methylating the compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide (2R,3R)-3-(3- methoxyphenyl)-N,N,2-trimethylpentan-1-amine compound of formula-8, d) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide 3-[(1R,2R)-3- (dimethylamino)-l-ethyl-2-methyl propyl] phenol compound of formula- 1.
Wherein,
In step-a) the "suitable dehydrating agent" is selected from inorganic acids, organic acids, acid anhydrides, phosphorous pentoxide; phosphoryl chloride; phosphoric acid; dicyclohexyl carbodiimide; and the "suitable solvent" used is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents; and
the "suitable metal catalyst", "suitable methylating agent", "suitable demethylating agent" and "suitable solvents" used in step-(b), step-(c) & step-(d) are same as defined in step-(b), step-(c) & step-(d) of sixth aspect of the present invention respectively; The eighth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyl]phenol compound of formula- 1, comprising of the following steps:
a) Acylating the (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N-substituted-N-(l- phenylethyl)amino)pent-l-en-3-ol compound of general formula- 10 with a suitable acylating agent in presence or absence of a base in a suitable solvent to provide its corresponding acylated derivative compound of general formula- 1 1, b) hydrogenating the compound of general formula- 11 in presence of a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2R,3R)-3- (3-methoxyphenyl)-2-methyl-N-substituted-pentan-l -amine compound of general formula-7, c) N-methylating the compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide (2R,3R)-3-(3- methoxyphenyl)-N,N,2-trimethylpentan-l -amine compound of formula-8, d) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide 3-[(1R,2R)-3- (dimethylamino)-l-ethyl-2-methyl propyl]phenol compound of formula- 1.
Wherein, the "suitable acylating agent", "base", "suitable metal catalyst", "suitable methylating agent", "suitable demethylating agent" and "suitable solvents" used in step-(a), step-(b), step-(c) & step-(d) are same as defined in step-(a), step-(b), step-(c) & step-(d) of sixth aspect of the present invention respectively;
The ninth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyljphenol compound of formula- 1, comprising of the following steps:
a) Hydrogenating the (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N-substituted-N- (lR-phenyl ethyl)amino)pent-l-en-3-ol compound of general formula- 10 in presence of a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2S,3R)-3-(3-methoxyphenyl)-2-methyl-l-(N-substituted-amino) pentan-3-ol compound of general formula- 12,
b) dehydrating the compound of general formula- 12 with a suitable dehydrating agent in a suitable solvent to provide (2R)-3-(3-methoxyphenyl)-2-methyl-N- substituted-pent-3-en- 1 -amine derivatives compound of general formula- 14, c) hydrogenating the compound of general formula- 14 in presence of a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2R,3R)-3- (3 -methoxyphenyl)-2-methyl-N-substituted-pentan- 1 -amine compound of general formula-7,
d) N-methylating the compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide (2R,3R)-3-(3- methoxyphenyl)-N,N,2-trimethylpentan-l -amine compound of formula-8, e) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide 3-[(1R,2R)-3- (dimethylamino)- 1 -ethyl-2-methyl propyl] phenol compound of formula-1.
Wherein, the "suitable metal catalyst", "suitable methylating agent", "suitable demethylating agent" and "suitable solvents" used in step-(a), step-(c), step-(d) & step-(e) are same as defined in step-(b), step-(c) & step-(d) of sixth aspect of the present invention respectively;
The "suitable dehydrating agent" and "suitable solvent" used in step-(b) are same as defined in step-(a) of seventh aspect of the present invention.
In an alternative process, (2R)-3-(3-methoxyphenyl)-2-methyl-N-substituted- pent-3 -en- 1 -amine compound of general formula-14 in the above aspect undergoes methylation, followed by catalytic hydro genation and then demethylation to provide 3- [(l/?,2 ?)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula-1.
The tenth aspect of the present invention is to provide a process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methyl propyl]phenol compound of formula-1, comprising of the following steps:
a) Hydrogenating the (3R,4S)-3-(3-methoxyphenyl)-4-methyl-5-(N-substituted-N- (1 -phenyl ethyl)amino)pent-l-en-3-ol compound of general formula- 10 in presence of a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2S,3R)-3-(3-methoxyphenyl)-2-methyl-1-(N-substituted-amino) pentan-3-ol compound of general formula- 12,
b) acylating the compound of general formula- 12 with a suitable acylating agent in presence or absence of a base in a suitable solvent to provide its corresponding acylated derivative compound of general formula- 13,
c) hydrogenating the compound of general formula- 13 with a suitable metal catalyst in a suitable solvent under hydrogen pressure to provide (2R,3R)-3-(3-methoxy phenyl)-2-methyl-N-substituted-pentan-1-amine compound of general formula-7, d) N-methylating the compound of general formula-7 with a suitable methylating agent in presence or absence of a suitable solvent to provide (2R,3R)-3-(3- methoxyphenyl)-N,N,2-trimethylpentan-l -amine compound of formula-8, e) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide 3-[(1R,2R)-3- (dimethylamino)-1-ethyl-2-methyl propyl] phenol compound of formula- 1. Wherein, the "suitable metal catalyst", "suitable acylating agent", "base",
"suitable methylating agent", "suitable demethylating agent" and "suitable solvents" used in step-(a), step-(b), step-(c), step-(d) & step-(e) are same as defined in step-(a), step-(b), step-(c) & step-(d) of sixth aspect of the present invention respectively; In an alternative process, the compound of general formula- 13 in the above aspect undergoes methylation, followed by catalytic reduction and then demethylation to provide 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol compound of formula- 1. In an alternative process, the compounds of general formula- 13 and 14 of the present invention undergoes methylation and demethylation, followed by catalytic reduction provides 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula- 1. The eleventh aspect of the present invention is to provide a process for the preparation of crystalline form-B of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methyl propyljphenol hydrochloride compound of formula- la, comprising of:
a) Dissolving the 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol compound of formula-1 in ethyl acetate,
b) filtering the reaction mixture,
c) adjusting pH of filtrate to 1-2 with ethyl acetate-HCl,
d) stirring the reaction mixture,
e) filtering the precipitated solid and washing with ester solvent,
f) drying the solid to get crystalline form-B of compound of formula- la.
The compound of general formula- 14 is commercially available and can be prepared by any of the known methods. In the present invention, compounds of general formula-5, 10, 12 and compound of formula- 15 are undergoes tosylation or mesylation to provide its corresponding tosylated or mesylated derivatives. The obtained compound further hydrogenated in presence of suitable metal catalyst under hydrogen pressure to provide (2R,3R)-3-(3- methoxyphenyl)-2-methyl-N-substituted-pentan-1-amine compound of general formula- 7.
The starting materials used in the present invention are commercially available and can be also prepared by the known methods.
All the intermediate compounds of the present invention are converted into their acid addition salts like hydrochloride, hydrobromide and hydrogen sulfate salts.
The twelfth aspect of the present invention is to provide novel compounds represented by structural formulae
Figure imgf000022_0001
which is an useful intermediate in the synthesis of Tapentadol.
The twelfth aspect of the present invention also provides a process for the preparation of (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula- 15, comprising of reacting the (S)-3-(dimethylamino)-l-(3- methoxyphenyl)-2-methylpropan-l-one compound of formula- 14 with vinyl magnesium halide in a suitable solvent to provide compound of formula- 15.
Wherein, the term "vinyl magnesium halide" is selected from vinyl magnesium chloride and vinyl magnesium bromide; and the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and hydrocarbon solvents. The thirteenth aspect of the present invention provides a process for preparation of 3 -[(lR,2R)-3-(dimethyl amino)- 1 -ethyl-2-methylpropyl]phenol compound of formula- 1, comprising of:
a) Hydrogenating the (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methyl pent-l-en-3-ol compound of formula- 15 in presence of a suitable metal catalyst and hydrogen gas in a suitable solvent to provide (2S,3R)-l-(dimethylamino)-3- (3-methoxyphenyl)-2-methylpentan-3-ol compound of formula- 16,
b) dehydrating the compound of formula- 16 in-situ by treating it with a suitable dehydrating agent in a suitable solvent to provide (R,Z)-3-(3-methoxyphenyl)- N,N,2-trimethylpent-3-en-l -amine compound of formula- 17,
c) reducing the compound of formula- 17 in-situ with a suitable reducing agent in a suitable solvent to provide (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan- 1 -amine compound of formula-8,
d) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide compound of formula-1.
Wherein,
In step-a) the "suitable metal catalyst" is selected from Pd, Pt, Ru and Rh catalysts such as Pd, Pd-C, Pd(OH)2, Pd(OAc)2, PdCl2, Pt, PtO2, Pt-C, Ru-C and Rh-C; and Raney-Ni; and the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and alcoholic solvents;
In step-b) the "suitable dehydrating agent" is selected from inorganic acids, organic acids, acid anhydrides, phosphorous pentoxide; phosphoryl chloride; phosphoric acid; and dicyclohexyl carbodiimide; and the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents;
In step-c) the "suitable reducing agent" is selected from Ru, Rh metal catalysts such as Ru-C and Rh-C in presence of hydrogen; and Raney-Ni in presence of hydrogen; sodium borohydride; and Pd, Pt, Ru, Rh and Re catalysts such as Pd, Pd-C, Pd(OH)2, PdCl2, Pd(OAC)2, Pt, Pt-C, Pt02, Ru-C, Rh-C, ReIO2(PPh3)2, ReOCl3(PPh3)2, ReOCl3(dppm), and Re2O7 in presence of hydrogen source such as silane and sodium borohydride; the "silane" is selected from dimethylphenyl silane, phenyl silane, triethyl silane, triphenyl silane and poly methylhydrosiloxane; and the
"suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof; preferably hydrocarbon solvents, alcoholic solvents, chloro solvents and polar aprotic solvents; and
In step-d) the "suitable demethylating agent" is selected from hydrobromic acid optionally in combination with carboxylic acid such as formic acid, acetic acid; methane sulfonic acid, methionine, diisobutyl aluminium hydride, pyridine chloride, lewis acid such as aluminium chloride, boron tribromide and mixtures thereof; and the "suitable solvent" is selected from is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents and chloro solvents.
The fourteenth aspect of the present invention provides a process for preparation of 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula- 1, comprising of:
a) Acylating the (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l- en-3-ol compound of formula- 15 with a suitable acylating agent in presence or absence of a base in a suitable solvent to provide its corresponding acyl derivative compound of general formula- 18,
b) hydrogenating the compound of general formula- 18 in-situ in presence of a suitable metal catalyst and hydrogen gas in a suitable solvent to provide (2R,3R)- 3-(3-methoxyphenyl)-N,N,2-trimethyl pentan-1 -amine compound of formula-8, c) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide compound of formula- 1.
Wherein, In step-a) the "suitable acylating agent" is selected from anhydrides and halides of acetic acid, phenyl acetic acid, chloro acetic acid, trifluoro acetic acid, dichloro acetic acid, trichloro acetic acid, benzoic acid, chlorobenzoic acid, terephthalic acid, phthalic acid, succinic acid, mono C1-C4 alkyl esters of succinic acid, oxalic acid, mono C1-C4 alkyl esters of oxalic acid such as ethyl oxalyl chloride and methyl oxalyl chloride, and mixed anhydride of formic acid such as ethyl chloroformate, methyl chloroformate and acetyl salicyloyl chloride; the "base" is inorganic or organic base; and the "suitable solvent" is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and alcoholic solvents; and
the "suitable metal catalyst", "suitable demethylating agent" and "suitable solvents used in step-(b) and step-(c) are same as defined in step-(a) and step-(d) of thirteenth aspect of the present invention respectively. 3-[(1R,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol compound of formula- 1 obtained by the present invention is further converted into its hydrochloride salt compound of formula-1a by treating it with a suitable HC1 source such as HC1, aq.HCl, ethyl acetate-HCl, isopropanol-HCl, diethyl ether-HCl and diisopropyl ether- HC1.
Another object of the present invention is to provide pure and stable crystalline form-B of Tapentadol hydrochloride compound of formula-1a and its process for the preparation. All the prior art processes for the preparation of Tapentadol hydrochloride involves the usage of ethyl acetate-hydrochloric acid, isopropanol-hydrochloric acid in various solvents. All the processes leading to the formation of crystalline form-A, mixture of crystalline form-A and form-B and unstable crystalline form-B of Tapentadol hydrochloride.
With an intention to prepare stable crystalline form, the present inventors have conducted various experiments on recrystallization of Tapentadol hydrochloride compound of formula- la from various solvents as mentioned below:
Figure imgf000026_0001
Based on the above table, all the experiments are lea ing to t e ormat on o crystalline form-A, a mixture crystalline form-A and form-B and in some experiments the product is not isolated. The present inventors also conducted various experiments on preparation of
Tapentadol hydrochloride compound of formula- la from Tapentadol free base compound of formula- 1, by salt formation technique using hydrochloric acid source in various solvents as mentioned below:
Figure imgf000027_0001
Figure imgf000028_0001
All the above experiments leading to the formation of crystalline form-A, mixture of crystalline form-A and form-B and unstable crystalline form-B of compound of formula-1a (i.e., converting into stable crystalline form-A during storage).
Hence there is a need in the art to develop a stable crystalline form-B of 3- [(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride compound of formula- 1a. After conducting various experiments, the present inventors found that the usage of aliphatic carboxylic acid like formic acid, acetic acid (or) its esters like ethyl formate, methyl formate enhances the stability of crystalline form-B of Tapentadol hydrochloride.
The fifteenth aspect of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
a) Adding a suitable solvent to Tapentadol free base,
b) cooling the reaction mixture,
c) adding a lower aliphatic carboxylic acid to the reaction mixture,
d) adding a hydrochloric acid source to the reaction mixture,
e) filtering the precipitated solid and then dried to get crystalline form-B of Tapentadol hydrochloride.
Wherein, the lower aliphatic carboxylic acid is selected from formic acid and acetic acid; hydrochloric acid source is selected from hydrochloric acid gas, ethyl acetate- hydrochloric acid, isopropanol-hydrochloric acid, diisopropyl ether-hydrochloric acid and diethylether-hydrochloric acid; and the suitable solvent is selected from ester solvent such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and tertiary butyl acetate.
In a preferred embodiment of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
a) Adding ethyl acetate to Tapentadol free base,
b) cooling the reaction mixture,
c) adding formic acid to the reaction mixture,
d) adding ethyl acetate-hydrochloric acid to the reaction mixture,
e) filtering the precipitated solid and then dried to get crystalline form-B of Tapnetadol hydrochloride.
In another preferred embodiment of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of: a) Adding ethyl acetate to Tapentadol free base,
b) cooling the reaction mixture,
c) adding acetic acid to the reaction mixture,
d) adding ethyl acetate-hydrochloric acid to the reaction mixture,
e) filtering the precipitated solid and then dried to get crystalline form-B of Tapentadol hydrochloride.
The sixteenth aspect of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
a) Adding an alkyl formate to Tapentadol free base in the presence or absence of a suitable solvent,
b) cooling the reaction mixture,
c) adding a hydrochloric acid source to the reaction mixture,
d) filtering the precipitated solid and then dried to get crystalline form-B of Tapentadol hydrochloride.
Wherein, the suitable hydrochloric acid source is same as defined in fifteenth aspect; alkyl formate is selected from methyl formate, ethyl formate and isopropyl formate; and the suitable solvent is selected from ester solvent such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and tertiary butyl acetate.
In a preferred embodiment of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
a) Adding ethyl formate to Tapentadol free base,
b) cooling the reaction mixture,
c) adding ethyl acetate-hydrochloric acid to the reaction mixture,
d) filtering the precipitated solid and then dried to get crystalline form-B of Tapentadol hydrochloride.
In another preferred embodiment of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of: a) Adding ethyl formate to Tapentadol free base in ethyl acetate, b) cooling the reaction mixture,
c) adding ethyl acetate-hydrochloric acid to the reaction mixture,
d) filtering the precipitated solid and then dried to get crystalline form-B of Tapentadoi hydrochloride.
The seventeenth aspect of the present invention is to provide a process for the preparation of pure Tapentadoi hydrochloride compound of formula- la, comprising the following steps of:
a) Treating the Tapentadoi hydrochloride with an aqueous base in water immiscible solvent, followed by concentrating the organic layer to provide Tapentadoi free base as a residue,
b) isolating the compound with a suitable solvent,
c) converting the compound obtained in step-(b) to its hydrochloride salt compound of formula- la by the process disclosed in fifteenth and sixteenth aspects of the present invention.
Wherein, the suitable base is selected from inorganic bases like alkali metal alkoxides, hydroxides, carbonates and bicarbonates; the water immiscible solvent used in step-(a) is selected from ester solvents; and in step-(b) is selected from hydrocarbon solvents.
In a preferred embodiment of the present invention is to provide pure Tapentadoi hydrochloride compound of formula- la, comprising the following steps of:
a) Treating the Tapentadoi hydrochloride with aq.sodium carbonate in ethyl acetate, followed by concentrating the organic layer to provide Tapentadoi free base as a residue,
b) isolating the compound with cyclohexane,
c) converting the compound obtained in step-(b) to its hydrochloride salt compound of formula- la by the process disclosed in fifteenth and sixteenth aspects of the present invention.
Tapentadoi hydrochloride obtained by the prior art process such as USRE39593 does not able to meet the desired ICH purity. Whereas in the present invention, when converting the Tapentadol hydrochloride into Tapentadol free base and isolating the compound with a suitable solvent like cyclohexane and then converting it into its hydrochloride salt results in the formation of highly pure Tapentadol hydrochloride compound of formula- la.
The eighteenth aspect of the present invention is to provide one pot process for the preparation of pure Tapentadol hydrochloride compound of formula-1a, comprising the following steps of:
a) Reacting (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine compound of formula-8 with hydrobromic acid in presence or absence of a suitable solvent, followed by treating with a suitable base to provide Tapentadol free base,
b) converting the obtained compound in step-(a) into its hydrochloride salt compound of formula- la from the fifteenth and sixteenth aspects of the present invention.
Wherein,
in step-a) the suitable base is selected from inorganic base and the suitable solvents is selected from ester solvents, ether solvents, hydrocarbon solvents, . polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents.
The nineteenth aspect of the present invention is to provide a novel process for the preparation of crystalline modification B of Tapentadol free base, comprising the following steps of:
a) Adding cyclohexane to residue of Tapentadol free base at 35-40°C,
b) cooling the reaction mixture to 25-30°C and stirring the reaction mixture, c) cooling the reaction mixture to 10-15°C and stirring the reaction mixture, d) filtering the solid and then dried to get crystalline modification-B of Tapentadol free base.
The Tapentadol free base used in step-(a) is obtained from the step-(a) of seventeenth aspect of the present invention. Stable crystalline form-B of Tapentadol hydrochloride compound of formula- la of the present invention indicates that the crystalline form-B never converts into crystalline form-A as like crystalline form-B obtained as per the prior known methods.
The crystalline form-B of compound of formula- la obtained by the present invention is stable during storage for a longer period of time.
The stable crystalline form-B of Tapentadol hydrochloride obtained as per the present invention is stable under the following conditions:
Figure imgf000033_0001
Most of the batches for the preparation of stable crystalline form-B of Tapentadol hydrochloride showing MR: 178-182°C.
3-[(li?,2i?)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride compound of formula- la of the present invention can be further micronized or milled to get the desire particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
PXRD analysis of l-[(li?,2i?)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride compound of formula- la of the present invention was carried out using BRUKER/AXS X-ray diffractometer using Cu Ka radiation of wavelength 1.5406 A0 at a continuous scan speed of 0.03 min
Tapentadol hydrochloride compound of formula- la and Tapentadol Free base compound of formula- 1 obtained by the present invention was analyzed by HPLC under the following conditions:
Apparatus: A liquid chromatograph equipped with variable wavelength UV detector; Column: Symmetry C18, 250 x 4.6mm, 5μm or equivalent; Flow rate: 1.0 ml/min; Wavelength: 220 nm; Column temperature: 45°C; Injection volume: 5 μL.; Run time: 55 min; Diluent: acetonitrile:methanol (50:50)v/v; Mobile phase-A: Buffer; Mobile phase-B: Buffer: Acetonitrile:methanol (30:20:50)v/v.
The present invention is schematically represented by following schemes:
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention:
Examples:
Example-1: Preparation of crystalline form-B of 3-[(lR,2R)-3-(dimethylamino)-1- ethyI-2-methylpropyl]phenol hydrochloride (Formula-la)
3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol (19 gms) was dissolved in ethyl acetate (80 ml) and the reaction mixture was filtered on hyflow bed. The PH of the obtained filtrate was adjusted to 1.5 using ethyl acetate-HC1 at 25-35°C and the reaction mixture was stirred for 4 hours at 25-35°C. Filtered the precipitated solid and washed with ethyl acetate. Dried the obtained solid to get title compound. Yield: 19 gms. Example-2: Preparation of (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4- methylpent-l-en-3-ol (Formula-15)
A solution of (S)-3-(dimethylamino)-l-(3-methoxyphenyl)-2-methylpropan-1-one compound of formula- 14 (50 gms) in tetrahydrofuran (200 ml) was added slowly to vinyl magnesium bromide (88 gms) at 0-5°C under nitrogen atmosphere. The temperature of the reaction mixture was raised to 25-30°C and stirred for 3 hours. After completion of reaction, the reaction mixture was quenched with 15% ammonium chloride solution at 0- 5°C. The temperature of the reaction mixture was raised to 20-30°C and stirred for 15 minutes. Both the organic and aqueous layers were separated; the aqueous layer was extracted with tetrahydrofuran. Both the organic layers were combined and dried with sodium sulfate and then distilled under reduced pressure to provide title compound. Yield: 40 gms.
Example-3: Preparation of (2S,3R)-l-(dimethylamino)-3-(3-methoxyphenyl)-2- methyl pentan-3-ol (Fomrula-16)
(3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol (5 gms) compound of formula-15 was dissolved in 13 ml ethanol. A suspension of palladium on active charcoal (0.35 gms) in ethanol (3 ml) was added to the reaction mixture under nitrogen atmosphere. Hydrogen gas with pressure of 5 bar was passed into the reaction mixture. After completion of the reaction, the reaction mixture was filtered and the filtrate was distilled off completely under reduced pressure to get title compound. Yield: 3.4 gms.
Example-4: Preparation of (R,Z)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-l- amine (Formula-17)
36 wt. % aqueous hydrochloric acid (5.25 ml) was added slowly to (2S,3R)-1-
(dimethylamino)-3-(3-methoxyphenyl)-2-methyl pentan-3-ol (3 gms) compound of formula- 16 obtained in example-3. The reaction mixture was heated slowly to 50°C and stirred for 6 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to room temperature and water was added into it. The reaction mixture was basified with 32 wt% sodium hydroxide at an internal temperature of 20°C. Ethyl acetate was added to the reaction mixture; Both the organic and aqueous layers were separated, the organic layer was distilled off completely under reduced pressure to get title compound. Yield: 2.5 gms.
Example-5: Preparation of. (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l- amine (Formula-8)
A solution of sodium borohydride (0.65 gms) in ethanol (5 ml) was added slowly to a mixture of (R,Z)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en- 1 -amine compound of formula-17 (2 gms) and 10 ml of ethanol at room temperature and stirred for 3 hours at room temperature. After completion of the reaction, water was added to the reaction mixture. Reaction mixture was extracted with ethyl acetate. Both the organic and aqueous layers were separated; the solvent from the organic layer was distilled off completely under reduced pressure to get title compound. Yield: 1.32 gms.
Exampel-6: Preparation of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2- methylpropyl] phenol (Formula-1)
(2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-8 (4.9 gms) was dissolved in methane sulfonic acid (25 ml). Methionine (4.7 gms) was added to the obtained solution and the reaction mixture was stirred for 20 hours at 75-80°C. After completion of the reaction, the reaction mixture was cooled to 15-25°C and water was added to it. The reaction mixture was basified with aq.sodium hydroxide solution at a temperature below 50°C. Ethyl acetate was added to the reaction mixture and stirred for 30 minutes. Both the organic and aqueous layers were separated; the organic layer was filtered over the silica gel and washed with ethyl acetate. The solvent from the obtained filtrate was distilled off completely under reduced pressure to get title compound. Yield: 5.5 gms.
Example-7: Preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l- amine (Formula-8)
(3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en-3-ol compound of formula- 15 (15 gms) was dissolved in 2-methyl tetrahydrofuran (90 ml) and trifluoroacetic anhydride (18.9 gms) was added it. The reaction mixture was heated to 40- 45°C and stirred for 4 hours under stirring. After completion of the reaction, the reaction mixture containing (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methylpent-l-en- 3-yl 2,2,2-trifluoroacetate compound of formula- 18a (where "acyl"=CF3-CO-) was cooled to room temperature and Pd-C (2 gms) was added to the reaction mixture under nitrogen atmosphere. The reaction mixture was transferred to autoclave and applied hydrogen gas with pressure of 3 bar to the reaction mixture over a period of 16 hours. Filtered the catalyst through hyflow bed, water was added to the filtrate and extracted with dichloromethane. Both the organic and aqueous layers were separated; the solvent from organic layer was distilled off completely under reduced pressure to get title compound. Yield: 13 gms.
Example-8: Preparation of Tapentadol free base (Formula-1) from Tapentadol hydrochloride
A mixture of Tapentadol hydrochloride compound of formula- la (1000 gms), ethyl acetate (6000 ml) and water (4000 ml) was cooled to 0-5°C. Basify the reaction mixture with a solution of sodium carbonate (453 gms) and water (4500 ml) at 0-5°C. The temperature of the reaction mixture was raised to 20-25°C and then both organic and aqueous layers were separated. The organic layer was dried with sodium sulfate and then distilled off the solvent completely under reduced pressure to obtain a residue. The obtained residue was cooled to 35-40°C and cyclohexane (1000 ml) was added to the residue and stirred for 2 hours at 25-30°C. The reaction mixture was cooled to 10-15°C and stirred for 60 minutes. Filtered the solid and then dried to get title compound.
Yield: 802 gms; MR: 88-90°C; purity by HPLC: 99.98%.
Purity of Input material: 99.78%; impurity at 0.5 RRT: 0.13% PXRD of the obtained compound was matched with crystalline modification B of Tapentadol free base of US8134032.
Example-9: Preparation of stable crystalline form-B of Tapentadol hydrochloride (Formula-1a) in the presence of ethyl formate
A solution of ethyl acetate - hydrochloric acid (415 ml) was cooled to 0-5 °C and drop wise added to a pre-cooled solution of Tapentadol free base compound of formula- 1 (100 gms), ethyl formate (500 ml) and ethyl acetate (500 ml) at -5 to 0°C under nitrogen atmosphere. Filtered the precipitated product and then dried to get title compound.
Yield: 108 gms; MR: 156-176°C;
Purity by HPLC: 99.93%, Impurity at 0.19 RRT: 0.06%.
Particle size distribution: D(0.1) is 94.43 μm; D(0.5) is 174.37 μm; D(0.9) is 299.94 μm, D(4,3) is 186.42 μm.
Example-10: Process for the preparation of Tapentadol hydrochloride (Formula-la) Step-a) Preparation of Tapentadol Free base (Formula-1)
A mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-2 (25 gms) and 47 % hydrobromic acid (100 ml) was heated to 115-120°C and stirred for 6 hours. After completion of the reaction, the reaction mixture was cooled to 40-50°C and water was added to it. The reaction mixture was further cooled to 0-5°C and basified the reaction mixture with ammonia solution. The temperature of the reaction mixture was raised to 25-30°C and ethyl acetate was added to the reaction mixture. Both the organic and aqueous layers were separated; the organic layer was dried with sodium sulphate and then distilled off the solvent to get semi solid type of residue of Tapentadol free base compound of formula-1.
Purity by HPLC: 99.74%; impurity at 1.77 RRT: 0.12%; Yield: 17.5 gms.
Step-b) Preparation of Tapentadol Hydrochloride (Formula-1a)
To the compound obtained in step-(a) ethyl formate (100 ml) and ethyl acetate (100 ml) were added under nitrogen atmosphere and the reaction mixture was cooled to -5 to 0°C. A pre-cooled solution of ethyl acetate-hydrochloric acid (83 ml) was added to the reaction mixture. The precipitated product was isolated and then dried to get Tapentadol hydrochloride compound of formula-la. Yield: 18.3 gms; Purity by HPLC: 99.75%; Impurity at 1.77 RRT: 0.09%. Particle size distribution: D(0.1) is 94.43 μm; D(0.5) is 174.37 μm; D(0.9) is 299.94 μm, D(4,3) is 186.42 μm.
Example-11: Preparation of stable crystalline form-B of Tapentadol hydrochloride (Formula-la) in the presence of formic acid.
To a clean and dry round bottomed flask Tapentadol free base compound of formula- 1 (20 gms) was added followed by ethyl acetate (300 ml) and cooled to -5 to 5°C. Formic acid (0.34 ml) was added to the reaction mixture at the same temperature and stirred for 10 minutes. Ethyl acetate-hydrochloric acid (38.1 ml) with assay of 7-8% was added to the reaction mixture for about 2 hours at the same temperature. Filtered the precipitated product and then dried to get title compound.
Yield: 21.2 gms; MR: 189-194°C; Purity by HPLC: 99.99%; formic acid content: 3.0%; chloride content: 10.9%.
Particle size distribution: D(0.1) is 94.43 μm; D(0.5) is 174.37 μm; D(0.9) is 299.94 μm, D(4,3) is 186.42 μm.
PXRD of the obtained compound was matched with the crystalline form-B of Tapentadol hydrochloride.
Example-12: Preparation of stable crystalline form-B of Tapentadol hydrochloride
(Formula-la) in the presence of acetic acid.
To a clean and dry round bottomed flask Tapentadol free base compound of formula- 1 (20 gms) was added followed by ethyl acetate (300 ml) and cooled to -5 to
5°C. Acetic acid (0.5 ml) was added to the reaction mixture at the same temperature and stirred for 10 minutes. Ethyl acetate-hydrochloric acid (38.1 ml) with assay of 7-8% was added to the reaction mixture for about 2 hours at the same temperature. Filtered the precipitated product and then dried to get title compound.
Yield: 20.0 gms; MR: 195.8-201.2°C; Purity by HPLC: 99.97%; chloride content: 12.9%.
Particle size distribution: D(0.1) is 94.43 μm; D(0.5) is 174.37 μm; D(0.9) is 299.94 μm,
D(4,3) is 186.42 μm.
PXRD of the obtained compound was matched with the crystalline form-B of Tapentadol hydrochloride.
Example-13: Preparation of stable crystalline form-B of Tapentadol hydrochloride (Formula-la) in the presence of ethyl formate To a clean and dry round bottomed flask Tapentadol free base compound of formula-1 (350 gms) was added followed by ethyl formate (3500 ml) and cooled to -5 to 5°C. Ethyl acetate-hydrochloric acid (38.1 ml) with 13% assay was added to the reaction mixture for about 2 hours at the same temperature. Filtered the precipitated product and then dried to get title compound.
Yield: 360 gms; MR: 166-179°C; Purity by HPLC: 99.98%.
Particle size distribution: D(0.1) is 94.43 μm; D(0.5) is 174.37 μm; D(0.9) is 299.94 μm, D(4,3) is 186.42 μm.
PXRD of the obtained compound was matched with crystalline form-B of Tapentadol hydrochloride.
Example-14: Preparation of stable crystalline form-B of Tapentadol hydrochloride (Formula-la) in the presence of formic acid.
To a clean and dry round bottomed flask Tapentadol free base compound of formula-1 (20 gms) was added followed by ethyl acetate (300 ml) and cooled to -5 to 5°C. Formic acid (0.34 ml) was added to the reaction mixture at the same temperature and stirred for 10 minutes. Ethyl acetate-hydrochloric acid (38.1 ml) with assay of 7-8% was added to the reaction mixture for about 2 hours at the same temperature. Filtered the precipitated product and then dried to get title compound.
Yield: 21.2 gms; MR: 178-182°C; Purity by HPLC: 99.99%; formic acid content: 3.2%. PXRD of the obtained compound was matched with the crystalline form-B of Tapentadol hydrochloride.
Particle size distribution: D(0.1) is 94.43 μm; D(0.5) is 174.37 μm; D(0.9) is 299.94 μm, D(4,3) is 186.42 μm.

Claims

We claim: 1. A process for the preparation of stable crystalline form-B of Tapentadol hydrochloride from Tapentadol free base by treating with a suitable hydrochloric acid source in a suitable solvent in presence of a lower aliphatic carboxylic acid.
2. A process according to claim 1, wherein, the suitable hydrochloric acid source is selected from hydrochloric acid gas, ethyl acetate-hydrochloric acid, isopropanol- hydrochloric acid, diisopropyl ether-hydrochloric acid and diethylether- hydrochloric acid; the suitable solvent is selected from ester solvent such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and tertiary butyl acetate; and the lower aliphatic acid is selected from acetic acid, formic acid and propanoic acid.
3. A process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
a) Adding ethyl acetate to Tapentadol free base,
b) cooling the reaction mixture,
c) adding formic acid to the reaction mixture,
d) adding ethyl acetate-hydrochloric acid to the reaction mixture,
e) filtering the precipitated solid and then dried to get crystalline form-B of Tapentadol hydrochloride.
4. A process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
a) Adding ethyl acetate to Tapentadol free base,
b) cooling the reaction mixture,
c) adding acetic acid to the reaction mixture,
d) adding ethyl acetate-hydrochloric acid to the reaction mixture,
e) filtering the precipitated solid and then dried to get crystalline form-B of
Tapentadol hydrochloride.
5. A process for the preparation of stable crystalline form-B of Tapentadol hydrochloride from Tapentadol free base by treating with a suitable hydrochloric acid source in presence of an alkyl formate and in presence or absence of a suitable solvent.
6. A process according to claim 5, wherein, the suitable hydrochloric acid source is selected from hydrochloric acid gas, ethyl acetate-hydrochloric acid, isopropanol- hydrochloric acid, diisopropyl ether-hydrochloric acid and diethylether- hydrochloric acid; the suitable solvent is selected from ester solvent such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and tertiary butyl acetate; and alkyl formate is selected from methyl formate and ethyl formate.
7. A process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
a) Adding ethyl formate to Tapentadol free base,
b) cooling the reaction mixture,
c) adding ethyl acetate-hydrochloric acid to the reaction mixture,
d) filtering the precipitated solid and then dried to get crystalline form-B of
Tapentadol hydrochloride.
8. A process for the preparation of stable crystalline form-B of Tapentadol hydrochloride, comprising the following steps of:
a) Adding ethyl formate to Tapentadol free base in ethyl acetate,
b) cooling the reaction mixture,
c) adding ethyl acetate-hydrochloric acid to the reaction mixture,
e) filtering the precipitated solid and then dried to get crystalline form-B of
Tapentadol hydrochloride.
9. A process for the preparation of pure Tapentadol hydrochloride compound of formula- la, comprising the following steps of: a) Treating Tapentadol hydrochloride with an aqueous base in a water immiscible solvent, followed by concentrating the organic layer to provide Tapentadol free base as a residue,
b) isolating the compound with a suitable solvent,
c) converting the compound obtained in step-(b) to its hydrochloride salt compound of formula- 1 a.
10. A process according to claim 9, wherein, the water immiscible solvent used in step-(a) is selected from ester solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate and n-butyl acetate; and in step-(b) is hydrocarbon solvent such as cyclohexane; and the suitable base is inorganic base selected from alkali metal carbonates, hydroxides, alkoxides and bicarbonates.
11. A process for the preparation of pure Tapentadol hydrochloride compound of formula-1a, comprising the following steps of:
a) Treating the Tapentadol hydrochloride with aq. sodium carbonate in ethyl acetate, followed by concentrating the organic layer to provide Tapentadol free base compound of formula- 1,
b) isolating the compound with cyclohexane,
c) converting the compound obtained in step-(b) to its hydrochloride salt compound of formula- 1 a.
12. One pot process for the preparation of pure Tapentadol hydrochloride compound of formula- la, comprising the following steps of:
a) Reacting (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan- 1 -amine compound of formula-8
Figure imgf000045_0001
with hydrobromic acid in presence or absence of a suitable solvent, followed by treating with a suitable base to provide Tapentadol free base,
b) converting the compound obtained in step-(a) into its hydrochloride salt compound of formula-1a.
13. A process according to claim 12, wherein, the suitable base is inorganic base and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents.
14. One pot process for the preparation of pure Tapentadol hydrochloride compound of formula-1a, comprising the following steps of:
a) Reacting (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan- 1 -amine compound of formula-8 with aq.hydrobromic acid, followed by treating with ammonia to provide Tapentadol free base,
b) converting the compound obtained in step-(a) into its hydrochloride salt compound of formula-1a.
15. A process for the preparation of crystalline modification-B of Tapentadol free base, comprising the following steps of:
a) Adding cyclohexane to a residue of Tapentadol free base at 35-40°C, b) cooling the reaction mixture to 25-30°C and stirring the reaction mixture, c) cooling the reaction mixture to 10-15°C and stirring the reaction mixture, d) filtering the solid and then dried to get crystalline modification-B of Tapentadol free base.
16. (3R,4S)-5-(dimethylamino)-3-(3 -methoxyphenyl)-4-methylpent- 1 -en-3 -ol
compound of formula- 15 represented by the following structure formula:
Figure imgf000046_0001
17. A process for preparation of (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4- methylpent-l-en-3-ol compound of formula- 15, comprising of reacting the (S)-3- (dimethylamino)- 1 -(3-methoxyphenyl)-2-methylpropan-1-one compound of formula- 14
Figure imgf000047_0001
with vinyl magnesium halide in a suitable solvent to provide compound of formula- 15.
18. A process according to claim-17, wherein, the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and hydrocarbon solvents; and the vinyl magnesium halide is selected from vinyl magnesium chloride and vinyl magnesium bromide.
19. A process according to claim 17, wherein the vinyl magnesium halide employed is in molar proportions ranging from 0.8 to 2.5 molar equivalents per one mole of compound of formula-14.
20. A process for the preparation of (3R,4S)-5-(dimethylamino)-3-(3-methoxy phenyl)-4-methylpent-l-en-3-ol compound of formula-15, comprising of reacting the (S)-3-(dimethylamino)- 1 -(3 -methoxyphenyl)-2-methylpropan- 1 -one compound of formula- 14 with vinyl magnesium bromide in tetrahydrofuran to provide compound of formula- 15.
21. A process for the preparation of crystalline form-B of 3-[(1R,2R)-3- (dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride compound of formula- 1a, comprising of: a) Dissolving the 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol compound of formula-1 in ethyl acetate,
b) filtering the reaction mixture,
c) adjusting pH of filtrate to 1-2 with ethyl acetate-HCl,
d) stirring the reaction mixture,
e) filtering the precipitated solid,
f) drying the solid to get crystalline form-B of compound of formula- la.
22. A process for preparation of 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methyl propyl] phenol compound of formula- 1, comprising of:
a) Hydrogenating the (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4- methylpent-1-en-3-ol compound of formula- 15 in presence of a suitable metal catalyst and hydrogen gas in a suitable solvent to provide (2S,3R)-1- (dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol compound of formula- 16,
Figure imgf000048_0001
b) dehydrating the compound of formula- 16 in-situ by treating it with a suitable dehydrating agent in a suitable solvent to provide (R,Z)-3 -(3 -methoxyphenyl)- N,N,2-trimethylpent-3-en-1-amine compound of formula- 17,
Figure imgf000048_0002
c) reducing the compound of formula- 17 in-situ with a suitable reducing agent in a suitable solvent to provide (2R,3R)-3-(3-methoxyphenyl)-N,N,2- trimethylpentan- 1 -amine compound of formula-8,
Figure imgf000049_0001
d) O-demethylating the compound of formula-8 with a suitable demethylating agent in presence or absence of a suitable solvent to provide compound of formula- 1.
23. The process according to claim 22, wherein,
In step-a) the suitable metal catalyst is selected from Pd, Pt, Ru and Rh catalysts such as Pd, Pd-C, Pd(OH)2, Pd(OAc)2, PdCl2, Pt, PtO2, Pt-C, Ru-C and Rh-C; and Raney-Ni; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and alcoholic solvents;
In step-b) the suitable dehydrating agent is selected from inorganic acids, organic acids, acid anhydrides, phosphorous pentoxide; phosphoryl chloride; phosphoric acid; and dicyclohexyl carbodiimide; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably polar solvents;
In step-c) the suitable reducing agent is selected from Ru, Rh metal catalysts such as Ru-C and Rh-C in presence of hydrogen; and Raney-Ni in presence of hydrogen; sodium borohydride; and Pd, Pt, Ru, Rh and Re catalysts such as Pd, Pd-C, Pd(OH)2, PdCl2, Pd(OAC)2, Pt, Pt-C, PtO2, Ru-C, Rh-C, ReI02(PPh3)2, ReOCl3(PPh3)2, ReOCl3(dppm), and Re2O7 in presence of hydrogen source such as silane and sodium borohydride; the silane is selected from dimethylphenyl silane, phenyl silane, triethyl silane, triphenyl silane and poly methylhydrosiloxane; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvent, chloro solvents and/or mixtures thereof; preferably hydrocarbon solvents, alcoholic solvents, chloro solvents and polar aprotic solvents; and
In step-d) the suitable demethylating agent is selected from hydrobromic acid, optionally in combination with carboxylic acid such as formic acid, acetic acid; methane sulfonic acid, methionine, diisobutyl aluminium hydride, pyridine chloride, lewis acids like aluminium chloride, boron tribromide and mixtures thereof; and the suitable solvent is selected from is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvent, chloro solvents and/or mixtures thereof, preferably polar solvents and chloro solvents.
24. A process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2- methylpropyl] phenol compound of formula- 1 , comprising of:
a) Acylating the (3R,4S)-5-(dimethylamino)-3-(3-methoxyphenyl)-4-methyl pent-l-en-3-ol compound of formula- 15 with a suitable acylating agent in presence or absence of a base in a suitable solvent to provide its corresponding acyl derivative compound of general formula- 18,
Figure imgf000050_0001
b) hydrogenating the compound of general formula- 18 in-situ in presence of a suitable metal catalyst and hydrogen in a suitable solvent to provide (2R,3R)- 3-(3-methoxyphenyl)-N,N,2-trimethyl pentan-1 -amine compound of formula- c) O-demethylating the compound of formula- 8 with a suitable demethylating agent in a suitable solvent to provide compound of formula- 1.
25. The process according to claim 24, wherein,
In step-a) the suitable acylating agent is selected from anhydrides and halides of acetic acid, phenyl acetic acid, chloro acetic acid, trifluoro acetic acid, dichloro acetic acid, trichloro acetic acid, benzoic acid, chlorobenzoic acid, terephthalic acid, phthalic acid, succinic acid, mono C1-C4 alkyl esters of succinic acid, oxalic acid, mono C 1-C4 alkyl esters of oxalic acid such as ethyl oxalyl chloride and methyl oxalyl chloride, and mixed anhydride of formic acid such as ethyl chloroformate, methyl chloroformate and acetyl salicyloyl chloride; the "base" is inorganic or organic base; and the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents and/or mixtures thereof, preferably ether solvents and alcoholic solvents; and
In step-b) and step-c) the suitable metal catalyst, demethylating agent and solvent used are same as defined in step-(a) and step-(d) of claim 23 respectively.
26. Tapentadol hydrochloride obtained according to the present invention having purity greater than 99.5%, preferably 99.7%, more preferably 99.9% by HPLC.
27. Stable crystalline form-B of Tapentadol hydrochloride.
28. Usage of stable crystalline form-B of Tapentadol hydrochloride for the preparation of pharmaceutical composition.
PCT/IN2013/000017 2012-01-10 2013-01-09 Process for the preparation of 3-aryl-2-methyl-propanamine derivatives and polymorphs thereof WO2013111161A2 (en)

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