Title of Invention	PROCESS FOR PREPARATION OF TAZAROTENE
Abstract	The present invention relates to process for the preparation of ethyl 6 - [2 - (4, 4 -dimethylthiochroman - 6 - yl) ethynyl] nicotinate and its pharmaceutical acceptable salt.

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FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "PROCESS FOR PREPARATION OF TAZAROTENE" 2. APPLICANT: (a) NAME: INDOCO REMEDIES LIMITED (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION: The following specification describes the invention. FIELD OF INVENTION: The present invention relates to process for the preparation of ethyl 6 - [2 - (4, 4 -dimethylthiochroman - 6 - yl) ethynyl] nicotinate of Formula - I and its pharmaceutical acceptable salt. Formula -1 BACKGROUND AND PRIOR ART: The compound ethyl 6 - [2 - (4, 4 - dimethylthiochroman - 6 - yl) ethynyl] nicotinate of Formula - I having international proprietary name Tazarotene, is a new third generation topical acetylenic, receptor-selective, synthetic retinoid used for the topical treatment of mild to moderate plaque psoriasis, acne vulgaris and photoaging. The preparation of Tazarotene first time disclosed in US Patent No US.5, 089,509, wherein thiophenol (Formula - II) is reacted with 1-bromo - 3 - methyl - but - 2 - en (Formula - III) to give phenyl - 3 - methylbut - 2 - enyl sulfide (Formula - IV). The compound phenyl - 3 - methylbut - 2 - enyl sulfide is cyclised by refluxing with phosphorous pentoxide and phosphoric acid in solvent benzene to give 4, 4 - dimethyl thiochroman (Formula - V). 4, 4 - dimethyl thiochroman is reacted with acetyl chloride in presence of tin (IV) chloride resulting in 4, 4 - dimethyl - 6 - acetylthiochroman (Formula - VI), which on reaction with lithium diisopropyl amide (LDA) and diethyl chlorophosphate in tetrahydrofuran results in formation of 4, 4 - dimethyl - 6 -ethynylthiochroman (Formula - VII). 4, 4 - dimethyl - 6 - ethynylthiochroman is reacted with ethyl - 6 - chloronicotinate (Formula - VIII) in presence of butyl lithium and palladium triphenyl phosphene ligand catalyst, zinc chloride and solvent tetrahydrofuran results in formation of Tazarotene (Formula- I). The reaction sequence is represented as per scheme - I below: Scheme -1 CH3 H3Q. pH3 H3C CH, US Patent No. US 5602130, discloses reaction of 4 - Bromothiophenol (Formula - IX) with 1 - bromo - 3 - methyl - but - 2 - en (Formula - III) to give 4 - bromophenyl - 3 - methylbut - 2 - enyl sulfide (Formula X), which undergoes cyclisation on heating in presence of phosphorous pentachloride and phosphoric acid yields 6 - bromo - 4, 4 - dimethyl thiochroman (Formula - XI). 6 - Bromo - 4, 4 - dimethyl - thiochroman is coupled with trimethyl silylacetylene in presence of palladium complex as catalyst, triethyl amine as base and copper iodide to yield 6 - (trimethylsilylethynyl) - 4,4 - dimethyl thiochroman(Formula - XII), which on treatment with base undergoes desilylation results in 6 - ethynyl - 4, 4 - dimethylthiochroman (Formula - XIII). 6 - ethynyl - 4, 4 - dimethylthiochroman on reaction with ethyl - 6 - chloronicotinate (Formula - VIII) in presence of palladium complex, butyl lithium and anhydrous zinc chloride in solvent tetrahydrofuran results in the formation of Tazarotene (Formula - I). The reaction sequence is represented as per scheme - II below: Scheme - II H3C .CH3 H3Q H3C CH3 /Si(Me)3 Formula -I Formula - XIII Formula - XII The drawbacks of the above schemes are; i) use of lithium diisopropyl amide and diethyl chlorophosphate which are highly flammable, moisture sensitive are not industrially safe to handle; ii) Low temperature required to carry out dehydration reaction necessitates use of dedicated utilities; iii) Use of costly palladium complex as catalyst from which it is very tedious to recover metal, iv) Anhydrous condition of the reaction and use of anhydrous zinc chloride along with butyl lithium and excess of triethyl amine base makes the process moisture sensitive, v) Use of chromatographic separation to isolate pure tazarotene and its intermediate renders the process industrially uneconomical. US Patent No. US7273937 discloses the process for tazarotene, wherein 4,4 - dimethyl -6 - bromo - thiochroman (Formula - XI) is oxidized to the corresponding 6 - bromo -4,4 - dimethylthiochroman - 1 - oxide (Formula - XIV), which is reacted with 2 -methyl - 3 - butyn - 2 - ol to give 4 - (4, 4 - Dimethyl - 1 - oxo - thiochroman - 6 - yl) - 2 - methyl - but - 3 - yn - 2 - ol (Formula - XV). The compound 4 - (4, 4 - Dimethyl - 1 - oxo - thiochroman - 6 - yl) - 2 - methyl - but - 3 - yn - 2 - ol is deprotected to 4,4 - dimethyl - 6 - ethynylthiochroman - S - oxide (Formula - XVI). 4,4 - dimethyl - 6 - ethynylthiochroman - S - oxide on reaction with ethyl - 6 - chloronicotinate results in compound of formula XVII, which on deoxygenation yields Tazarotene (Formula - I). The reaction sequence is represented as per scheme - III below: Scheme - III H3C £113 H3Q CH3 H3C .CH3 HaQ O Formula - XVI H3Q Formula • The drawbacks observed in the process are; i) The use of palladium ligand makes the process uneconomical and recovery of the costly metal from the complex is difficult; ii) Oxidation of the chroman and deoxygenation of the final moiety to get tazarotene increases the number of steps which increases the time and cost of the product. Thus, there remains a need for an improved process for preparing tazarotene that overcomes the drawbacks of the prior art and reduces the number of steps in a convenient and cost efficient manner. The present inventors have come out with a robust process which ameliorates the problems in the prior art for the preparation of tazarotene without increasing the number of steps by employing Sonogashira coupling, using the environment friendly solvent water and Pd / C as catalyst, involving the preparation of novel intermediate 6 - (1, 1 -Dichloroethyl) - 4, 4 - dimethylchroman of Formula XVIII. OBJECTIVES OF THE INVENTION: The main objective of the present invention is to provide a process for the preparation of Tazarotene of higher purity and yield. Another objective of the present invention is to prepare Tazarotene by an industrially useful and cost effective process. Yet another objective of the present invention is to prepare Tazarotene by using the novel intermediate 6 - (1, 1 - Dichloroethyl) - 4, 4 - dimethylchroman of Formula XVI. Yet another objective of the present invention is to prepare 6 - (1, 1 - Dichloroethyl) - 4, 4 - dimethylchroman of Formula XVIII compound. SUMMARY OF THE INVENTION: Accordingly a process is provided for the preparation of Tazarotene comprising of; i) reacting 4, 4 - dimethyl - 6 - acetylthiochroman of Formula - VI with chlorinating reagent in presence of chlorinated solvent to get 6-(l, 1 -Dichloroethyl) - 4, 4 - dimethylthiochroman of Formula XVIII, H,C CH3 Cl CI s Formula XVIII ii) reacting compound of Formula XVIII with base to isolate 4, 4 - dimethyl - 6 - ethynylthiochroman of Formula - VII, H,C CH, S Formula VII iii) reacting compound of Formula VII with Ethyl - 6 - chloronicotinate of Formula VIII in presence of heterogeneous metal catalyst, base and solvent to isolate 6 - [2 - (4, 4 - dimethylthiochroman - 6 - yl) ethynyl] nicotinate of Formula-I. o OC,H5 CI N Formula VIII In another embodiment a process is provided for the preparation of 6-(l, 1 -Dichloroethyl) - 4, 4 - dimethylthiochroman of Formula XVIII comprising of; reacting 4, 4 - dimethyl - 6 - acetylthiochroman of Formula - VI with chlorinating reagent in presence of chlorinated solvent to get 6-(l, 1 - Dichloroethyl) - 4, 4 -dimethylthiochroman of Formula XVIII H,C CH, Cl CI i; i CH, s Formula XVIII In another embodiment of the present invention provided the compound 6-(l, 1 -Dichloroethyl) - 4, 4 - dimethylthiochroman of Formula XVIII. Detailed description of the Invention: This invention provides an industrial useful process for the preparation of Tazarotene employing a novel intermediate 6-(l, 1 - Dichloroethyl) - 4, 4 - dimethylthiochroman of Formula XVIII. The present invention avoids use of costly metal complex as catalyst and highly flammable, moisture sensitive lithium diisopropyl amide and diethyl chlorophosphate. In one aspect of the present invention the compound 4, 4 - dimethyl - 6 -acetylthiochroman of Formula - VI is reacted with chlorinating agent selected from phosphorous trichloride, phosphorous pentachloride and triphenyl phosphene carbon tetra chloride system in presence of chlorinated solvents. The preferred chlorinating agent used is phosphorous pentachloride. The chlorinated solvents used are selected from dichloromethane, dichloroethane, trichloroethane and tetrachloroethane. The preferred chlorinated solvent used is dicloroethane. The starting compound 4, 4 - dimethyl - 6 - acetylthiochroman of Formula VI can be prepared as per the process disclosed in the US patent No. US 4,826,984 , in the journal J. Med. Chem., 1985, 28, 116 or can be prepared by reacting thiophenol of Formula II with 1-bromo - 3 - methyl - but - 2 - en of Formula - III as per the process disclosed in the US patent No. US5602130. The compound 4, 4 - dimethyl - 6 - acetylthiochroman is charged under Nitrogen in solvents selected from toluene, n-hexane, Dichloromethane, dichloroethane and trichloroethane. The chlorinating agent is charged to the reaction mixture at temperature maintaining in the range of -10°C to 40°C. The reaction is maintained for about 3 hours to 7 hours at temperature of 20°C to 50°C. After the reaction is completed the solvent is distilled out under reduced pressure. To the residue, charged n - Hexane and stirred to make a uniform solution. The n - hexane layer is washed with sodium hydroxide solution and water. Separated the hexane layer and concentrated under reduced pressure to get geminal dichloro compound 6-(l, 1 - Dichloroethyl) - 4, 4 - dimethylthiochroman of Formula XVIII. Further the isolated compound 6 - (1, 1 - Dichloroethyl) - 4, 4 - dimethylthiochroman is charged in presence of a base under Nitrogen in an organic solvent selected from dimethyl sulfoxide, dimethyl formamide and tetrahydrofuran. The reaction mass is heated and maintained at temperature of 50 - 55°C till the complete disappearance of the compound 6 - (1, 1 - Dichloroethyl) - 4, 4 - dimethylthiochroman. Charged n - hexane and stirred, separated the hexane layer and extracted further the reaction mass with n -hexane and mixed with the main hexane layer. The hexane layer concentrated under reduced pressure to isolate 6 - ethynyl - 4, 4 - dimethylthiochroman of Formula - VII. In another aspect of the present invention the compound 6 - ethynyl - 4, 4 -dimethylthiochroman of Formula - VII is reacted with ethyl 6 - chloro - nicotinate of Formula VIII in presence of heterogeneous metal catalyst, base and solvent along with copper (I) iodide and triphenylphosphine to isolate Tazarotene of Formula I. The compound 6 - ethynyl - 4, 4 - dimethylthiochroman of Formula - VII is dissolved in solvent selected from dimethoxy ethane, tetrahydro furan N, N - dimethyl formamide, and water either single or mixture thereof. The preferred solvent used is mixture of dimethoxy ethane and water. The ratio of the selected solvent and water is 10: 1 to 1: 10. The base charged is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide, preferred base used are sodium carbonate, potassium carbonate, sodium bicarbonate. The heterogeneous metal catalyst used is 5% to 10% palladium on carbon. The reaction is carried out at elevated temperature in the range of 60°C to 90°C. After completion of the reaction the reaction mass is cooled and diluted with water and filtered. The filtrate obtained is extracted with solvent selected from ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone. The organic layer is separated and concentrated to get crude Tazarotene. The solid crude tazarotene is further crystallized from n-hexane, ethyl acetate or mixture thereof to obtain pure Tazarotene. The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention and should not be read as limiting the scope of the invention. Examples: Example 1 Preparation of 6-(l, 1 - Dichloroethyl) - 4, 4 - dimethylthiochroman (Formula XVIII): 4, 4-dimethyl-6-acetylthiochroman (5 gm) was dissolved in dichloroethane and stirred under Nitrogen atmosphere for 30 min at 30 ± 5°C. Phosphorous pentachloride (7.5 gm) was then added. Stirred and maintained the reaction mass six hrs at 30 ± 5°C. After the reaction completion concentrated the solvent under reduced pressure and to the residue charged n-hexane (300 ml) and stirred. The hexane layer was separated and washed with dil. Sodium hydroxide solution. The layers were separated and the hexane layer was distilled under reduced pressure to yield geminal dichloride i.e. 6-(l, 1 - Dichloroethyl) -4, 4 - dimethylthiochroman. Example 2 Preparation of 6 - ethynyl - 4, 4 - dimethylthiochroman (Formula - VII): The compound 6-(l, 1 - Dichloroethyl) - 4, 4 - dimethylthiochroman (5 gm) was dissolved in dimethyl sulfoxide under nitrogen atmosphere and kept for stirring. Potassium tert-butoxide (4 gm) was added and the temperature of the reaction mass was raised to 50°C and maintained. After the reaction completion, solvent n-hexane (3 x 200 ml) was charged and the layers were separated. The lower layer was further extracted with n-hexane. The n-hexane layers were combined and distilled under reduced pressure to get 6 - ethynyl - 4, 4 - dimethylthiochroman. Example 3 Preparation of ethyl 6 - [2 - (4, 4 - dimethylthiochroman - 6 - yl) ethynyl] nicotinate (Formula -1): Ethyl chloronicotinate (0.5 gm) was dissolved in dimethoxyethane (15 ml) and then water (10 ml) potassium carbonate (1.5 gm), copper (1) iodide (0.02 gm), triphenylphosphine (0.1 gm) and 10% w/w Pd-C (0.1 gm) were added. This mixture was stirred for 4 - 5 hours at 30 ± 5°C. 6-ethynyl - 4, 4-dimethyl thiochroman (2 gm) was then added, and the mixture was heated at 80°C for 4-5 hours, then cooled and diluted with water (50 ml) and filtered. The filtrate was extracted with ethyl acetate. The separated organic layer was then evaporated under reduced pressure to yield Tazarotene which was purified from n-hexane: ethyl acetate mixture to get pure Tazarotene.

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