INTRODUCTION

Aspects of the present invention relates to (S)-1,3-dimethyl-4-piperidone and its process, process for the preparation of (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester using (S)-1,3-dimethyl-4-piperidone, process for the preparation of (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol using (S)-1,3-dimethyl-4-piperidone and process for the preparation of alvimopan or its hydrates or salts using (S)-1,3-dimethyl-4-piperidone.

The drug compound having the adopted name "alvimopan dihydrate" can be represented by structural formula (I), and is a peripherally-acting u-opioid receptor (PAM-OR) antagonist.

A chemical name for alvimopan is the single stereoisomer [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate and it is active ingredient in Entereg® (alvimopan) capsule for the treatment of to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.

U.S. Patent No. 5,250,542, U.S. Patent No. 5,136,040, U.S. Patent No. 5,498,718 and Journal of Organic Chemistry (1996), 61(2), 587-97 disclose process for the preparation of alvimopan or its intermediates. In the art, the starting material used for the preparation of key starting material of alvimopan involves the use of racemic 1,3-dimethyl-4-piperidone. The resolution produce required isomer is carried out at the next stages which enhance the cost of the product.

There remains a need for additional processes for the preparation of alvimopan in an environmentally-friendly, cost-effective, and industrially applicable manner.

SUMMARY
In an aspect, the invention provides (S)-1,3-dimethyl-4-piperidone.

In an aspect, the invention provides process for preparing (S)-1,3-dimethyl-4-piperidone.

In an aspect, the invention provides process for racemization of (R)-1,3-dimethyl-4-piperidone.

In another aspect, the invention provides process for the preparation of (3S.4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester comprising:

(a) resolving racemic 1,3-dimethyl-4-piperidone with chiral acid to obtain (S)-1,3-dimethyl-4-piperidone;

(b) condensation of (S)-1,3-dimethyl-4-piperidone obtained in step a) with 3-bromo-isopropoxy benzene to produce c/s-(3S,4/:?)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol; and

(c) reacting c/s-(3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol obtained in step b) with ethyl chloroformate to produce (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester.

In an embodiment, the invention provides process for the preparation of (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol comprising:

(a) resolving racemic 1,3-dimethyl-4-piperidone with chiral acid to obtain (S)-1,3-dimethyl-4-piperidone;

(b) condensation of (S)-1,3-dimethyl-4-piperidone obtained in step a) with 3-bromo-isopropoxy benzene to produce c/s-(3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol;

(c) reacting c/s-(3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol obtained in step b) with ethyl chloroformate to produce (3S,4/?)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester; and

(d) converting (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester obtained in step c) to (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol.

In an aspect, the invention provides process for the preparation of Alvimopan (or) its hydrates (or) its salts comprising:

(a) resolving racemic 1,3-dimethyl-4-piperidone with chiral acid to obtain (S)-1,3-dimethyl-4-piperidone;

(b) converting (S)-1,3-dimethyl-4-piperidone to (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol; and

(c) converting (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol to Alvimopan or its hydrates or its salts.

DETAILED DESCRIPTION
In an aspect, the invention provides (S)-1,3-dimethyl-4-piperidone. In an aspect, the invention provides process for the preparation of (S)-1,3-dimethyl-4-piperidone comprising:

(a) resolving racemic 1,3-dimethyl-4-piperidone with chiral acid in a solvent to obtain a salt of (S)-1,3-dimethyl-4-piperidone; and

(b) converting the salt of (S)-1,3-dimethyl-4-piperidone obtained in step a) to (S)-1,3-dimethyl-4-piperidone.

In embodiments of step a), the resolution of racemic 1,3-dimethyl-4-piperidone can be carried out by using chiral acids such as mandelic acid, malic acid, lactic acid, p-toluoyl tartaric acid, di-p-toluyl tartaric acid, tartaric acid, benzoyl tartaric acid, dibenzoyl tartaric acid, camphoric acid, camphorsulphonic acid, 2-cyclopentylmethyl-propanedioic acid 1-ethyl ester, methyl 3-methylglutalate, 2,2-dimethyl-1 -cyclopropane carboxylic acid, ethyl 2,2-dimethyl-1-cyclopropane carboxylate, 2-phenylcyclopropanecarboxylic acid, 1,2-cyclopropanedicarboxylic acid monomethyl ester, or 2-cyclohexyl-2-hydroxy-2-phenylacetic acid, etc.

In embodiments of step a), the resolution of 1,3-dimethyl-4-piperidone can be carried out in a suitable solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Solvents that are useful in the reaction include, but are not limited to: C1-6 alcohols; such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like. C3-6 ketones; such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, or the like. C2-6 ethers; such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, dimethoxyethane, anisole, or the like. C3-6 esters; such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like. C2-6 nitriles; such as acetonitrile, propionitrile, butanenitrile, or the like, halogenated hydrocarbons; such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perch loroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like, aliphatic or aromatic hydrocarbons; such as n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or mixtures thereof, aprotic polar solvents; such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, nitrobenzene; pyridine-based organic solvents, such as pyridine, picoline; sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane, 3-sulfolene, sulfolane; sulfoxide-based solvents such as dimethylsulfoxide (DMSO); or any mixtures of two or more thereof; or their combinations with water in various proportions.

In embodiments of step a), resolution of 1,3-dimethyl-4-piperidone can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.

In embodiments of step a), the salt of (S)-1,3-dimethyl-4-piperidone with chiral acid can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent. In embodiments, solvent as described above may be added and stirred for sufficient time after evaporation before isolation of the product.

In embodiments of step a), the salt of (S)-1,3-dimethyl-4-piperidone with chiral acid can be purified by any method known in the art to improve its chemical and optical purities. Any of the solvents listed above can be used for the purification. The purification can be done by using crystallization, recrystallization, slurry washing, column chromatography, or any methods known in the art by using the solvents which are described above for reaction.

In embodiments of step a), the salt of (S)-1,3-dimethyl-4-piperidone with chiral acid can be dried at suitable temperatures, such as from about 50°C to about 100°C and suitable pressures using drying equipment known in the art, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. Drying temperatures and times will be sufficient to achieve desired product purity.

In embodiments of step b), the salt of (S)-1,3-dimethyl-4-piperidone with chiral acid can be converted to (S)-1,3-dimethyl-4-piperidone i.e., free base in presence of suitable base. The base can be any organic or inorganic base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates; such as for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, or the like; hydrogen carbonates; such as for example, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; oxides, such as for example, calcium oxide, aluminium oxide, magnesium oxide, chromium oxide or the like; hydroxides; such as for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline metal hydroxides, such as for example, aluminum hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, or the like; organic bases; such as for example, ammonia, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole.

In embodiments of step b), free base formation can be carried out in a suitable solvent that is not limited to: halogenated hydrocarbon; such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perch loroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like. C1-6 alcohols; such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like. C3^ ketones; such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, or the like; or any mixtures thereof; or their combinations with water in various proportions.

In embodiments, the reaction mass is brought to a temperature from about -25°C to about 30°C during the addition of base. The temperatures of the reaction mass may be maintained at the same temperature for about 1 hour to about 10 hours or longer.

In embodiments of step b), after addition of base, optionally organic layer may be separated. (S)-1,3-dimethyl-4-piperidone can be isolated using techniques such as evaporation, filtration by gravity or suction, decantation centrifugation, and the like, optionally including washing the solid with a solvent.

In embodiments of step b), (S)-1,3-dimethyl-4-piperidone, can be purified by any method known in the art to improve its chemical and optical purities. Any of the solvents listed above can be used for the purification of (S)-1,3-dimethyl-4-piperidone. The purification of (S)-1,3-dimethyl-4-piperidone can be done by using crystallization, recrystallization, slurry washing, column chromatography, or any methods known in the art by using the solvents which are described above.

In embodiments, (S)-1,3-dimethyl-4-piperidone, can be optionally converted into acid addition salt by the methods known in the art. Examples of such acids used for salt formation include but are not limited to: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, or the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, citric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid or the like. The salts of (S)-1,3-dimethyl-4-piperidone can be useful for storing this product for longer duration.

In embodiments, pure (S)-1,3-dimethyl-4-piperidone can be obtained by converting chiral acid-addition salt (S)-1,3-dimethyl-4-piperidone by neutralization with a base. Any of the bases listed above, can be used for the conversion of acid-addition salt into freebase. The nature of the solvent, solvent ratios, heating temperatures or heating rates, maintenance time, cooling temperature or cooling rate, and drying conditions also play a significant role in the purity of the (S)-1,3-dimethyl-4-piperidone obtained after the purification. The methods known in the art or the methods described above can be used for the isolation and drying of (S)-1,3-dimethyl-4-piperidone.

In embodiments, (S)-1,3-dimethyl-4-piperidone can be isolated or used in the next stage without isolation i.e. in situ.

In an aspect, the invention provides process for the preparation of racemic 1,3-dimethyl-4-piperidone comprising racemization of (R)-1,3-dimethyl-4-piperidone in the presence of base.

In embodiments, racemization of (R)-1,3-dimethyl-4-piperidone can be carried out in a suitable solvent that is not limited to: aliphatic or aromatic hydrocarbons; such as n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or mixtures thereof; halogenated hydrocarbon; such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like. Ci_6 alcohols; such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like. C3-6 ketones; such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, or the like; or any mixtures thereof; or their combinations with water in various proportions.

In embodiments, racemization of (R)-1,3-dimethyl-4-piperidone can be carried out in presence of a suitable base. The base can be any organic or inorganic base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates; such as for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, or the like; hydrogen carbonates; such as for example, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; oxides, such as for example, calcium oxide, aluminium oxide, magnesium oxide, chromium oxide or the like; hydroxides; such as for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline metal hydroxides, such as for example, aluminum hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, or the like; carboxylates, such as for example, sodium acetate, potassium acetate, lithium acetate or the like; alkoxides, such as for example, sodium methoxide, potassium methoxide, lithium methoxide, or the like; organic bases; such as ammonia, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole.

In embodiments, racemization of (R)-1,3-dimethyl-4-piperidone can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.

In embodiments, the racemic 1,3-dimethyl-4-piperidone can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent. In embodiments, solvent as described above may be added and stirred for sufficient time after evaporation before isolation of the product.

In embodiments, the racemic 1,3-dimethyl-4-piperidone obtained above can be resolved to produce (S)- 1,3-dimethyl-4-piperidone using the procedures described herein.

In another aspect, the invention provides process for the preparation of (3S,4f?)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester comprising:

(a) resolving racemic 1,3-dimethyl-4-piperidone with chiral acid to obtain (S)-1,3-dimethyl-4-piperidone;

(b) condensation of (S)-1,3-dimethyl-4-piperidone obtained in step a) with 3-bromo-isopropoxy benzene to produce c/s-(3S,4/?)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol; and

(c) reacting c/s-(3S,4/?)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol obtained in step b) with ethyl chloroformate to produce (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester.

In embodiments of step a), resolution of racemic 1,3-dimethyl-4-piperidone to produce (S)-1,3-dimethyl-4-piperidone can be carried out using the procedures described herein above.

In embodiments, (R)- 1,3-dimethyl-4-piperidone obtained in step a) can be racemized to produce racemic 1,3-dimethyl-4-piperidone using the procedures described herein above. The racemic 1,3-dimethyl-4-piperidone can be again resolved to produce (S)-1,3-dimethyl-4-piperidone using the procedures described herein above.

In embodiments of step b), condensation of (S)-1,3-dimethyl-4-piperidone with 3-bromo-isopropoxy benzene can be carried out in presence of suitable base. The base can be any organic or inorganic base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal hydrides, such as for example, lithium hydride, sodium hydride, potassium hydride, or the like; sodamide; n-butyl lithium; lithium diisopropylamide; alkali metal or alkaline earth metal carbonates; such as for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, or the like; hydrogen carbonates; such as for example, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; hydroxides; such as for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline metal hydroxides, such as for example, aluminum hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, or the like; organic bases; such as for example, ammonia, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole.

In embodiments of step b), reaction can be carried out in a suitable solvent that is not limited to: C2-6 ethers; such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, dimethoxyethane, anisole, or the like; aromatic or aliphatic hydrocarbons; such as n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or mixtures thereof.

In embodiments of step b), condensation of (S)-1,3-dimethyl-4-piperidone with 3-bromo-isopropoxy benzene can be optionally carried out under nitrogen atmosphere.

In embodiments of step b), condensation of (S)-1,3-dimethyl-4-piperidone with 3-bromo-isopropoxy benzene can be carried out by initially taking 3-bromo-isopropoxy benzene in a solvent followed by adding base and (S)-1,3-dimethyl-4-piperidone. In an embodiment, the sequence of addition of reagent/reactant can be altered. In an embodiment, the temperature ranging from about -80°C to about 40°C can be maintained during the addition of reagent/ reactant.

In embodiments of step b), reaction can be carried out at a temperature ranging from about -80°C to about 40°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.

In embodiments of step b), after completion of the reaction optionally water can be added to the reaction mass and then combined with inorganic acids such as hydrochloric acid, or hydrobromic acid efc. after the completion of the reaction. Water or aqueous acids can be used for this step. The aqueous layer may be washed with water immiscible solvents such as xylene, toluene, diisopropylether, pentane, methyl ethyl ketone, methyl-t-butyl ether, hexane, heptane, di-ethyl ether, ethyl acetate, dichloromethane, 1,2-dichloroethane, cyclohexane, chloroform, carbon tetrachloride, butyl acetate, n-butanol, benzene, or decalin etc.

The pH of the aqueous layer can be adjusted with a base to a range from about 9 to about 12. The bases that are described above may be used for the pH adjustment. The product can be extracted into water immiscible solvents such as xylene, toluene, diisopropylether, pentane, methyl ethyl ketone, methyl-t-butyl ether, hexane, heptane, di-ethyl ether, ethyl acetate, dichloromethane, 1,2-dichloroethane, cyclohexane, chloroform, carbon tetrachloride, butyl acetate, n-butanol, benzene, or decalin efc.

In embodiments of step b), the organic layer containing c/s-(3S,4f?)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol can be used in the next stage without isolation i.e. in situ.

In embodiments of step b), after completion of the reaction optionally water can be added to the reaction mass followed by adjustment of pH to a value from about 9 to about 14, by adding a suitable base. The bases that are described can be used for this step. The product can be extracted into water immiscible solvents such as xylene, toluene, diisopropylether, pentane, methyl ethyl ketone, methyl-t-butyl ether, hexane, heptane, di-ethyl ether, ethyl acetate, dichloromethane, 1,2-dichloroethane, cyclohexane, chloroform, carbon tetrachloride, butyl acetate, n-butanol, benzene, or decalin etc.

In embodiments of step b), the product can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like. In embodiments, solvent as described above may be added and stirred for sufficient time after evaporation before isolation of the product.

In embodiments of step b), the product can be isolated from the reaction mass using any suitable techniques known in the art. The reaction mass can be evaporated at suitable temperatures, under suitable pressures. In embodiments, the solvent is evaporated completely under vacuum to obtain a solid residue.

In embodiments of step c), reaction of c/s-(3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol treated with ethyl chloroformate to produce (3S.4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester can be carried out in presence of suitable base. The base can be any organic or inorganic base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates; hydrogen carbonates; oxides; hydroxides; carboxylates; alkoxides.

In embodiments of step c), reaction can be carried out in a suitable solvent that is not limited to: hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; C3-6 ketones; or any mixtures thereof; or their combinations with water in various proportions.

In embodiments of step c), reaction can be optionally carried out under nitrogen atmosphere.

In embodiments of step c), reaction can be carried out at a temperature ranging from about 0°C to about 60°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.

In embodiments of step c), after completion of the reaction water can be added to the reaction mass followed by adjustment of pH to a value from about 1 to about 3, by adding inorganic acids such as hydrochloric acid, or hydrobromic acid etc.

In embodiments of step c), after completion of the reaction optionally water can be added to the reaction mass followed by adjustment of pH to a value from about 10 to about 14, by adding a suitable base. The suitable bases that are described can be used for this step. The product can be extracted into water immiscible solvents such as xylene, toluene, diisopropylether, pentane, methyl ethyl ketone, methyl-t-butyl ether, hexane, heptane, di-ethyl ether, ethyl acetate, dichloromethane, 1,2-dichloroethane, cyclohexane, chloroform, carbon tetrachloride, butyl acetate, n-butanol, benzene, or decalin etc.

In embodiments of step c), after completion of the reaction water can be added to the reaction mass and optionally purified by combining with inorganic acids such as hydrochloric acid, or hydrobromic acid ete. after the completion of the reaction. Water or aqueous acids can be used for this step. The aqueous layer may be washed with water immiscible solvents such as xylene, toluene, diisopropylether, pentane, methyl ethyl ketone, methyl-t-butyl ether, hexane, heptane, di-ethyl ether, ethyl acetate, dichloromethane, 1,2-dichloroethane, cyclohexane, chloroform, carbon tetrachloride, butyl acetate, n-butanol, benzene, or decalin etc. The pH of the aqueous layer can be adjusted with a base to a range from about 9 to about 14. The bases that are described above may be used for the pH adjustment. The product can be extracted into water immiscible solvents such as xylene, toluene, diisopropylether, pentane, methyl ethyl ketone, methyl-t-butyl ether, hexane, heptane, di-ethyl ether, ethyl acetate, dichloromethane, 1,2-dichloroethane, cyclohexane, chloroform, carbon tetrachloride, butyl acetate, n-butanol, benzene, or decalin etc.

In embodiments of step c), the organic layer containing (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester i.e., before or after the purification step as described above can be used in the next stage without isolation i.e. in situ.

In embodiments of step c), the product can be isolated from the reaction mass using any suitable techniques known in the art. The reaction mass can be evaporated at suitable temperatures, under suitable pressures. In embodiments, the solvent is evaporated completely under vacuum to obtain a solid residue.

In an another aspect, the invention provides process for the preparation of (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol comprising:

(a) resolving racemic 1,3-dimethyl-4-piperidone with chiral acid to obtain (S)-1,3-d imethyl-4-piperidone;

(b) condensation of (S)-1,3-dimethyl-4-piperidone obtained in step a) with 3-bromo-isopropoxy benzene to produce c/s-(3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol;

(c) reacting c/s-(3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol obtained in step b) with ethyl chloroformate to produce (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester; and

(d) converting (3S,4R)-1,3-dimethyl-4-[3-(1 -methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester obtained in step c) to (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol.

In embodiments, (S)-1,3-dimethyl-4-piperidone or c/s-(3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol or (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester prepared according to the processes described herein above.

In embodiments of step c), the procedure described can be adopted to produce the similar compounds using the reagents such as methyl chloroformate, phenyl chloroformate, or tosylates etc. These derivates can be used for the next step to produce (R)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]pyridine.

In an embodiment of step d), process for preparing (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol from (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester, embodiments comprising:

(i) converting (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester to (R)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]pyridine by pyrolysis;

(ii) methylating (R)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methylethoxy) phenyl]pyridine to produce (3R,4S)-1,2,3,4-tetrahydro-1,3,4-trimethyl-4-[3-
(1-methylethoxy) phenyl] pyridine;

(iii) converting (3f,4S)-1,2,3,4-tetrahydro-1,3,4-trimethyl-4-[3-(1-methylethoxy) phenyl] pyridine to (3R,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine by reduction followed by purification; and (iv) converting (3S,4ft)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine to produce (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol by demethylation followed by hydrolysis. In embodiments of step i), (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester converted to (R)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]pyridine at a temperature above 100°C optionally in presence of a solvent having boiling point higher than 100°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 10 to about 50 hours or longer.

In embodiments of step i), (3S,4ft)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester used in the above step can be directly from the previous step.

In embodiments of step i), after completion of the reaction optionally water can be added to the reaction mass and then combined with inorganic acids such as hydrochloric acid, or hydrobromic acid etc. after the completion of the reaction water or aqueous acids can be used for this step. The aqueous layer may be washed with water immiscible solvents such as xylene, toluene, diisopropylether, pentane, methyl ethyl ketone, methyl-t-butyl ether, hexane, heptane, di-ethyl ether, ethyl acetate, dichloromethane, 1,2-dichloroethane, cyclohexane, chloroform, carbon tetrachloride, butyl acetate, n-butanol, benzene, or decalin etc. The pH of the aqueous layer can be adjusted with a base to a range from about 9 to about 14. The bases that are described above may be used for the pH adjustment. The product can be extracted into water immiscible solvents such as xylene, toluene, diisopropylether, pentane, methyl ethyl ketone, methyl-t-butyl ether, hexane, heptane, di-ethyl ether, ethyl acetate, dichloromethane, 1,2-dichloroethane, cyclohexane, chloroform, carbon tetrachloride, butyl acetate, n-butanol, benzene, or decalin etc.
In embodiments of step i), the product can be isolated from the reaction mass using any suitable techniques known in the art. The reaction mass can be evaporated at suitable temperatures, under suitable pressures. In embodiments, the solvent is evaporated completely under vacuum to obtain a solid residue.

In embodiments of step ii), methylating (R)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methylethoxy) phenyljpyridine to produce (3R,4S)-1,2,3,4-tetrahydro-1,3,4-trimethyl-4-[3-(1-methylethoxy) phenyl] pyridine in presence of suitable methylating agent. The reaction also can contain suitable solvent and suitable base.

In embodiments of step ii), the methylating agent used in this reaction can be selected from dimethyl sulfoxide, diazomethane, 2,2-dimethoxypropane, dimethyl carbonate, dimethyl sulfate, dimethyl zinc, methyl fluorosulfonate, methyl iodide, methyl trifluoromethanesulfonate, methyl cobalamin, trimethyloxonium tetrafluoroborate.

In embodiments of step ii), reaction can be carried out in presence of suitable base. The base can be any organic or inorganic base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal hydrides, such as for example, lithium hydride, sodium hydride, potassium hydride, or the like; sodamide; n-butyl lithium; lithium diisopropylamide; alkali metal or alkaline earth metal carbonates; such as for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, or the like; hydrogen carbonates; such as for example, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; oxides, such as for example, calcium oxide, aluminium oxide, magnesium oxide, chromium oxide or the like; hydroxides; such as for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline metal hydroxides, such as for example, aluminum hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, or the like; carboxylates, such as for example, sodium acetate, potassium acetate, lithium acetate or the like; alkoxides, such as for example, sodium methoxide, potassium methoxide, lithium methoxide, or the like; organic bases; such as ammonia, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole.

In embodiments of step ii), reaction can be carried out in a suitable solvent that is not limited to: C2-6 ethers; aromatic or aliphatic hydrocarbons, or mixtures thereof.

In embodiments of step ii), reaction can be optionally carried out under nitrogen atmosphere.

In embodiments of step ii), reaction can be carried out by initially taking (R)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methylethoxy) phenyljpyridine in a solvent followed by adding base and methylating agent. In an embodiment, the sequence of addition of reagents can be altered. In an embodiment, the temperature ranging from about -80°C to about 40°C can be maintained during the addition of reagents.

In embodiments of step ii), reaction can be carried out at a temperature ranging from about -80°C to about 40°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 30 minutes to about 10 hours or longer.

In embodiments of step ii), the reaction mass can be combined with water containing a base such as aqueous ammonia, aqueous sodium hydroxide, or aqueous sodium bicarbonate etc. The product can be extracted into water immiscible solvents such as xylene, toluene, diisopropylether, pentane, methyl ethyl ketone, methyl-t-butyl ether, hexane, heptane, di-ethyl ether, ethyl acetate, dichloromethane, 1,2-dichloroethane, cyclohexane, chloroform, carbon tetrachloride, butyl acetate, n-butanol, benzene, or decalin etc.

In embodiments of step ii), the product can be isolated from the reaction mass using any suitable techniques known in the art. The reaction mass can be evaporated at suitable temperatures, under suitable pressures. In embodiments, the solvent is evaporated completely under vacuum to obtain a solid residue.

In embodiments of step iii), reduction of (3R,4S)-1,2,3,4-tetrahydro-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl] pyridine in presence of suitable reducing agent.

In embodiments of step iii), the reducing agent that is useful in the reaction include, but are not limited to: catalytic hydrogenation using palladium-on-carbon, platinum(IV) oxide, or Raney™ nickel, or the like; metal mediated reduction such as zinc and acetic acid, zinc and hydrochloric acid, zinc-mercury amalgam, tin and hydrochloric acid, sodium amalgam in ethanol, or iron and acetic acid; tin chloride (II), titanium (III) chloride, or the like; alkali metal hydrides, such as lithium aluminum hydride, sodium borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, sodium cyanoborohydride or the like; sodium dithionite in alkaline medium; Lindlar catalyst, any combination thereof; or any other suitable reducing agent known in the art. Optionally reaction may be carried out under an atmosphere of hydrogen.

In embodiments of step iii), reaction can be carried out in a suitable solvent that is not limited to: C1-6 alcohols; C3-6 ketones; C2-6 ethers; aromatic hydrocarbons, or mixtures thereof.

In embodiments of step iii), reaction can be carried out at any suitable temperatures, such as from about -20°C to about 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 30 minutes to about 10 hours or longer.

In embodiments of step iii), after completion of the reaction, the product can be isolated using any of the techniques known in the art. The product may be isolated by combining the reaction mass with any of the solvents described above followed by removing the solvent by the methods known in the art.

In embodiments of step iii), the product can be isolated from the reaction mass using any suitable techniques known in the art. The reaction mass can be evaporated at suitable temperatures, under suitable pressures. In embodiments, the solvent is evaporated completely under vacuum to obtain a solid residue.

In embodiments of step iii), the obtained product i.e., (3R,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine can be further purified by salt formation with chiral acid.

In an embodiment of step iii), the purification of the product can be carried out by the methods known in the art. In an embodiment, the product can be purified by treating with a chiral acids such as mandelic acid, malic acid, lactic acid, p-toluoyl tartaric acid, di-p-toluyl tartaric acid, tartaric acid, benzoyl tartaric acid, dibenzoyl tartaric acid, camphoric acid, camphorsulphonic acid, 2-cyclopentylmethyl-propanedioic acid 1-ethyl ester, methyl 3-methylglutalate, 2,2-dimethyl-1 -cyclopropane carboxylic acid, ethyl 2,2-dimethyl-1 -cyclopropane carboxylate, 2-phenylcyclopropanecarboxylic acid, 1,2-cyclopropanedicarboxylic acid monomethyl ester, or 2-cyclohexyl-2-hydroxy-2-phenylacetic acid, etc.

In embodiments of step iii), the purification of the product can be carried out in a suitable solvent to produce purified compound. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Solvents that are useful in the reaction include, but are not limited to: C1-6 alcohols; C3-6 ketones; C2-6 ethers; C33-6 esters; C2-6 nitrites; halogenated hydrocarbons; aliphatic or aromatic hydrocarbons; aprotic polar solvents; any mixtures of two or more thereof; or their combinations with water in various proportions.

In embodiments of step iii), purification of product can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from about 1 hour to about 24 hours or longer.

In embodiments of step iii), the salt of (3H,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine with chiral acid can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent. In embodiments, solvent as described above may be added and stirred for sufficient time after evaporation before isolation of the product.

In embodiment of step iii), the salt of (3R,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine with chiral acid can be purified by any method known in the art to improve its chemical and optical purities. Any of the solvents listed above can be used for the purification. The purification can be done by using crystallization, recrystallization, slurry washing, column chromatography, or any methods known in the art by using the solvents which are described above for reaction.

In embodiment of step iii), the salt of (3R,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine with chiral acid can be optionally dried at suitable temperatures, such as from about 50°C to about 100°C and suitable pressures using drying equipment known in the art, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. Drying temperatures and times will be sufficient to achieve desired product purity.

In embodiment of step iii), the salt of (3R,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine with chiral acid can be converted to the (3R,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine i.e., free base in presence of suitable base. The base can be any organic or inorganic base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal hydrides, alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, carboxylates, or alkoxides.

In embodiment of step iii), free base formation can be carried out in a suitable water immiscible solvent that is not limited to: xylene, toluene, diisopropylether, pentane, methyl ethyl ketone, methyl-t-butyl ether, hexane, heptane, di-ethyl ether, ethyl acetate, dichloromethane, 1,2-dichloroethane, cyclohexane, chloroform, carbon tetrachloride, butyl acetate, n-butanol, benzene, or decalin etc.

In embodiment of step iii), the reaction mass is brought to a temperature from about -25°C to about 40°C during the addition of base.

In embodiment of step iii), after the treatment with a base, organic layer may be separated. In embodiments, the aqueous layer can be further extracted with the water immiscible solvent as described above.

In embodiment of step iii), (3R,4f?)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine can be isolated using techniques such as evaporation, filtration by gravity or suction, decantation centrifugation, and the like.

In embodiment of step iii), (3R,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine, can be purified by any method known in the art to improve its chemical and optical purities. Any of the solvents listed above can be used for the purification of (3R,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine. The purification of (3R,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine can be done by using crystallization, recrystallization, slurry washing, column chromatography, or any methods known in the art by using the solvents which are described above.

In embodiment of step iv), (3R,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine can be converted to (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol by the methods known in the art.

In another aspect, the invention provides a process comprising resolution of racemic 1,3-dimethyl-4-piperidone (II) to produce (S)-1,3-dimethyl-4-piperidone (III).

In an embodiment, the invention provides the process further comprising condensation of (S)-1,3-dimethyl-4-piperidone (III) with 3-bromo-isopropoxy benzene (IV) to produce c/s-(3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol (V).

In an embodiment, the invention provides the process further comprising treating cis-(3S,4R)-1,3-dimethyM-[3-1-methylethoxy)phenyl-4-piperidinol (V) with ethyl chloroformate (VI) to produce (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester (VII).

In an aspect, alvimopan or its hydrate or its salts can be prepared by involving the use of (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol which is produced according to the processes described herein above.

In an embodiment, any of the intermediates described herein may be purified by the procedures known in the art. In an embodiment, any of the intermediates described herein may be in the state of crystalline, amorphous, hydrate, solvate, or anhydrous form.

DEFINITIONS

The following definitions are used in connection with the compounds of the present invention unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated "Cx-Cy", where x and y are the lower and upper limits, respectively. For example, a group designated as "C1-C6" contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. The term "reacting" is intended to represent bringing the chemical reactants together under conditions such to cause the chemical reaction indicated to take place.

"Alcohols" are organic solvents containing a carbon bound to a hydroxyl group. "C1-C6 alcohols" include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.

An "aliphatic or aromatic hydrocarbon" is a liquid hydrocarbon, which may be linear, branched, or cyclic and may be saturated, unsaturated, or aromatic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of "C5-C8 aliphatic or aromatic hydrocarbons", include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or mixtures thereof.

A "aprotic polar solvent" has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, nitrobenzene; pyridine-based organic solvents, such as pyridine, picoline; sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane, 3-sulfolene, sulfolane; sulfoxide-based solvents such as dimethylsulfoxide (DMSO).

An "ester" is an organic solvent containing a carboxyl group -(C=0)-0- bonded to two other carbon atoms. "C3-C6Esters" include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.

An "ether" is an organic solvent containing an oxygen atom -O- bonded to two other carbon atoms. "C2^Ether solvents" include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, dimethoxyethane, anisole, or the like.

A "halogenated hydrocarbon" is an organic solvent containing a carbon bound to a halogen. "Halogenated hydrocarbons" include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.

A "ketone" is an organic solvent containing a carbonyl group -(C=0)- bonded to two other carbon atoms. "C3-6Ketones" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, or the like.

A "nitrile" is an organic solvent containing a cyano -(C=N) bonded to another carbon atom. "C2-6Nitrile solvents" include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

An "inorganic base" is an inorganic compound, which acts as a base. Examples of such bases include, but are not limited to, alkali metal hydrides, such as for example, lithium hydride, sodium hydride, potassium hydride, or the like; sodamide; n-butyl lithium; lithium diisopropylamide; alkali metal hydroxides, such as for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline metal hydroxides, such as for example, aluminum hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, or the like; alkali metal carbonates, such as for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as for example, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; oxides, such as for example, calcium oxide, aluminium oxide, magnesium oxide, chromium oxide or the like; carboxylates, such as for example, sodium acetate, potassium acetate, lithium acetate or the like; alkoxides, such as for example, sodium methoxide, potassium methoxide, lithium methoxide, or the like;

An "organic base" is an organic compound, which acts as a base. Examples of such bases include, but are not limited to, ammonia, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole.

A "methylating agent" is a compound, which is useful for methylation in organic synthesis. Examples of such methylating agent include, but are not limited to, dimethyl sulfoxide, diazomethane, 2,2-dimethoxypropane, dimethyl carbonate, dimethyl sulfate, dimethyl zinc, methyl fluorosulfonate, methyl iodide, methyl trifluoromethanesulfonate, methyl cobalamin, trimethyloxonium tetrafluoroborate.

A "reducing agent" is a compound, which is useful for reduction in organic synthesis. Examples of such reducing agent include, but are not limited to, catalytic hydrogenation using palladium-on-carbon, platinum(IV) oxide, or Raney™ nickel, or the like; metal mediated reduction such as zinc and acetic acid, zinc and hydrochloric acid, zinc-mercury amalgam, tin and hydrochloric acid, sodium amalgam in ethanol, or iron and acetic acid; tin chloride (II), titanium (III) chloride, or the like; alkali metal hydrides, such as lithium aluminum hydride, sodium borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, sodium cyanoborohydride or the like; sodium dithionite in alkaline medium; Lindlar catalyst, any combination thereof; or any other suitable reducing agent known in the art. Optionally reaction may be carried out under an atmosphere of hydrogen.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES
Example 1a: Preparation of (S)-1,3-dimethylpiperidin-4-one (-)-di-p-toluoyl-L-tartaric acid.H2O.

Racemic 1,3-dimethylpiperidin-4-one (150 g), (-)-di-p-toluoyl-L-tartaric acid.H2O (597 g), and methanol (900 ml) are charged into a round bottom flask at 28°C, the reaction mass is stirred, and the reaction mass is heated to 65°C to produce a clear solution. The reaction mass is evaporated at 70°C. After completion of 95% evaporation, methanol is added(900 ml), and stirred for 3 hours at 30°C to produce a solid. The precipitated solid is filtered off and washed with methanol (75 ml). The solid is dried under vacuum at 60°C for 3 hours. Product weight: 345 g; Chiral purity: 92.77% by HPLC.

Example 1b: Preparation of (S)-1,3-dimethylpiperidin-4-one.
(S)-1,3-Dimethyl piperidin-4-one salt (15 g), dichloromethane (900 ml), and water (900 ml) are charged into a round bottom flask at 28°C, the reaction mass is stirred and cooled to 10°C, aqueousNhb (90 ml) is added at 7°C, and stirred at the same temperature for about 45 minutes to produce a clear solution. It appears milky nature. The organic layer is separated, washed with water, (400 ml), and dried with Na2SO4 (50 g). The reaction mass is evaporated under vacuum at 32°C for 1 hour 15 minutes. Product weight: 33.2 g; Chiral purity: 91.25% by HPLC.

Example 2a: Preparation of (S)-1,3-dimethylpiperidin-4-one (-)-di-p-toluoyl-L-tartaric acid.H2O.
Racemic 1,3-dimethylpiperidin-4-one (150 g), (-)-di-p-toluoyl-L-tartaric acid.H2O (595 g), and methanol (1050 ml) are charged into a round bottom flask at 28°C and the reaction mass is stirred, The reaction mass is heated to produce a clear solution, the reaction mass is evaporated at 75°C, methanol is added(900 ml), and maintained for 3 hours 30 minutes at 30°C to produce a solid. The precipitated solid is filtered off and washed with methanol (150 ml). The solid is dried under vacuum at 30°C for 3 hours. Product wet weight: 400 g; Chiral purity: 92.86% by HPLC.

Example 2b: Preparation of (S)-1,3-dimethylpiperidin-4-one.
Wet (S)-1,3-dimethylpiperidin-4-one salt , dichloromethane (2.4 L), and water (2.4 L) are charged into a round bottom flask at 30°C and the reaction mass is stirred.

The reaction mass is cooled to 10°C, aqueous NH3 (210 ml) is added at 5°C, and maintained at the same temperature for about 1 hour 20 minutes Then, the organic and aqueous layers are separated, the aqueous layer is extracted with dichloromethane (500 ml), the combined extracts washed with water (750 ml) and with NaCI solution, and dried with Na2SO4 (30 g). The organic extracts are evaporated under vacuum at 35°C for 2 hours 30 minutes. Product weight: 80 g; Chiral purity: 89.79% by HPLC.

Example 3: Process for racemization of unwanted (R)-1,3-dimethylpiperidin-4-one isomer.
Racemic 1,3-dimethylpiperidin-4-one (100 g), (-)-di-p-toluoyl-L-tartaric acid.H2O (397 g), and methanol (700 ml) are charged into a round bottom flask at 28°C and the reaction mass is stirred. The reaction mass is heated to produce a clear solution, the reaction mass is evaporated at 70°C to produce a solid, methanol is added (600 ml), and stirred for 3 hours at 30°C to produce a solid. The precipitated solid is filtered off and washed with methanol (60 ml). The solid is dried under vacuum at 30°C for 20 minutes. Product wet weight: 237 g. The filtrate is evaporated using rotatory evaporator at 60°C to produce residue. Water is added (700 ml) to the residue at 30°C to obtain a solution and sodium hydroxide (70 g) is added to adjust to pH above 12.0. The mixture is stirred for 1 hour 30 minutes, dichloromethane is added (500 ml) at 30°C, and the mixture is stirred at the same temperature for 30 minutes. The organic and aqueous layers are separated. The aqueous layer is extracted with dichloromethane (300 ml) and combined organic layers evaporated completely at 40°C under vacuum. The residue is brought to 28°C, (-)-di-p-toluoyl-L-tartaric acid.H2O (109 g) is added, methanol (192.5 ml) is added at 30°C, the reaction mass is stirred, and the reaction mass is heated to produce a clear solution. The reaction mass is evaporated at 70°C to produce a solid, methanol is added(165 ml), and stirred for 3 hours 30 minutes at 30°C to produce a solid. The precipitated solid is filtered off and washed with methanol (20 ml). The solid is dried under vacuum at 30°C for 30 minutes. Product wet weight: 57 g; Wet (S)-1,3-dimethylpiperidin-4-one salts (294 g), dichloromethane (2.0 L), and water (2.0 L) are charged into a round bottom flask at 30°C, the reaction mass is stirred and cooled to 7°C, the reaction mass is adjusted to a pH greater than 11.0 with a aqueous NH3 (210 ml) at 7°C, and maintained at the same temperature for 40 minutes.

Then, the organic and aqueous layers are separated, the aqueous layer is extracted with dichloromethane (500 ml), the organic layer is washed with water (170 ml), and dried with Na2SO4 (20 g). The reaction mass is evaporated under vacuum at 40°C for 2 hours. Product weight: 61 g; Chiral purity: 89.15% by HPLC.

Example 4: Preparation of cis-(3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl] -4-piperidinol.
3-Bromo-isoproxy benzene (55 gm) and tetrahydrofuran (150 ml) are charged into a round bottom flask at 28°C, the reaction mass is stirred under nitrogen atmosphere, the reaction mass is cooled to -75°C, n-butyllithium (166.5 gm) is added over 1 hour and maintained at the same temperature for 1 hour. (S)-1,3-Dimethyl piperidin-4-one (25 gm) is added at -75°C over 30 minutes and maintained at the same temperature for 1 hour. After completion of the reaction, 50% HCI solution (211.6 ml) is added to the reaction mass at the same temperature, the temperature of the reaction mass is raised to 27°C, and n-hexane (116.5 ml) is added. Then, the organic and aqueous layers are separated, the aqueous layer is washed with n-hexane (116.5 ml), n-hexane (116.5 ml) is added to the aqueous layer, and the reaction mass is adjusted to pH 10-12 with a 20% aqueous sodium hydroxide solution (100 ml) at 28°C. The reaction mass is maintained for 15 minutes, the organic and aqueous layers are separated, the aqueous layer is extracted with n-hexane (116.5 ml), the combined organic layer is washed with water (100 ml) and dried with Na2SO4 (6 g). The reaction mass is evaporated under vacuum at 55°C for 30 minutes. Product weight: 37.7 g; HPLC purity: 87.99.

Example 5: Preparation of (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester.
cis-(3S,4R)-1,3-Dimethyl-4-[3-(1-methyl ethoxy)phenyl]-4-piperidinol (43 gm) and toluene (430 ml) are charged into a round bottom flask at 28°C, the reaction mass is stirred and cooled to 2°C, triethyl amine (23.7 ml) is added over 10 minutes, ethyl chloroformate (23.9 ml) is added at the same temperature over 40 minutes, the reaction mass temperature is raised to 28°C, and maintained at the same temperature for 1 hour 20 minutes. After completion of the reaction, water is added (430 ml) at 28°C and the reaction mass is adjusted to pH 2-3 with a aqueous HCI (60 ml) at 28°C over 10 minutes, maintained at the same temperature for 10 minutes, and then the organic and aqueous layers are separated. Toluene (430 ml) is added to the aqueous layers, the reaction mass is adjusted to pH 12-14 with a 20% aqueous sodium hydroxide (86 ml) at 28°C, and maintained at the same temperature for 20 minutes. Then the organic and aqueous layers are separated, the aqueous layer is extracted with toluene (430 ml), the combined organic layer is washed with water (100 ml) and dried with Na2SO4 (5 g). The reaction mass is evaporated under vacuum at 55°C over 55 minutes. Product weight: 47.3 g; HPLC purity: 89.98%.

Example 6: Preparation of (R)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methyl ethoxy)phenyl]pyridine.
(3S,4R)-1,3-DimethyM-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester (47 gm) and decalin (352.5 ml) are charged into a round bottom flask at 28°C, the reaction mass is stirred, evacuated and purged three times with nitrogen at 28°C, and purged one time at 105°C. The reaction mass is heated to 185°C and maintained at the same temperature for 23 hours. After completion of reaction, 1N HCI solution (470 ml) is added at 28°C and maintained at the same temperature for 20 minutes. Then, the organic and aqueous layers are separated, the aqueous layer is washed with n-hexane (782.8 ml), n-hexane (781.4 ml) is added to the aqueous layer, the reaction mass is adjusted to pH 12-14 with a 50% aqueous NaOH (74 ml) at 28°C, and maintained at the same temperature for 10 minutes. Then the organic and aqueous layers are separated, the aqueous layer is extracted with n-hexane (781.4 ml), the combined organic layers are dried with Na2SO4 (5 gm). The reaction mass is evaporated under vacuum at 55°C over 55 minutes. Product weight: 32.0 g; Chiral purity: 87.9% by HPLC, Impurities found at 7.97 RT and HPLC purity: 84.89%.

Example 7: Preparation of (3S,4S)-1,2,3,4-tetrahydro-1,3,4-trimethyl-4-[3-(1-methylethoxy) phenyl] pyridine.
(R)-1,2,3,6-Tetrahydro-1,3-dimethyl-4-[3-(1-methyl ethoxy)phenyl]pyridine (40 gm) and THF (343.8 ml) are charged into a round bottom flask at 27°C, the reaction mass is stirred and cooled to -15°C, n-butyllithium (137 ml) is added over 30 minutes, and maintained at the same temperature for 20 minutes. During the addition of n-butyllithium, the reaction mass appears in dark reddish brown color. The reaction mass further cooled to -50°C, dimethyl sulphate (12.9 ml) is added over 30 minutes, and maintained at the same temperature for 45 minutes. During the addition of dimethyl sulphate, the reaction mass appears in greenish color. The reaction mass is quenched with aqueous NH3 (32 ml) and water (120 ml) at -50°C. After quenching, n-hexane (120 ml) is added at -40°C, the temperature of the reaction is raised to 27°C, and maintained at the same temperature for 20 minutes. Then the organic and aqueous layers are separated, the aqueous layer is extracted with n-hexane (120 ml), the organic layer is washed with water (50 ml), and the combined organic layers are dried with Na2SO4 (5 gm). The reaction mass is evaporated under vacuum at 42°C over 35 minutes. Product weight: 39.0 g; Chiral purity: 65.89% by HPLC.

Example 8: Preparation of (3S,4S)-1,2,3,4-tetrahydro-1,3,4-trimethyl-4-[3-(1-methylethoxy) phenyl] pyridine.
(R)-1,2,3,6-Tetrahydro-1,3-dimethyl-4-[3-(1-methyl ethoxy)phenyl]pyridine (40 gm) and THF (200 ml) are charged into a round bottom flask at 27°C, the reaction mass is stirred and cooled to -17°C, n-butyllithium (140 ml) is added over 30 minutes, and maintained at the same temperature for 30 minutes. During the addition of n-butyllithium, the reaction mass appears in dark brown red color. The reaction mass is further cooled to -50°C, dimethyl sulphate (15.46 ml) is added over 35 minutes, and maintained at the same temperature for 50 minutes. After completion of the reaction THF (200 ml) is added at -50°C, The reaction mass is quenched with aqueous NH3 (32 ml), water (112 ml), and hexane (145 ml) at -50°C. The temperature of the reaction is raised to 30°C and maintained at the same temperature for 30 minutes. Then the organic and aqueous layers are separated, the aqueous layer is extracted with n-hexane (290 ml), and organic layer is washed with water (100 ml). The reaction mass is evaporated under vacuum at 60°C over 30 minutes. Product weight: 44.0 g; HPLC purity: 51.5%.

Example 9: Preparation of (3R,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine.
(3S,4S)-1,2,3,4-Tetrahydro-1,3,4-trimethyl-4-[3-(1 -methylethoxy)phenyl] pyridine (43 gm) and methanol (430 ml) are charged into a round bottom flask at 28°C and the reaction mass is stirred. The reaction mass appears like a homogeneous solution. The reaction mass is cooled to 02°C, NaBH4 is added over 45 minutes, the temperature of the reaction is raised to 28°C, and maintained at the same temperature for 3 hours. After completion of the reaction, acetone (43 ml) and NaHCO3 solution (43 ml) are added to the reaction mass at 28°C and maintained at the same temperature for 15 minutes. The reaction mass is evaporated under vacuum at 55°C over 30 minutes, ethyl acetate (430 ml) is added to the reaction mass at 28°C, maintained at the same temperature for 15 minutes, the organic and aqueous layers are separated, the aqueous layer is extracted with ethyl acetate (645 ml), the organic layer is washed with water (143 ml) and dried with Na2SO4 (9 g). The reaction mass is evaporated under vacuum at 55°C over 30 minutes obtained a solid residue (37.5 g). The above obtained solid residue, (+)-di-p-toluoyl-D-tartaric acid anhydrous (55.45 gm), and ethanol (430 ml) are charged into a round bottom flask at 28°C and the reaction mass is stirred for 5 minutes as a solid separated. The temperature of the reaction is raised to 82°C and maintained at the same temperature for 45 minutes. The reaction mass appears like heterogeneous. The reaction mass is cooled to 4°C, maintained at the same temperature for 1 hour 30 minutes, the obtained solid is filtered off, and is washed with ethanol (30 ml). The solid compound obtained (57 gm (wet)) is dried with suction at 30°C for 30 minutes. The solid (42 gm (dry)) compound and ethanol (190 ml) are charged into a round bottom flask at 30°C, the reaction mass is stirred, the temperature of the reaction is raised to 80°C, and maintained at the same temperature for 1 hour. The reaction mass appears like heterogeneous. The reaction mass is cooled to 4°C, maintained at the same temperature for 1 hour 5 minutes, the obtained solid is filtered off, and washed with ethanol (10 ml). The solid compound obtained (50 gm (wet)) is dried with suction at 30°C for 20 minutes. The above obtained solid, toluene (200 ml), and 2N NaOH (100 ml) are charged into a round bottom flask at 30°C and the reaction mass is stirred. Then the organic and aqueous layers are separated, the aqueous layer is extracted with toluene (150 ml), the combined organic extracts are evaporated under vacuum at 60°C over 30 minutes to obtain a solid residue. Product weight: 17.5 g; HPLC purity: 92.86%.

Example 10: Preparation of (3R,4R)-phenyl 4-(3-isopropoxyphenyl)-3,4-dimethyl piperidine-1 -carboxylate.

(3R,4R)-1,3,4-trimethyl-4-[3-(1-methylethoxy)phenyl]-piperidine (17 gm) and toluene (126 ml) are charged into a round bottom flask at 28°C, the reaction mass is stirred under nitrogen atmosphere, the temperature of the reaction is raised to 89°C during the addition of phenyl chloroformate (12.6 gm) over 15 minutes, and the temperature of the reaction mass further is raised to 110°C for 2 hours. If the reaction not completed, then 3 ml of phenyl chloroformate is added to the reaction mass. After completion of the reaction, the reaction mass is cooled to 45°C, 10% aqueous NaOH solution (25.1 ml) is added, maintained at the same temperature for 20 minutes, the temperature of the reaction is decreased to 28°C, and maintained at the same temperature for 15 minutes. Then the organic and aqueous layers are separated, the organic layer is washed with 1N aqueous NaOH:MeOH (1:1) (124 ml), 1N aqueous HCI:MeOH (1:1) (186 ml) and water, and dried with Na2SO4 (2 gm). The dried organic extract is evaporated under vacuum at 55°C over 5 minutes obtained solid residue. Product weight: 24.9 g; HPLC purity: 83.33%.

Example 11: Preparation of (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol. 3R,4R)-Phenyl 4-(3-isopropoxyphenyl)-3,4-dimethylpiperidine-1-carboxylate (24 gm), HBr (30.5 ml), and acetic acid (30.5 ml) are charged into a round bottom flask at 28°C, the reaction mass is stirred, and the temperature of the reaction is raised to 100°C for 16 hours and 30 minutes. After completion of the reaction, the temperature of the reaction mass decreased to 28°C, water (109 ml) and MTBE (87.2 ml) is added, and the reaction mass is stirred for 10 minutes. Then the organic and aqueous layers are separated, the aqueous layer is washed with MTBE (174.4 ml), the reaction mass is adjusted to pH 8.5 with a 15% aqueous NaOH solution over 30 minutes, methanol is added(37.1 ml) to the reaction mass, and the reaction mass is adjusted to pH 10.5 with a 15% aqueous NaOH solution over 5 minutes. A solid separates, the reaction mass is stirred for 1 hour 30 minutes, the reaction mass is cooled to 2°C, maintained at the same temperature for 30 minutes, the obtained solid is filtered off, and washed with water (43.6 ml). The solid compound obtained is dried with suction at 25°C for 45 minutes and then dried at 61 °C under vacuum for 6 hours. Product weight: 7.5 g; HPLC purity: 97.74%.

Example 12: Preparation of (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester.
3-Bromo-isoproxy benzene (103 gm) and tetrahydrofuran (327 ml) are charged into a round bottom flask at 27°C, the reaction mass is stirred and cooled to -75°C, n-butyllithium (360 ml) is added over 50 minutes, and maintained at the same temperature for 1 hour. (S)-1,3-Dimethylpiperidin-4-one (54.5 gm) is added at -65°C over 45 minutes, and maintained at the same temperature for 1 hour. After completion of the reaction, 6N HCI (405 ml) is added to the reaction mass at the same temperature over 35 minutes, the temperature of the reaction mass is raised to 27°C. Then the organic and aqueous layers are separated, the aqueous layer is washed with n-hexane (411.7 ml), toluene (327 ml) is added to the aqueous layer, and the reaction mass is adjusted to pH 12.8 with a 20% aqueous sodium hydroxide solution (218 ml) at 33°C. The temperature of the reaction mass is raised to 45°C and maintained at the same temperature for 20 minutes. Then the organic and aqueous layers are separated, the aqueous layer is extracted with toluene (300 ml), and the combined organic layer is washed with water (218 ml). Triethylamine (45 gm) and organic layer are charged into a round bottom flask at 27°C, the reaction mass is stirred and cooled to 2°C , and ethyl chloroformate is added over 45 minutes. The reaction mass temperature is raised to 27°C and maintained at the same temperature for 30 minutes. After completion of the reaction, water is added (558 ml), the reaction mass is stirred for 10 minutes, the reaction mass is adjusted to pH 11.5 with a 20% aqueous sodium hydroxide solution (98 ml) at 28°C, and maintained at the same temperature for 20 minutes. Then the organic and aqueous layers are separated, the aqueous layer is extracted with toluene (120 ml), the combined organic layer is washed with 10% NH4CI (558 ml) and dried with Na2SO4 (15 gm). The dried organic extract is evaporated under vacuum at 55°C over 55 minutes. Product weight: 95.3 g; HPLC purity: 72.13%, Chiral purity: 82.99% by HPLC.

Example 13: Preparation of (R)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methyl ethoxy)phenyl]pyridine.
(3S,4R)-1,3-Dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester (85 gm) and decalin (637.5 ml) are charged into a round bottom flask at 27°C, the reaction mass is stirred for 5 minutes under nitrogen atmosphere, the temperature of the reaction mass is raised to 195°C, and maintained at the same temperature for 21 hours 10 minutes. After completion of the reaction, the temperature of the reaction mass is decreased to 27°C, 1N HCI solution (312 ml) is added, and maintained at the same temperature for 45 minutes. Then the organic and aqueous layers are separated, n-hexane (291.4 ml) is added to the aqueous layer, the reaction mass is stirred for 10 minutes, and the organic and aqueous layers are separated, n-Hexane (485.7 ml) is added to the aqueous layer, the reaction mass is adjusted to pH 13 with a 50% aqueous NaOH solution (133.5 ml) at 27°C over 10 minutes, and the reaction mass is stirred. Then the organic and aqueous layers are separated, the aqueous layer is extracted with n-hexane (291.4 ml), the combined organic layers are dried with Na2SO4 (12.1 gm). The reaction mass is evaporated under vacuum at 45°C over 55 minutes. Product weight: 55.8 gm; Chiral purity: 89.89% by HPLC and HPLC purity: 80.54%.

Example 14: Preparation of (R)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methyl ethoxy)phenyl]pyridine.
3-Bromo-isoproxy benzene (37.8 gm) and tetrahydrofuran (120 ml) are charged into a round bottom flask at 27°C, the reaction mass is stirred and cooled to -75°C, n-butyllithium (132 ml) is added over 30 minutes, and maintained at the same temperature for 55 minutes. (S)-1,3-Dimethylpiperidin-4-one (20 gm) is added at -70°C over 30 minutes and maintained at the same temperature for 40 minutes. After completion of the reaction, aqueous HCI (135 ml) is added to the reaction mass at the same temperature for 35 minutes, and the temperature of the reaction mass is raised to 27°C. Then the organic and aqueous layers are separated, the aqueous layer is washed with n-hexane (200 ml), decalin (120 ml) is added to the aqueous layer, the temperature is raised to 48°C, the reaction mass is adjusted to pH 12.8 with a 20% aqueous sodium hydroxide solution (80 ml) at the same temperature over 10 minutes, the reaction mass is extracted with decaline (120 ml), washed with water (75 ml) and dried with Na2SO4.

Above obtained decaline layer and triethylamine (15 gm) are charged into a round bottom flask at 28°C, the reaction mass is stirred and cooled to 4°C, ethyl chloroformate (23.6 gm) is added over 35 minutes, the reaction mass temperature is raised to 28°C, and maintained at the same temperature for 1 hour. After completion of the reaction, water is added (186 ml), the reaction mass is stirred for 10 minutes, the reaction mass is adjusted to pH 12.8 with a 20% aqueous NaOH solution (36 ml) at 28°C, and maintained at the same temperature for 20 minutes. Then the decalin layer and aqueous layers are separated, the decalin layer is washed with aqueous NH4CI solution (372 ml), and dried with Na2SO4 (25 gm). Decalin (40 ml) is added to the reaction mass, the reaction mass temperature is raised to 190°C, and maintained at the same temperature for 20 hour. After completion of the reaction, the reaction mass is cooled to 27°C and 1N HCI solution (132.2 ml) is added. Then the decalin layer is separated, the decalin layer is washed with hexane (60 ml), hexane (200 ml) is added to the reaction mass, the reaction mass is adjusted to pH 12.8 with a 20% aqueous NaOH solution (150 ml) at 27°C, and maintained at the same temperature for 10 minutes. Then the organic layer and aqueous layers are separated, the aqueous layer is extracted with hexane (150 ml), and the combined organic layers are dried with Na2SO4 (25 gm). The reaction mass is evaporated under vacuum at 45°C over 20 minutes. Product weight: 23.5 gm; HPLC purity: 91.14%.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the application described and claimed herein.

While particular embodiments of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the application. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this application.

We claim:

1. A process for the preparation of (S)-1,3-dimethyl-4-piperidone comprising:

(a) resolving racemic 1,3-dimethyl-4-piperidone with chiral acid in a solvent to obtain a salt of (S)-1,3-dimethyl-4-piperidone; and

(b) converting the salt of (S)-1,3-dimethyl-4-piperidone obtained in step a) to (S)-1,3-dimethyl-4-piperidone.

2. The process according to claim 1, wherein the chiral acid is selected from tartaric acid, mandelic acid, malic acid, lactic acid, camphoric acid and camphorsulphonic acid.

3. The process according to claim 1 and 2, wherein the chiral acid is (-)-di-p-toluoyl-L-tartaric acid.

4. The process according to claim 1, wherein the solvent is selected from methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, dichloromethane and toluene.

5. A process for the preparation of (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester comprising:

(a) resolving racemic 1,3-dimethyl-4-piperidone with chiral acid to obtain (S)-1,3-dimethyl-4-piperidone;

(b) condensation of (S)-1,3-dimethyl-4-piperidone obtained in step a) with 3-bromo-isopropoxy benzene to produce c/s-(3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol; and

(c) reacting c/s-(3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]-4-piperidinol obtained in step b) with ethyl chloroformate to produce (3S,4R)-1,3-dimethyl-4-[3-(1-methylethoxy)-phenyl]-4-piperidinyl carbonic acid ethyl ester.

6. A process for the preparation of (3R,4R)-3-(3,4-dimethyl-4-piperidinyl)phenol comprising the use of (S)-1,3-dimethyl-4-piperidone obtained according any one of the claims 1-4.

7. A process for the preparation of Alvimopan (or) its hydrates (or) its salts comprising the use of (S)-1,3-dimethyl-4-piperidone obtained according any one of the claims 1-4.

8. (S)-1,3-dimethyl-4-piperidone.

9. A process for the preparation of racemic 1,3-dimethyl-4-piperidone comprising
racemization of (R)-1,3-dimethyl-4-piperidone in the presence of base.

10. The process according to claim 9, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.