Nothing Special   »   [go: up one dir, main page]

WO2012089181A1 - Acides (2r, 3r)-3-(3-hydroxyphényle)-2-méthyl-4-penténoïques o-substitués et leur procédé d'obtention - Google Patents

Acides (2r, 3r)-3-(3-hydroxyphényle)-2-méthyl-4-penténoïques o-substitués et leur procédé d'obtention Download PDF

Info

Publication number
WO2012089181A1
WO2012089181A1 PCT/CZ2011/000128 CZ2011000128W WO2012089181A1 WO 2012089181 A1 WO2012089181 A1 WO 2012089181A1 CZ 2011000128 W CZ2011000128 W CZ 2011000128W WO 2012089181 A1 WO2012089181 A1 WO 2012089181A1
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
acids
methyl
formula
tapentadol
Prior art date
Application number
PCT/CZ2011/000128
Other languages
English (en)
Inventor
Ruzena Vlasakova
Josef Hajicek
Josef Zezula
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
Priority claimed from CZ20100998A external-priority patent/CZ2010998A3/cs
Priority claimed from CZ20100996A external-priority patent/CZ303116B6/cs
Priority claimed from CZ20100995A external-priority patent/CZ2010995A3/cs
Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Priority to HU1300623A priority Critical patent/HUP1300623A2/hu
Publication of WO2012089181A1 publication Critical patent/WO2012089181A1/fr

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
    • 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
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • This invention relates to a method of producing O-substituted (2R,3R)-3-(3- hydroxyphenyl)-2-methyl-4-pentenoic acids of general formula I.
  • the compounds of general formula I are new and represent important intermediates in the synthesis of tapentadol.
  • Tapentadol (I) acts as an agonist of ⁇ -opioid receptors and an inhibitor of noradrenaline reuptake. It has been developed in the form of hydrochloride of (27?,3i?)-enantiomer by the firm Johnson & Johnson based on development of the firm Gruenenthal, as a general analgetic.
  • tapentadol is produced from (25 , ,35)- 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?,3 ?)-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 /ZnCl2, to (2Z?,3i?)-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 diastereoselective 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 diastereoselective hydrogenation with formation of (2R,3R)- C, accompanied by a (2R,3S)-C epimer as a by-product.
  • Disadvantages involve formation of diastereoisomeric mixtures and the necessity of stereo-chemical purification of products at the end of the synthesis.
  • 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 (i?, ⁇ )-dibenzoyltartaric acid, and reacting its (iS)-enantiomer with ethylmagnesium bromide with formation of the (2 1 S',35 , )-stereo-isomer of compound A as a predominating stereo-isomer.
  • D l -dimethylamino-3-(3-methoxyphenyl)-2-methyl-l - propanone
  • the present invention provides production of optically pure or enriched O-substituted (2/?,3i?)-3-(3-hydroxyphenyl)-2-methyl-4-pentenoic acids of general formula II wherein R stands for H, an alkyl group with 1 to 4 carbon atoms, e.g. methyl, ethyl, isopropyl or tert-butyl group, or benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
  • the invention provides a new effective method of producing tapentadol of formula I
  • O-Substituted (27?,3 ⁇ )-3-(3-hydroxyphenyl)-2-methyl-4-pentenoic acids of general formula II are new compounds, representing key intermediates in the synthesis of pure tapentadol. This statement is based on the experimental finding that the acids of general formula II are available in a highly diastereoselective process, followed by resolving, during which final diastereoisomeric purification takes also place.
  • R stands for an alkyl group with 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl or tert-butyl group, or benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
  • racemic acids of general formula ( ⁇ )-II;
  • R stands for an alkyl group with 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl or tert-butyl group, or benzyl or 4-methoxybenzyl, benzhydryl or trityl group, are resolved by crystallization of the salt of compound ( ⁇ )-II with a chiral base in suitable solvents, selected from the group of CI to C4 lower alcohols, acetone, methyl ethyl ketone, diethyl ether, tert-butyl methyl ether, ethyl acetate, dichloromethane and water, or their mixtures.
  • suitable solvents selected from the group of CI to C4 lower alcohols, acetone, methyl ethyl ketone, diethyl ether, tert-butyl methyl ether, ethyl acetate, dichloromethane and water, or their mixtures.
  • the present method of producing O-substituted (2/?,3i?)-3-(3-hydroxyphenyl)-2- methyl-4- pentenoic acids of general formula II, optically pure or optically enriched comprises the following steps:
  • dimethylaminopyridine tributylphosphine, lithium perchlorate, trimethylsilyl triflate, scandium or indium triflate, or tetrabromomethane.
  • Propionylation is performed in inert organic solvents, such as dichloromethane, chloroform, toluene, or under solvent-free conditions in temperature range of from 10 to 100°C.
  • the process is performed by heating alcohols of general formula IV, wherein R has the above mentioned meaning, with propionic anhydride without a solvent, in presence or absence of catalytic tetrabromomethane, to a temperature of from 30 to 100°C.
  • acylation of alcohols of general formula IV is carried out by the action of propionyl chloride in inert solvents.
  • a key step of the whole process includes rearrangement of cinnamyl propanoates of general formula III, wherein R stands for an alkyl group with 1 to 4 carbon atoms, e.g. methyl, ethyl, isopropyl or tert-butyl group, or benzyl or 4-methoxybenzyl, benzhydryl or trityl group; it comprises enolisation of the compounds of formula III by the action of a strong base of the type of metal amides in presence of a tertiary amine at low temperatures; the enolates generated then, during heating to higher temperatures, undergo rearrangement to expected ( ⁇ )- acids of general formula II.
  • R stands for an alkyl group with 1 to 4 carbon atoms, e.g. methyl, ethyl, isopropyl or tert-butyl group, or benzyl or 4-methoxybenzyl, benzhydryl or trityl group; it
  • the enolisation is carried out in excess of both metal amide, e.g. lithium hexamethyldisilazide or lithium diisopropylamide, and tertiary amine, e.g. triethylamine, in an amount of at least 2 equivalents, preferably 2.5 to 3 equivalents, in the temperature range of from -40 to -80°C, preferably from -60 to -70°C.
  • metal amide e.g. lithium hexamethyldisilazide or lithium diisopropylamide
  • tertiary amine e.g. triethylamine
  • the rearrangement takes place during gradual heating of the reaction mixture to the laboratory temperature.
  • the process is performed in inert organic solvents, preferably in toluene.
  • the whole process is highly diastereoselective and provides racemic diastereoisomer having the relative configuration shown in formula II with high selectivity.
  • Diastereoselectivity of the rearrangement is only slightly influenced by the temperature during metalation; this procedure provides the compound of formula II with an erythro : threo ratio of diastereoisomers 25 : 1 to 35 : 1.
  • the temperature at which the enolisation is carried out is of key importance for reaching high chemical yield.
  • a great advantage of protecting groups R consists in that the produced (2 ⁇ ,3i?)-acids of general formula II are generally crystalline substances. This particularly relates to acids in which R is phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group.
  • R is phenylmethyl group, substituted or non-substituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, benzhydryl or trityl group.
  • a product of an erythro : threo diastereoisomeric purity higher than 99 : 1 is then prepared in high yield of more than 85% by crystallization of - the crude acid Ila from suitable solvents, such as hexane, heptane, toluene, petroleum ether, or their mixtures with diethyl ether, tert-butyl methyl ether.
  • suitable solvents such as hexane, heptane, toluene, petroleum ether, or their mixtures with diethyl ether, tert-butyl methyl ether.
  • the process is performed in suitable solvents, such as lower alcohols with 1 to 4 carbon atoms, e.g. methanol, ethanol, 2-propanol, tert-butanol, or ketones, e.g. acetone or methyl ethyl ketone, or ethyl acetate, or dichloromethane, or their mixtures.
  • suitable solvents such as lower alcohols with 1 to 4 carbon atoms, e.g. methanol, ethanol, 2-propanol, tert-butanol, or ketones, e.g. acetone or methyl ethyl ketone, or ethyl acetate, or dichloromethane, or their mixtures.
  • ethers e.g. diethyl ether or tert-butyl methyl ether
  • the resolving is carried out in mixtures of the said solvents with water. During resolving, effective diastereoselective pur
  • a considerable purifying effect can also be attained by stirring the isolated salt with a suitable solvent, such as dichloromethane or methyl tert-butyl ether.
  • a suitable solvent such as dichloromethane or methyl tert-butyl ether.
  • stirring of the salt in dichloromethane results in increasing the content of the R,R enantiomer in the mixture from 93.6% to 98.7%.
  • the acid of general formula II is isolated from the resolved salt by standard procedures, e.g. acidification followed by aspiration (in case of solid acids), or usual extraction in other cases.
  • the method according to this invention includes, as a key step, production of racemic O-substituted (2 ?5 , ,3i?5)-3-(3-hydroxyphenyl)-2-methyl-4-pentenoic acids of general formula
  • R stands for an alkyl group with 1 to 4 carbon atoms, e.g. methyl, ethyl, isopropyl or tert-butyl group, or benzyl or 4-methoxybenzyl, benzhydryl or trityl group, in which cinnamyl propionates of general formula III
  • benzyl or 4- methoxybenzyl, benzhydryl or trityl group comprises enolisation of the esters of general formula III, wherein R has the above mentioned meaning, by the action of a strong base of the type of metal amides in presence of a tertiary amine at low temperatures; then the enolates generated undergo, during heating to higher temperatures, rearrangement to the expected racemic acids of general formula II.
  • the enolisation is carried out by means of an excess of both the metal amide, e.g. lithium hexamethyldisilazide or lithium diisopropylamide, and tertiary amine, e.g.
  • triethylamine in the amount of at least 2 equivalents, preferably 2.5 to 3 equivalents, 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 process is performed in inert organic solvents, preferably in toluene.
  • the whole process is highly diastereoselective and provides a racemic diastereoisomer with high selectivity.
  • compounds of general formula ( ⁇ )-II are obtained with an erythro : threo ratio of diastereoisomers of 25 : 1 to 35 : 1.
  • Crystallization of the crude acid Ila (R benzyl) from suitable solvents, such as hexane, heptane, toluene, petroleum ether, or their mixtures with diethyl ether, tert-butyl methyl ether, then provides a product with an erythro : threo diastereoisomeric purity higher than 99 : 1 , in a high yield of more than 85%.
  • the method according to this invention also includes production of O-substituted (2 ⁇ ,3/?)-3-(3-hydroxyphenyl)-2-methyl-4-pentenoic acids, optically pure or optically enriched, of general formula II, wherein R stands for an alkyl group with 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl or tert-butyl group, or benzyl or 4-methoxybenzyl, benzhydryl or trityl group, in which racemic O-substituted (2i?5,3 ?5)-3-(3-hydroxyphenyl)-2-methyl-4- pentenoic acids of general fo
  • R stands for an alkyl group with 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl or tert-butyl group, or benzyl or 4-methoxybenzyl, benzhydryl or trityl group,
  • the method is carried out in organic solvents, using, e.g., lower alcohols with 1 to 4 carbon atoms, e.g. methanol, ethanol, 2-propanol, tert-butanol; further, ketones, e.g. acetone or methyl ethyl ketone, or ethyl acetate, or their mixtures, are used.
  • Mixtures of the said solvents with ethers e.g. diethyl ether or tert-butyl methyl ether, can also be used.
  • the resolving is carried out in mixtures of the said solvents with water, wherein diastereoselective purification also takes place.
  • the isolated salt with the above said basic resolving agents is optically purified by recrystallization from the said solvents or their mixtures. Preferably, this can be carried by stirring the isolated salt with a chlorinated hydrocarbon, such as dichloromethane.
  • a chlorinated hydrocarbon such as dichloromethane.
  • Another aspect of the present invention comprises synthesis of tapentadol, which uses compounds of formula II, which,
  • R which stands for an alkyl group with 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl or tert-butyl group
  • 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 i-Bu-CO-Cl
  • step B the obtained compounds of general formula V
  • step C the obtained N,N-dimethylamides of general formula VI
  • step D the produced alkeneamines of general formula VII
  • step E the produced alkaneamines of general formula VIII
  • the obtained tapentadol is converted by the action of pharmaceutically acceptable acids to respective salts.
  • the method of producing tapentadol from the acids of general formula II, wherein R stands for an alkyl group with 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl or tert- butyl group comprises the following synthetic steps:
  • Step A The conversion of optically pure or optically enriched O-protected (2R,3R)- acids of general formula II to the activated compounds of general formula V, wherein X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR 1 , wherein R 1 stands for methyl or ethyl, or pivaloyloxyl group 0-CO-/-Bu, is carried out by means of activating agents:
  • the activating agents used are, for instance, 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, e.g. in chloroform, dichloromethane or toluene, in a temperature range of from 10°C to the boiling temperature of the mixture, preferably from 25°C to the boiling temperature of the mixture.
  • 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.
  • the activating agents used can also include alkyl chloroformates Cl-COOR 1 , wherein
  • R 1 has the above mentioned meaning, or the pivalic acid chloride t-Bu-CO-Cl.
  • a base e.g. triethylamine
  • an inert organic solvent in the temperature range of from 0°C to 50°C, preferably from 0 to 30°C.
  • the compounds of general formula V are not isolated or purified, but directly reacted with dimethylamine.
  • Step B The synthesis of N,N-dimethylamides of general formula VI from activated compounds of general formula V, wherein X stands for chloro or an alkoxycarbonyloxyl group O-CO-OR 1 , wherein R 1 stands for methyl or ethyl, or pivaloyloxyl group O-CO-t-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. of 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.
  • Step C The reduction of N,N-dimethylamides of general formula VI to amines of general formula VII is carried out by means of hydride agents based on aluminium, such as lithium hydrido aluminate or sodium bis(2-methoxyethoxy)hydrido aluminate, in an inert organic solvent, such as ethers, e.g. tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, or toluene, in a temperature range of from 20°C to the boiling temperature of the mixture, preferably from 20 to 100°C.
  • hydride agents based on aluminium such as lithium hydrido aluminate or sodium bis(2-methoxyethoxy)hydrido aluminate
  • an inert organic solvent such as ethers, e.g. tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, or toluene, in
  • the reduction of a compound of general formula VI is carried out by means of sodium bis(2-methoxyethoxy)hydrido aluminate in toluene at a temperature of from 25°C to the boiling temperature of the mixture, preferably from 60 to 10 °C.
  • Step D The saturation of the terminal double bond in the compound of general formula
  • VII is carried out by reduction with hydrogen on metal catalysts, such as e.g. palladium or platinum.
  • the hydrogenation is carried out in an inert organic solvent, such as lower alcohols, e.g. methanol, ethanol or isopropyl alcohol, or cyclic ethers, such as tetrahydrofuran or 1 ,4- dioxane, or ethyl acetate, or their mixtures, at a pressure of from 0. 1 to 5 MPa in a temperature range of from 10 to 60°C.
  • R stands for an alkyl group with 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl or tert-butyl group
  • dealkylation agents such as e.g. hydrobromic acid, boron tribromide, or trimethylsilyl iodide.
  • the obtained compound of formula I (tapentadol) is, if desired, finally converted, by the action of pharmaceutically acceptable acids, to a corresponding salt and purified by crystallization from a suitable organic solvent or a mixture of solvents, such as ethyl acetate, 2-propanol or methanol, or their combinations with water.
  • racemic acids of general formula II which are transformed, by the above said procedures, via racemic activated compounds of general formula V, 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 pivaloyloxyl group 0-CO-/-Bu
  • racemic 7V,N-dimethylamides of general formula VI wherein R has the above mentioned meaning
  • racemic alkeneamines of general formula VII wherein R stands for the same as above.
  • Tapentadol includes a procedure, which uses, as starting materials, compounds of formula II, wherein R stands for a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, the benzhydryl or trityl group,
  • Me denotes the methyl group is reduced by means of hydride agents in a suitable solvent
  • the obtained tapentadol is converted to the respective salts by the action of pharmaceutically acceptable acids, e.g. to the hydrochloride.
  • optically pure, optically enriched, or racemic is carried out by reduction with hydrogen on metallic catalysts, such as palladium on carbon or platinum.
  • the hydrogenation is performed in an inert organic solvent such as in C I to C3 lower alcohols, e.g. in methanol, ethanol or isopropyl alcohol, or in cyclic ethers, such as tetrahydrofuran, 2-methyl tetrahydrofuran or 1 ,4- dioxane, or in ethyl acetate, or in their mixtures, at a pressure of 0. 1 to 5 MPa in the temperature range of from 1 0 to 60°C, preferably 20 to 40°C.
  • the reduction can be conducted in the presence or absence of strong acids, such as hydrochloric or sulphuric acid.
  • hydrogen on Pd/C in the environment of an alcohol such as methanol or ethanol, or their mixtures with water, at a pressure of 0.1 to 2 MPa is used.
  • activating agents used include, e.g., 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 performed in the presence of a catalytic amount of dimethylformamide.
  • the process is carried out in the 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 point of the mixture, preferably from 25°C to the boiling point 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.
  • the chloride of formula X is not isolated or purified but directly reacted with dimethylamine.
  • N,N-dimethylamide of formula XI from the activated compound of formula X is carried out by reaction with dimethylamine in an inert organic solvent, in the temperature range of 0°C to 40°C, preferably at 10 to 25°C.
  • dimethylamine is used in the gaseous form or the form of an aqueous solution, or a salt, e.g. hydrochloride, in the presence of a base, such as triethylamine, or of an aqueous solution of an inorganic base, e.g. sodium or potassium carbonate or hydrogencarbonate.
  • ethers e.g. tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, or toluene
  • R stands for a phenylmethyl group, substituted or unsubstituted in the benzene ring, e.g. benzyl or 4-methoxybenzyl, the benzhydryl or trityl group,
  • Simultaneous saturation of the vinylic double bond and deprotection of O-protecting group R, which has the same meaning as above, in the compound of general formula II is achieved by reduction with hydrogen on metallic catalysts, e.g. palladium or platinum on carbon.
  • the hydrogenation is carried out in an inert organic solvent, such as in lower alcohols, e.g. in methanol, ethanol or isopropyl alcohol, or in cyclic ethers, such as tetrahydrofuran or 1 ,4-dioxane, or in ethyl acetate, or in their mixtures, at a pressure of 0. 1 to 5 MPa in the temperature range of 1 0 to 60°C, preferably 20 to 40°C.
  • the reduction can be carried out in the presence or absence of strong acids, e.g. hydrochloric or sulphuric acid.
  • hydrogen on Pd/C in the environment of an alcohol e.g. methanol or ethanol, or their mixtures with water, at a pressure of 0.1 to 2 MPa, is used.
  • optically pure, optically enriched, or racemic is a new compound and represents a key intermediate in the production of tapentadol.
  • the resulting compound of formula I (tapentadol) is finally converted, by the action of pharmaceutically acceptable acids, to a corresponding salt a purified by crystallization from a suitable organic solvent, such as ethyl acetate, 2-propanol or methanol, or mixtures of such solvents with water.
  • a suitable organic solvent such as ethyl acetate, 2-propanol or methanol, or mixtures of such solvents with water.
  • Tapentadol or (2 ?,3 ?)-A ⁇ ,N-dimethyl-3-(3-hydroxyphenyl)-2-methylpentylamine by its chemical name, and its salts are prepared by the above described procedures in a chemical and/or optical purity higher than 99.5%.
  • the mixture is stirred at - 65°C for 2.5 h and then left to heat up spontaneously (within about 3 h) to the laboratory temperature.
  • the reaction mixture is poured into 1270 ml of 5 % sodium hydroxide (the mixture spontaneously heats up to ca. 30 °C), stirred for 10 min, and diluted with 200 ml of methyl tert-butyl ether (MTBE) and 200 ml of water.
  • MTBE methyl tert-butyl ether
  • the product is extracted with l x 500 ml and 2x 250 ml of MTBE.
  • the combined organic extracts are dried with Na 2 S0 4 , and, after filtration, evaporated in a rotating vacuum evaporator.
  • the reaction mixture is poured into 570 ml of 5 % sodium hydroxide, stirred for 10 min, and the phases are separated.
  • the aqueous phase is shaken with 2x 100 ml of methyl tert-butyl ether (MTBE), cooled in an ice bath, and acidified by dropwise adding of 95 ml of concentrated hydrochloric acid.
  • the product is extracted with 2x 150 ml MTBE.
  • the combined extracts are dried with Na 2 S0 4; filtered, and evaporated in a rotating vacuum evaporator.
  • reaction mixture cooled in an ice bath to 5°C is added gradually under stirring to 500 ml of a cooled saturated solution of ammonium chloride. Then, 1 N hydrochloric acid (500 ml) and, thereafter, concentrated hydrochloric acid (145 ml) are added. Methyl tert-butyl ether (MTBE; 400 ml) is added and the mixture is stirred for another 30 minutes. The aqueous phase is separated and shaken with MTBE (400 ml, 150 ml). The combined organic portions are washed with 0.5 N sodium hydroxide (380 ml), water (380 ml), and brine (350 ml).
  • MTBE Methyl tert-butyl ether
  • a suspension of 15 g (84 mmol) of 3-methoxycinnamic acid in 200 ml of dried toluene is cooled down in an ice bath under nitrogen atmosphere, and a 1 M solution of diisobutylalane in toluene (280 ml, 280 mmol) is then added dropwise within 30 min with the temperature kept within the range of -15 to 0°C.
  • the formed yellow solution is stirred in an ice bath for 20 min and at the laboratory temperature overnight.
  • the reaction mixture is cooled down in an ice bath, 12 ml of methanol is added dropwise, and then 200 ml of 2 M hydrochloric acid is added within 40 min.
  • the two-phase mixture is stirred at the laboratory temperature for 1 h and diluted with 150 ml of water.
  • the separated aqueous phase is additionally extracted with ethyl acetate (2x 100 ml).
  • the combined organic portions are washed with 2x 100 ml of 2 M sodium hydroxide and 100 ml of brine, dried with Na 2 S0 4 , and evaporated in a rotating vacuum evaporator.
  • 12.22 g (88 %) of alcohol of general formula II: R Me) is obtained as a yellow oil.
  • Benzyl triethylammonium chloride (2.14 g; 9.4 mmol), potassium carbonate (162.4 g; 1 .1 75 mol), and dimethylformamide (470 ml) are added to 90.36 g (0.47 mol) of ethyl-(E)-3 ' - hydroxy cinnamate under N 2 and the mixture is stirred at 25°C until most of the substance is dissolved. Then. 101 ml of benzyl bromide is added and the mixture is heated to 80°C (bath). The residual amount of benzyl bromide (38.8 ml; total of 1 .175 mol, 2.5 eq.) is added after two hours and the mixture is stirred at the same temperature for 20 h.
  • the reaction mixture is diluted with ice-cold water (825 ml) and extracted three times with ether (500 ml, 300 ml, 150 ml).
  • the combined organic phases are washed with water (200 ml) and brine (150 ml), and, after drying (Na 2 S0 4 ) and filtration, evaporated in a rotating vacuum evaporator.
  • the oily evaporation residue is then connected to an oil vacuum pump and the volatile portion (boiling point 44 to 45°/13 Pa) is distilled off.
  • the distillation residue is cooled, mixed with hexane or light petroleum (about 125 ml), and optionally seeded.
  • a 1 M solution of diisobutylalane in toluene (51 ml, 51 mmol) is added dropwise to a solution of 8.0 g (23 mmol) of benzyl-(£)-3 ' -benzyloxy cinnamate in 55 ml of dry toluene at - 15°C within 15 min, maintaining the temperature to be ⁇ -5°C.
  • the reaction mixture is stirred for 2.5 h; then, the reaction is quenched by the addition of 30 ml of a saturated solution of ammonium chloride and 30 ml of 2M HC1.
  • the substance can be isolated in the form of a crystalline hydrochloride, which is prepared by adding a solution of hydrogen chloride in Et 2 0 to a solution of the above described base in isopropyl alcohol.
  • the mixture is stirred at the laboratory temperature for 1 h, filtered through a layer of diatomaceous earth, and diluted with 10 ml of water and 20 ml of ethyl acetate. Layers are separated and the organic portion is washed with 2x 20 ml of 1 M hydrochloric acid.
  • the combined acidic aqueous portions are basified with 30 ml of 2M sodium hydroxide, and extracted with 2x 20 ml of ethyl acetate.
  • the hydrogenation vessel is rinsed with hydrogen three times and then hydrogenated at 450 kPa at the laboratory temperature for 16 hours.
  • the catalyst is filtered off and washed with methanol.
  • the dripping funnel is rinsed with another 5 ml of toluene and the reaction mixture is heated at 100°C (bath) under a reflux condenser in an inert atmosphere for 1 h, left to cool down to the laboratory temperature in 20 minutes and decomposed by gradual dropwise addition of 1 .5 ml of water and 2 ml of a 10% sodium hydroxide solution.
  • the mixture is stirred at the laboratory temperature for 15 min, 30 ml of water are added and the mixture is stirred for further 45 minutes.
  • the suspension is filtered over a kieselguhr layer, and the filter is washed with 20 ml of ethyl acetate.
  • the filtrate is extracted with 3x 20 ml of 1 M hydrochloric acid.
  • the combined acidic aqueous fractions are neutralized with a 2M solution of sodium hydroxide (pH ca. 7) and extracted with 1 x50 ml and 2x 25 ml of ethyl acetate.
  • the combined extracts are washed with l x 25 ml of brine, dried with Na 2 S04, and evaporated in vacuo in a rotatory vacuum evaporator. 2.04 g (85.3 %) of crude tapentadol of formula I are obtained.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention a pour objet des composés de la formule générale II qui sont nouveaux et représentent d'importants intermédiaires dans la synthèse de tapentadol. Dans la synthèse de tapentadol de formule I et de ses sels pharmaceutiquement acceptables, des acides (2R, 3R) O-protégés de formule générale II, dans l'étape A, sont mis à réagir dans un solvant organique inerte avec un agent activateur, facultativement en présence d'un catalyseur ou d'une base ; dans l'étape B, les composés obtenus de formule générale V, dans laquelle R possède la signification mentionnée ci-dessus et X représente le chlore ou un groupe alcoxycarbonyloxyle O-CO-OR1 ou un groupe pivaloyloxyle O-CO-t-Bu, où R1 est un méthyle ou un éthyle, sont mis à réagir avec de la diméthylamine ou ses sels facultativement en présence d'une base ; dans l'étape C, les N, N-diméthylamides obtenus de formule générale VI, dans laquelle R possède la signification mentionnée ci-dessus, sont réduits au moyen d'agents hydrure dans un solvant approprié ; dans l'étape D, les alcène amines produites de formule générale VII, dans laquelle R possède la signification mentionnée ci-dessus, sont hydrogénées sur un catalyseur métallique dans un solvant approprié ; et, finalement, dans l'étape E, les alcane amines produites de formule générale VIII, dans laquelle R possède la signification mentionnée ci-dessus, sont O-désalkylées au moyen d'agents de désalkylation, et, si nécessaire, le tapentadol obtenu est converti par l'action d'un acide pharmaceutiquement acceptable en sels respectifs, par exemple le chlorhydrate.
PCT/CZ2011/000128 2010-12-30 2011-12-30 Acides (2r, 3r)-3-(3-hydroxyphényle)-2-méthyl-4-penténoïques o-substitués et leur procédé d'obtention WO2012089181A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
HU1300623A HUP1300623A2 (en) 2010-12-30 2011-12-30 O-substituted (2r,3r)-3-(3-hidroxiphenil)-2-metyil-4-pentenoic acids and a method of obtaining the same

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CZPV2010-995 2010-12-30
CZ20100998A CZ2010998A3 (cs) 2010-12-30 2010-12-30 Zpusob výroby (2R,3R)-N,N-dimethyl-3-(3-hydroxyfenyl)-2-methylpentylaminu (tapentadolu)
CZPV2010-996 2010-12-30
CZ20100996A CZ303116B6 (cs) 2010-12-30 2010-12-30 Zpusob výroby O-substituovaných kyselin (2R,3R)-3-(3-hydroxyfenyl)-2-methyl-4-pentenových
CZPV2010-998 2010-12-30
CZ20100995A CZ2010995A3 (cs) 2010-12-30 2010-12-30 Zpusob výroby (2R,3R)-N,N-dimethyl-3-(3-hydroxyfenyl)-2-methylpentylaminu

Publications (1)

Publication Number Publication Date
WO2012089181A1 true WO2012089181A1 (fr) 2012-07-05

Family

ID=45606889

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2011/000128 WO2012089181A1 (fr) 2010-12-30 2011-12-30 Acides (2r, 3r)-3-(3-hydroxyphényle)-2-méthyl-4-penténoïques o-substitués et leur procédé d'obtention

Country Status (2)

Country Link
HU (1) HUP1300623A2 (fr)
WO (1) WO2012089181A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014067281A1 (fr) * 2012-10-31 2014-05-08 合肥市新星医药化工有限公司 Forme cristalline c de chlorhydrate de tapentadol, son procédé de préparation et son application
EP3166923A4 (fr) * 2014-07-10 2018-02-21 Mallinckrodt LLC Procédé pour préparer des phénylalcanes substitués

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004108658A1 (fr) * 2003-06-06 2004-12-16 Grünenthal GmbH Procede de production des composes d'amine 3-aryle-butyle substitue
WO2007051576A1 (fr) * 2005-11-02 2007-05-10 Grünenthal GmbH Procede de fabrication de composes dimethyl-(3-arylbutyl)amine substitues a l’aide d’une catalyse homogene
WO2008012283A1 (fr) * 2006-07-24 2008-01-31 Janssen Pharmaceutica Nv Préparation de (2r,3r)-3-(3-méthoxyphényl)-n,n,2-triméthylpentanamine
WO2008012046A1 (fr) * 2006-07-24 2008-01-31 Grünenthal GmbH Élaboration de 3-[(1r,2r)-3-(diméthylamino)-1éthyl-2-méthylpropyl]phénol

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004108658A1 (fr) * 2003-06-06 2004-12-16 Grünenthal GmbH Procede de production des composes d'amine 3-aryle-butyle substitue
WO2007051576A1 (fr) * 2005-11-02 2007-05-10 Grünenthal GmbH Procede de fabrication de composes dimethyl-(3-arylbutyl)amine substitues a l’aide d’une catalyse homogene
WO2008012283A1 (fr) * 2006-07-24 2008-01-31 Janssen Pharmaceutica Nv Préparation de (2r,3r)-3-(3-méthoxyphényl)-n,n,2-triméthylpentanamine
WO2008012046A1 (fr) * 2006-07-24 2008-01-31 Grünenthal GmbH Élaboration de 3-[(1r,2r)-3-(diméthylamino)-1éthyl-2-méthylpropyl]phénol

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014067281A1 (fr) * 2012-10-31 2014-05-08 合肥市新星医药化工有限公司 Forme cristalline c de chlorhydrate de tapentadol, son procédé de préparation et son application
EP3166923A4 (fr) * 2014-07-10 2018-02-21 Mallinckrodt LLC Procédé pour préparer des phénylalcanes substitués

Also Published As

Publication number Publication date
HUP1300623A2 (en) 2014-03-28

Similar Documents

Publication Publication Date Title
KR101766503B1 (ko) 타펜타돌의 제조 방법 및 이의 중간체
WO2011092719A2 (fr) Procédé de préparation de dérivés l-phényl-3-diméthylaminopropane
CN106336349A (zh) 溴代三氟甲氧基化合物及其合成方法
EP2403823A2 (fr) Procédé de préparation de cinacalcet et de ses sels, et intermédiaires destinés à être utilisés dans le procédé
NO328015B1 (no) Nye hydronaftalenforbindelsen fremstilt ved rhodiumkatalysert ringapningsreaksjon i naervaer av fosfinligand, samt preparater som innbefatter slike forbindelser
AU2008344922A2 (en) Chromane derivatives as TRPV3 modulators
MX2008013539A (es) Produccion de intermediarios de amino alcohol quiralmente puros, derivados de los mismos, y usos de los mismos.
AU2017200463B2 (en) The process for the preparation of metaraminol
WO2012062229A1 (fr) Procédé de fabrication du composé (-)-l-(3-hydroxypropyl)-5-[(2r)-2-({2,2,2-trifluoroéthoxy)-phénoxyéthyl}amino)propyl]-2,3-dihydro-lh-indole-7-carboxamide
US8552219B2 (en) Process for preparing L-phenyl-3-dimethylaminopropane derivative
WO2012089177A1 (fr) Procédé de production de (2r,3r)-na-diméthyl-3-(3-hydroxyphényle)-2-méthylpentylamine (tapentadol)
WO2012089181A1 (fr) Acides (2r, 3r)-3-(3-hydroxyphényle)-2-méthyl-4-penténoïques o-substitués et leur procédé d'obtention
JP5748848B2 (ja) 窒素置換（ｓ）−５−アルコキシ−２−アミノテトラリン誘導体の分割方法
EP2674414A1 (fr) Appareils dýimpression
FR2645532A1 (fr) Composes ammonium quaternaire ayant une activite myorelaxante et leur procede de preparation
JP4540197B2 (ja) （ｅ）−３−メチル−２−シクロペンタデセノンの製造法
EA026224B1 (ru) Способ получения 3,4-диметоксибицикло[4.2.0]окта-1,3,5-триен-7-карбонитрила и применение для получения ивабрадина и его солей присоединения с фармацевтически приемлемой кислотой
CZ302993B6 (cs) Zpusob výroby (2R,3R)-N,N-dimethyl-3-(3-hydroxyfenyl)-2-methylpentylaminu (tapentadolu)
CZ2010996A3 (cs) Zpusob výroby O-substituovaných kyselin (2R,3R)-3-(3-hydroxyfenyl)-2-methyl-4-pentenových
CZ303115B6 (cs) Zpusob výroby (2R,3R)-N,N-dimethyl-3-(3-hydroxyfenyl)-2-methylpentylaminu
JP3134786B2 (ja) ２−アザビシクロ［３．３．０］オクタン誘導体とその製造法およびジオールまたはアミノアルコール類の光学分割法
CZ293791B6 (cs) Způsob výroby N,N-diisopropyl-3-(2-hydroxy-5-methylfenyl)-3-fenylpropylaminu v jeho racemické nebo opticky aktivní formě
JP2015516384A (ja) （ｓ）−エクオールを生成するための改善された方法
JP2004224740A (ja) 立体選択的なフルオロシクロプロパン誘導体の製造方法
TW201329061A (zh) 做為ｔｒｐｖ３調節劑的色原烷衍生物

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: 11817507

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2013/07659

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: 11817507

Country of ref document: EP

Kind code of ref document: A1