Title of Invention	AM IMPROVED PROCESS FOR THE PREPARATION OF DULOXETINE HYDROCHLORIDE
Abstract	An improved process for the preparation of Duloxetine hydrochloride Duloxetine hydrochloride (Formula -I) illustrated as below

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CLAIMS (not applicable for provisional specification. Claims should start with the preamble—--"I/We claim" on separate page) 6. DATE AND SIGNATURE (to be given at the end of last page of specification) 7. ABSTRACT OF THE INVENTION (to be given along with complete specification on separate page) An improved process for the preparation of Duloxetine hydrochloride Field of the Invention The present invention relates to an improved process for the preparation of Duloxetine and its pharmaceutically acceptable salts, preferably hydrochloride, which is chemically known as (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine hydrochloride, represented by formula (I). Duloxetine and related class of compounds like fluoxetine, tomoxetine etc., are important for treating psychiatric disorders. Fluoxetine is selective inhibitor of serotonin in serotonergic neurons, tomoxetine and nisoxetine are selective inhibitors of norepinephrine in noradrenergic neurons while duloxetine is a dual inhibitor of serotonin and norepinephrine reutake and thus have a better pharmacological profile as an antidepressant drug. Serotonin and norepinephrine neuro transmitters are intimately involved in a number of physiological and behavioral processes, suggesting that duloxetine (ability to produce robust increase of extra cellular serotonin and norepinephrine levels) is not only a highly efficient antidepressant agent for treating psychiatric disorders but also can be used for treating other symptoms like alcoholism, urinary incontinence, fatigue, stroke, intestinal cystitis, obsessive compulsive disorder, panic disorder, hyperactivity disorder, sleep disorder, sexual dysfunction etc. Background of the Invention The synthesis of duloxetine is described in detail in EP-A-273 658, EP-A-457 559 and EP-A-650 965. Starting from 2-acetylthiophene, an aminomethylation with dimethylamine and formaldehyde (Mannich reaction) is carried out in step -A. The 3-dimethylamino-1 -(2-thienyl)-1 -propanone formed is reduced to the corresponding alcohol, 1-hydroxy-l-(2-thenyl)-3-dimethylaminopropane, by means of complex hydrides in step B. The alcohol is then converted in step C with an alkali metal hydride and 1-fluoro-naphthalene, optionally in the presence of a potassium compound (cf EP-A-650 965), to the naphthyl derivative, N,N-dimethyl-3-(l-nap hthyloxy)-3-(2-thienyl) propylamine. In the final step D, the amino group is then demethylated by reaction with a chloroformic acid ester, preferably phenyl chloroformate or trichloroethyl chloroformate, optionally in the presence of a mixture of zinc and formic acid (EP-A-457 559), followed by alkaline hydrolysis of the carbamate to give N-methyl-3-(l-naphthyloxy)-3-(2-thienyl) propylamine. The US Patent 5362886 described the process for the preparation of (+) Duloxetine hydrochloride by isolating the (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine phosphoric acid salt and preparation of hydrochloride salt using aqueous hydrochloric acid and ethyl acetate as a solvent. The US Patent 5023269 claims Duloxetine and its pharmaceutically acceptable salts and method of treating anxiety and obesity. The patent also discloses the processes for the preparation of Duloxetine and its pharmaceutically acceptable salts, however the patent not disclosed the process for the preparation of hydrochloride salt. The EP patent 0650965 Bl discloses the process for the preparation of (S)-(+)-N,N-dimethyl-3-(l-napththalenyloxy)-3-(2-thienyl)propanamine an intermediate of Duloxetine which was isolated as a phosphoric acid salt and disclosed the process for the preparation of Duloxetine hydrochloride using aqueous hydrochloric acid and ethylacetate as a solvent. The US Patent 5491243 and US 5362886 discloses the stereospecific process for the synthesis of (S)-(+)-N1N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine and claimed the same. In both the patents the above said compound isolated as a phosphoric acid salt. Disadvantages of the prior art processes The US Patent 5362886 describes the process for the preparation of (+) Duloxetine hydrochloride by isolating the (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine as phosphoric acid salt and preparation of hydrochloride salt of Duloxetine using aqueous hydrochloric acid and ethyl acetate as a solvent leads to degradation of the obtained compound. Isolation of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2- thienyl)propanamine as phosphoric acid salt leads to one more step and preparation of hydrochloride salt using aqueous hydrochloric acid leads to degradation of the obtained compound and formation of gummy material. Brief description of the Invention The present invention provides an improved process for the preparation of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine hydrochloride of formula (I). The present invention comprises of the following steps a) Reacting l-(thiophen-2-yl)ethanone compound of formula (II) with dimethylamine hydrochloride compound of formula (III) in presence of paraformaldehyde in a suitable solvent gives the compound of formula (IV). b) Reducing the compound of formula (IV) with an alkali metal borohydrides in a suitable solvent gives the compound of formula (V). c) Resolving the compound of formula (V) with chiral acid in a suitable solvent and further treating the obtained compound with weak inorganic base in a suitable chloro solvents or ester solvents gives the compound of formula (VI). d) Reacting the compound of formula (VI) with the compound of formula (VII) in presence of an alkali base and in a suitable polar aprotic solvent, then in situ demethylation and converting into oxalate salt of compound of formula (VIII). e) Converting the Duloxetine oxalate salt into its hydrochloride salt compound of formula (I) using ethylacetate HC1, methanolic HC1, isopropyl alcohol HC1, preferably ethylacetate HC1 in a suitable solvent like alcoholic solvents or ester solvents. f) Purifying the above obtained compound of formula (I) from step (e) using suitable solvent or mixture of solvents selected from ester solvents or alcohol solvents or mixture of ester and alcohol solvents. The process of the present invention is simple, cost effective environment friendly and commercially suitable over the prior art references. Advantages over prior art processes • Usage of ethylacetate HC1 for the preparation of Duloxetine hydrochloride instead of using aqueous hydrochloride for avoiding degradation of Molecule as well as formation of free flow solid. • As per the present invention the isolation of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine as phosphoric acid salt is avoided. • Present invention provides process for the preparation of (S)-(+)-N- methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate without isolating intermediate compounds (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine and (S)-(+)-N-phenyloxy carbonyl-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine thereby reduces two steps in the synthesis of Duloxetine hydrochloride. • Present invention provides process for producing Duloxetine hydrochloride substantially free from other isomer (i.e., other isomer is NMT 0.2%). • Present invention provides the process for • Cost effective process. • Reduction of cycle time. • Environment friendly and easy scale-up. Detailed description of the Invention The present invention provides an improved process for the preparation of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl)-propanamine hydrochloride of formula (I). The present invention comprises of the following steps a) Reacting l-(thiophen-2-yl)ethanone compound of formula (II) with dimethylamine hydrochloride compound of formula (III) in presence of paraformaldehyde in a suitable solvent selected from acloholic solvents, preferably isopropyl alcohol gives the compound of formula (IV). b) Reducing the compound of formula (IV) with an alkali metal borohydrides like sodium borohydride, potassium borohydride in a suitable solvent selected from Cl-C4 alcoholic solvents, preferably methanol gives the compound of formula (V). c) Resolving the compound of formula (V) with chiral acid like mandelic acid, tartaric acid,di-p-tolyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid, preferably mandelic acid in a suitable solvent selected from ester solvents like ethylacetate, propylacetate, preferably ethylacetate and further treating the obtained compound with weak inorganic base like sodium carbonate, sodium bicarbonate in suitable chloro solvents or ester solvents, preferably chloro solvents more preferably methylene chloride gives the compound of formula (VI). d) Reacting the compound of formula (VI) with the compound of formula (VII) in presence of an alkali base like sodium hydroxide, potassium hydroxide preferably sodium hydroxide and in a suitable polar aprotic solvent like dimethylsulfoxide, dimethylformamide, then in situ demethylation and converting into oxalate salt of compound of formula (VIII). g) Converting the Duloxetine oxalate salt into its hydrochloride salt compound of formula (I) using ethylacetate HC1, methanolic HC1, isopropyl alcohol HC1, preferably ethylacetate HC1 in a suitable solvent like alcoholic solvents or ester solvents, preferably ester solvents more preferably ethylacetate. h) Purifying the above obtained compound of formula (I) from step (e) using suitable solvent or mixture of solvents selected from ester solvents like ethyl acetate, propyl acetate, methyl acetate or alcohol solvents like methanol, ethanol, isopropylalcohol or mixture of ester and alcohol solvents like ethylacetate and methanol, ethylacetate and ethanol, ethylacetate and isopropylalcohol, preferably mixture of solvents, more preferably ethylacetate and methanol. Related substances by HPLC of Duloxetine hydrochloride is carried out using a liquid chromotograph is equipped with variable wavelength UV-Detector, symmetry C8, 250x4.6 mm, 5jam or equivalent column, 1.0 ml/min flow rate at 215 nm, ambient temperature, and the buffer is used 1.38 gr of sodium dihydrogen phosphate monohydrate in 300 ml water, dilute with water to 1000 ml, add 1.0 ml of TEA and pH is adjusted to 2.5 with phosphoric acid. Mobile phase A (degassed phosphate buffer), Mobile phase B (Acetonitrile : water in the ratio of 90:10 V/V) w Isomer content by Chiral HPLC is carried out using a liquid chromotograph is equipped with variable wavelength UV-Detector, Chiralcel OJ-H, 250X4.6 mm column, 1.0 ml flow rate at 230 nm, 40°C temperature and mobile phase is a mixture of 90 volumes of n-Hexane, 10 volumes of ethanol, and 0.1 volumes of diethyl amine. The thermal analysis of Duloxetine hydrochloride was carried out on Waters DSC Q-10 model differential scanning calorimeter and the FT-IR spectrum of Duloxetine hydrochloride was recorded on Thermo model Nicolet-380 as KBr pellet. Brief description of the drawings : • Figure-1 is DSC Thermogram of Duloxetine hydrochloride. • Figure-2 is IR Spectrum of Duloxetine hydrochloride. The present invention schematically represents as follows. The process described in the present invention were demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples Example-1 Preparation of 3-(dimethylamino)-l-(thiophen-2-yI) propan-1-one hydrochloride Hydrochloric acid (3.8 ml) was added to a solution of l-(thiophen-2-yl)ethanone (lOOgr), 81.5 gr of dimethylamine hydrochloride, 35.4 gr of paraformaldehyde and 250 ml of isopropyl alcohol. Heated the reaction mixture to 60-65°C. Stirred the reaction mixture for 6 hours. Cooled the reaction mixture to 0-5°C. Filtered the compound and dried at 50-55°C. Yield 148 gr ; M.R : 174-176°C. Example-2 Preparation of 3-(dimethyIamino)-l-(thiophen-2-yl) propan-1-ol A solution of methanol (100ml), 3-(dimethylamino)-l-(thiophen-2-yl) propan-1-one hydrochloride (lOOgr) and 25 ml of water is cooled to 0-5°C. Slowly added 50 ml of 20% sodium hydroxide solution. Slowly added sodium borohydride (lOgr) and 20% sodium hydroxide (50ml) solution at 0-5°C in 4 -5 hours duration. Stirred the reaction mixture at 25-30°C for 6 hours. Extracted the reaction mixture with methylene chloride, washed the organic phase with 10% brine solution. Distilled the solvent completely under reduced pressure at below 50°C. Isolated the solid using hexanes and dried the material at 50-55°C. Yield 75 gr ; MR : 70-80°C. Example-3 Preparation of Mandelate salt of (S) 3-(dimethylamino)-l-(thiophen-2-yI) propan-1-ol L(+) Mandelic acid (50gr) was added to a solution of 3-(dimethylamino)-l-(thiophen-2-yl) propan-1-ol (100 gr) and ethylacetate (1000ml). Stirred the reaction mixture at 25-35°C for 90 minutes. Heated the reaction mixture to 60-65°C and stirred the reaction mixture at 60-65°C for 2 hours. Cooled the reaction mixture to 25-35°C and stirred the reaction mixture for 10 hours. Filtered the solid and washed with ethylacetate, dried the material at 60-65°C. Yield 80 gr ; MR : 113-115°C ; SOR : (+) 31° (C=l; Methanol). Example-4 Preparation of (S) 3-(dimethyIamino)-l-(thiophen-2-yI) propan-l-ol A solution of Mandelate salt of (S) 3-(dimethylamino)-l-(thiophen-2-yl) propan-l-ol (lOOgr), water (200ml) and methylene chloride (600ml) is cooled to 0-5°C. 10% sodium carbonate solution is slowly added to the reaction mixture. Stirred at 0-5°C for 30 minutes. Separated the organic phase and washed the organic phase with 10% brine solution. Distilled the solvent completely under reduced pressure at below 35°C. Isolated the solid using hexanes and dried the material at 40-45°C. Yield : 60 gr ; MR : 70-80°C ; SOR : (-) 6.2° (C=l; Methanol). Example-5 Preparation of (S)-(+)-N-methyl-3-(l«naphthaIenyIoxy)-3-(2-thienyl) propanamine oxalate. A solution of 1.0 lit of dimethylsulfoxide and 108 gr of sodium hydroxide is heated to 50-55°C. Stirred the mass for 45 minutes. Added 100 gr of (S) 3-(dimethylamino)-l-(thiophen-2-yl) propan-1-ol and 10 gr of tetra butyl ammonium bromide and 1-fluoro naphthalene (120gr) mixture with dimethyl sulfoxide (100ml). Stirred the reaction mixture at 60-65°C for 50 hours. Cooled the reaction mixture to 10-15°C. Quenched the reaction mixture with water at 15-20°C. Extracted the reaction mixture with toluene and washed the organic layer with water. Dried the organic layer over sodium sulfate. Diisopropylethylamine is added at 25-35°C. Heated the reaction mixture to 45-50°C, Phenylchloroformate (lOOgr) is slowly added at 45-50°C. Stirred the reaction mixture at 45-50°C for 2 hours. Cooled the reaction mixture to 10-15°C, quenched the reaction mixture with water. Separated the organic phase and washed with acetic acid solution, followed by washed with sodium bicarbonate solution. Distilled the solvent completely under reduced pressure at below 45°C. Dimethylsulfoxide (2000 ml) is added to the above obtained crude and heated to 40-45°C. Added sodium hydroxide solution to the reaction mixture at 40-45°C and heated further to 50-55°C. Stirred the reaction mixture at 50-55°C for 30 hours. Cooled the reaction mixture to 10-15°C and quenched the mass with water. Extracted the reaction mixture with toluene and washed the organic phase with water. Oxalic acid solution is added to the above organic layer at 25-30°C in 4 hours duration. Stirred the reaction mixture at 20-25°C for 4 hours. Filtered the solid washed with toluene and dried the material at 25-30°C. Yield : 160 gr ; MR : 126-130°C. Example-6 Preparation of (S)-(+)-N-methyl-3-(l~naphthaIenyloxy)-3-(2-thienyI) propanamine hydrochloride. A solution of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate (lOOgr), water (400ml) and methylene chloride (400ml) is cooled to 0-5°C. pH of the reaction mixture adjusted to 8-9 with aqueous ammonia. Stirred for 15 minutes. Separated the organic phase and washed the organic phase with water. Distilled the solvent completely under reduced pressure at below 40°C. Ethylacetate (400ml) was added to the above obtained crude. Cooled the reaction mixture to 0-5°C. pH of the reaction mixture adjusted to 3-4 with ethylacetate HC1. Stirred the reaction mixture for 2 hours. Filtered the solid and washed the solid with ethylacetate. Dried the material at 45-50°C. Yield : 45 gr ; MR : 145-150°C ; SOR : (+) 90° (C=l; Methanol). The above obtained crude (lOOgr) is dissolved in ethylacetate and methanol. Stirred the mass for 90 minutes. Cooled the mass to 20-25°C. Stirred the mass for 4 hours. Filtered the solid and washed with ethylacetate, dried the material at 55-60°C. Yield : 70gr ; MR : 164-166°C ; SOR : (+) 118° (C=l; Methanol); Particle size : (d, 90) : below 100 microns; Micronized material : (d, 90) : below 25 microns; Chiral Purity : 99.70%, 0.13% (other isomer); HPLC Purity : 99.80%. We Claim : 1. A Process for the preparation of Duloxetine hydrochloride compound of Formula (I) which comprises of the following steps a) Reacting l-(thiophen-2-yl)ethanone compound of formula (II) with dimethylamine hydrochloride compound of formula (III) in presence of paraformaldehyde in a suitable solvent selected from acloholic solvents, preferably isopropyl alcohol gives the compound of formula (IV), b) Reducing the compound of formula (IV) with an alkali metal borohydrides like sodium borohydride, potassium borohydride in a suitable solvent selected from Cl-C4 alcoholic solvents, preferably methanol gives the compound of formula (V), c) Resolving the compound of formula (V) with chiral acid like mandelic acid, tartaric acid,di-p-tolyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid, preferably mandelic acid in a suitable solvent selected from ester solvents like ethylacetate, propylacetate, preferably ethylacetate and further treating the obtained compound with weak inorganic base like sodium carbonate, sodium bicarbonate in suitable chloro solvents or ester solvents, preferably chloro solvents more preferably methylene chloride gives the compound of formula (VI), d) Reacting the compound of formula (VI) with the compound of formula (VII) in presence of an alkali base like sodium hydroxide, potassium hydroxide preferably sodium hydroxide and in a suitable polar aprotic solvent like dimethylsulfoxide, dimethylformamide, then in situ demethylation and converting into oxalate salt of compound of formula (VIII), e) Converting the Duloxetine oxalate salt into its hydrochloride salt compound of formula (I) using ethylacetate HC1, methanolic HC1, isopropyl alcohol HC1, preferably ethylacetate HC1 in a suitable solvent like alcoholic solvents or ester solvents, preferably ester solvents more preferably ethylacetate, f) Purifying the above obtained compound of formula (I) from step (e) using suitable solvent or mixture of solvents selected from ester solvents like ethyl acetate, propyl acetate, methyl acetate or alcohol solvents like methanol, ethanol, isopropylalcohol or mixture of ester and alcohol solvents like ethylacetate and methanol, ethylacetate and ethanol, ethylacetate and isopropylalcohol, preferably mixture of solvents, more preferably ethylacetate and methanol. 2. Resolving agent according to claim 1 c) is L(+) Mandelic acid. 3. Solvent according to claim 1 c) is ethylacetate. 4. Hydrochloric acid in a solvent according to claim 1 e) is ethylacetate (i.e,. ethylacetate HC1). 5. Process for the preparation of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate compound of formula (VIII) without isolating intermediate compounds (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine and (S)-(+)-N-phenyloxy carbonyl-N-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine. 6. Solvents according to claim 1 f) is mixture of ethylacetate and methanol for the purification of crude Duloxetine hydrochloride.

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