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• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B23—MACHINE TOOLS; METAL-WORKING NOT OTHERWISE PROVIDED FOR
  • B23C—MILLING
  • B23C5/00—Milling-cutters
  • B23C5/16—Milling-cutters characterised by physical features other than shape
  • B23C5/20—Milling-cutters characterised by physical features other than shape with removable cutter bits or teeth or cutting inserts
  • B23C5/22—Securing arrangements for bits or teeth or cutting inserts
  • B23C5/24—Securing arrangements for bits or teeth or cutting inserts adjustable
  • B23C5/2472—Securing arrangements for bits or teeth or cutting inserts adjustable the adjusting means being screws
• • 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
  • C07C213/10—Separation; Purification; Stabilisation; Use of additives
• • 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
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T407/00—Cutters, for shaping
  • Y10T407/22—Cutters, for shaping including holder having seat for inserted tool
  • Y10T407/2222—Tool adjustable relative to holder

Definitions

• the present invention relates to an improved process for the preparation of 3-[(2R,3R)-l- (dimethylamino)-2-methylpentan-3-yl]phenol of Formula - I and its pharmaceutically acceptable salt.
• the compound 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - 1 and its hydrochloride salt having international non proprietary name as tapentadol hydrochloride is a centrally - acting analgesic with a dual mode of action as an agonist at the ⁇ -opioid receptor and as a norepinephrine reuptake inhibitor.
• the compound of Formula - IV is converted to its base and subjected to enantiomeric separation using chiral HPLC column to obtain (2S,3R)-l-(dimethylamino)-3-(3-methoxyphenyl)-2- methylpentan-3-ol of Formula - V, which on chlorination using thionyl chloride forms (2S,3R)-3-chloro-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine of Formula - VI.
• WO2004/108658 ('658) describes process for the preparation of (2R,3R)-3-(3- methoxyphenyl)-N,N,2-trimethylpentan-l -amine of Formula - VII, the penultimate intermediate to prepare tapentadol, wherein the compound (2S,3S)-l-dimethylamino-3- (3-methoxyphenyl)-2-methylpentan-3-ol of Formula - VA, is heated in acidic medium to get intermediate compound (Z,E)-(R)-[3-(3-methoxyphenyl)-2-methyl-pent-3-enyl]- dimethylamine HC1 of Formula - X, which on catalytic hydrogenation yields enantiomeric mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine of Formula - VII and (2R,3S)-3-(3-methoxyphenyl)-N,N,
• WO2005/000788 describes another method of preparing tapentadol, wherein compound (2S,3S)-l-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3-pentanol of Formula - VA is subjected to dehydration reaction using heterogeneous catalyst to get intermediate compound (Z,E)-(S)-[3-(3-methoxyphenyl)-2-methyl-pent-3-enyl]-dimethyl amine hydrochloride of Formula - X, which on catalytic reduction yields enantiomeric mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l -amine of Formula - VII and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l -amine of Formula - VIIA The required stereoisomer is separated to get (2R,3R)-3-
• WO2008/012Q46 describes another method for the preparation of tapentadol, wherein l-(3-(benzyloxy)phenyl)propan-l-one is reacted with N-Methyl-N-methylene- methaneaminium chloride in presence of acetyl chloride and solvent acetonitrile to obtain compound 1 -(3-(benzyloxy)phenyl)-3-(dimethylamino)-2-methylpropan-l-one. The compound is resolved with L-(-)-dibenzoyltartaric acid to get (S)-l-(3- (benzyloxy)phenyl)-3-(dimethylamino)-2-methylpropan-l-one.
• the isolated compound is then reacted with ethyl magnesium bromide undergoing Grignard reaction to isolate (2S,3R)-3-(3-(benzyloxy)phenyl)-l-(dimethylamino)-2-methylpentan-3-ol, which on reaction with trifluoroacetic anhydride in acetic acid results in acetylated compound.
• the acetylated compound on hydrogenolysis results in the compound 3-[(2R,3R)-l- (dimethylamino)-2-methylpentan-3-yl]phenol of Formula - 1.
• WO2008012047 describes yet another method for the preparation of tapentadol, wherein l-(3-methoxyphenyl)propan-l-one is reacted with dimethylamine hydrochloride and paraformaldehyde under Mannich reaction condition to get 3-(dimethylamino)-l-(3- methoxyphenyl)-2-methylpropan-l-one hydrochloride, which after treating with sodium hydroxide is reacted with (2R,3R)-0,0'-dibenzoyl tartaric acid monohydrate to get (S)-3- (dimethylamino)-l-(3-methoxyphenyl)-2-methylpropan-l-one L-(-)-dibenzoyltartarate.
• the dibenzoyltartrate salt is further reacted with diethylamine to isolate keto compound (S)-3-(dimethylamino)-l-(3-methoxyphenyl)-2-methylpropan-l-one.
• the keto compound is reacted with ethyl magnesium halide under Grignard condition to isolate the compound (2S,3R)-l -(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol.
• the present inventors have come out with an improved process which ameliorates the problems in the prior art by carrying out regioselective one pot demethylation and dehydration reaction reducing the number of steps and carrying out chemical purification thus avoiding the resolution or chromatographic separation of the required isomer and use of catalyst to improve the yield, safety and economy for the preparation of the compound 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - 1.
• the advantage of the process lies in the simultaneous demethylation and dehydration in single step maintaining the chiral purity of the intermediate compound and reducing the number of steps to prepare the compound of Formula - 1.
• the main objective of the present invention is to prepare 3-[(2R,3R)-l-(dimethylamino)- 2-methylpentan-3-yl]phenol of Formula - I and its pharmaceutically acceptable salt by robust, rigid and industrial friendly process.
• Yet another objective of the present invention is to carry out regioselective one pot demethylation and dehydration reaction of the compound (2S,3R)-l-(dimethyIamino)-3- (3-methoxyphenyl)-2-methyl pentan-3-ol of Formula - V.
• Another objective of the present invention is to prepare 3-[(2R,3R)-l-(dimethylamino)-2- methylpentan-3-yl]phenol of Formula - I and its pharmaceutically acceptable salt by reduced number of steps of the reaction.
• the present invention provides a process for the preparation of 3- [(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - I, comprising reacting (2S,3R)-1 -(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol of Formula - V with a mixture of methanesulfonic acid and dimethyl sulfide, which undergoes demethylation along with dehydration of tertiary hydroxyl group to yield the compound (2R)-3-(3-hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l -amine of Formula VIII;
• Formula - VIII In another aspect of the present invention the compound of Formula VIII is reacted with an acid to get acid addition salt, which on catalytic hydrogenation in presence of solvent yields mixture of diastereomeric compounds 3-[(2R,3R)-l-(dimethylamino)-2- methylpentan-3-yl]phenol of Formula - I and 3-[(2R,3S)-l -(dimethylamino)-2- methylpentan-3-yl]phenol of Formula - 1 A;
• the mixture of diastereomeric compounds of Formula - I and Formula - IA on reaction with base followed by reaction with an acid yields corresponding acid addition salt which on purification in an organic solvent yields pharmaceutically acceptable salt of the compound 3-[(2R,3R)-l-(dimethylamino)-2- methylpentan-3-yl]phenol of Formula - 1.
• optically pure in the context of the present invention means the chiral isomeric purity exceeding 99.5%.
• substantially free in the context of the present invention means the stated product is free from contamination of stated impurities at least less than 0.5%, preferably less than 0.1% and most preferably less than 0.05%.
• the present invention provides a process for the preparation of 3-[(2R,3R)-l- (dimethylamino)-2-methylpentan-3-yl]phenol [Tapentadol] of Formula - I and its pharmaceutically acceptable salt.
• the compound (2S,3R)-l-(dimethylamino)-3- (3-methoxyphenyl)-2 -methyl pentan-3-ol of Formula - V undergoes demethylation along with dehydration of tertiary hydroxyl group on reaction with mixture of methanesulfonic acid and dimethyl sulfide to yield the compound (2R)-3-(3-hydroxyphenyl)-N,N,2- trimeihyl-3-pentene-l -amine of Formula - VIII.
• the mixture of methanesulfonic acid to dimethyl sulfide is taken in the ratio of 10:3.
• the preferred ratio of the mixture of methanesulfonic acid and dimethyl sulfide taken for the reaction is 8:2, wherein the most preferred ratio of methanesulfonic acid to dimethyl sulfide mixture is 4: 1.
• the reaction is carried out at temperature in the range of -10°C to 60°C.
• the preferred temperature for the reaction is -5°C to 55°C, wherein the most preferred temperature for the reaction is 0°C to
• solvent selected from n-hexane, diisopropyl ether, diethyl ether, dichloromethane, dichloroethane, ethyl acetate and methyl isobutyl ketone.
• the preferred solvents used for extraction are ethyl acetate, dichloromethane and methyl isobutyl ketone, wherein the most preferred solvent used is ethyl acetate.
• the compound (2S,3R)-l-(dimethylamino)-3-(3-methoxyphenyl)-2 -methyl pentan-3-ol of Formula - V used in the present invention can be prepared as per the available prior art or by the following scheme - 3 wherein the compound 3-pentanone together with formaldehyde and dimethylamine hydrochloride undergoes stereoselective Mannich reaction in presence of L-proline and solvent n-butanol, to give (S)-l-(dimethylamino)-2- methylpentan-3-one, which on Grignard reaction with 3-bromoanisole yields the compound (2S,3R)-l-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol of Formula - V.
• the compound (2R)-3-(3- hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l -amine of Formula - VIII was reacted with aqueous hydrochloric acid solution in presence of solvent selected from acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and ethyl isopropyl ketone to isolate the hydrochloride salt of (2R)-3-(3-hydroxyphenyl)-N,N,2-trimethyl-3-pentene- 1-amine of Formula VIII.
• solvent used is acetone and methyl ethyl ketone, wherein the most preferred solvent used is acetone.
• the compound (2R)-3-(3- hydroxyphenyl)-N,N,2-trimethyl-3-pentene-l -amine of Formula - VIII or its hydrochloride salt was taken for catalytic hydrogenation in presence of solvent at a pressure of 5 kg/cm 2 to 8 kg/cm 2 and temperature of 25 - 40°C to get the mixture of diastereomeric compounds of 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3- yfjphenol of Formula - 1 and 3-[(2R,3S)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - IA.
• the solvent for the catalytic hydrogenation reaction is selected from methanol ethanol, n-propanol and isopropanol, wherein the most preferred solvent used for hydrogenation reaction is methanol.
• the catalyst used for the hydrogenation reaction is selected from platinum or palladium, preferably palladium in the form of Palladium on carbon or palladium (II) chloride. It is preferable for the invention the catalyst used in the process is Palladium on carbon.
• the quantity of the catalyst used is 1 wt % to 10 wt%, the preferred is 5 wt % to 10 wt %, wherein the most preferred quantity used is 10 wt % of Palladium on carbon.
• the mixture of diastereomeric compounds of 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - 1 and 3-[(2R,3S)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - IA is converted to their hydrochloride salt by suspending the residual mass in solvent acetone or mixture of acetone and methanol and purging hydrochloric acid gas till pH is 6 - 6.5. Cooled the reaction mixture to 0 - 5°C and maintained under stirring for 2 - 3 hours.
• the hydrochloride salt of diastereomeric compounds of 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - I and 3-[(2R,3S)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - IA is purified using solvent selected from C1-C4 linear or branched alcohol either single or mixture thereof and an anti-solvent selected from ketone to isolate pure isomer 3-[(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - I substantially free of its isomeric impurity of 3-[(2R,3S)-l-(dimethylamino)-2- methylpentan-3-yl]phenol of Formula - IA.
• the solvent C1 -C4 linear or branched alcohol used for the purification are selected from methanol, ethanol, n-propanol, isopropanol and butanol, the preferred solvent used are methanol, ethanol and isopropanol wherein the most preferred solvent used is methanol.
• the anti-solvent ketones used are selected from acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and ethyl isopropyl ketone.
• the preferred anti-solvent used is acetone and methyl ethyl ketone, wherein the most preferred anti-solvent used is acetone.
• the temperature used for the purification is 50°C to the reflux temperature of the alcoholic solvent used, whereas the preferred temperature for the purification is between 50°C to 90°C.
• the mixture of hydrochloride salt of diastereomeric compounds of 3- [(2R,3R)-l-(dimethylamin0)-2-methylpentan-3-yl]phenol of Formula - 1 and 3-[(2R,3S)- l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - IA was taken in methanol and raised the temperature under stirring to 65°C ⁇ 2°C. Charged antisolvent acetone slowly, maintaining the temperature at 65°C ⁇ 2°C and maintained the reaction mass at the same temperature for 30 minutes. Cooled the reaction mass slowly to 20 - 25°C and maintained for 1.0 hour.
• the present invention provides optically pure compound 3- [(2R,3R)-l-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula - 1 substantially free from the stereoisomer especially with no detectable amount of 3-[(2R,3S)-l- (dimethylamino)-2-methylpentan-3-yl]phenol of Formula - IA.
• the sequence of present invention is represented as shown in scheme - 4 below;
• reaction mass After complete reaction cooled the reaction mass to 25 - 30°C.Quenched reaction mass in ice cold water (600 ml) and cooled to 5°C. Adjusted pH of the aq. layer to 9 - 10 with 45 % aqueous sodium hydroxide solution. Extracted the aqueous solution with ethyl acetate (3 x 100 ml) and separated the organic layer. Concentrated the organic layer under reduced pressure below 50°C to get the residual mass. Charged solvent acetone (210 ml) and started addition of concentrated hydrochloric acid slowly maintaining temperature at 20 - 25°C to adjust the pH of the reaction mass to 6.5 - 7.0. Maintained the reaction mass under stirring at 20-25°C for 2.0 hours.

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• 2012
  • 2012-11-08 WO PCT/IN2012/000735 patent/WO2013105109A1/fr not_active Ceased

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