A NOVEL PROCESS FOR THE PREPARATION OF TAPENTADOL OR A

PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

FIELD OF THE INVENTION

[0001] The present invention relates to a novel, commercially viable and industrially advantageous process for the preparation of 3-[(li?,2i?)-3-(dimethylamino)-l-ethyl-2- methylpropyl]phenol (Tapentadol), or a pharmaceutically acceptable salt thereof, in high yield and purity. The present invention also relates to novel intermediates useful for preparing tapentadol or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

[0002] U.S. Patent No. 6,248,737 reissued as USRE39593 discloses a variety of l-phenyl-3- dimethylaminopropane compounds, processes for their preparation, pharmaceutical compositions comprising the compounds, and methods of use thereof. These compounds have the utility as analgesic active ingredients in pharmaceutical compositions. Among them, Tapentado 1 hydro chloride, 3 -[( 1 R,2R)-3 -(dimethylamino)- 1 -ethyl-2-methylpropyl]pheno 1 hydrochloride, is a centrally-acting analgesic with a unique dual mode of action as an agonist at the μ-opioid receptor and as a norepinephrine reuptake inhibitor. Tapentadol hydrochloride is represented by the followin structural formula:

[0003] Various processes for the preparation of tapentadol, its enantiomers and related compounds, and their pharmaceutically acceptable salts are disclosed in U.S. Patent Nos. USRE39593 and 6,344,558; and PCT Publication Nos. WO 2004/108658, WO 2005/000788, WO 2008/012046, WO 2008/012047 and WO 2008/012283.

[0004] As per the process exemplified in example 25 of the USRE39593 (hereinafter referred to as the '593 patent), (-)-(li?,2i?)-3-(3-dimethylamino-l-ethyl-2-methylpropyl)-phe nol hydrochloride is prepared by the reaction of (-)-(25',35)-l-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol hydrochloride with thionyl chloride to produce (-)- (25',35)-[3-chloro-3-(3-methoxyphenyl)-2-methylpentyl]-dimet hylamine hydrochloride; followed by subsequent removal of the 'CI' substituent by treatment with zinc boro hydride, zinc cyanoborohydride or tin cyanoborohydride, to produce (-)-(2i?,3i?)-[3-(3- methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride; which is then converted into (-)-(li?,2i?)-3-(3-dimethylamino-l-ethyl-2-methylpropyl)-phe nol hydrochloride by reaction with concentrated hydrobromic acid at reflux.

[0005] The synthesis of (2i?5',3i?5)-l-dimethylamino-3-(3-methoxyphenyl)-2-methylpen tan- 3-ol is described in the '593 patent. The separation of the diastereoisomers, that is the two enantiomeric pairs, is carried out by hydrochloride precipitation with trimethylchlorosilane/water in 2-butanone. The resolution of the racemic mixture of the two enantiomers of (2R,3R) and (2S,3S) configuration is carried by separation on a chiral HPLC column.

[0006] Methods involving column chromatographic separation of enantiomers on chiral stationary phases are generally undesirable for large-scale operations as they require additional expensive setup, adding to the cost of production, thereby making the processes commercially unfeasible.

[0007] U.S. Patent application No. 2008/0269524 (hereinafter referred to as the '524 application) discloses a resolution method for the separation of the two enantiomers from the enantiomeric pair, (2i?,3i?)/(25',35)-l-dimethylamino-3-(3-methoxyphenyl)-2-met hylpentan- 3-ol, with the aid of a chiral auxiliary, such as (+)-di-0,0'-p-toluyltartaric acid, (-)-di-0,0'- p-toluyltartaric acid and L-(+)-tartaric acid, in the presence of a suitable solvent such as 2- butanone.

[0008] However, the resolution method described in the '524 application suffers from the disadvantages such as high cost of reagents, lower yields of the product, longer process times (about 50 hours), repeated crystallizations/purifications, and health hazards.

[0009] PCT Publication No. WO 2008/012047 (hereinafter referred to as the '047 application) discloses a process for the preparation of tapentadol from 3-(Dimethylamino)-l- (3-methoxyphenyl)-2-methylpropan-l-one. The reaction involves resolving 3- (dimethylamino)- 1 -(3-methoxyphenyl)-2-methylpropan- 1 -one with (2R,3R)-0,0- 'dibenzoyltartaric acid monohydrate, followed by treatment with a base to produce (S)-3- (dimethylamino)-l-(3-methoxyphenyl)-2-methylpropan-l-one; which is then reacted with a Grignard reagent, preferably ethyl magnesium bromide, in an ether solvent to produce (2S,3R)-3-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan -3-ol, followed converting into its hydrochloride salt. The hydrochloride salt of (2S, 3R)-3-(dimethylamino)-3-(3- methoxyphenyl)-2-methylpentan-3-ol is then subjected to dehydration in the presence of an acid to produce (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-l -amine, followed by subsequent hydrogenation via homogeneous catalysis in the presence of hydrogen to produce a mixture of (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine and (2R,3R)-3- (3-methoxyphenyl)-N,N,2-trimethylpentan-l -amine. The mixture was then treated with hydrogen chloride in acetone to produce (2R,3R)-3-(3-methoxyphenyl)-N,N,2- trimethylpentan-1 -amine hydrochloride, which is then deprotected by reacting with a deprotecting agent to produce tapentadol, followed by converting into its hydrochloride salt.

[0010] The '047 application further describes a process for the preparation of tapentadol intermediate, 3-(dimethylamino)-l-(3-methoxyphenyl)-2-methypropan-l-one, by reacting 1- (3-methoxyphenyl)propan-l-one with dimethylamine hydrochloride, paraformaldehyde and aqueous hydrochloric acid to produce 3-(Dimethylamino)-l-(3-methoxyphenyl)-2- methylpropan- 1 -one hydro chloride .

[0011] PCT Publication Nos. WO 2008/012283 (hereinafter referred to as the '283 application) and WO 2008/012046 (hereinafter referred to as the '046 application) disclose processes for the preparation of tapentadol involving acylation of (2S,3R)-1- (dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3 -pentanol and (2S,3R)- 1 -(dimethylamino)- 3-(3-0-protected phenyl)-2-methyl-3-pentanol respectively, followed by subsequent hydrolysis to produce tapentadol.

[0012] The process as described in the '283 application involves treating l-(3- methoxyphenyl)-l-propanone with dimethylamine hydrochloride and paraformaldehyde to produce 3-(dimethlamino)-l-(3-methoxyphenyl)-2-methy-lpropanone, followed by resolution with L-(-)-dibenzoyl-tartaric acid monohydrate in ethanol to produce (2S)-3- (dimethylamino)-l-(3-methyoxyphenyl)-2-methyl-l-propanone, which is then reacted with ethyl magnesium bromide under Grignard conditions to produce (2S,3R)-l-(dimethylamino)- 3-(3-methoxyphenyl)-2-methyl-3-pentanol. The resulting (2S,3R)-l-(dimethylamino)-3-(3- methoxyphenyl)-2-methyl-3 -pentanol is reacted with trifluoroacetic anhydride, followed by subsequent hydrogenation using Palladium on charcoal catalyst to produce (2R,3R)-3-(3- methoxyphenyl)-N,N,2-trimethylpentanamine, which is further deprotected to produce tapentadol.

[0013] However, the processes for the preparation of tapentadol described in the above mentioned prior art suffer from the disadvantages since the process involves tedious and cumbersome procedures such as lengthy processes, formation of chiral and regio isomers at intermediate stages, multiple process steps, tedious work up procedures, multiple crystallizations or isolation steps, and thus resulting in low overall yields of the product. [0014] Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of tapentadol at lab scale and in commercial scale operations.

[0015] A need remains for an improved and commercially viable process of preparing tapentadol or a pharmaceutically acceptable salt thereof with high yields and high enantiomeric purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation. Desirable process properties include non-hazardous conditions, environmentally friendly and easy to handle reagents, reduced reaction time periods, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of tapentadol and its pharmaceutically acceptable acid addition salts in high purity and in high yield.

SUMMARY OF THE INVENTION

[0016] In one aspect, provided herein is an efficient, industrially advantageous and environmentally friendly process for the preparation of 3-[(li?,2i?)-3-(dimethylamino)-l- ethyl-2-methylpropyl]phenol of formula I (tapentadol) or a pharmaceutically acceptable salt thereof in high yield and with high chemical and enantiomeric purity. Moreover, the process disclosed herein involves non-hazardous and easy to handle reagents, reduced reaction times and reduced synthesis steps. The process avoids the tedious and cumbersome procedures of the prior processes and is convenient to operate on a commercial scale.

[0017] The process for the preparation of tapentadol or a pharmaceutically acceptable salt thereof disclosed herein has the following advantages over the processes described in the prior art:

i) the amount of hydrobromic acid (2 to 4 volumes) used for the demethylation reaction is minimized with the modification of reaction conditions, thereby reducing the acidic waste produced;

ii) the process avoids the use of hazardous chemicals, and tedious and cumbersome procedures like HBr distillation at post reaction completion;

iii) the process involves the use of reduced and more appropriate volumes of the solvents; iv) the process involves easy work-up methods and simple isolation processes; and v) the overall yield and purities of the product are increased.

[0018] The best mode of the process for preparing tapentadol hydrochloride disclosed herein is shown in the scheme: Scheme:

2. Dimethyl amine

Reduction Demethylation

Resolution by DBTA † Resolution by DBTA

IPA HCI

IPA HCI

Tapentadol HCI Tapentadol HCI DETAILED DESCRIPTION OF THE INVENTION

[0019] According to one aspect, there is provided a process for preparing tapentadol, 3- [(li?,2i?)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol, of formula I:

or a pharmaceutically acceptable salt thereof, comprising

a) reacting a propiophenone compound of formula IX:

wherein 'R' represents H or a hydroxy protecting group R ¹ , wherein R ¹ is -Ci_6-alkyl or - C ₃ -8-cycloalkyl;

with an alkyl 2-bromopropionate compound of formula VIII:

wherein the R ² is -Ci_6-alkyl; in the presence of a metal catalyst in a first solvent to produce a 3-hydroxy-pentanoate compound of formula VII:

wherein R and R ² are as defined above;

b) dehydrating the compound of formula VII in the presence of a dehydrating agent in a second solvent to produce an alkyl 2-pentenoate compound containing the mixture of cis/trans- isomers of formula VI: wherein R and R are as defined above;

c) hydrolyzing the compound of formula VI in the presence of a base in a third solvent to produce a reaction mass, followed by hydro genating in the presence of a hydro genation catalyst in the third solvent to produce a pentanoic acid compound of formula V:

wherein R is as defined above;

d) resolving the compound of formula V obtained in step-(c) with a suitable optically active amine reagent to produce an enantiomerically pure pentanoic acid compound of formula IV:

wherein R is as defined above;

e) optionally, deprotecting the compound of formula IV in the presence of a deprotecting agent in a fourth solvent to produce a compound of formula IV(i) (formula IV, wherein R is H):

f) reacting the compound of formula IV with a chlorinating reagent in a fifth solvent to produce a reaction mass containing corresponding acid chloride compound, followed by reaction with dimethyl amine in the fifth solvent to produce an amide compound of formula III: or an acid addition salt thereof, wherein R is as defined above;

g) reducing the amide compound of formula III in the presence of a reducing agent in a sixth solvent to produce a dimethylamine compound of formula II:

wherein R ¹ is as defined above;

or the tapentadol of formula I, and optionally converting the tapentadol of formula I obtained into a pharmaceutically acceptable salt thereof; and

h) optionally, deprotecting the compound of formula II in the presence of a deprotecting agent in the fourth solvent to produce the tapentadol of formula I, and optionally converting the tapentadol of formula I obtained into a pharmaceutically acceptable salt thereof.

[0020] The compounds of formulae I, II, III, IV, V, VI and VII can exist in different isomeric forms such as cis/trans isomers, enantiomers, or diastereomers. The process disclosed herein includes all such isomeric forms and mixtures thereof in all proportions unless otherwise specified.

[0021] All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

[0022] In one embodiment, the group 'R ¹ ' in the compounds of formulae II, III, IV, V, VI, VII and IX is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or benzyl; and most specifically R ¹ is methyl.

[0023] In another embodiment, the group 'R ² ' in the compounds of formulae VI, VII and VIII is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl; and most specifically R ² is ethyl.

[0024] Exemplary metal catalysts used in step-(a) include, but are not limited to, Zn, Sc, Ti, V, Cr, Mn, Fe, Co, Ni and Cu. A most specific metal catalyst is Zn.

[0025] Exemplary first solvents used in step-(a) include, but are not limited to, a hydrocarbon solvent, an ether solvent, and a mixture thereof. The term solvent also includes mixtures of solvents.

[0026] Specifically, the first solvent is selected from the group consisting of n-pentane, n- hexane, n-heptane, cyclohexane, benzene, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl-tert-butyl ether, monoglyme, diglyme, diisopropyl ether, methyl cyclopentylether, 1,4-dioxane, and mixtures thereof; and a most specific solvent is tetrahydro furan.

[0027] In one embodiment, the reaction in step-(a) is initiated by using a metal activator, which helps to activate the reactivity of the metal. The metal activators used herein include, but are not limited to, iodine and 1,2-dibromoehane; and most specifically iodine.

[0028] In another embodiment, the reaction in step-(a) is carried out at a temperature of below about 100°C for at least 1 hour, specifically at a temperature of about 50°C to about 75°C for about 1 hour to about 10 hours, and more specifically at a temperature of about 65°C to about 75 °C for about 4 hours.

[0029] The reaction mass containing the 3-hydroxy-pentanoate compound of formula VII obtained in step-(a) may be subjected to usual work up such as a washing, an extraction, a pH adjustment, an evaporation, or a combination thereof. The reaction mass may be used directly in the next step or the compound of formula VII may be isolated and then used in the next step.

[0030] In one embodiment, the 3-hydroxy-pentanoate compound of formula VII is isolated from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.

[0031] Exemplary dehydrating agents used in step-(b) include, but are not limited to, hydrochloric acid, methane sulphonic acid, potassium hydrogen sulphate, sodium hydrogen sulphate, 4-methylbenzene sulfonic acid, benzene sulphonic acid, polyphosphoric acid and phosphorus pentoxide.

[0032] Exemplary second solvents used in step-(b) include, but are not limited to, a hydrocarbon solvent, an ether solvent, and a mixture thereof. The term solvent also includes mixtures of solvents.

[0033] Specifically, the second solvent is selected from the group consisting of n-pentane, n- hexane, n-heptane, cyclohexane, benzene, toluene, xylene, and mixtures thereof; and a most specific second solvent is toluene.

[0034] In one embodiment, the reaction in step-(b) is carried out at a temperature of below 120°C for at least 30 minutes, specifically at a temperature of about 50°C to about 120°C for about 1 hour to about 10 hours, and more specifically at a temperature of about 95°C to about 115°C for about 3 hours to about 6 hours.

[0035] The reaction mass containing the 2-pentenoate compound of formula VI obtained in step-(b) may be subjected to usual work up methods as described above. The reaction mass may be used directly in the next step or the compound of formula VI may be isolated by the methods as described above and then used in the next step.

[0036] In one embodiment, the base used for hydrolyzing the compound of formula VI in step-(c) is an alkali metal base. Specifically, the base is sodium hydroxide or potassium hydroxide; and a more specific base is sodium hydroxide.

[0037] Exemplary third solvents used in step-(c) include, but are not limited to, water, an alcohol, a ketone, an ester, a nitrile, and mixtures thereof.

[0038] In one embodiment, the third solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, hexanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert- butyl methyl acetate, ethyl formate, and mixtures thereof.

[0039] In another embodiment, the hydrolyzation in step-(c) is carried out at a temperature of below 100°C for at least 1 hours, specifically at a temperature of about 50°C to about 90°C for about 2 hours to about 15 hours, and more specifically at a temperature of about 60°C to about 80°C for about 10 hours to about 14 hours.

[0040] The reaction mass containing obtained after hydrolyzation in step-(c) is subjected to usual work up methods as described above and then used for hydro genation. [0041] Exemplary hydrogenation catalysts used in step-(c) include, but are not limited to, palladium hydroxide, palladium on carbon, platinum on carbon, platinum oxide, rhodium on carbon, and rhodium on alumina. A specific hydrogenation catalyst is platinum on carbon.

[0042] In one embodiment, the hydrogenation reaction in step-(c) is carried out at a temperature of 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 20°C to about 65°C, and more specifically at about 50°C to about 60°C.

[0043] In one embodiment, the hydrogenation reaction in step-(c) is carried out under hydrogen pressure or in the presence of a hydrogen transfer reagent, specifically under hydrogen pressure.

[0044] The reaction mass containing the pentanoic acid compound of formula V obtained in step-(c) may be subjected to usual work up methods as described above. The reaction mass may be used directly in the next step or the compound of formula V may be isolated by the methods as described above and then used in the next step.

[0045] Exemplary optically active amine reagents used for resolution in step-(d) include, but are not limited to, (S)-Phenyl ethyl amine and brucine. A most specific optically active amine is (S)-Phenyl ethyl amine.

[0046] Exemplary solvents used for resolution in step-(d) include, but are not limited to, water, an alcohol, a ketone, an ester, a nitrile, a hydrocarbon solvent, an ether solvent, and mixtures thereof.

[0047] In one embodiment, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, hexanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert- butyl methyl acetate, ethyl formate, n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl-tert-butyl ether, monoglyme, diglyme, diisopropyl ether, methyl cyclopentylether, 1,4-dioxane, and mixtures thereof.

[0048] In one embodiment, the resolution process in step-(d) comprises the following steps: i) treating the compound of formula V with a suitable optically active amine reagent in a suitable solvent to produce a reaction mass containing the diastereomeric mixture; ii) separating the desired diastereomeric salt from the diastereomeric mixture obtained in step- (i); and iifjneutralizing the desired diastereomeric salt obtained in step-(ii) with an acid such as hydrochloric acid in a suitable solvent to produce the enantiomerically pure pentanoic acid compound of formula IV. [0049] Exemplary deprotecting agents used in steps-(e) and (h), each independently, include, but are not limited to, hydrobromic acid, aluminum chloride/thiourea, aluminium triiodide/tetrabutylammonium iodide, ClBH ₂ .Me ₂ S, iodotrimethylsilane, sodium ethyl suphide and lithium iodide. A most specific deprotecting agent is hydrobromic acid.

[0050] Exemplary fourth solvents used in step-(e) include, but are not limited to, water, an alcohol, a ketone, a cyclic ether, an aliphatic ether, a hydrocarbon, a chlorinated hydrocarbon, a nitrile solvent, and mixtures thereof. The term solvent also includes mixtures of solvents.

[0051] In one embodiment, the fourth solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, dichloromethane, dichloro ethane, chloroform, carbon tetrachloride, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, n-pentane, n- hexane, n-heptane, cyclohexane, toluene, xylene, and mixtures thereof.

[0052] In another embodiment, the deprotection reaction in steps-(e) and (h) is, each independently, carried out at a temperature of 0°C to the reflux temperature of the solvent used for at least 1 hour, specifically at a temperature of about 50°C to about 120°C for about 2 hours to about 10 hours, and more specifically at a temperature of about 90°C to about 1 15°C for about 4 hours to about 8 hours.

[0053] In one embodiment, the chlorinating reagent used in step-(f) is thionyl chloride.

[0054] Exemplary fifth solvents used in step-(f) include, but are not limited to, a chlorinated hydrocarbon, a hydrocarbon, and mixtures thereof.

[0055] In one embodiment, the fifth solvent is selected from the group consisting of dichloromethane, ethylene dichloride, chloroform, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, and mixtures thereof; and most specifically dichloromethane.

[0056] In another embodiment, the reactions in step-(f) are, each independently, carried out at a temperature below 50°C, specifically at a temperature of about 0°C to about 30°C and more specifically at a temperature of 0°C to about 10°C.

[0057] The reaction mass containing the amide compound of formula III obtained in step-(f) may be subjected to usual work up methods as described above. The reaction mass may be used directly in the next step or the compound of formula III may be isolated by the methods as described above and then used in the next step.

[0058] Exemplary reducing agents used in step-(g) include, but are not limited to, lithium aluminium hydride, vitride, sodium borohydride, sodium cyanoborohydride and sodium triacetoxyboro hydride . [0059] Exemplary fifth solvents used in step-(g) include, but are not limited to, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl-tert-butyl ether, monoglyme, diglyme, diisopropyl ether, methyl cyclopentylether, 1 ,4-dioxane, and mixtures thereof.

[0060] In another embodiment, the reaction in step-(g) is carried out in an inert atmosphere, preferably under nitrogen atmosphere.

[0061] In another embodiment, the reaction in step-(g) is carried out at a temperature of below about 100°C, specifically at a temperature of about 10°C to about 80°C, and more specifically at a temperature of about 20°C to about 70°C.

[0062] The reaction mass containing the tapentadol obtained in step-(g) or step-(h) may be subjected to usual work up such as a washing, a filtration, an extraction, an evaporation, a pH adjustment, or a combination thereof.

[0063] In one embodiment, the tapentadol of formula I formed in step-(g) or step-(h) is isolated from a suitable solvent by the methods as described above.

[0064] Pharmaceutically acceptable salts of tapentadol can be prepared in high purity by using the highly pure tapentadol obtained by the method disclosed herein, by known methods.

[0065] Specific pharmaceutically acceptable salts of tapentadol include, but are not limited to, hydrochloride, hydrobromide, oxalate, nitrate, sulphate, phosphate, fumarate, succinate, maleate, besylate, tosylate, palmitate and tartrate; and more specifically hydrochloride.

[0066] The solvent used to isolate the tapentadol of formula I or a pharmaceutically acceptable acid addition salt thereof is selected from the group comprising water, alcohols, chlorinated hydrocarbons, hydrocarbons, ketones, nitriles, esters, ethers, polar aprotic solvents, and mixtures thereof. Specifically the solvent is selected from the group consisting of water, acetone, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, dichloromethane, n-pentane, n-hexane, n-heptane, cyclohexane, toluene and mixture thereof, more specifically isopropyl alcohol.

[0067] The highly pure tapentadol or a pharmaceutically acceptable salt thereof obtained by the above process may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. [0068] In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 70°C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like. Drying equipment selection is well within the ordinary skill in the art.

[0069] In another embodiment, the highly pure tapentadol or a pharmaceutically acceptable salt thereof obtained by the process disclosed herein has a total purity, includes both chemical and enantiomeric purity, of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the highly pure tapentadol or a pharmaceutically acceptable salt thereof is about 99% to about 99.9%, or about 99.5% to about 99.99%.

[0070] The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES

Example 1

Preparation of 3-Methoxy propiophenone

[0071] 3 -Hydroxy propiophenone (250 g) and potassium hydroxide (94 g) were taken into a round bottom flask, acetone (1000 ml) was added to the resulting mixture and then stirred for 30 minutes at 40°C. Potassium carbonate (60 gm) and tetrabutylammonium bromide (20 gm) were added to the reaction mass, followed by the addition of methyl iodide (260 g) at 40- 45°C and then stirring for 12 hours at the same temperature. After completion of the reaction, the reaction mass was filtered, washed with acetone (50 ml) and the solvent was distilled under vacuum at temperature 40°C. Water (500 ml) and dichloromethane (600 ml) were added to the concentrated reaction mass, the resulting mass was stirred for 30 minutes and then the layers were separated. The aqueous layer was extracted with dichloromethane (400 ml). The organic layers were combined, washed with water (2 x 250 ml) and then dried over anhydrous sodium sulphate. The residue was exposed to vacuum at 40°C till constant weight. The resulting crude product was purified under high vacuum distillation (conditions for HVD: External temperature: 130-140°C; Vapor Temperature: 90-92°C at 5mm/Hg vacuum) to give 206 g of 3-methoxy propiophenone (Yield: 99%).

Example 2

Preparation of 3-Hydroxy-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid ethyl ester

[0072] Benzene (200 ml) and zinc metal (65 g) were taken under nitrogen atmosphere, followed by the addition of one crystal of iodine to initiate reaction and the mixture was heated at 70±2°C. A mixture of 3-methoxy propiophenone (80 g), ethyl 2-bromopropionate (132.3 g) and benzene (400 ml) was added to the above reaction mass while maintaining the temperature at 65-75°C. After completion of the addition process, the reaction mass was refluxed for 4 hours and then cooled to 0-5°C. 5N Hydrochloric acid (400 ml) was added to the reaction mass at below 20°C, followed by the addition of toluene (400 ml) and the reaction mass was stirred for 30 minutes. The reaction mass was transferred into a separating funnel and allowed to settle for 10-15 minutes, followed by the separation of the upper organic layer. The resulting aqueous layer was separated and then placed into a flask, followed by the addition of toluene (400 ml). The reaction mixture was stirred for 30 minutes, followed by transferring into the separating funnel and allowing it to settle for 10-15 minutes. The upper organic layer was separated. The entire extracted organic layer was combined and washed with water (400 ml). The organic layer was dried over anhydrous sodium sulphate (25 g), followed by distillation of the solvent completely at 40±2°C and further applying high vacuum at 50±2°C for 30 minutes in order to distil out the solvents completely to produce 121 g of 3-hydroxy-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid ethyl ester.

Example 3

Preparation of 3-Hydroxy-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid ethyl ester

[0073] Tetrahydrofuran (100 ml) and zinc metal (100 g) were taken under nitrogen atmosphere, the mixture was heated at 65±2°C, followed by the addition of ethyl 2- bromopropionate (20 g) and then drop-wise addition of trimethylsilyl chloride (10 ml). A mixture of 3-methoxy propiophenone (100 g), ethyl 2-bromopropionate (120 g) and tetrahydrofuran (300 ml) was added to the resulting mixture, followed by maintaining at 65- 75 °C. After complete addition of the above mixture the reaction mass was refluxed for 1-2 hours and then cooled to 0-5°C. Saturated potassium bisulphate solution (250 ml) was added to the reaction mass at below 20°C, followed by the addition of ethyl acetate (500 ml) and then stirring the reaction mass for 30 minutes. The reaction mass was transferred into a separating funnel and allowed it to settle for 10-15 minutes, followed by the separation of the upper organic layer. The resulting aqueous layer was separated and then placed into a flask, followed by the addition of ethyl acetate (500 ml). The reaction mixture was stirred for 30 minutes, followed by transferring into the separating funnel and allowing it to settle for 10-15 minutes. The upper organic layer was separated. The entire extracted organic layer was combined and washed with saturated sodium chloride solution (250 ml). The organic layer was dried over anhydrous sodium sulphate (50 g), followed by the distillation of solvent completely at 50±2°C and further applying high vacuum at 50±2°C for 30 minutes in order to distil out the solvent completely to produce 251 g of 3-hydroxy-3-(3-methoxy-phenyl)-2- methyl-pentanoic acid ethyl ester (Yield: 100%).

Example 4

Preparation of 3-(3-Methoxy-phenyl)-2-methyl-pent-3-enoic acid ethyl ester

[0074] 3-Hydroxy-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid ethyl ester (5 g), methane sulfonic acid (3.6 g) and toluene were taken into a reaction flask and the mixture was stirred for 3 hours at 110±2°C. The reaction mixture was allowed to cool to 20-25°C. Water (25 ml) was added to the reaction mass and then stirred for 20 minutes. The reaction mass was transferred into a separating funnel and allowed to settle for 10-15 minutes, followed by the separation of the upper organic layer. The resulting aqueous layer was separated and then placed into a reaction flask, followed by the addition of toluene (25 ml). The reaction mixture was stirred for 30 minutes, followed by transferring into the separating funnel and allowing it to settle for 10-15 minutes. The upper organic layer was separated, followed by combining the total organic layer and washing with water (25 ml). The resulting organic layer was dried over anhydrous sodium sulphate (25 g), followed by the distillation of solvent completely at 40±2°C and further applying high vacuum at 50±2°C for 30 minutes in order to distil out the solvent completely to produce 4.3 g of 3-(3-methoxy-phenyl)-2-methyl-pent-3-enoic acid ethyl ester.

Example 5

Preparation of 3-(3-Methoxy-phenyl)-2-methyl-pent-3-enoic acid ethyl ester

[0075] 3-Hydroxy-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid ethyl ester (5 gm), toluene (25 ml) and 4-methylbenzene sulfonic acid (3.57 gm) were stirred for 3 hours at 110±2°C. The reaction mixture was cooled to 20-25 °C, water (25 ml) was added to it and then stirred for 20 minutes. The reaction mass was transferred into a separating funnel and allowed to settle for 10-15 minutes, followed by the separation of the upper organic layer. The aqueous layer was separated and then placed into a flask, followed by the addition of toluene (25 ml). The reaction mixture was stirred for 30 minutes, followed by transferring into the separating funnel and allowing it to settle for 10-15 minutes. The upper organic layer was separated, followed by combining the total organic layer and washing with water (25 ml). The resulting organic layer was dried over anhydrous sodium sulphate (25 g), followed by distillation of solvent completely at 40±2°C and further applying high vacuum (5mm/Hg Vacuum) at 50±2°C for 30 minutes in order to distil out the solvent completely to produce 4.6 g of 3-(3- methoxy-phenyl)-2-methyl-pent-3-enoic acid ethyl ester (Yield: 100%).

Example 6

Preparation of 3-(3-Methoxy-phenyl)-2-methyl-pent-3-enoic acid ethyl ester

[0076] 3-Hydroxy-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid ethyl ester (5 g), toluene (25 ml) and potassium hydrogen sulphate (2.5 gm) were taken into a round bottom flask, the reaction mass was stirred for 8 hours at 1 10±2 °C and then cooled to 20-25 °C. Water (25 ml) was added to the reaction mixture and the mass was stirred for 20 minutes. The reaction mass was transferred into a separating funnel and allowed to settle for 10-15 minutes, followed by the separation of the upper organic layer. The aqueous layer was separated, toluene (25 ml) was added to the separated aqueous layer and the reaction mass was stirred for 30 minutes at 20-25 °C. The resulting mass was transferred into the separating funnel and allowing it to settle for 10-15 minutes. The organic layer was separated and combined with the previously separated organic layers and then washed with water (25 ml). The resulting organic layer was dried over anhydrous sodium sulphate (25 g), followed by the distillation of solvents completely at 50±2°C under vacuum. The resulting organic layer was further distilled out by applying high vacuum at 50±2°C for 30 minutes to produce 4.5 g of 3-(3-methoxy-phenyl)-2- methyl-pent-3-enoic acid ethyl ester (Yield: 96%).

Example 7

Preparation of 3-(3-Methoxy-phenyl)-2-methyl-pent-3-enoic acid ethyl ester

[0077] 3-Hydroxy-3-(3-methoxy-phenyl)-2-methyl-pentanoic acid ethyl ester (160 g), toluene (1000 ml) and phosphorus pentoxide (80 g) were taken into a reaction flask, followed by the addition of toluene (200 ml) and stirring the mixture for 6-8 hours at 70±2°C. The resulting mass was cooled to 20-25°C, followed by the addition of water (200 ml) and stirring the mass for 20 minutes. The resulting reaction mass was taken into a separating funnel and was allowed to settle for 10-15 minutes, followed by the separation of the upper organic layer. The organic layer was dried over anhydrous sodium sulphate (25 g), followed by distillation of solvents completely at 50±2°C by applying high vacuum (5mm/Hg) in order to distil out the solvent completely to produce 120 g of 3-(3-Methoxyphenyl)-2-methyl-pent-3- enoic acid ethyl ester (Yield: 81%).

Example 8

Preparation of 3-(3-Methoxyphenyl)-2-methyl-pent-3-enoic acid ethyl ester

[0078] 3-Hydroxy-3-(3-methoxyphenyl)-2-methyl-pentanoic acid ethyl ester (2 g), polyphosphoric acid (70 g) and toluene were taken into a reaction flask, the mixture was stirred for 6 hours at 72±2°C and then cooled to 10°C. Water (140 ml) was added to the reaction mixture and then stirred for 30 minutes. The reaction mass was taken into a separating funnel and then allowed to settle for 10-15 minutes, followed by the separation of the upper organic layer. The resulting aqueous layer was then collected into a flask, followed by the addition of toluene (150 ml) and stirring the reaction mixture for 30 minutes. The resulting mass was transferred into the separating funnel and then allowed to settle for 10-15 minutes. The organic layer was separated and the entire organic layer was combined, followed by washing with water (2 x 105 ml). The resulting organic layer was dried over anhydrous sodium sulphate (25 g), followed by the distillation of solvents completely at 50±2°C under vacuum and further applying high vacuum at 50±2°C for 30 minutes in order to distil out the solvent completely to produce 32 g of 3-(3-methoxyphenyl)-2-methyl-pent-3- enoic acid ethyl ester (Yield: 98%).

Example 9

One pot synthesis of 3-(3-Methoxyphenyl)-2-methyl-pent-3-enoic acid ethyl ester from 3- Methoxy propiophenone

[0079] Tetrahydrofuran (200 ml) and zinc metal (100 g) were taken under nitrogen atmosphere, the mixture was heated at 65±2°C, followed by the addition of ethyl 2- bromopropionate (20 g) and then drop-wise addition of trimethylsilyl chloride (10 ml). A mixture of 3-methoxy propiophenone (100 g), ethyl 2-bromopropionate (120 g) and tetrahydrofuran (300 ml) was added to the above mixture while maintaining the temperature at 65-75 °C. After complete addition of the above mixture, the reaction mass was refluxed for 1-2 hours and then cooled to 0-5°C, followed by the addition of 15% dilute HC1 solution (200 ml) at below 20°C. Toluene (300 ml) was added to the resulting mixture and then stirred for 30 minutes. The reaction mass was transferred into a separating funnel and then allowed to settle for 10-15 minutes, followed by the separation of the upper organic layer. The resulting aqueous layer was separated and then placed into a reaction flask. Toluene (200 ml) was added to the aqueous layer and the reaction mixture was stirred for 30 minutes, followed by transferring into the separating funnel and allowing it to settle for 10-15 minutes. The upper organic layer was separated. The entire extracted organic layer was combined and then washed with saturated sodium chloride solution (200 ml). The organic layer was dried over anhydrous sodium sulphate (50 g), followed by the distillation of solvents completely at 55°C and further applying high vacuum (5mm/Hg) at 55°C for 5-7 hours to produce 237 g of 3-(3- Methoxy-phenyl)-2-methyl-pent-3-enoic acid ethyl ester (Yield: 100%).

Example 10

Preparation of racemic 3-(3-Methoxyphenyl)-2-methyl-pentanoic acid

[0080] Sodium hydroxide (100 g) and water (250 ml) were added to a solution of 3-(3- methoxy-phenyl)-2-methyl-pent-3-enoic acid ethyl ester (162 g) in methanol (500 ml) in a round bottom flask. The resulting mass was heated at 70-75°C for 10-12 hours. The reaction mass was cooled to 0-5°C, followed by the addition of concentrated hydrochloric acid (300 ml). The resulting mass was extracted with dichloromethane (700 ml) and then stirred for 10- 15 minutes. The bottom organic layer was separated and then combined with the first organic layer. Dichloromethane (700 ml) was added to the flask and then stirred for 10-15 minutes. The bottom organic layer was separated and then combined with the second organic layer. The organic layer was dried over anhydrous sodium sulphate and the resulting mass was distilled under atmospheric pressure at 45-50°C to remove dichloromethane to form an oily mass. 5% Pt/C (5 g), methanol (1300 ml) and the above oily mass (90 g) were placed in an autoclave, followed by applying hydrogen pressure (5-7 Kg) at 50°C. The resulting mass was distilled at 50±2°C under 5mm/Hg vacuum to produce 83.2 g of racemic 3-(3- methoxyphenyl)-2-methyl-pentanoic acid as an oily mass (Yield: 92.4%).

Content of desired enantiomeric pair (RR & SS): 63.88%;

Content of undesired enantiomeric pair (SR & RS): 31.27%).

Example 1 1

Separation of diastereomers of racemic 3-(3-Methoxyphenyl)-2-methyl-pentanoic acid using

(S)-Phenyl ethyl amine

Step-1 :

[0081] (S)-Phenyl ethyl amine (12 g) and diisopropyl ether (220 ml) were added to a mixture of racemic 3-(3-methoxyphenyl)-2-methyl-pentanoic acid (22 g) and diisopropyl ether (220 ml) in a RB flask. The resulting mass was heated at 70-75°C for 2 hours. The reaction mass was cooled to 20-25°C and then stirred for 10-12 hours. The resulting solid was filtered and then washed with diisopropyl ether (50 ml) to produce 47 g of a diastereomeric salt as a wet solid [content of desired diastereomer: 89%>; content of undesired diastereomer: 11%]. The obtained solid was processed for further purification to get pure desired diastereomer. Step-2:

[0082] The wet salt (45 g, obtained in step-1) and diisoproylether (450 ml) were taken into a RB flask and the resulting mass was heated at 70-75°C for 2 hours. The reaction mass was cooled to 20-25°C and then stirred for 10-12 hours. The obtained solid was filtered and then washed with diisopropyl ether (50 ml) to produce 19 g of pure diastereomeric salt [content of desired diastereomer: 97%; content ofundesired diastereomer: 3%].

Example 12

Preparation of (RR, SS)-3-(3-Methoxyphenyl)-2-methyl-pentanoic acid amide

Step-1 :

[0083] 5% Dilute hydrochloric acid (10ml) was added to a mixture of pure diastereomeric salt (19 g, obtained in step-2 of example 11) and water (190 ml) at 20-25°C. The product was extracted with dichloro methane (200 ml), followed by the separation of layers and collecting the organic layer. The aqueous layer was again extracted with dichloromethane (200 ml), the resulting organic layer was combined with the first organic layer. The combined organic layer was washed with water (100ml) and then treated with anhydrous sodium sulfate (10 g). The resulting organic layer was distilled to remove the dichloromethane completely to produce 12 g of (RR,SS)-3-(3-methoxyphenyl)-2-methyl-pentanoic acid as an oily mass.

Step-2:

[0084] (RR,SS)-3-(3-Methoxyphenyl)-2-methyl-pentanoic acid (10 g, obtained in step-1) and dichloromethane (50 ml) were taken into a round bottom flask and the mixture was cooled to 0°C. Thionyl chloride (10 gm) was added to the reaction mass at 0-10°C and the resulting mixture was stirred for 4 hours at 20-25 °C. The reaction mass was then added to a round bottom flask containing 40% aqueous solution of dimethylamine (50 ml) while maintaining the temperature between 0-10°C during the addition, followed by cooling the mass to 0°C. The resulting reaction mass was stirred for 2 hours at 20-25°C, the organic layer was separated and the aqueous layer was transferred into the same RB flask. Dichloromethane (50 ml) was added to the RB flask and stirred for 10-15 minutes. The resulting organic layer was separated and then combined with the first organic layer, followed by washing with water (25 ml) and then dried over anhydrous sodium sulphate. The solvent was distilled under atmospheric pressure at 45-50 °C to remove dichloromethane and further exposed to high vacuum distillation at 40±2°C for 1 hour to produce 11 g of (RR,SS)-3-(3-methoxyphenyl)-2- methyl-pentanoic acid amide as an oily mass (Purity: 97.16%).

Example 13

Preparation of (RR, SS)-3-(3-Methoxyphenyl)-2-methylpentyl]-dimethylamine [0085] A solution of (RR,SS)-3-(3-methoxyphenyl)-2-methyl-pentanoic acid amide (10 g) in tetrahydrofuran (50 ml) was added to a solution of lithium aluminium hydride (4 g) in tetrahydrofuran (50 ml) under nitrogen atmosphere at 20-25°C. The reaction mass was heated at 65-70°C, the resulting mass was stirred under reflux for 12 hours and then cooled to 0°C. Water (25 ml) and dichloro methane (100 ml) were added to the reaction mass at below 20°C and then stirred for 30 minutes. The reaction mass was filtered through hyflo and then transferred into a separating funnel, followed by the separation of the organic layer. The resulting aqueous layer was placed into a reaction flask and then extracted with dichloromethane. The extracted organic layers were combined, washed with water (25 ml) and then dried over anhydrous sodium sulphate (2 g), followed by distillation of solvents completely at 40±2°C and further applying high vacuum at 40±2°C for 30 minutes in order to distil out the solvents completely. Isopropyl alcohol (30 ml) and isopropanolic HC1 (4ml) were added to resulting oil (Weight: 10 g; Purity: 94.10%).

Example 14

Preparation of (R,R)-Tapentadol hydrochloride Salt

[0086] (RR,SS)-3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine (9 g) taken in a reaction flask and then 48% Hydrobromic acid (27 ml) was added. The reaction mass was heated at 110-115°C and then stirred for 6 hours at 110-115 °C. The resulting mass cooled to 10-15°C, followed by the addition of water (18 ml), ethyl acetate (90 ml) and ammonia solution (27 ml) and adjusting the pH to 8 to 9. The mixture was stirred for 30 minutes, followed by the separation of the layers and extracting the aqueous layer with ethyl acetate (25 ml). The organic layer was washed with water (25 ml), followed by distillation of solvents at 50-55 °C under vacuum and then high vacuum distillation at 50±2°C for 1 hour to remove ethyl acetate completely. To the resulting oily mass isopropyl alcohol (44 ml) was added and the reaction mass was cooled to 20-25°C. To the reaction mixture isopropanolic HC1 (7 ml) was added, the resulting mass was stirred for 10-15 minutes at 20-25°C and then stirred for 10-12 hours at the same temperature. The resulting solid was filtered and washed with isopropanol (4ml). The solid was dried at 40-45°C under vacuum for 4 hours to produce 8 g of tapentadol hydrochloride salt (Purity by HPLC: 97.75%).

Example 15

Preparation of Tapentadol hydrochloride

Step-1 :

[0087] (RS,SR)-tapentadol hydrochloride salt (8 g) and dichloromethane (15 ml) were taken in a reaction flask, followed by the addition of 5% sodium hydroxide solution till the pH of the mixture reaches to 8.5-9. The resulting organic layer was separated and then washed with water (25 ml). The organic layer was dried over anhydrous sodium sulphate (5 g), followed by distillation of organic layer completely to get oily mass. To the resulting oily mass isopropyl alcohol (44 ml) was added and the reaction mass was cooled to 20-25°C. To the reaction mixture D-dibenzoyl tartaric acid (DBTA) (7 g) was added and the reaction mass was heated at 80-85°C, followed by stirring for 10-15 minutes at 80-85°C. The resulting mass was cooled to 20-25° C and then stirred at the same temperature for 10-12 hours. The resulting solid was filtered and washed with isopropanol (4 ml). The solid was dried at 40- 45°C under vacuum for 4 hours to produce to tapentadol DBTA salt.

Step-2:

[0088] (R,R)-Tapentadol DBTA salt (4 g) and dichloromethane (15 ml) were taken into a reaction flask, followed by the addition of 5% sodium hydroxide solution till the pH of the mass reaches to 8.5-9. The resulting organic layer was separated and washed with water (25 ml). The organic layer was dried over anhydrous sodium sulphate (5 g), followed by distillation of organic layer completely to get oily mass. Isopropanolic HC1 (3 ml) was added to the mixture of the resulting oily mass and isopropyl alcohol (15 ml) and then stirred for 2-3 hours at 20-25°C. The resulting mass further cooled to 0-5° C and then filtered through the Buckner flask and washed with isopropanol (2 ml). The residue so collected was dried at 40- 45°C under vacuum for 4 hours to produce 2 g of pure (1R,2R) tapentadol hydrochloride salt (Purity by HPLC: 98%).

Example 16

Purification of Tapentadol hydrochloride

[0089] Tapentadol hydrochloride (5 g) and isopropanol (17.5 ml) were taken into a RB flask, the mixture was heated at 80-82°C, followed by the addition of methanol (7.5 ml) at the same temperature to form a clear solution. The solution was further cooled to 20 to 25°C and then stirred for 10-12 hours. The resulting solid was filtered and washed with isopropanol (3 ml). The filtered solid was dried at 40-45 °C under vacuum for 4 hours to produce 3.8 g of pure tapentadol hydrochloride (Purity by HPLC: 99.75%).

Example 17

Preparation of (RR, SS)-3-(3-Hydroxyphenyl)-2-methyl-pentanoic acid

[0090] 5% Dilute hydrochloric acid (20ml) was added to a mixture of pure 3-(3-methoxy- phenyl)-2-methyl-pentanoic acid alpha-phenyl ethylamine salt (40 g) and water (400 ml) at 20-25°C. The resulting product was extracted with dichloromethane (400 ml), followed by separation of the layers to collect the organic layer. The aqueous layer was again extracted with dichloromethane (200 ml) and the organic layer was combined with first organic layer. The combined organic layer was washed with water (400 ml) and then finally treated with anhydrous sodium sulfate (30 g), followed by complete distillation of dichloromethane to get oily mass (Wt: 25 g). Thiourea (18.18 g), aluminium chloride (43.2 g) and toluene (200ml) were taken into another reaction flask and the mixture was stirred for 2-3 hours, followed by the addition of a solution of (RR,SS)-3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine (18 g) in toluene (200 ml) at 20-25°C. The reaction mass was heated at 90°C and the reaction mass was stirred for 18-24 hours and then cooled to 20-25°C. To the resulting mass water (500 ml) and 50% aqueous hydrochloric acid (200ml) were added, followed by the separation of aqueous layer and extracting again with toluene (100 ml). The extracted organic layers were combined, washed with water (100 ml) and then dried over anhydrous sodium sulphate (10 g), followed by distillation of solvent completely at 50±5°C as an oil mass (Weight: 14 g).

Example 18

Preparation of (RR, SS) 3-(3-Hydroxyphenyl)-2-methyl-pentanoic acid amide

[0091] (RR,SS)-3-(3-Hydroxyphenyl)-2-methyl-pentanoic acid (14 g) and dichloromethane (70 ml) were taken into a round bottom flask and the mixture was cooled to 0°C. Thionyl chloride (42 ml) was added to the reaction mass at 20-25°C and the resulting mass was heated at 60-65°C for 12 hours. The resulting reaction mass was cooled, followed by the addition of 40% aqueous Ν,Ν-dimethylamine solution at 0-5°C and then stirring for 2 hours. Dichloromethane (200 ml) and water (200ml) were added to the resulting mass and then stirred for 10-15 minutes and the organic layer was separated. The resulting organic layer was washed with water (200ml) and then dried over anhydrous sodium sulphate. The solvent was distilled under atmospheric pressure at 45-50 °C to remove dichloromethane and further exposed to high vacuum distillation at 40±2°C for 1 hour to produce (RR,SS)-3-(3- hydroxyphenyl)-2-methyl-pentanoic acid amide as an oily mass (Weight: 15 g).

Example 19

Preparation of (R, R)-Tapentadol Hydrochloride Salt

[0092] A solution of (RR,SS)-3-(3-hydroxy-phenyl)-2-methyl-pentanoic acid amide (14 g) in tetrahydrofuran (140 ml) was added to a solution of lithium aluminium hydride (7.1 g) in tetrahydrofuran (140 ml) under nitrogen atmosphere at 20-25°C. The reaction mass was heated at 65-70°C, the resulting mass was stirred at reflux for 5-6 hours and then cooled to 0°C. Water (140 ml) and ethyl acetate (140 ml) were added to the reaction mass at below 20°C and then stirred for 3 hours. The reaction mass was filtered through hyflo bed and then transferred into a separating funnel, followed by separation of the organic layer. The resulting aqueous layer was placed into a reaction flask and then extracted repeatedly with ethyl acetate (280 ml). The extracted organic layers were combined, washed with water (200 ml) and then dried over anhydrous sodium sulphate (50 g), followed by distillation of solvents completely at 50±2°C and further applying high vacuum at 50±2°C for 30 minutes in order to distil out the solvents completely. To the resultant oily mass isopropanolic HC1 (14 ml) and isopropanol (28 ml) were added and the reaction mass was cooled to 0-5°C. The resulting mass was stirred at 20-25° C and stirring was continued for 10-12 hours at the same temperature. The resulting solid was filtered and washed with isopropanol (14 ml). The solid was dried at 40-45 °C under vacuum for 4 hours to produce to 5 g of tapentadol hydrochloride salt.

Example 20

Preparation of Tapentadol hydrochloride

[0093] (RS,SR)-tapentadol hydrochloride salt (5 g) and dichloromethane (15 ml) were taken into a reaction flask, followed by the addition of 5% sodium hydroxide solution to adjust the pH of the mass to 8.5-9.0. The organic layer was separated and then washed with water (25 ml). The organic layer was dried over anhydrous sodium sulphate (5gm), followed by the distillation of organic layer completely to produce an oily mass. To the resulting oily mass isopropyl alcohol (30 ml) was added and the reaction mass cooled to 20-25°C. D-dibenzoyl tartaric acid (DBTA) (4 g) was added to the reaction mixture and reaction mass was heated at 80-85°C and then stirred for 10-15 minutes at 80-85°C. The resulting mass cooled to 20-25° C and stirred at the same temperature for 10-12 hours. The resulting solid was filtered and washed with isopropanol (4 ml). The solid was dried at 40-45°C under vacuum for 4 hours to produce to tapentadol dibenzoyl tartrate salt. The (R,R)-tapentadol dibenzoyl tartrate salt (4 g) and dichloromethane (15 ml) were taken into a reaction flask, followed by the addition of 5% sodium hydroxide solution to adjust the pH to 8.5-9. The resulting organic layer was separated and washed with water (25 ml). The organic layer was dried over anhydrous sodium sulphate (5 g), followed by the distillation of the organic layer completely to produce an oily mass. Isopropanolic HC1 (3 ml) was added to a mixture of the above oily mass and isopropanol (15 ml), followed by stirring at 20-25°C for 2-3 hours. The resulting mass was further cooled to 0-5°C and then filtered through a Buckner flask and then washed with isopropanol (2 ml). The resulting residue was dried under vacuum at 40-45°C for 4 hours to produce 2 g of pure (1R,2R) tapentadol hydrochloride (Purity by HPLC: 98%).