WO2012089177A1 - Method of producing (2r,3r)-na-dimethyl-3-(3-hydroxyphenyi)-2-methylpentylamine (tapentadol) - Google Patents

Method of producing (2r,3r)-na-dimethyl-3-(3-hydroxyphenyi)-2-methylpentylamine (tapentadol) Download PDF

Info

Publication number
WO2012089177A1
WO2012089177A1 PCT/CZ2011/000122 CZ2011000122W WO2012089177A1 WO 2012089177 A1 WO2012089177 A1 WO 2012089177A1 CZ 2011000122 W CZ2011000122 W CZ 2011000122W WO 2012089177 A1 WO2012089177 A1 WO 2012089177A1
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
production according
substituted
group
stands
Prior art date
Application number
PCT/CZ2011/000122
Other languages
French (fr)
Inventor
Ruzena Vlasakova
Josef Hajicek
Original Assignee
Zentiva, K.S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Priority to HU1300523A priority Critical patent/HUP1300523A3/en
Publication of WO2012089177A1 publication Critical patent/WO2012089177A1/en

Links

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
    • C07C213/02—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 involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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

  • This invention relates to a new method of producing (2 ?,3 ?)-N,N-dimethyl-3-(3- hydroxyphenyl)-2-methylpentylamine of formula I, known also under the name of tapentadol, and its salts.
  • Tapentadol (I), chemically (2i?,3i?)-N,N-dimethyl-3-(3-hydroxyphenyl)-2-methylpentyl amine, acts as an agonist of ⁇ -opioid receptors and an inhibitor of noradrenaline reuptake. It has been developed in the form of hydrochloride of (2/?,3/?)-enantiomer by the firm Johnson & Johnson based on development of the firm Gruenenthal, as a general analgetic.
  • tapentadol is produced from (2S,3S)- l -dimethylamino-3-(3- methoxyphenyl)-2-methylpentane-3-ol (A), which is obtained by two methods by means of the Grignard addition to a ketone, e.g. by addition of 2-methoxyphenylmagnesium bromide to 1 - dimethylamino-2-methyl-3-pentanone.
  • the reaction is non-stereo-selective and obtaining of the (27?,3i?)-stereo-isomer requires separation on a chiral HPLC column.
  • Compound A is then converted to a chloride by means of thionyl chloride and the obtained chloro-derivative is converted by reduction, e.g. by means of NaBH 4 /ZnCl 2 , to (2i?,37?)-N,N-dimethyl-3-(3- methoxyphenyl)-2-methylpentylamine (B), which is finally demethylated by hydrobromic acid.
  • the method is inherently disadvantageous because of demanding HPLC separation of stereo-isomers on a chiral column.
  • the compound (2S,3S)-A is converted, by the action of acidic agents, such as concentrated hydrochloric acid, to alkene B, which is subjected to diastereo-selective hydrogenation with formation of (2R,3R)-C, accompanied by a (2R,3S)-C epimer as a by-product.
  • acidic agents such as concentrated hydrochloric acid
  • alkene B which is subjected to diastereo-selective hydrogenation with formation of (2R,3R)-C, accompanied by a (2R,3S)-C epimer as a by-product.
  • Disadvantages involve formation of diastereo-isomeric mixtures and the necessity of stereo-chemical purification of products at the end of the synthesis.
  • step A reacting 0-substituted (2i?,3 ⁇ )-3-(3-hydroxyphenyl)-2-methyl-4-pentenoic acids of general formula II,
  • R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
  • an activating agent such as thionyl chloride, oxalyl chloride or an alkyl chloroformate, in presence of a catalyst or a base, and then with dimethylamine;
  • step B reducing the obtain -dimethylamide of general formula IV,
  • step C transforming the produced amines of general formula V,
  • R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
  • Step A) are reacted, in an inert organic solvent, with an activating agent, such as thionyl chloride, oxalyl chloride, or an alkyl chloro formate Cl-COOR 1 , wherein R 1 stands for methyl or ethyl, or pivalic acid chloride f-Bu-CO-Cl, optionally in presence of a catalyst or a base (Step A), b) the obtained compounds of general formula III,
  • an activating agent such as thionyl chloride, oxalyl chloride, or an alkyl chloro formate Cl-COOR 1 , wherein R 1 stands for methyl or ethyl, or pivalic acid chloride f-Bu-CO-Cl, optionally in presence of a catalyst or a base
  • Step B the obtained N,N-dimethylamides of general formula IV, wherein R has the same meaning as above,
  • step C) are reduced by means of hydride agents in a suitable solvent.
  • step D) are hydrogenated on a metal catalyst in a suitable solvent
  • the obtained tapentadol is converted by the action of pharmaceutically acceptable acids to respective salts, e.g. hydrochloride.
  • Step A Conversion of optically pure or optically enriched O-protected (2R,3R)-atids of general formula II, wherein R stands for phenylmethyl group, substituted or non-substituted in the benzene ring, e.g.
  • the activating agents used include, for example, chlorides of inorganic acids, e.g. thionyl chloride, phosphoryl chloride or phosphorus pentachloride, or chlorides of organic acids, e.g. oxalyl chloride.
  • the reaction is preferably carried out in presence of a catalytic amount of dimethylformamide.
  • the reaction is carried out in presence or absence of an inert organic solvent, such as chloroform, dichloromethane or toluene, in the temperature range of from 10°C to the boiling temperature of the mixture, preferably from 25°C to the boiling temperature of the mixture.
  • an inert organic solvent such as chloroform, dichloromethane or toluene
  • thionyl chloride and a catalytic amount of dimethylformamide in dichloromethane, chloroform or toluene, in the temperature range of from 25 to 100°C is used.
  • Activating agents used also include alkyl chloroformates Cl-COOR 1 , wherein R 1 has the above mentioned meaning, or the pivalic acid chloride i-Bu-CO-Cl. These reactions are carried out in presence of a base, such as triethylamine, in an inert organic solvent, in the temperature range of from 0°C to 50°C, preferably from 0 to 30°C. According to a preferable embodiment, the compounds of general formula III are neither isolated nor purified, but reacted directly with dimethylamine.
  • a base such as triethylamine
  • Step B Production of N,N-dimethylamides of general formula IV, wherein R has the above mentioned meaning, from activated compounds of general formula III, wherein X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR 1 , wherein R 1 stands for methyl or ethyl, or the pivaloyloxyl group 0-CO-/-Bu, is carried out by the reaction with dimethylamine in an inert organic solvent, in the temperature range of from 0°C to 40°C, preferably from 10 to 25°C.
  • dimethylamine is used in the gaseous form or in the form of an aqueous solution, or in the form of a salt, e.g. hydrochloride, in presence of a base, such as e.g. triethylamine, or an aqueous solution of an inorganic base, such as sodium or potassium carbonate or hydrogencarbonate.
  • Step C Reduction of A V-dimethylamides of general formula IV, wherein R has the above mentioned meaning, to amines of general formula V is carried out by means of hydride agents based on aluminium, such as lithium hydridoaluminate, sodium bis-(2-methoxyethoxy) hydridoaluminate, or diisobutyl aluminium hydride, in an inert organic solvent, such as ethers, e.g. tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, or toluene, in the temperature range of from 20°C to the boiling temperature of the mixture, preferably from 20 to 100°C.
  • ethers e.g. tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, or toluene
  • the reduction of the compound of general formula IV is carried out by means of sodium bis-(2-methoxyethoxy)hydridoaluminate in toluene at a temperature from 25°C to the boiling temperature of the mixture, preferably at 60-100°C.
  • Step D Simultaneous saturation of the terminal double bond and removal of the O- protecting group R, which has the same meaning as above, in the compound of general formula V is carried out by reduction with hydrogen on metal catalysts, such as palladium.
  • the hydrogenation is carried out in an inert organic solvent, such as lower alcohols, e.g. methanol, ethanol or isopropyl alcohol, or in cyclic ethers, such as tetrahydrofuran or 1 ,4- dioxane, or in ethyl acetate, or their mixtures, at a pressure 0.1 to 5 MPa in the temperature range of from 10 to 60°C, preferably from 20 to 40°C.
  • the reduction can be carried out in presence or absence of strong acids, such as hydrochloric or sulphuric acid.
  • hydrogen on Pd/C is used in the environment of an alcohol, such as methanol or ethanol, or a mixture thereof with water, at a pressure of from 0.1 to 2 MPa.
  • the obtained compound of formula I (tapentadol) is finally converted by the action of pharmaceutically acceptable acids to a corresponding salt and purified by crystallization from a suitable organic solvent, such as ethyl acetate, 2-propanol or methanol, or a mixture of solvents with water.
  • a suitable organic solvent such as ethyl acetate, 2-propanol or methanol, or a mixture of solvents with water.
  • the process may comprise using, as the starting compounds, racemic acids of general formula II, wherein R stands for a phenylmethyl group, substituted or non- substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group, and transforming the same, using the above-mentioned methods, via racemic activated compounds of general formula III, wherein R has the above mentioned meaning, X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR 1 , wherein R 1 stands for methyl or ethyl, or the pivaloyloxyl group O-CO-Z-Bu, to racemic N,N-dimethylamides of general formula IV, wherein R has the above mentioned meaning, and then to racemic amines of general formula V, wherein R stands for the same as above.
  • Their hydrogenation provides racemic tapentadol of formula I, which is subsequently resolved by means of acidic resolv
  • This method has a disadvantage of using, in all steps, higher amounts of starting compounds of general formulas II, III, IV and V, which makes this variant disadvantageous from both economic and environmental points of view.
  • the method according to this invention includes, as a key step, production of optically pure or optically enriched tapentadol of formula I
  • R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
  • the obtained tapentadol is converted by the action of pharmaceutically acceptable acids to respective salts, such as hydrochloride.
  • Simultaneous saturation of the vinyl double bond and deprotection of the O-protective group R, which has the same meaning as above, in the compound of general formula V is carried out by reduction with hydrogen on metal catalysts, such as palladium.
  • the hydrogenation is carried out in an inert organic solvent, such as in lower alcohols, e.g. methanol, ethanol or isopropyl alcohol, or in cyclic ethers, such as tetrahydrofuran or 1 ,4- dioxane, or in ethyl acetate, or their mixture, at pressure of 0.1 to 5 MPa bar in the temperature range of from 10 to 60°C, preferably from 20 to 40°C.
  • the reduction can be carried out in presence or absence of strong acids, such as hydrochloric or sulphuric acid.
  • hydrogen on Pd/C in an alcohol such as methanol or ethanol, or their mixtures with water, at pressure of 0. 1 to 2 MPa, is used.
  • the method according to this invention comprises the production of optically pure optically enriched, or racemic, -N,N-dimethylamides of general formula IV,
  • R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
  • an activating agent such as thionyl chloride, oxalyl chloride, or an alkyl chloroformate Cl-COOR 1 , wherein R 1 stands for methyl or ethyl, or the pivalic acid chloride t- Bu-CO-Cl,
  • R and R have the above mentioned meanings and X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR 1 , or the pivaloyloxyl group O-CO-i-Bu, with dimethylamine.
  • the activating agents used include, for instance, inorganic acid chloride, e.g. thionyl chloride, phosphoryl chloride or phosphorus pentachloride, or organic acid chlorides, e.g. oxalyl chloride.
  • the reaction is preferably carried out in presence of a catalytic amount of dimethylformamide.
  • the reaction is carried out in presence or absence of an inert organic solvent, such as e.g. chloroform, dichloromethane or toluene, in the temperature range of from 10°C to the boiling temperature of the mixture, preferably from 25°C to the boiling temperature of the mixture.
  • an inert organic solvent such as e.g. chloroform, dichloromethane or toluene
  • thionyl chloride and a catalytic amount of dimethylformamide, in dichloromethane, chloroform or toluene, in the temperature range of from 20°C to the boiling temperature of the mixture is used.
  • the activating agents used can also include alkyl chloroformates Cl-COOR , wherein R 1 has the above mentioned meaning, or the pivalic acid chloride -Bu-CO-Cl. These reactions are carried out in presence of a base, such as triethylamine, in an inert organic solvent, in the temperature range of from 0°C to 50°C, preferably from 0°C to 30°C.
  • the compounds of general formula III are neither isolated nor purified, but reacted directly with dimethylamine.
  • the activated compounds of general formula III, wherein X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR 1 , wherein R 1 stands for methyl or ethyl, or the pivaloyloxyl group O-CO-i-Bu, are then converted to N,N-dimethylamides of general formula IV, wherein R has the above mentioned meaning, by the reaction with dimethylamine in an inert organic solvent, in the temperature range of from 0°C to 40°C, preferably from 10 to 25°C.
  • dimethylamine is used in the gaseous form or in the form of an aqueous solution, or in the form of a salt, e.g. hydrochloride, in presence of a base, such as triethylamine, or an aqueous solution of an inorganic base, such as sodium or potassium carbonate or hydrogencarbonate.
  • the method according to this invention also comprises production of later-stage intermediates, (27?,3i?)-amines of general formula V,
  • R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
  • the reduction of the compounds of general formula V is carried out by means of sodium bis-(2-methoxyethoxy)hydridoaluminate in toluene at a temperature of from 25°C to the boiling temperature of the mixture, preferably from 60 to 100°C.
  • the method can also be realized by using, in the above mentioned method, racemic acids of general formula II, and by carrying the resolving out at the stage of amines of general formula V, wherein R has the above mentioned meaning, by means of acidic resolving agents, such as camphorsulphonic or mandelic acid.
  • R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
  • esters of general formula VI are preferably produced by a method comprising rearrangement of esters of general formula VI,
  • the enolisation is carried out in inert organic solvents, preferably in toluene, by means of min. 2.5 equivalent of both the metal amide and tertiary amine, in the temperature range of from -40 to -80°C, preferably from -60 to -70°C; the rearrangement takes place during gradual heating of the reaction mixture to the laboratory temperature.
  • the whole process is highly diastereo-selective and provides the racemic diastereo-isomer with high selectivity.
  • a compound of formula II with an erythro : threo ratio of diastereo-isomers of from 25 : 1 to 35 : 1 is obtained by this method.
  • the protecting group R used is the benzyl group; the racemic acid II
  • suitable solvents such as hexane, heptane, toluene, petroleum ether or their mixtures with diethyl ether, tert-butyl methyl ether
  • racemic acids of general formula II are then resolved by means of basic resolving agents, their final diastereo-selective purification thus taking place at the same time (erythro : threo ratio of at least 99 : 1).
  • R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group, in the optically pure, optically enriched, or racemic form, are new and represent useful intermediates in the synthesis of tapentadol.
  • R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group, both optically pure and optically enriched, or racemic, are also new intermediates.
  • the reaction mixture is heated under a reflux condenser in an inert atmosphere at 100°C (bath) for 1 h; after free cooling, it is cooled down in an ice bath and decomposed by gradual dropwise addition of 8.5 ml of water and 8.5 ml of a 15% solution of sodium hydroxide.
  • the mixture is stirred at the laboratory temperature for 40 min., filtered through a layer of diatomaceous earth, and the filter is washed with 70 ml of ethyl acetate.
  • the filtrate is extracted with l x 150 ml and 2x 30 ml of 1M hydrochloric acid.
  • the combined acidic aqueous fractions are alkalinized with 1 10 ml of 2 M sodium hydroxide and the separated oil is extracted with l x 100 ml and 2x 50 ml of ethyl acetate.
  • the combined extracts are washed with l x 50 ml of brine, dried with Na 2 S0 4 , and evaporated in vacuo in a rotatory vacuum evaporator.

Abstract

The present solution relates to a method comprising, as a key step, production of optically pure or optically enriched tapentadol of formula I, in which optically pure or optically enriched (2R,3R)-amines of general formula V, wherein R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group, are hydrogenated on a metal catalyst and, if desired, the obtained tapentadol is converted by the action of pharmaceutically acceptable acids to respective salts, such as to hydrochloride.

Description

Method of producing (2R,3R)-N -dimethyl-3-(3-hydroxyphenyI)-2-methylpentylamine (tapentadol)
Technical Field
This invention relates to a new method of producing (2 ?,3 ?)-N,N-dimethyl-3-(3- hydroxyphenyl)-2-methylpentylamine of formula I, known also under the name of tapentadol, and its salts.
Figure imgf000002_0001
(I)
State of the art
Tapentadol (I), chemically (2i?,3i?)-N,N-dimethyl-3-(3-hydroxyphenyl)-2-methylpentyl amine, acts as an agonist of μ-opioid receptors and an inhibitor of noradrenaline reuptake. It has been developed in the form of hydrochloride of (2/?,3/?)-enantiomer by the firm Johnson & Johnson based on development of the firm Gruenenthal, as a general analgetic.
According to the original method disclosed in document EP 0 693 475 (CZ 286441 ; Gruenenthal GmbH), tapentadol is produced from (2S,3S)- l -dimethylamino-3-(3- methoxyphenyl)-2-methylpentane-3-ol (A), which is obtained by two methods by means of the Grignard addition to a ketone, e.g. by addition of 2-methoxyphenylmagnesium bromide to 1 - dimethylamino-2-methyl-3-pentanone. The reaction is non-stereo-selective and obtaining of the (27?,3i?)-stereo-isomer requires separation on a chiral HPLC column. Compound A is then converted to a chloride by means of thionyl chloride and the obtained chloro-derivative is converted by reduction, e.g. by means of NaBH4/ZnCl2, to (2i?,37?)-N,N-dimethyl-3-(3- methoxyphenyl)-2-methylpentylamine (B), which is finally demethylated by hydrobromic acid. The method is inherently disadvantageous because of demanding HPLC separation of stereo-isomers on a chiral column.
According to international application WO 2004/108658 (Gruenenthal GmbH), the compound (2S,3S)-A is converted, by the action of acidic agents, such as concentrated hydrochloric acid, to alkene B, which is subjected to diastereo-selective hydrogenation with formation of (2R,3R)-C, accompanied by a (2R,3S)-C epimer as a by-product. Disadvantages involve formation of diastereo-isomeric mixtures and the necessity of stereo-chemical purification of products at the end of the synthesis.
A similar method, i.e. acidic dehydration of A followed by hydrogenation of alkene B, is also claimed in WO 2005/000788 and WO 2007/051576 (Gruenenthal GmbH).
Alternatively, the same tertiary amine C is produced according to WO 2008/012047
(Gruenenthal GmbH) by resolving l -dimethylamino-3-(3-methoxyphenyl)-2-methyl- l - propanone (D), obtained by the Mannich reaction from 3 '-methoxypropiophenone, by means of (7?, ?)-dibenzoyltartaric acid, and reacting its (5)-enantiomer with ethylmagnesium bromide with formation of the (25',35)-stereo-isomer of compound A as a predominating stereo-isomer. In a subsequent method, similar to that mentioned above, compound A is subjected to acidic dehydratation; the subsequent hydrogenation of alkene B provides predominantly amine (2R,3R)-C, which is demethylated to finally produce tapentadol. The disadvantages are similar to those of the previous methods.
Initial steps of a further method according to WO 2008/012283 (Janssen Pharmaceutica) are similar to those of the previous method; here, compound (S)-D is finally converted by the Grignard reaction to predominating (2R,3S)-A. The claimed deoxygenation is carried out by a method in which 0-trifluoroacetylation is first carried out by means of trifluoroacetic anhydride; followed by hydrogenolysis with hydrogen on Pd/C, leading to (2R,3R)-C with ee 92.6%. The deoxygenation method specifically relates to methyl as a protecting group for the phenolic hydroxyl.
The same deoxygenation method, with utilization of hydrogenolysis of trifluoroacetyl derivatives, is also claimed in WO 2008/012046 (Gruenenthal GmbH); however, it relates to phenolic hydroxyl protecting groups other than the methyl group. Deprotection, and optionally formation of salts, is also claimed. A disadvantage of both methods involves the problem of ensuring stereo-chemical homogeneity of the whole process.
Disclosure of Invention
The present invention provides a new effective method of producing optically pure or optically enriched tapentadol of formula I
Figure imgf000003_0001
(I) and its pharmaceutically acceptable salts,
which comprises:
in step A, reacting 0-substituted (2i?,3^)-3-(3-hydroxyphenyl)-2-methyl-4-pentenoic acids of general formula II,
Figure imgf000004_0001
(Π) where R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
with an activating agent, such as thionyl chloride, oxalyl chloride or an alkyl chloroformate, in presence of a catalyst or a base, and then with dimethylamine;
in step B, reducing the obtain -dimethylamide of general formula IV,
Figure imgf000004_0002
(IV)
wherein R has the above mentioned meaning,
by means of hydride agents;
and, finally, in step C, transforming the produced amines of general formula V,
Figure imgf000004_0003
(V)
wherein R has the above mentioned meaning,
by hydrogenation to tapentadol of formula I, or its salts with pharmaceutically acceptable acids.
Detailed description of invention
A method of producing optically pure or optically enriched tapentadol of formula I
Figure imgf000005_0001
and its pharmaceutically acceptable salts,
characterized in that the O-protected (2i?,3 ?)-acids of general formula II,
Figure imgf000005_0002
(Π) wherein R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
a) are reacted, in an inert organic solvent, with an activating agent, such as thionyl chloride, oxalyl chloride, or an alkyl chloro formate Cl-COOR1, wherein R1 stands for methyl or ethyl, or pivalic acid chloride f-Bu-CO-Cl, optionally in presence of a catalyst or a base (Step A), b) the obtained compounds of general formula III,
Figure imgf000005_0003
(III) wherein R and R have the above mentioned meaning and X stands for chloro alkoxycarbonyloxyl group O-CO-OR1 or the pivaloyloxyl group 0-CO-/-Bu,
are reacted with dimethylamine or its salts, optionally in presence of a base (Step B), c) the obtained N,N-dimethylamides of general formula IV,
Figure imgf000005_0004
wherein R has the same meaning as above,
are reduced by means of hydride agents in a suitable solvent (step C),
d) and, finally, the produced amines of general formula V,
Figure imgf000006_0001
wherein R stands for the same as above,
are hydrogenated on a metal catalyst in a suitable solvent (step D),
and, if desired, the obtained tapentadol is converted by the action of pharmaceutically acceptable acids to respective salts, e.g. hydrochloride.
We have found that optically pure or optically enriched tapentadol of formula I can be produced effectively and in high purity by a method, which is based on using diastereo- selectively and optically pure, or enriched, acids of general formula Π as intermediates. The method of producing tapentadol from the acids of general formula II comprises the following synthetic steps:
Step A. Conversion of optically pure or optically enriched O-protected (2R,3R)-atids of general formula II, wherein R stands for phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group, to activated compounds of general formula III, wherein X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR1 , wherein R1 stands for methyl or ethyl, or the pivaloyloxyl group O-CO-t- Bu, is carried out by means of activating agents: The activating agents used include, for example, chlorides of inorganic acids, e.g. thionyl chloride, phosphoryl chloride or phosphorus pentachloride, or chlorides of organic acids, e.g. oxalyl chloride. The reaction is preferably carried out in presence of a catalytic amount of dimethylformamide. The reaction is carried out in presence or absence of an inert organic solvent, such as chloroform, dichloromethane or toluene, in the temperature range of from 10°C to the boiling temperature of the mixture, preferably from 25°C to the boiling temperature of the mixture.
According to a preferable embodiment, thionyl chloride and a catalytic amount of dimethylformamide in dichloromethane, chloroform or toluene, in the temperature range of from 25 to 100°C is used.
Activating agents used also include alkyl chloroformates Cl-COOR1 , wherein R1 has the above mentioned meaning, or the pivalic acid chloride i-Bu-CO-Cl. These reactions are carried out in presence of a base, such as triethylamine, in an inert organic solvent, in the temperature range of from 0°C to 50°C, preferably from 0 to 30°C. According to a preferable embodiment, the compounds of general formula III are neither isolated nor purified, but reacted directly with dimethylamine.
Step B. Production of N,N-dimethylamides of general formula IV, wherein R has the above mentioned meaning, from activated compounds of general formula III, wherein X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR1, wherein R1 stands for methyl or ethyl, or the pivaloyloxyl group 0-CO-/-Bu, is carried out by the reaction with dimethylamine in an inert organic solvent, in the temperature range of from 0°C to 40°C, preferably from 10 to 25°C. Herein, dimethylamine is used in the gaseous form or in the form of an aqueous solution, or in the form of a salt, e.g. hydrochloride, in presence of a base, such as e.g. triethylamine, or an aqueous solution of an inorganic base, such as sodium or potassium carbonate or hydrogencarbonate.
Step C. Reduction of A V-dimethylamides of general formula IV, wherein R has the above mentioned meaning, to amines of general formula V is carried out by means of hydride agents based on aluminium, such as lithium hydridoaluminate, sodium bis-(2-methoxyethoxy) hydridoaluminate, or diisobutyl aluminium hydride, in an inert organic solvent, such as ethers, e.g. tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, or toluene, in the temperature range of from 20°C to the boiling temperature of the mixture, preferably from 20 to 100°C.
Preferably, the reduction of the compound of general formula IV is carried out by means of sodium bis-(2-methoxyethoxy)hydridoaluminate in toluene at a temperature from 25°C to the boiling temperature of the mixture, preferably at 60-100°C.
Step D. Simultaneous saturation of the terminal double bond and removal of the O- protecting group R, which has the same meaning as above, in the compound of general formula V is carried out by reduction with hydrogen on metal catalysts, such as palladium.
The hydrogenation is carried out in an inert organic solvent, such as lower alcohols, e.g. methanol, ethanol or isopropyl alcohol, or in cyclic ethers, such as tetrahydrofuran or 1 ,4- dioxane, or in ethyl acetate, or their mixtures, at a pressure 0.1 to 5 MPa in the temperature range of from 10 to 60°C, preferably from 20 to 40°C. The reduction can be carried out in presence or absence of strong acids, such as hydrochloric or sulphuric acid. According to a preferable embodiment, for instance, hydrogen on Pd/C is used in the environment of an alcohol, such as methanol or ethanol, or a mixture thereof with water, at a pressure of from 0.1 to 2 MPa.
The obtained compound of formula I (tapentadol) is finally converted by the action of pharmaceutically acceptable acids to a corresponding salt and purified by crystallization from a suitable organic solvent, such as ethyl acetate, 2-propanol or methanol, or a mixture of solvents with water.
Alternatively, the process may comprise using, as the starting compounds, racemic acids of general formula II, wherein R stands for a phenylmethyl group, substituted or non- substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group, and transforming the same, using the above-mentioned methods, via racemic activated compounds of general formula III, wherein R has the above mentioned meaning, X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR1, wherein R1 stands for methyl or ethyl, or the pivaloyloxyl group O-CO-Z-Bu, to racemic N,N-dimethylamides of general formula IV, wherein R has the above mentioned meaning, and then to racemic amines of general formula V, wherein R stands for the same as above. Their hydrogenation provides racemic tapentadol of formula I, which is subsequently resolved by means of acidic resolving acids of the type of carboxyl or sulphonic acids.
This method has a disadvantage of using, in all steps, higher amounts of starting compounds of general formulas II, III, IV and V, which makes this variant disadvantageous from both economic and environmental points of view.
The method according to this invention includes, as a key step, production of optically pure or optically enriched tapentadol of formula I
Figure imgf000008_0001
Figure imgf000009_0001
wherein R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
are hydrogenated on a metal catalyst
and, if desired, the obtained tapentadol is converted by the action of pharmaceutically acceptable acids to respective salts, such as hydrochloride.
Simultaneous saturation of the vinyl double bond and deprotection of the O-protective group R, which has the same meaning as above, in the compound of general formula V is carried out by reduction with hydrogen on metal catalysts, such as palladium. The hydrogenation is carried out in an inert organic solvent, such as in lower alcohols, e.g. methanol, ethanol or isopropyl alcohol, or in cyclic ethers, such as tetrahydrofuran or 1 ,4- dioxane, or in ethyl acetate, or their mixture, at pressure of 0.1 to 5 MPa bar in the temperature range of from 10 to 60°C, preferably from 20 to 40°C. The reduction can be carried out in presence or absence of strong acids, such as hydrochloric or sulphuric acid.
According to a preferable embodiment, for instance, hydrogen on Pd/C in an alcohol, such as methanol or ethanol, or their mixtures with water, at pressure of 0. 1 to 2 MPa, is used.
The method according to this invention comprises the production of optically pure optically enriched, or racemic, -N,N-dimethylamides of general formula IV,
Figure imgf000009_0002
(IV) wherein R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
characterized in subjecting O-protected (27?,3i?)-acids of general formula II,
Figure imgf000010_0001
wherein R has the above mentioned meaning,
a) to reaction with an activating agent, such as thionyl chloride, oxalyl chloride, or an alkyl chloroformate Cl-COOR1, wherein R1 stands for methyl or ethyl, or the pivalic acid chloride t- Bu-CO-Cl,
b) and reacting the obtained compounds of general formula III,
Figure imgf000010_0002
wherein R and R have the above mentioned meanings and X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR1, or the pivaloyloxyl group O-CO-i-Bu, with dimethylamine.
The conversion of optically pure or optically enriched, or racemic, O-protected (2/?,37?)-acids of general formula II, wherein R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group, to activated compounds of general formula III, wherein X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR1, wherein R1 stands for methyl or ethyl, or the pivaloyloxyl group 0-CO-/-Bu, is carried out by means of activating agents: The activating agents used include, for instance, inorganic acid chloride, e.g. thionyl chloride, phosphoryl chloride or phosphorus pentachloride, or organic acid chlorides, e.g. oxalyl chloride. The reaction is preferably carried out in presence of a catalytic amount of dimethylformamide. The reaction is carried out in presence or absence of an inert organic solvent, such as e.g. chloroform, dichloromethane or toluene, in the temperature range of from 10°C to the boiling temperature of the mixture, preferably from 25°C to the boiling temperature of the mixture.
According to a preferable embodiment, thionyl chloride and a catalytic amount of dimethylformamide, in dichloromethane, chloroform or toluene, in the temperature range of from 20°C to the boiling temperature of the mixture, is used. The activating agents used can also include alkyl chloroformates Cl-COOR , wherein R1 has the above mentioned meaning, or the pivalic acid chloride -Bu-CO-Cl. These reactions are carried out in presence of a base, such as triethylamine, in an inert organic solvent, in the temperature range of from 0°C to 50°C, preferably from 0°C to 30°C.
According to a preferable embodiment, the compounds of general formula III are neither isolated nor purified, but reacted directly with dimethylamine.
The activated compounds of general formula III, wherein X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR1 , wherein R1 stands for methyl or ethyl, or the pivaloyloxyl group O-CO-i-Bu, are then converted to N,N-dimethylamides of general formula IV, wherein R has the above mentioned meaning, by the reaction with dimethylamine in an inert organic solvent, in the temperature range of from 0°C to 40°C, preferably from 10 to 25°C. Herein, dimethylamine is used in the gaseous form or in the form of an aqueous solution, or in the form of a salt, e.g. hydrochloride, in presence of a base, such as triethylamine, or an aqueous solution of an inorganic base, such as sodium or potassium carbonate or hydrogencarbonate.
The method according to this invention also comprises production of later-stage intermediates, (27?,3i?)-amines of general formula V,
Figure imgf000011_0001
(V)
wherein R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
optically pure or optically enriched, or racemic,
characterized in reducing N, -dimethylamides of general formula IV,
Figure imgf000011_0002
(IV)
wherein R stands for the same as above,
by means of hydride agents based on aluminium. The reduction of N,N-dimethylamides of general formula IV, wherein R has the above mentioned meaning, to amines of general formula V, is carried out by means of hydride agents based on aluminium, such as lithium hydridoaluminate or sodium bis-(2-methoxyethoxy) hydridoaluminate, in an inert organic solvent, such as ethers, e.g. tetrahydrofuran, 2- methyltetrahydrofuran, diethyl ether, or toluene, in the temperature range of from 20°C to the boiling temperature of the mixture, preferably from 20 to 100°C
Preferably, the reduction of the compounds of general formula V is carried out by means of sodium bis-(2-methoxyethoxy)hydridoaluminate in toluene at a temperature of from 25°C to the boiling temperature of the mixture, preferably from 60 to 100°C.
The method can also be realized by using, in the above mentioned method, racemic acids of general formula II, and by carrying the resolving out at the stage of amines of general formula V, wherein R has the above mentioned meaning, by means of acidic resolving agents, such as camphorsulphonic or mandelic acid.
The starting optically pure or optically enriched 0-protected (2i?,3i?)-acids of general formula II,
Figure imgf000012_0001
(Π)
wherein R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
are preferably produced by a method comprising rearrangement of esters of general formula VI,
Figure imgf000012_0002
wherein R stands for the same as above,
by the action of a strong base of the type of metal amides, e.g. lithium hexamethyldisilazide, and a tertiary amine, e.g. triethylamine. The method of producing acids of general formula II, wherein R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4- methoxybenzyl, benzhydryl or trityl group, comprising enolisation of esters of general formula VI, wherein R has the above mentioned meaning, by the action of a strong base of the type of metal amides, e.g. lithium hexamethyldisilazide, and a tertiary amine, e.g. triethylamine, at low temperatures, and then the enolates generated on heating undergo rearrangement to the expected acids of general formula II. The enolisation is carried out in inert organic solvents, preferably in toluene, by means of min. 2.5 equivalent of both the metal amide and tertiary amine, in the temperature range of from -40 to -80°C, preferably from -60 to -70°C; the rearrangement takes place during gradual heating of the reaction mixture to the laboratory temperature. The whole process is highly diastereo-selective and provides the racemic diastereo-isomer with high selectivity.
A compound of formula II with an erythro : threo ratio of diastereo-isomers of from 25 : 1 to 35 : 1 is obtained by this method.
Most preferably, the protecting group R used is the benzyl group; the racemic acid II
(R = benzyl) is a crystalline substance prepared with an erythro : threo diastereo-isomeric purity of from 30 : 1 to 35 : 1. Crystallization of the crude acid II (R = benzyl) from suitable solvents, such as hexane, heptane, toluene, petroleum ether or their mixtures with diethyl ether, tert-butyl methyl ether, then leads to a product is then prepared with an erythro : threo diastereo-isomeric purity higher than 99 : 1 , in a high yield of more than 85%.
These racemic acids of general formula II are then resolved by means of basic resolving agents, their final diastereo-selective purification thus taking place at the same time (erythro : threo ratio of at least 99 : 1). O-Protected (2/?,37?)-3-(3-hydroxyphenyl)-7V,N,2-trimethylpent-4-enamides of general formula IV,
Figure imgf000013_0001
(IV) wherein R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group, in the optically pure, optically enriched, or racemic form, are new and represent useful intermediates in the synthesis of tapentadol.
Of particular importance is the amide of general formula IV, wherein R is the benzyl group, i.e. (27?,3i?)-3-(3-benzyloxyphenyl)-N,N,2-trimethylpent-4-enamide of formula IVa,
Figure imgf000014_0001
(IVa) both optically pure and optically enriched, or racemic.
O-Protected (27?,3 ?)-3-(3-hydroxyphenyl)-N,N,2-trimethylpent-4-en- l -amines of general formula V,
Figure imgf000014_0002
(V)
wherein R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group, both optically pure and optically enriched, or racemic, are also new intermediates.
Of these compounds, the amine of general formula V, wherein R stands for the benzyl group, i.e. (2 ?,3i?)-3-(3-benzyloxyphenyl)-N,N,2-trimethylpent-4-en- l -amine of formula Va,
(Va) in the optically pure, optically enriched, or racemic form, is of particular usefulness.
The following working examples of embodiment illustrate, without limiting it in any way, the generality of the method of production according to this invention.
Working Examples Example 1
a) Preparation of 3-[(l i?,2/?)-3-(dimethylamino)- l -ethyl-2-methylpropyl]phenol (compound of formula I, tapentadol)
5% Pd/C (5.2 g) is added to a solution of 24.81 g (80.17 mmol) of an amine of general formula V (R = Bn) in methanol (250 ml) in an inert nitrogen atmosphere. The hydrogenation vessel is rinsed three times with hydrogen and then the hydrogenation runs under pressure of 300 kPa, at the laboratory temperature for 20 hours. After the atmosphere has been replaced with nitrogen, the catalyst is filtered off, washed with methanol, and the solvent is evaporated in a rotatory vacuum evaporator. 96 % of crude compound of formula I is obtained as a yellow oil. b) Preparation of 3 -[(li?,2 ?)-3-(dimethylamino)- l -ethyl-2-methylpropyl] phenol hydrochloride (hydrochloride of the compound of formula I, tapentadol hydrochloride)
17.03 g of the crude compound of formula I is dissolved in 130 ml of methyl ethyl ketone (MEK) and 26 ml of a solution of hydrogen chloride in diethyl ether is added dropwise. The product separates in the form of white crystals. The mixture is stirred under cooling with water of 8°C for 2 h. The separated crystals are aspirated through sintered glass S2, washed with 15 ml of MEK, and dried at the laboratory temperature. 16.97 g (82 %) of a salt with melting point 181 - 203°C is obtained; chemical purity according to HPLC 99.7%, optical purity according to HPLC on a chiral column 96.9%.
16.87 g of the salt is dissolved under boiling in 180 ml of isopropyl alcohol (IPA) and the obtained solution is left to cool for 0.5 h; then, the mixture is kept in an ice bath for 1 h. The separated crystals are aspirated, washed with 18 ml of IPA, and dried in a vacuum drier at 45 °C. 1 5.28 g of tapentadol hydrochloride (74%) is obtained with melting point = 202 - 206°C, [a]D = - 29.7 (c = 2, MeOH); chemical purity 99.9% (HPLC), optical purity 99.6% (chiral HPLC).
Ή-NMR (CDC13) δ 0.73 (3H, t, J = 7.5 Hz), 1.1 5 (3H, d, J = 5 Hz), 1.53- 1.66 (1H, m), 1 .83- 1 .93 ( 1 H, m), 2.1 3-2.32 (2H, m), 2.77 (6H, s), 2.85-2.89 (2H, m), 6.64-6.70 (3H, m), 7.15 ( 1 H, t, J = 7.5 Hz).
Example 2
Preparation of (2/?,3 ?)-3-(3-benzyloxyphenyl)-N,N,2-trimethylpent-4-en-l -amine (general formula V: R = Bn) A 70% w/w solution of synhydride (Red Al; 42 ml, 147 mmol) is charged into a flask under an inert N2 atmosphere; 70 ml of toluene is added; then, a solution of 24.4 g (75.4 mmol) of the crude amide of general formula IV (R = Bn) in 70 ml of toluene is added, the temperature of the mixture spontaneously increasing to ca. 50°C. The reaction mixture is heated under a reflux condenser in an inert atmosphere at 100°C (bath) for 1 h; after free cooling, it is cooled down in an ice bath and decomposed by gradual dropwise addition of 8.5 ml of water and 8.5 ml of a 15% solution of sodium hydroxide. The mixture is stirred at the laboratory temperature for 40 min., filtered through a layer of diatomaceous earth, and the filter is washed with 70 ml of ethyl acetate. The filtrate is extracted with l x 150 ml and 2x 30 ml of 1M hydrochloric acid. The combined acidic aqueous fractions are alkalinized with 1 10 ml of 2 M sodium hydroxide and the separated oil is extracted with l x 100 ml and 2x 50 ml of ethyl acetate. The combined extracts are washed with l x 50 ml of brine, dried with Na2S04, and evaporated in vacuo in a rotatory vacuum evaporator. The amine of general formula V (R = Bn) is obtained in quantitative yield; HPLC purity 96.2%.
Ή-NMR (CDC13) δ 0.91 (2H, d, J = 6.3 Hz), 1.94- 2.06 (3H, m), 2.14 (6H, s), 3.21
(1H, dd, J = 5.5, 9.3 Hz), 5.03- 5.10 (4H, m), 5.96 (1H, dt, J = 9.3, 17.8), 6.78-6.82 (3H, m), 7.30-7.42 (6H, m).
Example 3
a) Preparation of (2/?,37?)-3-(3-benzyloxyphenyl)-2-methylpent-4-enoic acid chloride (general formula III: R = Bn, X = CI)
34 ml of thionyl chloride (6 equivalents) is added to a solution of 23.09 g (77.9 mmol) of (2 ?,3/?)-acid of general formula II (R = Bn) in 320 ml of dried toluene, and the mixture is heated in a bath at t = 90°C for 4 h. The mixture is cooled and then evaporated in a rotatory vacuum evaporator (at t = 60°C). The crude chloride of general formula III (R = Bn, X = CI) is used directly in the following step. b) Preparation of (2/^,37?)-3-(3-benzyloxyphenyl)-N,N,2-trimethylpent-4-enamide (general formula IV: R = Bn)
9.49 g of dimethylamine hydrochloride (1 16.4 mmol; 1.5 equivalent) is added to a solution of the crude chloride of general formula III (R = Bn, X = CI) in 230 ml of dichloromethane, the mixture is cooled down in an ice bath, and 30 ml of triethylamine is added dropwise within 20 min. The reaction mixture is stirred under cooling for another 20 min, at laboratory temperature for 30 min, and diluted with 130 ml of water and 130 ml of dichloromethane. The organic phase is separated, washed with lx 50 ml of water, l x 50 ml of brine, dried with Na2S04, and evaporated in a rotatory vacuum evaporator. 24.45 g (97%) of the crude amide of general formula IV (R = Bn) is obtained as a partially solidified brown oil.
Ή-NMR (CDC13) δ 1 .17 (3H, d, J = 6.7 Hz), 2.71 (6H, s), 2.96-3.06 (l H, m), 3.54
(1 H, t, J = 9.8 Hz), 5.02 (2H, s), 5.08-5.17 (2H, m), 5.90 ( 1 H, dt, J = 9.8, 19.5 Hz), 6.76-6.84 (3H, m), 7.13-7.28 (6H, m).
Example 4
Preparation of (2i?,37?)-3-(3-benzyloxyphenyl)- 2-methylpent-4-enoic acid (general formula II: R = Bn)
5.05 g ( 12.1^mmol) of a salt of (2R,3R)-acid of general formula II (R = Bn) with (R)- phenylethylamine is suspended in 80 ml of methyl tert-butyl ether (MTBE) and 15 ml of 1M hydrochloric acid is added dropwise under stirring. The mixture is stirred at the laboratory temperature for 15 min, the layers are separated, and the aqueous fraction is extracted with additional lx 20 ml of MTBE. The combined organic fractions are dried with Na2S04, filtered, and evaporated in a rotatory vacuum evaporator. 3.60 g (100%) of the optically active acid of general formula II (R = Bn) is obtained; [α]ο =,+ 65.7 (c= 2, MeOH), optical purity 99.5%.
Ή-NMR (CDCI3) δ 1.22 (3H, d, J = 7.0 Hz), 2.84 ( 1 H, dq, J = 7.0, 9.3 Hz), 3.51 (1 H, t, J = 9.3 Hz), 5.03 (2H, s), 5.06-5.16 (2H, m), 5.89 (1 H, dt, J = 9.3, 19.4 Hz), 6.80-6.83 (3H, m), 7.16-7.42 (6H, m).

Claims

C L A I M S
1) A method of producing optically pure or optically enriched tapentadol of formula I
Figure imgf000018_0001
(I)
and its pharmaceutically acceptable salts,
characterized in that O-protec -acids of general formula II,
Figure imgf000018_0002
(H) wherein R stands for a phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
are, in step A, reacted with an activating agent in an inert organic solvent, optionally in presence of a catalyst or a base;
in step B, the obtained compounds of general formula III,
Figure imgf000018_0003
(III) wherein R and R1 have the above mentioned meaning and X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR1 or the pivaloyloxyl group O-CO-i-Bu, are reacted with dimethylamine or its salts, optionally in presence of a base;
in step C, the obtained N,N-dimethylamides of general formula IV,
Figure imgf000018_0004
(IV) wherein R has the above mentioned meaning,
are reduced by means of hydride agents in a suitable solvent; in step D, the produced amines of general formula V,
Figure imgf000019_0001
(V)
wherein R has the above mentioned meaning,
are hydrogenated on a metal catalyst in a suitable solvent;
followed, if desired, by conversion by the action of pharmaceutically acceptable acids to respective salts, e.g. to hydrochloride.
2) The method of production according to Claim 1 , characterized in that thionyl chloride or oxalyl chloride is used as the activating agent in step A in presence of a catalytic amount of dimethylformamide.
3) The method of production according to Claim 1 , characterized in that methyl chloroformate, ethyl chloroformate, or pivaloyl chloride is used as the activating agent in step A in presence of a base, such as triethylamine, in the temperature range of from 0°C to 50°C, preferably from 0 to 30°C.
4) The method of production according to Claims 1 to 3, characterized in that chloroform, dichloromethane, or toluene is used as the inert organic solvent. 5) The method of production according to Claim 1 , characterized in that dimethylamine in the gaseous form, or in the form of an aqueous solution, or in the form of a salt is used in step B in presence of a base, which is triethylamine or an aqueous solution of an inorganic base, such as sodium or potassium carbonate or hydrogencarbonate. 6) The method of production according to Claim 1 , characterized in that the hydride agents used in step C are hydride agents based on aluminium, selected from the series of lithium hydridoaluminate, sodium bis-(2-methoxyethoxy)hydridoaluminate, or diisobutyl aluminium hydride. 7) The method of production according to Claims 1 and 6, characterized in that the reduction in step C is carried out by means of sodium bis-(2-methoxyethoxy) hydridoaluminate in toluene, tetrahydrofuran, 2-methyltetrahydrofuran, or their mixture.
8) The method of production according to Claims 1 , 6 and 7, characterized in that the reduction is carried out in toluene at a temperature of from 25°C to the boiling temperature of the solvent.
9) The method of production according to Claim 1 , characterized in that platinum or palladium on coal is used as the metal catalyst in step D.
10) The method of production according to Claims 1 and 9, characterized in that the solvent used in step D is a solvent selected from the series of C I to C3 alcohols, such as methanol, ethanol or isopropyl alcohol, cyclic ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, or 1 ,4-dioxane, or in ethyl acetate, or in their mixtures.
1 1 ) The method of production according to Claims 1 to 10, characterized in that tapentadol and its salts are produced with chemical purity higher than 99.5%.
The method of production according to Claims 1 to 10, characterized in that tapentadol and its salts are produced with optical purity higher than 99.5%.
O-Protected (2i?,3i?)-3-(3-hydroxyphenyl)-N,N,2-trimethylpent-4-enamides of general formula IV,
Figure imgf000020_0001
wherein R stands for a phenylmethyl group, substituted or non-substituted benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
optically pure, optically enriched, or racemic. 14) (2i?,3i?)-3-(3-Benzyloxyphenyl)-jV,7V,2-trimethylpent-4-enamide of formula IVa,
Figure imgf000021_0001
optically pure, optically enriched, or racemic. 15) O-Protected (2i?,3 ?)-3-(3-hydroxyphenyl)-N,N,2-trimethylpent-4-en- l -amines of general formula V,
Figure imgf000021_0002
wherein R stands for a phenylmethyl group, substituted or non-substituted benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
optically pure, optically enriched, or racemic.
(2R, 3 ?)-3-(3-Benzyloxyphenyl)-N,N,2-trimethylpent-4-en-l -amine of formula Va,
Figure imgf000021_0003
(Va) optically pure, optically enriched, or racemic.
PCT/CZ2011/000122 2010-12-30 2011-12-23 Method of producing (2r,3r)-na-dimethyl-3-(3-hydroxyphenyi)-2-methylpentylamine (tapentadol) WO2012089177A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
HU1300523A HUP1300523A3 (en) 2010-12-30 2011-12-23 Method of producing (2r,3r)-na-dimethil-3-(3-hidroxyphenil)-2-methylpentylamine (tapentadol)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ20100997A CZ2010997A3 (en) 2010-12-30 2010-12-30 Process for preparing (2R,3R)-N,N-dimethyl-3-(hydroxyphenyl)-2-methyl pentylamine (tapentadol)
CZPV2010-997 2010-12-30

Publications (1)

Publication Number Publication Date
WO2012089177A1 true WO2012089177A1 (en) 2012-07-05

Family

ID=45557773

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2011/000122 WO2012089177A1 (en) 2010-12-30 2011-12-23 Method of producing (2r,3r)-na-dimethyl-3-(3-hydroxyphenyi)-2-methylpentylamine (tapentadol)

Country Status (3)

Country Link
CZ (1) CZ2010997A3 (en)
HU (1) HUP1300523A3 (en)
WO (1) WO2012089177A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102838493A (en) * 2012-09-20 2012-12-26 合肥市新星医药化工有限公司 Synthesis method for 3-[(1R, 2R)-3-( dimethylamino)-1-ethyl-2-methylpropyl] phenol
WO2013090161A1 (en) * 2011-12-12 2013-06-20 Boehringer Ingelheim International Gmbh Stereoselective synthesis of tapentadol and its salts
EP2674414A1 (en) * 2012-06-15 2013-12-18 Siegfried AG Method for the preparation of 1-aryl-1-alkyl-3-dialkylaminopropane compounds
WO2015117576A1 (en) 2014-02-04 2015-08-13 Zentiva, K.S. A solid form of tapentadol maleate and a method of its preparation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004108658A1 (en) * 2003-06-06 2004-12-16 Grünenthal GmbH Method for the production of substituted 3-aryl-butyl amine compounds
WO2007051576A1 (en) * 2005-11-02 2007-05-10 Grünenthal GmbH Process for preparing substituted dimethyl(3-arylbutyl)amine compounds by means of homogeneous catalysis
WO2008012047A1 (en) * 2006-07-24 2008-01-31 Grünenthal GmbH Process for the preparation of (1r,2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
WO2008012283A1 (en) * 2006-07-24 2008-01-31 Janssen Pharmaceutica Nv Preparation of (2r,3r)-3-(3-methoxyphenyl)-n,n,2-trimethylpentanamine

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4426245A1 (en) * 1994-07-23 1996-02-22 Gruenenthal Gmbh 1-phenyl-3-dimethylamino-propane compounds with pharmacological activity
SE9701144D0 (en) * 1997-03-27 1997-03-27 Pharmacia & Upjohn Ab Novel compounds, their use and preparation
JP2005112768A (en) * 2003-10-07 2005-04-28 Hitachi Zosen Corp Method for producing [1-13c]1-deoxy-d-xylulose

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004108658A1 (en) * 2003-06-06 2004-12-16 Grünenthal GmbH Method for the production of substituted 3-aryl-butyl amine compounds
WO2007051576A1 (en) * 2005-11-02 2007-05-10 Grünenthal GmbH Process for preparing substituted dimethyl(3-arylbutyl)amine compounds by means of homogeneous catalysis
WO2008012047A1 (en) * 2006-07-24 2008-01-31 Grünenthal GmbH Process for the preparation of (1r,2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
WO2008012283A1 (en) * 2006-07-24 2008-01-31 Janssen Pharmaceutica Nv Preparation of (2r,3r)-3-(3-methoxyphenyl)-n,n,2-trimethylpentanamine

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013090161A1 (en) * 2011-12-12 2013-06-20 Boehringer Ingelheim International Gmbh Stereoselective synthesis of tapentadol and its salts
EP2674414A1 (en) * 2012-06-15 2013-12-18 Siegfried AG Method for the preparation of 1-aryl-1-alkyl-3-dialkylaminopropane compounds
WO2013185928A1 (en) 2012-06-15 2013-12-19 Siegfried Ag Method for the preparation of 1-aryl-1-alkyl-2-alkyl-3-dialkylaminopropane compounds
CN102838493A (en) * 2012-09-20 2012-12-26 合肥市新星医药化工有限公司 Synthesis method for 3-[(1R, 2R)-3-( dimethylamino)-1-ethyl-2-methylpropyl] phenol
WO2015117576A1 (en) 2014-02-04 2015-08-13 Zentiva, K.S. A solid form of tapentadol maleate and a method of its preparation

Also Published As

Publication number Publication date
HUP1300523A3 (en) 2014-04-28
HUP1300523A2 (en) 2013-12-30
CZ302992B6 (en) 2012-02-08
CZ2010997A3 (en) 2012-02-08

Similar Documents

Publication Publication Date Title
CA2676712C (en) New process for the resolution of enantiomers of (3,4-dimethoxy-bicyclo¬4.2.0|octa-1,3,5-trien-7-yl)nitrile and application in the synthesis of ivabradine
KR20070057703A (en) Enantiomerically pure atomoxetine and tomoxetine mandelate
KR20110137336A (en) Process for the preparation of cinacalcet and salts thereof, and intermediates for use in the process
WO2012089177A1 (en) Method of producing (2r,3r)-na-dimethyl-3-(3-hydroxyphenyi)-2-methylpentylamine (tapentadol)
US6730803B2 (en) Synthetic intermediate for epothilone derivative and production method thereof
JP5301431B2 (en) Process for producing chiral cyclic β-aminocarboxamide
EP2606030B1 (en) Process for the preparation of tapentadol
EP2349976B1 (en) A process for producing (s)-3-[(1-dimethylamino)ethyl]phenyl-n-ethyl-n-methyl-carbamate via novel intermediates
EP2619174A1 (en) Process for preparing l-phenyl-3-dimethylaminopropane derivative
KR20120064668A (en) Process for the preparation of o-desmethyl venlafaxine and intermediate for use therein
CA2380854A1 (en) A process for the preparation of venlafaxin
CN101973897B (en) Synthesis method of valdoxan intermediate 2-(7-methoxy-1-naphthyl)ethylamine
JP2012507506A (en) Process for producing (3S, 4S) -4-((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone and novel intermediate used therefor
WO2012089181A1 (en) O-substituted (2r,3r)-3-(3-hydroxyphenyl)-2-methyl-4-pentenoic acids and a method of obtaining the same
KR100915551B1 (en) Process for the efficient preparation of 3-hydroxy pyrrolidine and derivatives thereof
EP2674414A1 (en) Method for the preparation of 1-aryl-1-alkyl-3-dialkylaminopropane compounds
CN102786441B (en) Preparation method of rivastigmine, intermediates and preparation method of intermediates
JP5748848B2 (en) Method for resolution of nitrogen-substituted (S) -5-alkoxy-2-aminotetralin derivative
JP4540197B2 (en) (E) Process for producing 3-methyl-2-cyclopentadecenone
CZ302993B6 (en) Process for preparing (2R,3R)-N,N-dimethyl-3-(hydroxyphenyl)-2-methylpentylamine (tapentadol)
CZ303115B6 (en) Process for preparing (2R,3R)-N,N-dimethyl-3-(3-hydroxyphenyl)-2-methylpentylamine
EP2803659A1 (en) Method for synthesising 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile and use for synthesising ivabradine and the added salts thereof with a pharmaceutically acceptable acid
US20100168385A1 (en) Process for preparing enantiomerically enriched amino-alcohols
CZ293791B6 (en) Process for preparing N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropyl amine in racemic or optically active form thereof
JP2002173472A (en) Method for producing optically active 1-(trifluoromethyl mono-substituted phenyl) ethylamine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11817505

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2013/07660

Country of ref document: TR

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11817505

Country of ref document: EP

Kind code of ref document: A1