Classifications

• • 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
  • 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
  • C07C213/10—Separation; Purification; Stabilisation; Use of additives
• • 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
  • C07C217/56—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 not further substituted by singly-bound oxygen atoms
  • C07C217/62—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 not further substituted by singly-bound oxygen atoms 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

Definitions

• the present invention relates to process for preparation of l-phenyl-3-aminopropane derivatives, stereospecific isomers and/or pharmaceutically acceptable salts thereof.
• the present invention also relates to novel intermediates for preparation of l-phenyl-3- aminopropane derivatives, stereospecific isomers and/or pharmaceutically acceptable salts thereof. Further, the present invention relates to a process for the preparation of Tapentadol and/or its pharmaceutically acceptable salts via novel intermediate.
• U.S. Patent No. 6248737 discloses an active compound class of l-phenyl-3-aminopropane derivatives compounds, with an excellent analgesic activity and very good tolerability of these substances as pharmaceutical active ingredients, in particular Tapentadol.
• Tapentadol is chemically known as 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2- methylpropyl] phenol or 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol.
• Tapentadol was approved as hydrochloride salt by the FDA in November 2008 for the treatment of moderate to severe acute pain. It is a centrally - acting analgesic with a dual mode of action as an agonist at the ⁇ -opioid receptor and as a norepinephrine reuptake inhibitor.
• Tapentadol and its analogue compounds were disclosed in U.S. Patent No. RE39593.
• the US '593 also discloses a process for the preparation of Tapentadol which involves reaction of 3-bromoanisole and l-dimethylamino-2-methylpentane-3-one under conditions of Grignard reaction to form diastereomeric mixture of l-dimethylamino-3-(3- methoxyphenyl)-2- methylpentan-3-ol, which is then subjected for separation of two enantiomeric pairs by precipitation and using a chiral HPLC column to provide (2S,35)-1- dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol.
• the resolved intermediate is then chlorinated, reduction with zinc borohydride or tin cyanoborohydride and finally demethylated by heating with concentrated hydrobromic acid to form 3-[(2R,3R)-l- (dimethylamino)-2-methylpentan-3-yl]phenol.
• 102936205 disclose the various alternative processes for the preparation of 3-amino-2- benzyl -1-phenylpropane derivatives, intermediates and separation of stereo isomeric N,N- dialkylamino-2-alkyl-3-hydroxy-3-pheny]alkanes, i.e. tapentadol and their analogue compounds.
• CN 102320984 discloses a process for the preparation of Tapentadol hydrochloride, which involves reaction of l-(3-methoxyphenyl)-l-propanone with ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethylmethanediamine to provide 3-dimethylamino-l-(3-methoxyphenyl)-2- methyl - 1-propanone, which is treated with L-(-) - dibenzoyl tartaric acid monohydrate to provide (5)-3-(dimethylamino)-l- (3-methoxyphenyl) -2 - methyl -propan-1 - one L-(-) - dibenzoyl tartaric acid salt, which is converted to (R)-3-(dimethylamino)-l - (3-methoxyphenyl) -2 - methyl-propan-l-one, which is then reacted with ethyl triphenylphosphonium bromide in presence of methyl
• the present invention provides novel intermediates and process for the preparation of 1- phenyl-3-aminopropane derivatives. Further, the present invention provides a process for the preparation of Tapentadol and/or pharmaceutically acceptable salts thereof.
• the present invention provides a process for preparing a (2R, 3R)-compound of formula-(I)
• Ri is a hydrogen atom or a hydroxyl-protecting group, independently selected from the group consisting of Ci-Cio straight or branched chain alkyl, C 2 -C 10 straight or branched chain alkenyl or alkynyl, C3-C14 aryl or alkyl-aryl, heteroaryl, carbocycle, or heterocycle, tri-Ci-4 alkyl silyl, phenyl di C 1 -4 alkyl and diphenyl mono C 1 -4 alkyl silyl; wherein aryl or alkyl-aryl group is optionally substituted by a halogen atom;
• R 2 and R3 are amino-protecting group, independently selected from the group consisting of hydrogen, C 1 -C 1 0 straight or branched chain alkyl, C 2 -C 1 0 straight or branched chain alkenyl or alkynyl, C3-C14 aryl or alkyl-aryl, heteroaryl, carbocycle, or heterocycle
• Ri, R 2 and R3 are the same as defined above;
• A is optically active acid, selected from tartaric acid or its derivatives such as (-)-0,0-dibenzyl-L-tartaric acidmonohydrate, D-(-)-tartaric acid, L-(+)-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (-)-dibenzoyl-L- tartaric acid, (+)-dibenzoyl-D-tartaric acid or S-naproxen or mixture thereof.
• the present invention provides a novel intermediate of formula (VI) or its salts:
• the present invention provides a process for preparation of novel intermediate of formula (VI) or its salts:
• the present invention provides a process for the preparation of Tapentadol of formula la:
• step b) resolution of the compound of step a) with chiral reagent of tartaric acid to provide salt of (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-l-amine with chiral reagent;
• step b) reaction of the salt of step b) with a base to provide (R) 3-(3-methoxyphenyl)- N,N,2-trimethylpent-en- Vila;
• step d) reduction of the compound of step c) with metal catalyst and ammonium formate to provide (2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan-l -amine of formula lb or its salts; and,
• step d) demethylation of the compound of step d) using an acid to provide Tapentadol or its pharmaceutically acceptable salts.
• the present invention provides a process for the preparation of intermediate of Tapentadol, (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-l-amine, which comprises:
• step b) resolution of the compound of step a) with (-)- ⁇ , ⁇ - dibenzoyl-L-tartaric acid to provide (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-l-amine (-)- ⁇ , ⁇ - dibenzoyl-L-tartaric acid salt;
• the present invention provides a process for preparation of intermediate of Tapentadol, 2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan- 1-amine or its salt, which comprises reduction of (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-l-amine with metal catalyst and ammonium formate to provide (2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan- 1-amine or its salts.
• substantially pure refers to Tapentadol, an intermediate thereof, or a salt thereof that contains purity greater than 99%.
• Tapentadol refers to all polymorphic forms of tapentadol pharmaceutically acceptable salts thereof, for example polymorphs of crystalline form, hydrates, and solvates thereof.
• Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate, tartrate and the like.
• the present invention provides a process for preparing a compound of formula- (I), its stereospecific isomers or pharmaceutically acceptable salts thereof,
• Ri is a hydrogen atom or a hydroxyl-protecting group, independently selected from the group consisting of Ci-Cio straight or branched chain alkyl, C 2 -C 1 0 straight or branched chain alkenyl or alkynyl, C3-C14 aryl or alkyl-aryl, heteroaryl, carbocycle, or heterocycle, tri-Ci-4 alkyl silyl, phenyl di C 1 -4 alkyl and diphenyl mono C 1 -4 alkyl silyl; wherin aryl or alkyl-aryl group is optionally substituted by a halogen atom;
• R 2 and R3 are amino-protecting group, independently selected from the group consisting of hydrogen, C 1 -C 1 0 straight or branched chain alkyl, C 2 -C 1 0 straight or branched chain alkenyl or alkynyl, C3-C14 aryl or alkyl-aryl, heteroaryl, carbocycle, or
• A is optically active acid, which is selected from the group consisting of (-)-0,0-dibenzyl-L-tartaric acidmonohydrate, D-(-)- tartaric acid, L-(+)-tartaric acid, S-naproxen, (-)-di-p-toluoyl-L-tartaric acid, (-)- dibenzoyl-L-tartaric acid, (+)-dibenzoyl-D-tartaric acid or mixture of thereof;
• the Wittig reaction involves reaction of compound of formula (IV) with a Wittig reagent:
• the compound of formula IV can be prepared by condensation reaction between 1- phenylpropan-l-one and dimethyl amine or its salt in the presence of paraformaldehyde and acid such as hydrochloric acid in suitable organic solvent such as alcohol, for example, isopropyl alcohol.
• the Wittig reaction is conducted between compound of formula (IV) and Wittig reagent in the presence of base in suitable organic solvent.
• the reaction is carried out with the suitable Wittig reagent such as ethyltriphenylphosphonium halides in the presence of suitable base. More preferably the wittig reagent is selected from ethyltriphenylphosphonium chloride and ethyltriphenylphosphonium bromide.
• the base is selected from metal alkoxides or metal carbonates or metal bicarbonates.
• the metal alkoxides are selected from sodium methoxide, potassium t-butoxide, lithium t-butoxide, sodium t-butoxide, alluminium t- butoxide and the like;
• the metal carbonates are selected from sodium carbonate, potassium carbonate and the like;
• the metal bicarbonates are selected from sodium bicarbonate or potassium bicarbonate and the like.
• the Wittig reaction may be carried out in presence of organic solvent which includes but are not limited to ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, and the like; haloalkanes such as dichloromethane, chloroform and the like; and mixtures thereof.
• the organic solvent is selected from diisopropyl ether, dichloromethane. More preferably the solvent is diisopropyl ether.
• the reaction may be carried out at a temperature of about 10°C to about 120°C. Preferably, the reaction is carried out at a temperature of about 20°C to about 40°C. The reaction may be carried out for a period of about 2 hours to about 5 hours. Preferably the reaction is carried out for about 2 hours to 3 hours.
• the resolution step involves the reaction between the compound of formula (V) with resolution agent-A in suitable organic solvents.
• the reaction is carried out with a suitable resolution agent-A which includes, but is not limited to optically active acid selected from the group consisting of S-naproxen, tartaric acid and its derivatives (-)-0,0-dibenzyl-L-tartaric acidmonohydrate, D-(-)-tartaric acid, L-(+)-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (-)-dibenzoyl -L-tartaric acid, (+) - dibenzoyl - D-tartaric acid and hydrates thereof.
• the resolution agent-A is (-)- 0,0-dibenzyl-L-tartaric acidmonohydrate.
• the compound of formula (VI) is obtained by the reaction step-b as described above, and may be isolated as solid.
• the resolution step is carried out in presence of organic solvent which is selected, but is not limited to alcoholic solvents such as branched or straight chain C1-C4 alcohols, selected from methanol, ethanol, isopropyl alcohol, and the like; esters like ethyl acetate, butyl acetate, and the like; ketones like acetone, methyl ethyl ketone, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, and the like; Haloalkanes such as dichloromethane, chloroform and the like; and mixtures thereof.
• organic solvent is ethyl acetate.
• the reaction is carried out at a temperature of about 10°C to about 150°C. Preferably, the reaction is carried out at a temperature of about 55°C to about 75°C. The reaction is carried out for a period of about 2 hours to about 12 hours. Preferably the reaction is carried out for about 3 hours to about 5 hours.
• reaction step-c is desaltification reaction which involves reaction between the compound of formula (VI) and base in suitable organic solvents.
• the reaction is carried out with a suitable base which includes, but is not limited to organic or inorganic base like ammonia, alkyl amine, metal alkoxides, metal carbonates. More particularly, the base includes, but is not limited to alkyl amine such as diethyl amine, triethyl amine, dimethyl amine, methyl ethyl amine, pyridine, and the like; alkali metal or alkali earth metal alkoxides such as sodium methoxide, potassium t-butoxide, lithium t-butoxide, sodium t-butoxide, alluminium t-butoxide and the like; alkali metal carbonate such as sodium carbonate, potassium carbonate, and the like; alkali metal bicarbonate agents such as sodium bicarbonate, potassium bicarbonate and the like.
• the base is weak base such as diethyl amine.
• the reaction step-c is carried out with the suitable organic solvent preferably selected, but not limited to alcoholic solvents such as branched or straight chain C1-C4 selected from methanol, ethanol, isopropyl alcohol, and the like; esters like ethyl acetate, butyl acetate, and the like; ketones like acetone, methyl ethyl ketone, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, and the like; Haloalkanes such as dichloromethane, chloroform and the like; and mixtures thereof.
• alcoholic solvents such as branched or straight chain C1-C4 selected from methanol, ethanol, isopropyl alcohol, and the like
• esters like ethyl acetate, butyl acetate, and the
• a preferred solvent is ethyl acetate.
• the reaction is carried out at a temperature of about 10°C to about 150°C. Preferably the reaction is carried out at about 20°C to about 40°C. The reaction is carried out for a period of about 2 hours to about 8 hours. Preferably the reaction is carried out for about 4 hours to about 5 hours.
• the step of reduction involves, reaction between an R-isomer of compound of formula (VII) with metal catalyst /carbon in the presence of hydrogen or ammonium formate, further optionally deprotection of hydroxyl group with suitable acid/s or acid derivatives in organic solvents. The reaction may takes place in an aqueous or non-aqueous medium.
• the reaction is carried out with a suitable metal catalyst which includes, but is not limited to metal or non-metal catalyst such as iron, zinc, magnesium, palladium, platinum, triphenylphosphine, and the like.
• a suitable metal catalyst which includes, but is not limited to metal or non-metal catalyst such as iron, zinc, magnesium, palladium, platinum, triphenylphosphine, and the like.
• the reducing agent is palladium.
• the reaction is carried out in presence of an organic solvent preferably selected, but not limited to alcoholic solvents such as branched or straight chain C1-C4 alcohols selected from methanol, ethanol, isopropyl alcohol, and the like; aprotic solvents like water, pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane, carbon tetrachloride, freon-11, toluene, triethyl amine, carbon disulfide, diisopropyl ether, diethyl ether (ether), t-butyl methyl ether (MTBE), chloroform, ethyl acetate, 1,2-dimethoxyethane (glyme), 2- methoxyethyl ether (diglyme), tetrahydrofuran (THF), methylene chloride, pyridine (Py), 2-butanone (MEK), acetone, hexa
• the reaction is carried out at a temperature of about 0°C to about 150°C. Preferably the reaction is carried out at about 20°C to about 40°C. The reaction is carried out for a period of about 1 hour to about 5 hour. Preferably the reaction is carried out for about 4 hour to about 5 hour.
• the reduction may also be conducted using Pd on carbon in presence of hydrogen gas.
• the reaction step of hydroxyl deprotection is carried out with a suitable acid/s or acid derivatives, which includes, but is not limited to organic acid or mineral acid such as acetic acid, lactic acid, formic acid, citric acid, oxalic acid, uric acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, methane sulphonic acid, boric acid, hydrofluoric acid, hydrobromic acid and perchloric acid.
• the acid is selected from methane sulphonic acid, or acetic acid.
• reaction step of hydroxyl deprotection is carried out with or without presence of DL- methionine. Absence of the DL-methionine reaction will proceed with longer times.
• reaction mass After completion of the reaction, the reaction mass may be diluted with water and then pH adjusted to 10-12 by using alkali solution. Then, the reaction mass may be extracted into organic solvent and distilled out completely till oily mass obtained, which is used for salt preparation directly using conventional methods by using suitable pharmaceutically acceptable acid.
• the present invention provides a novel intermediate of formula (VI) or its salts:
• DBTA (-)-0,0-dibenzyl-L-tartaiic acid or its monohydrate.
• the present invention provides a process for preparation of novel intermediate of for
• the Wittig reaction is conducted by using Wittig reagent such as ethyltriphenylphosphonium halides in the presence of base such as metal alkoxides or metal carbonates or metal bicarbonates in suitable organic solvent such as ether, haloalkanes.
• the resolution of the compound of formula (V) is performed by using resolving agent-A includes optically active acid such as tartaric acid and its derivatives in suitable organic solvents such as alcoholic solvent, ketone, ether, ester, haloalkane or mixture thereof.
• the present invention provides a process for the preparation of tapentadol of the following fo
• step d) reduction of the compound of step c) with metal catalyst and ammonium formate to provide (2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan-l- amine of formula lb or its salt; and, e) demethylation of the compound of step d) by using an acid to provide Tapentadol or its pharmaceutically acceptable salt.
• the reaction step-a involves reaction of compound of formula (IVa) with a Wittig reagent in presence of ether solvent.
• the Wittig reagent is selected from ethyltriphenylphosphonium chloride and ethyltriphenylphosphonium bromide.
• the reaction may be conducted in the presence of base, such as potassium t-butoxide.
• the Wittig reaction is carried out in presence of ether solvent such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, and the like.
• ether solvent such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, and the like.
• the solvent is diisopropyl ether.
• the reaction may be carried out at a temperature of about 10°C to about 120°C.
• the reaction is carried out at a temperature of about 20°C to about 40°C.
• the reaction may be carried out for a period of about 2 hours to about 5 hours.
• the reaction is carried out for about 2 hours to 3 hours.
• reaction mass may be filtered, the filtrate combined with water and then pH adjusted to less than 1 with acid such as hydrochloric acid to obtain aqueous layer.
• aqueous layer may be basified with ammonia and the reaction product extracted with an organic solvent.
• the organic layer may be subjected for complete distillation under vacuum to give oily product that may be subjected for solid isolation or used directly for further steps.
• the reaction step-b is resolution, the reaction between the compound of formula (Va) with resolution agent-A in suitable organic solvents.
• the reaction is carried out with a suitable resolution agent-A which includes, but is not limited to optically active acid selected from the group consisting of S-naproxen, tartaric acid and its derivatives, (-)-0,0-dibenzyl-L-tartaric acidmonohydrate, D-(-)-tartaric acid, L-(+)-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, (-)-dibenzoyl -L-tartaric acid, (+) - dibenzoyl - D-tartaric acid and hydrates thereof.
• the resolution agent-A is (-)- 0,0-dibenzyl-L-tartaric acid monohydrate.
• the resolution step is carried out in presence of organic solvent which includes but are not limited to ester like ethyl acetate, butyl acetate, and the like.
• organic solvent which includes but are not limited to ester like ethyl acetate, butyl acetate, and the like.
• the solvent is ethyl acetate.
• the reaction is carried out at a temperature of about 55°C to about 75°C for a period of about 3 hours to about 5 hours.
• reaction mixture After completion of reaction, the reaction mixture is cooled to about 0°C to 30°C, filtered and dried to use in further steps directly without purification.
• the reaction step-c involves reaction between the compound of formula (Via) and base in suitable organic solvents.
• the base is selected from ammonia, alkyl amine, metal alkoxides, metal carbonates. More particularly, the base includes, but is not limited to alkyl amine such as diethyl amine, triethyl amine, dimethyl amine, methyl ethyl amine, pyridine, and the like; alkali metal or alkali earth metal alkoxides such as sodium methoxide, potassium t-butoxide, lithium t-butoxide, sodium t-butoxide, alluminium t- butoxide and the like, preferably the metal alkoxide is potassium t-butoxide; alkali metal carbonate, alkali metal bicarbonate agents such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
• the base is weak base such as diethyl amine.
• the reaction step-c is carried out in presence of ester solvent like ethyl acetate, butyl acetate, and the like.
• the resolution step and desaltification step may be performed in same solvent.
• reaction is carried out at a temperature of about 20°C to about 40°C for a period of about 4 hours to about 5 hours. After completion of reaction, the reaction mixture may be cooled to about 0°C to 30°C, filtered and washed with organic solvent and dried to use for further steps directly.
• the reaction step-d is reduction reaction between an R-isomer of compound of formula (VII) with metal catalyst /carbon in the presence of hydrogen or ammonium formate, further optionally deprotection of hydroxyl group with suitable acid/s or acid derivatives in organic solvents.
• the reaction may take place in an aqueous or non-aqueous medium.
• the reaction is carried out with a suitable metal catalyst which includes, but is not limited to metal or non-metal catalyst such as iron, zinc, magnesium, palladium, platinum, triphenylphosphine, and the like.
• a suitable metal catalyst which includes, but is not limited to metal or non-metal catalyst such as iron, zinc, magnesium, palladium, platinum, triphenylphosphine, and the like.
• the reducing agent is palladium.
• the reaction is carried out in presence of an organic solvent such as Cl-C4-alcoholic solvent, for example, methanol, ethanol, isopropyl alcohol, n-butanol and the like.
• an organic solvent such as Cl-C4-alcoholic solvent, for example, methanol, ethanol, isopropyl alcohol, n-butanol and the like.
• the reaction is carried out at a temperature of about 0°C to about 150°C. Preferably the reaction is carried out at about 20°C to about 40°C. The reaction is carried out for a period of about 1 hour to about 5 hour. Preferably the reaction is carried out for about 4 hour to about 5 hour. In particular, the reaction will proceed for a period of about 2 to 3 hrs using metal catalyst /ammonium derivative as reducing agent in suitable solvents such as alcohols or chlorinating solvents.
• the hydrogenation reaction takes place in-situ by generation of hydrogen gas in presence of metal catalyst like palladium -on-active charcoal with ammonium derivatives like ammonium formate.
• reaction mixture may be filtered, diluted with water, pH adjusted to 10 to 12 by using aqueous base, which will not affect any racemization or increase any impurity, and then extracted into ester solvent, which is then distilled completely to provide crude.
• the crude may be converted into its pharmaceutically acceptable salt such as hydrochloride salt.
• the step e) involves demethylation by using an acid, which includes, but is not limited to methane sulphonic acid and acetic acid in presence of DL-methionine.
• the demethylation reaction may be conducted at a temperature of about 50 to about 100 °C, preferably, at about 75 to 85 °C.
• reaction mixture may be filtered, combined with water, pH adjusted to 10 to 12 by using aqueous base and then extracted into ester solvent, which is then distilled completely to provide crude.
• crude may be converted into its pharmaceutically acceptable salt such as hydrochloride salt.
• the purity of Tapentadol or its pharmaceutically acceptable salt of the present invention is greater than or equal to 99% determined by HPLC.
• the present invention provides a process for the preparation of intermediate of Tapentadol, (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-l-amine, which comprises:
• step b) resolution of the compound of step a) with (-)- ⁇ , ⁇ - dibenzoyl-L-tartaric acid (DBTA) to provide (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en- 1-amine (-)- 0,0- dibenzoyl-L-tartaric acid salt; and
• step b) reacting the salt of step b) with an amine to provide (R) 3-(3-methoxyphenyl)- N,N,2-trimethylpent-en- 1 -amine .
• the inventors of the present invention conducted experimentations for the preparation of key intermediate of Formula Vila according to prior art processes and found that the prior art process provides racemization in the later stages and in the work-up, due to the various reasons such as use of strong base, and the like. Therefore, there is a need for an alternative process, which involves Wittig reaction, resolution followed by desaltification to provide higher yield and purity.
• the present invention provides a process for preparation of intermediate of Tapentadol, (2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan- 1-amine or its salt, which comprises reduction of (R) 3-(3-methoxyphenyl)-N,N,2-trimethylpent-en-l-amine with metal catalyst and ammonium formate to provide (2R, 3R)-3-(3-methoxyphenyl)-N, N-2-trimethylpentan- 1-amine or its salt.
• the metal catalyst includes and is not limited to palladium catalyst on carbon.
• the use of ammonium formate provides simple work-up conditions, safe reaction conditions and requires lesser time period as compared to hydrogen gas.
• a pharmaceutical composition comprising Tapentadol or its pharmaceutically acceptable salt prepared according to processes disclosed in the present invention and one or more pharmaceutically acceptable excipients.
• the pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration.
• the tapentadol or its salt may also be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes.
• compositions further contain one or more pharmaceutically acceptable excipients.
• suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, which can be selected from but not restricted to methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, polyvinylpyrrolidone (povidone), polyvinylalcohol, crospovidone, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low- substituted hydroxypropyl cellulose, sodium alginate Croscarmellose Sodium, Carboxymethyl cellulose, sodium starch glycolate or a combination of both.
• Example 1 Preparation of (2R,3R)-3-(3-hydroxyphenyl)-N,N,2-trimethylpentan-l -amine [Tapentadol hydrochloride] .
• Step i l-(3-Methoxyphenyl)propan-l-one (230 g), dimethylamine hydrochloride (228 g), paraformaldehyde (78 g) was suspended in isopropyl alcohol (1150 ml) and then added 30 % of hydrochloric acid (20 ml) under stirring at below room temperature. The temperature of the reaction mass was raised at reflux temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was distilled completely under vacuum. Water (460 ml) was added to the reaction mass and stirred for 10 minutes. The aqueous layer was washed with toluene, cooled to 10-20°C and adjusted the pH of the reaction mass to 10-12 with 20% sodium hydroxide solution. The product was extracted with dichloromethane (1000 ml) and the organic layer was washed with water, and distilled out completely under vacuum to obtain the oily mass. This was directly taken as such for the next stage.
• aqueous layer was treated with aqueous ammonia till the pH reached to about 9 and then dichloromethane (1200 ml) was added. Distilled out the organic layer completely under vacuum and the resulting oily mass was dried and taken for the next stage.
• the pH of the reaction mass was adjusted to 10-12 with 10% sodium hydroxide solution.
• the product was extracted with ethyl acetate (200 ml) and the organic layer was washed with brine solution, distilled out completely under vacuum to obtain the residue.
• Acetone 100 ml was added to the residue and purged the dry hydrogen chloride gas till the pH was about 2.0.
• the reaction mass was cooled to 0- 5°C, maintained up to 2 hours, filtered and washed with acetone. The solid was dried under vacuum at 50°C to obtain (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l- amine hydrochloride salt (90 g).
• Acetone (360 ml) was added to the obtained residue, cooled to 10°C and purged the dry hydrogen chloride gas till the pH was about 2.0 at 10°C.
• the reaction mass was maintained for 2 hours, filtered and washed with acetone (180 ml).
• the obtained crude product was purified with mixture of acetone (540 ml) and methanol (90 ml), dried under vacuum at 50°C to obtain the pure tapentadol hydrochloride (58 gm). Yield: 68.7 % with chiral HPLC purity > 99%.
• Example 2 Preparation of 3-(dimethylamino-l-(3-methoxyphenyl)-2-methylpropan-l-one.
• l-(3-Methoxyphenyl)propan-l-one (0.870kg), dimethylamine hydrochloride (0.862kg), paraformaldehyde (0.295 kg) was suspended in Ethyl alcohol (4.4 L) and then added 30 % of hydrochloric acid (0.760 L) under stirring at below room temperature. The temperature of the reaction mass was raised at reflux temperature and stirred for 12 hours. After completion of the reaction, the reaction mixture was distilled out completely under vacuum. Water (1.74L) was added to the reaction mass and stirred for 10 minutes.
• the aqueous layer was washed with toluene, cooled to 10-20°C and adjusted the pH of the reaction mass to 10-12 with 20% sodium hydroxide solution.
• the product was extracted with toluene (8.7 L) and the organic layer was washed with water, distilled out completely under vacuum to obtain the oily mass.
• Example 4 Preparation of (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-l-amine 0,0'-dibenzoyl-(2R,3R)-tartaric acid (DBTA) salt.
• Example 6 Preparation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l -amine.
• (R)-3-(3-Methoxyphenyl)-N,N,2-trimethylpent-3-en-l-amine (300 gm) of above oily mass obtained from example-5 was suspended in ethyl alcohol (1200 ml), and palladium carbon (50% wet 30 g) and acetic acid (300 g) was added to the suspended mass. Further, slowly added ammonium formate solution (567 gm of ammonium formate in 1134 ml of water). The reaction mass was stirred at 40°-45°C for 2-3 hours.
• Acetone 750 ml was added to the obtained residue and cooled to 20° C, the dry hydrogen chloride gas was purged till the pH was about 2.0 at 0 - 5° C. The reaction mass was maintained for 2 hours, filtered and washed with acetone (450 ml). The obtained crude product was purified with mixture of acetone (1200 ml) and ethyl alcohol (300 ml), dried under vacuum at 50° C to obtain the pure tapentadol hydrochloride (105 gm). Yield: 74.46 % with HPLC purity > 99%.
• Example 9 Preparation of 3-[3-(benzyloxy)phenyl]-N,N,2-trimethylpent-3-en-l-amine l-[3-(Benzyloxy)phenyl]-3-(dimethylamino)-2-methylpropan-l-one (200 g) of oily mass obtained in example 8 and potassium t-butoxide (75.41 g) was suspended in diisopropyl ether (2000 ml) and added ethyl triphenyl phosphonium bromide (518.5 g) under stirring at room temperature. The reaction mass was stirred for 4 hours at room temperature. After completion of the reaction, cooled to 0-5°C and maintained for 45 minutes.
• reaction mass was filtered, washed with diisopropyl ether and distilled out completely under vacuum.
• Ammonium chloride solution was added to the residue and stirred for 45 minutes.
• the reaction was extracted with dichloromethane (800 ml) and then pH of the organic layer was adjusted to less than 1.0 with cone, hydrochloric acid.
• the resulted aqueous layer was treated with aqueous ammonia till pH was about 9 and added the dichloromethane (2000 ml). Distilled out the organic layer completely under vacuum and the resulting oily mass was dried and taken for the next stage.
• Example 10 Preparation of (R)-3-[3-(benzyloxy)phenyl]-N,N,2-trimethylpent-3-en-l- amine 0, 0'-dibenzoyl-(2R,3R)-tartaric acid (DBTA) salt.
• Ethyl acetate (600 ml) and 0,0'-dibenzoyl-(2R,3R)-tartaric acid (146 g) was added to the 3-[3-(benzyloxy)phenyl]-N,N,2-trimethylpent-3-en-l-amine (120 gm) of oily mass (obtained in example 8) at room temperature.
• reaction mass was refluxed for 4 to 5 hours, cooled to 15-25°C and maintained for 2.5 hours.
• the solid was filtered and washed with ethyl acetate (480 ml).
• the solid was dried at 45 to 50°C for 5 hours to obtain 102 gm of (R)- 3-[3-(benzyloxy)phenyl]-N,N,2-trimethylpent-3-en-l-amine ⁇ , ⁇ '-dibenzoyl- (2R,3R)-tartaric acid (DBTA) salt.

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