Novel process for preparing highly pure tapentadol or a pharmaceutically acceptable salt thereof
AssigneeActavis Group Ptc Ehf
InventorsMayur Devjibhai Khunt, Sandipan Prabhurao Bondge, Nilesh Sudhir Patil, Haushabhau Shivaji Pagire, Nitin Sharadchandra Pradhan
Life of this patent
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Abstract
Provided herein is a novel, commercially viable and industrially advantageous process for the preparation of 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol (Tapentadol), or a pharmaceutically acceptable salt thereof, and its intermediates, in high yield and purity. Provided also herein are novel solid state forms of tapentadol intermediates and processes for their preparation thereof. Provided further herein is a purification process for preparing highly pure tapentadol hydrochloride.
Claims21
A process for preparing tapentadol, 3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol, of formula I:
- or a pharmaceutically acceptable salt thereof, comprising
- a) reacting 3-hydroxypropiophenone of formula V:
- with N,N-dimethylamine hydrochloride in the presence of para-formaldehyde in a first solvent to produce a racemic 3-(dimethylamino)-1-(3-hydroxyphenyl)-2-methylpropan-1-one of formula IV:
- or an acid addition salt thereof;
- b) reacting the compound of formula IV or the acid addition salt thereof with an ethyl magnesium halide in a second solvent to produce a racemic mixture of (2R,3 S)/(2S,3R)-1-(Dimethylamino)-3-(3-hydroxyphenyl)-2-methylpentan-3-ol of formula III:
- or an acid addition salt thereof;
- c) treating the racemic mixture obtained in step-(b) with an optically active acid in a third solvent to produce a diastereomeric mixture containing a diastereomeric excess of a desired diastereomeric salt;
- d) separating the desired diastereomeric salt from the diastereomeric mixture obtained in step-(c);
- e) neutralizing the desired diastereomeric salt obtained in step-(d) with a base in a fourth solvent to produce an enantiomerically pure (2S,3R)-1-(Dimethylamino)-3-(3-hydroxyphenyl)-2-methylpentan-3-ol of formula II:
- and optionally converting the enantiomerically pure compound of formula II obtained into an acid addition salt thereof;
- and
- f) reacting the enantiomerically pure compound of formula II or the acid addition salt thereof obtained in step-(e) with trifluoroacetic anhydride in a fifth solvent to produce a reaction mass, followed by hydrogenating the reaction mass in the presence of a hydrogenation catalyst to produce the tapentadol of formula I, and optionally converting the tapentadol of formula I obtained into a pharmaceutically acceptable salt thereof.
Solid state form of a tapentadol intermediate selected from a racemic 3-(dimethylamino)-1-(3-hydroxyphenyl)-2-methylpropan-1-one hydrochloride salt, a racemic mixture of (2R,3 S)/(2S,3R)-1-(Dimethylamino)-3-(3-hydroxyphenyl)-2-methylpentan-3-ol, a racemic mixture of (2R,3 S)/(2S,3R)-1-(Dimethylamino)-3-(3-hydroxyphenyl)-2-methylpentan-3-ol hydrochloride salt, (2S,3R)-1-(Dimethylamino)-3-(3-hydroxyphenyl)-2-methylpentan-3-ol D-tartrate salt and (2S,3R)-1-(Dimethylamino)-3-(3-hydroxyphenyl)-2-methylpentan-3-ol, wherein:
- a) the solid state form of the racemic 3-(dimethylamino)-1-(3-hydroxyphenyl)-2-methylpropan-1-one hydrochloride salt is a crystalline form characterized by the following properties:
- i) a powder X-ray diffraction pattern having peaks at about 6.38, 7.34, 11.68, 13.81, 15.52, 16.9, 17.42, 17.67, 18.14, 18.51, 19.20, 20.47, 20.70, 20.96, 21.23, 21.58, 22.20, 23.55, 23.80, 24.16, 24.85, 25.53, 25.77, 26.31, 26.85, 27.39, 29.09, 30.99, 32.49 and 33.76±0.2 degrees 2-theta substantially in accordance with FIG. 1;
- ii) a powder X-ray diffraction pattern having peaks at about 6.42, 7.38, 11.71, 15.57, 18.19, 18.55, 19.26, 20.51, 20.77, 21.0, 22.25, 23.59, 23.85, 24.20, 25.81, 26.35, 26.87, 32.54 and 33.81±0.2 degrees 2-theta substantially in accordance with FIG. 2;
- b) the solid state form of the racemic mixture of (2R,3S)/(2S,3R)-1-(Dimethylamino)-3-(3-hydroxyphenyl)-2-methylpentan-3-ol is a crystalline form characterized by a powder X-ray diffraction pattern having peaks at about 12.1, 12.51, 13.13, 14.16, 14.7, 15.78, 17.25, 19.09, 21.28, 21.69, 22.01, 23.10, 23.4 and 24.36±0.2 degrees 2-theta substantially in accordance with FIG. 3;
- c) the solid state form of the racemic mixture of (2R,3S)/(2S,3R)-1-(Dimethylamino)-3-(3-hydroxyphenyl)-2-methylpentan-3-ol hydrochloride salt is a crystalline form characterized by a powder X-ray diffraction pattern having peaks at about 8.11, 9.27, 10.92, 13.30, 13.64, 14.62, 15.30, 18.32, 18.66, 19.65, 20.51, 20.90, 23.42, 23.93, 24.41, 25.25, 25.80, 27.32, 27.52, 29.59, 29.91, 30.22, 30.88, 31.63, 32.26, 35.34 and 36.43±0.2 degrees 2-theta substantially in accordance with FIG. 4;
- d) the solid state form of the (2S,3R)-1-(Dimethylamino)-3-(3-hydroxyphenyl)-2-methylpentan-3-ol D-tartrate salt is a crystalline form characterized by a powder X-ray diffraction pattern having peaks at about 5.78, 11.55, 15.86, 16.14, 17.35, 18.33, 18.88, 20.48, 21.24, 21.81, 23.17, 23.77, 28.59 and 29.07±0.2 degrees 2-theta substantially in accordance with FIG. 5;
- and
- e) the solid state form of the (2S,3R)-1-(Dimethylamino)-3-(3-hydroxyphenyl)-2-methylpentan-3-ol is a crystalline form characterized by a powder X-ray diffraction pattern having peaks at about 9.44, 11.25, 12.35, 12.83, 14.27, 15.6, 16.34, 17.85, 18.93, 21.42, 21.81, 22.63, 23.48, 24.91 and 25.92±0.2 degrees 2-theta substantially in accordance with FIG. 6.
9-11. (canceled)
A purification process for obtaining highly pure tapentadol hydrochloride substantially free of impurities of claim 9, comprising:
- a) providing a solution of tapentadol hydrochloride in a solvent or a solvent mixture at a temperature of above 40° C., wherein the solvent or the solvent mixture is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetonitrile, and mixtures thereof;
- b) optionally, subjecting the solution obtained in step-(a) to carbon treatment or silica gel treatment;
- and
- c) isolating and recovering the highly pure tapentadol hydrochloride substantially free of impurities from the solution obtained in step-(a) or step-(b), wherein the isolation is carried out by cooling the solution at a temperature of below 40° C.,
- wherein the highly pure tapentadol hydrochloride substantially free of impurities has one or more of a 3-[(1R,2S)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride impurity (isomer-A), a 3-[(1S,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride impurity (isomer-B) impurity, a 3-[(1S,2S)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol hydrochloride impurity (isomer-D), a ‘1.09 RRt’ impurity, a ‘1.14 RRt’ impurity, a ‘1.24 RRt’ impurity, a ‘1.47 RRt’ impurity and a ‘2.19 RRt’ impurity in an amount of less than about 0.15 area-% as measured by HPLC.
Dependencies are inferred from the claim text.