WO2006059345A2 - Process for the preparation of acetylenic retinoid - Google Patents

Process for the preparation of acetylenic retinoid Download PDF

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WO2006059345A2
WO2006059345A2 PCT/IN2005/000384 IN2005000384W WO2006059345A2 WO 2006059345 A2 WO2006059345 A2 WO 2006059345A2 IN 2005000384 W IN2005000384 W IN 2005000384W WO 2006059345 A2 WO2006059345 A2 WO 2006059345A2
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formula
compound
dimethyl
reacting
ethyl
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PCT/IN2005/000384
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French (fr)
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WO2006059345A3 (en
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Chirag Narendra Jain
Mukesh Nathalal Vaghela
Rajeev Budhdev Rehani
Rajamannar Thennati
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Sun Pharmaceutical Industries Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans

Definitions

  • the present invention provides an elegant process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, a compound of formula 1.
  • Tazarotene is the INN for compound of formula 1, which has a therapeutic use in the treatment of acne, cancer and psoriasis.
  • compound of formula 1 is structurally composed of two units viz. the thiochromane moiety and a nicotinic acid ester, linked with an acetylenic bond.
  • the synthesis of same as described in '509 is not readily achievable on an industrial scale.
  • Reaction time of step (a) is 64 hours a time consuming process which eventually affect the overall througput.
  • step (b) Utilizes moisture sensitive phosphorous pentoxide in step (b) at reflux temperature.
  • Step (d) is carried out under absolute anhydrous and sub-zero reaction conditions, in the presence of hazardous to handle, reactive bases like n-butyl lithium/lithium diispopropylamide, which renders the process less robust.
  • Step (e) prepares the zinc acetylide, compound of formula 4a, at low temperature i.e. O 0 C using moisture sensitive and expensive reagents like n-butyl lithium, /lithium diisopropylamide, anhydrous zinc chloride and the Sonogashira coupling of compound of formula 4a with compound of formula 5 requires forcing conditions.
  • (5) Most of the above intermediates obtained in step(a) to (d) and even the final product, Tazarotene, are isolated by flash chromatography, a process of isolation/purification, not feasible, industrially.
  • this patent carries out reaction of a compound of formula 4, with a compound of formula 5, in the presence of cuprous iodide, bis(triphenylphosphine) palladium II chloride and triethylamine.
  • this method does not require absolute anhydrous conditions, when we carried out this reaction, we observed that the reaction did not go to completion in spite of refluxing for 24 hours and starting compounds of formula 4 and formula 5 were present in substantial amounts.
  • the product, compound of formula 1 could not be isolated in pure form by simple recrystallization and was isolated in pure form by flash chromatography.
  • PCT publication Number WO 2005/003125 discloses process for the preparation of 4,4-dimethyl-6-ethynylthiochroman, a compound of formula 4 by a two step process involving the Vilsmeier-Haack reaction of 4,4-dimethyl-6- acetylthiochroman, a compound of formula 3 to give 3-[4,4-dimethyl-6- ethynylthiochroman-6-yl]-3-chloro-propene-l-al followed by treatment with base.
  • This process has a disadvantage in that the intermediate 3-[4,4-dimethyl-6- ethynylthiochroman-6-yl]-3-chloro-propene-l-al has to be purified by flash chromatography.
  • step (a) time required for carrying out step (a) is shortened to about 20 hours.
  • the present invention uses milder and industrially feasible process conditions for steps b and d.
  • the process of the present invention obviates the use of absolute anhydrous conditions and sensitive reagents like phosphorous pentoxide and n-butyl lithiuni/lithiumdiisopropyl amide, trimethylsilylacetylene and diethylchlorophosphate used in the prior art. It also results in lesser side products and does not require specialized purification techniques like flash chromatography.
  • An object of the present invention is to provide a new process for the preparation of ethyl-6-[2- (4,4-dimethyltliiochroman-6-yl)ethynyl]nicotinate, compound of formula 1 which is faster and utilizes milder & industrially viable process conditions,
  • the present invention in one aspect provides a process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, a compound of formula 1 ,
  • step (c) (i) reacting the compound of formula 3 with hydrazine; (ii) reacting resultant product of step (i) with iodine; (iii) converting the resultant product of step (ii) to 4,4-dimethyl-6- ethynyl thiochroman, a compound of formula 4 and
  • Formula 5 wherein X is CI or Br, in presence of cuprous halide, a transition metal and inorganic base in an organic solvent.
  • the present invention provides a process for the preparation of 4,4- dimethyl-6- ethynylthiochroman, a compound of formula 4, comprising
  • step (ii) reacting the resultant product of step (i) with iodine and
  • step (iii) converting the resultant product of step (ii) to a compound of formula 4.
  • the present invention provides a process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, compound of formula 1,
  • Formula 1 comprising reacting 4,4-dimethyl-6- ethynylthiochroman, a compound of formula 4, with ethyl-6-halonicotinate, a compound of formula 5, wherein X is Cl or Br,
  • Formula 4 in presence of cuprous halide, a transition metal and inorganic base in an organic solvent.
  • the present invention provides a process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4-dimethylthiochroman-6-yl ethynyl] nicotinate, a compound of formula 1, comprising subjecting the compound of formula 1 to recrystallization with a mixture of acetic acid and water,
  • the present invention in one embodiment provides a process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate a compound of formula 1,
  • step (c) (i) reacting the compound of formula 3 with hydrazine; (ii) reacting resultant product of step (i) with iodine; (iii) converting the resultant product of step (ii) to 4,4-dimethyl-6-ethynyl thiochroman, a compound of formula 4 and
  • ⁇ henyl-3-methylbut-2-enylsulfide a compound of formula 6 is cyclized in the presence of an acid selected from sulfuric acid or p- toluenesulfonic acid, to yield 4,4-dimethyl thiochroman, a compound of formula 2.
  • the cyclization may be advantageously carried out in aliphatic or aromatic hydrocarbon solvents such as hexane, heptane, toluene, xylene and the like at a temperature of about 20 to HO 0 C, for about 1 to 24 hours depending on the reagent chosen, to effect the cyclization.
  • aliphatic or aromatic hydrocarbon solvents such as hexane, heptane, toluene, xylene and the like at a temperature of about 20 to HO 0 C, for about 1 to 24 hours depending on the reagent chosen, to effect the cyclization.
  • the process of the present invention thus avoids use of moisture sensitive reagent like phosphoric acid used in the prior art process for preparation of compound of formula 2.
  • the resultant 4,4-dimethylthiochroman, a compound of formula 2 may be acetylated to 4,4-dimethyl-6-acetylthiochroman, a compound of formula 3, by any process known in the art, for example, as in United States Patent No. 5,089,509 which is incorporated herein by reference only.
  • the 4,4-dimethyl-6-acetylthiochroman, compound of formula 3, obtained by following the process of the present invention is reacted with hydrazine to prepare a hydrazone derivative of compound of formula 3.
  • the hydrazone derivative of compound of formula 3 is further reacted with iodine and the resultant product is subjected to dehydrohalogenating conditions to obtain 4,4-dimethyl-6-ethynylthiochroman, a compound of formula 4.
  • the hydrazone derivative of compound of formula 3 may be isolated.
  • the reaction of hydrazone derivative of compound of formula 3 with iodine may be carried out in presence of a suitable base, for example an amine base in solvent.
  • the amine base may be selected from triethylamine, tributylamine and the like and the solvent may be selected from alcohols such as methanol, ethanol and the like; haloalkanes such as dichloromethane, ethylene dichloride and the like; haloaromatic such as monohalobenzene and the like; nitriles such as acetonitrile and the like; ethers such as tetrahydrofuran, diethylether and the like; sulfoxides such as dimethylsulfoxide and the like; and amides such as dimethylformamide and the like.
  • This process may be carried out under ambient conditions at about 20 to 35 0 C for a period of about 1-5 hours.
  • the resultant product may or may not be isolated before subjecting to further transformation.
  • the resultant product is subjected to dehydrohalogenation conditions, such as treatment with a suitable base, for example, potassium hydroxide in an alcoholic solvent.
  • a suitable base for example, potassium hydroxide in an alcoholic solvent.
  • the alcoholic solvent may be selected from methanol, ethanol and the like.
  • the process may be carried out at reflux temperature of the solvent, preferably about 50 to 100 0 C for about 5 to 10 hours.
  • transition metal refers to metal or its complex.
  • the transition metal may be preferably selected from palladium, platinum and nickel.
  • Palladium complex may be selected from bis(triphenylphosphine) dichloropalladium [PdCl 2 (PPh 3 ) 2 ], tetrakis(tri ⁇ henylphosphine)palladium [(Ph 3 P) 4 Pd], bis(dibenzylideneacetone) ⁇ alladium [(dba ⁇ Pd] (or tris(dibenzylideneacetone) dipalladium (O)), (bisimidazole)Pd(Me)Cl, Pd (PhCN) 2 Ci 2 /P(t-bu) 3 , Pd/P(T-bu) 3 palladium polyfluorophenyl complex and the like; platinum polyfluorophenyl complex, Pt(hfac) 2 , [Pt(hfac)(Pme 3 ) 2 [hfac] and the like; Ni(PPh 3 ) 2 Cl 2 , [Ni(TAA-sal)(H 2 O
  • the copper halide may be selected from cuprous chloride or cuprous iodide and the like.
  • the inorganic base may be selected from a group consisting of alkali metal carbonates or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and the like.
  • the organic solvent may be selected from aliphatic or aromatic hydrocarbons such as n- pentane, n-hexane, n-octane, cyclohexane, toluene and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like; amides such as dimethylformamide, dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the mixtures thereof.
  • the reaction may be advantageously carried out at reflux temperature for about 1 to 8 hours.
  • the compound of formula 5, can be advantageously prepared by a process comprising reacting corresponding 6-halonicotinic acid with ethanol in the presence of carbonyldiimidazole.
  • the reaction may be carried out at ambient temperature in the absence of additional base in a suitable solvent such as acetonitrile, dimethylacetamide, dimethyl formamide, N-methylpyrrolidine, dichloromethane and the like.
  • 6-chloronicotinic acid is reacted with ethanol in presence of carbonyldiimidazole at ambient temperature for 2 hours in acetonitrile.
  • carbonyld ⁇ midazole leads to the activation of the carboxylic acid of 6-chloronicotinic acid to form a compound of formula 7.
  • the imidazole acts as a leaving group, hence the reaction requires no external base and can be performed under mild non- acidic conditions. Also the byproduct imidazole being water soluble it is easy to eliminate from the product.
  • the process of the present invention has an advantage in that it avoids use of moisture sensitive agent like dicyclohexylcarbodiimide and does not yield the byproduct dicyclohexylurea associated with the use of dicyclohexylcarbodiimide. It also does not require additional base like dimethylaminopyridine used in the '509 patent.
  • the reaction mixture may be subjected to filtration, followed by removal of the solvent to obtain a residue.
  • the resultant residue may be subjected to crystallization.
  • the compound of formula 1 can be obtained in pure form by directly subjecting the resultant residue to recystallization with a solvent like heptane repeatedly if desired.
  • the present invention provides a process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4- dimethylthiochroman-6-yl ethynyl] nicotinate, a compound of formula 1, comprising subjecting the compound of formula 1 to recrystallization with a mixture of acetic acid and water,
  • the recrystallization can be carried out by dissolving the compound of formula 1 in mixture of acetic acid and water, heating if required or dissolving the compound of formula 1 in acetic acid and then adding water as an antisolvent, and cooling to temperature below ambient or seeding with seed crystals to initiate crystallization, if desired.
  • the compound of formula 1, subjected to recrystallization may be prepared by any process known in the art. hi a preferred embodiment the compound of formula 1 is prepared by the process of the present invention and then subjected to recrystallization with a mixture of acetic acid and water.
  • acetic acid water is used in the ratio of 5 : 95 to 95 : 5, preferably 25 : 75 to 75 : 25 volume/volume.
  • the compound of formula is recrystallized with acetic acid : water in the ratio of 40 : 60.
  • the recrystallization process of the present invention provides a compound of formula 1 with purity at least 99.8% as determined by HPLC.
  • the starting material, a compound of formula 6, phenyl-3-methylbut ⁇ 2enylsulfide, used for the preparation of compound of formula 1, preferably may be prepared by addition of l-bromo-3-methyl-2-butene to thiophenol in presence of sodium hydroxide.
  • the addition may be carried out in polar aprotic solvent or mixture of polar aprotic solvent and aromatic hydrocarbon solvent.
  • the polar aprotic solvent may be selected from dimethylsulfoxide, dimethylformamide and the like.
  • the aromatic hydrocarbon solvent may be selected from benzene, toluene and the like.
  • the reaction is completed in about 20 to 25 hours at 60 to 65 0 C as against 64 hours required by the process of the '509 patent.
  • the present invention provides a process for preparation of 4,4-dimethyl-6-ethynylthiochroman, compound of formula 4
  • step (ii) reacting the resultant product of step (i) with iodine and
  • step (iii) converting the resultant product of step (ii) to a compound of formula 4,
  • the preparation of compound of fo ⁇ nula 4, from compound of formula 3, may be carried out using solvent(s) selected from alcohol, haloalkanes such as dichloromethane, ethylene dichloride, haloaromatic such as monohalobenzene; nitriles such as acetonitrile, ethers such as tetrahydrofuran, diethylether and the like; sulfoxides such as dimethylsulfoxide and amides such as dimethylformamide.
  • solvent(s) selected from alcohol, haloalkanes such as dichloromethane, ethylene dichloride, haloaromatic such as monohalobenzene; nitriles such as acetonitrile, ethers such as tetrahydrofuran, diethylether and the like; sulfoxides such as dimethylsulfoxide and amides such as dimethylformamide.
  • solvent(s) selected from alcohol, haloalkanes such as dichlor
  • the present invention provides a process for preparation of ethyl-6-[2-(4,4- dimethylthiochroman-6-yl)ethynyl]nicotinate, a compound of fo ⁇ nula 1
  • Formula 1 comprising reacting 4,4-dimethyl-6- ethynylthiochroman, a compound of formula 4, with ethyl-6-halonicotinate, a compound of formula 5, wherein X is Cl or Br,
  • Formula 4 in presence of cuprous halide, a transition metal and inorganic base, in an organic solvent.
  • the product enriched toluene layer was dried over anhydrous sodium sulfate and subjected for concentration in hi vacuo and the residue further purified by distillation (82-85 0 C, ca. 0.5 mm) to give 286g of the compound of formula 2 with purity > 98% by gas chromatography,
  • the recovered organic fractions were combined and washed with 5% sodium bicarbonate solution, water, saturated NaCl solution and then dried (MgSO 4 ), The solvent was removed in vacuo and the residual product taken up for the preparation of 4,4-dimethyl-6-ethynylthiochroman, compound of formula 4.
  • the residue can be purified by distillation (15O 0 C, 0.7 mm) to give 75 g of the compound of formula 3 with purity > 98% by gas chromatography
  • the syrupy mass was dissolved in 500 ml tetrahydrofuran. To this was added 225 ml triethylamine and 65 g ( 0.25 moles) iodine and maintained for 2 hours at room temperature with TLC control. The reaction mass was concentrated to obtain thick syrupy mass. To the reaction mixture was added 250 ml dichloromethane followed by 125 ml 2NHC1. The organic layer was separated and washed with 250 ml sodium thiosulfate solution (5% w/v) followed by Aq 1 NaCl wash. The organic layer was concentrated and to the residue was added 300 ml ethanol followed by 59 g ( 1.05 moles) of potassium hydroxide.
  • the reaction mixture was refiuxed for 8 hours with TLC control.
  • the solvent was distilled off and to the residual mass was added 250 ml hexane and washed the product enriched hexane phase with 175 ml 6N HCl followed by water wash.
  • the product enriched hexane phase was concentrated to obtain a thick residue which was then subjected to high vacuum distillation at 100 0 C at ⁇ 0.5mmhg, to obtain 12.5g compound of formula 4, 4,4-Dimethyl-6-ethynylthiochroman with purity > 98% by gas chromatography.
  • the solvent was distilled out completely under vacuum at 50° C to get a residual mass.
  • To the residual mass was added 200 ml n-heptane and distill off the solvents under vacuum at 60° C.
  • the filtrate was collected and solvent was distilled off from the filtrate at 60° C to obtain a syrupy residual mass.
  • the crude product was further dried at 80° C for 30 minutes to obtain 40 g crude dry product.
  • the crude product was suspended in 800 ml n-heptane and heated at 80° C to get almost clear solution.
  • To the clear solution was added 40 g hyflo, 20 g Basic alumina and 5 g activated charcoal and stirred at 80° C for further 30 minutes and hyflo + alumina + charcoal was filtered off in hot condition and washed the bed with 75 ml hot n- heptane.
  • the product layer was cooled gradually to room temperature and stirred for 20 hours at room temperature.
  • the crystallised product was filtered off and the product cake was washed with 25 ml n-heptane and suck dried.
  • the product was dried at 80° C for 30 minutes to get a compound of formula 1 having purity 92.5% as determined by HPLC.

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Abstract

A process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4- dimethylthiochroman-6-yl)ethynyl]nicotinate, a compound of formula 1,comprising, (a) cyclizing phenyl-3-methylbut-2-enylsulfide, a compound of formula 6, in presence of an acid selected from sulfuric acid or p-toluenesulfonic acid to yield 4,4-dimethylthiochroman, a compound of formula 2; (b)acetylating the compound of formula 2, to 4,4 -dimethyl-6-acetylthiochroman, a compound of formula 3; (c)(i) reacting the compound of formula 3 with hydrazine;(ii) reacting resultant product of step (i) with iodine; (iii) converting the resultant product of step (ii) to 4,4-dimethyl-6- ethynyl thiochroman, a compound of formula 4 and (d) reacting the compound of formula 4 with ethyl-6-halonicotinate, a compound of formula 5, wherein X is Cl or Br, in presence of cuprous halide, a transition metal and an inorganic base.

Description

PROCESS FOR THE PREPARATION OF ACETYLENIC RETINOID
The present invention provides an elegant process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, a compound of formula 1. Tazarotene is the INN for compound of formula 1, which has a therapeutic use in the treatment of acne, cancer and psoriasis.
Figure imgf000002_0001
Formula 1
United States Patent No. 5,089,509 (the '509 patent) discloses preparation of compound of formula 1 by the following steps:
(a) adding l-bromo-3-methyl-2-butene to thiophenol followed by
(b) ring closure with phosphorous pentoxide to yield 4,4-dimethylthiochroman, a compound of formula 2;
(c) The compound of formula 2 is then acetylated with acetyl chloride in the presence of stannic chloride to give 4,4-dimethyl-6-acetylthiochroman, a compound of formula 3;
Figure imgf000002_0002
Formula 2 Formula 3
(d) The compound of formula 3 is converted to 4,4-dimethyl-6-ethynylthiochroman, a compound of formula 4,
Figure imgf000003_0001
Formula 4 with lithium diisopropylamide and diethyl halophosphate; and (e) compound of formula 4a, prepared by reacting a compound of formula 4 with zinc chloride in dry THF at O0C in presence of n-butyllithium, is coupled with a compound of formula 5, wherein X is Cl or Br, to yield compound of formula 1.
Figure imgf000003_0002
Formula 4a Formula 5
It is evident that compound of formula 1 is structurally composed of two units viz. the thiochromane moiety and a nicotinic acid ester, linked with an acetylenic bond. The synthesis of same as described in '509 is not readily achievable on an industrial scale. Some of the limitations of the process disclosed in the '509 patent are:
(1) Reaction time of step (a) is 64 hours a time consuming process which eventually affect the overall througput.
(2) Utilizes moisture sensitive phosphorous pentoxide in step (b) at reflux temperature.
(3) Step (d) is carried out under absolute anhydrous and sub-zero reaction conditions, in the presence of hazardous to handle, reactive bases like n-butyl lithium/lithium diispopropylamide, which renders the process less robust.
(4) Step (e) prepares the zinc acetylide, compound of formula 4a, at low temperature i.e. O0C using moisture sensitive and expensive reagents like n-butyl lithium, /lithium diisopropylamide, anhydrous zinc chloride and the Sonogashira coupling of compound of formula 4a with compound of formula 5 requires forcing conditions. (5) Most of the above intermediates obtained in step(a) to (d) and even the final product, Tazarotene, are isolated by flash chromatography, a process of isolation/purification, not feasible, industrially.
hi an alternative route, this patent carries out reaction of a compound of formula 4, with a compound of formula 5, in the presence of cuprous iodide, bis(triphenylphosphine) palladium II chloride and triethylamine. Although this method does not require absolute anhydrous conditions, when we carried out this reaction, we observed that the reaction did not go to completion in spite of refluxing for 24 hours and starting compounds of formula 4 and formula 5 were present in substantial amounts. The product, compound of formula 1, could not be isolated in pure form by simple recrystallization and was isolated in pure form by flash chromatography.
PCT publication Number WO 2005/003125 (the '125 application) discloses process for the preparation of 4,4-dimethyl-6-ethynylthiochroman, a compound of formula 4 by a two step process involving the Vilsmeier-Haack reaction of 4,4-dimethyl-6- acetylthiochroman, a compound of formula 3 to give 3-[4,4-dimethyl-6- ethynylthiochroman-6-yl]-3-chloro-propene-l-al followed by treatment with base. This process has a disadvantage in that the intermediate 3-[4,4-dimethyl-6- ethynylthiochroman-6-yl]-3-chloro-propene-l-al has to be purified by flash chromatography.
We have now developed a new process for the preparation of compound of formula 1 which is carried out in shorter time, does not require anhydrous conditions and enables isolation of the compound of formula 1 in pure form without chromatography. In the process of the present invention time required for carrying out step (a) is shortened to about 20 hours. The formation of compound of formula 1, from compound of formula 4 and compound of formula 5, requires only about 5 hours for completion. The present invention uses milder and industrially feasible process conditions for steps b and d. The process of the present invention obviates the use of absolute anhydrous conditions and sensitive reagents like phosphorous pentoxide and n-butyl lithiuni/lithiumdiisopropyl amide, trimethylsilylacetylene and diethylchlorophosphate used in the prior art. It also results in lesser side products and does not require specialized purification techniques like flash chromatography.
OBJECT OF THE INVENTION
An object of the present invention is to provide a new process for the preparation of ethyl-6-[2- (4,4-dimethyltliiochroman-6-yl)ethynyl]nicotinate, compound of formula 1 which is faster and utilizes milder & industrially viable process conditions,
SUMMARY OF THE INVENTION
The present invention in one aspect provides a process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, a compound of formula 1 ,
Figure imgf000005_0001
Formula 1 comprising,
(a) cyclizing phenyl-3-methylbut-2-enylsulfide, a compound of formula 6, in presence of an acid selected from sulfuric acid or p-toluenesulfonic acid to yield 4,4-dimethylthiochroman, a compound of formula 2;
Figure imgf000005_0002
Formula 6 Formula 2 (b) acetylating the compound of formula 2, to 4,4 -dimethyl-6-acetylthiochroman, a compound of formula 3;
Figure imgf000006_0001
Formula 3
(c) (i) reacting the compound of formula 3 with hydrazine; (ii) reacting resultant product of step (i) with iodine; (iii) converting the resultant product of step (ii) to 4,4-dimethyl-6- ethynyl thiochroman, a compound of formula 4 and
Figure imgf000006_0002
Formula 4
(d) reacting the compound of formula 4 with ethyl-6-halonicotinate, a compound of formula 5,
Figure imgf000006_0003
Formula 5 wherein X is CI or Br, in presence of cuprous halide, a transition metal and inorganic base in an organic solvent.
In one aspect the present invention provides a process for the preparation of 4,4- dimethyl-6- ethynylthiochroman, a compound of formula 4, comprising
Figure imgf000007_0001
Formula 4
(i) reacting 4,4 -dimethyl-6-acetylthiochronian, a compound of formula 3, with hydrazine;
Figure imgf000007_0002
Formula 3
(ii) reacting the resultant product of step (i) with iodine and
(iii) converting the resultant product of step (ii) to a compound of formula 4.
hi one aspect the present invention provides a process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, compound of formula 1,
Figure imgf000007_0003
Formula 1 comprising reacting 4,4-dimethyl-6- ethynylthiochroman, a compound of formula 4, with ethyl-6-halonicotinate, a compound of formula 5, wherein X is Cl or Br,
Figure imgf000008_0001
Formula 4 Formula 5 in presence of cuprous halide, a transition metal and inorganic base in an organic solvent.
In one aspect the present invention provides a process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4-dimethylthiochroman-6-yl ethynyl] nicotinate, a compound of formula 1, comprising subjecting the compound of formula 1 to recrystallization with a mixture of acetic acid and water,
DETAILED DESCRIPTION OF THE INVENTION
In our attempt to develop a simple, efficient and convenient process we have envisaged a novel process for the preparation of compound of formula 1.
The present invention in one embodiment provides a process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate a compound of formula 1,
Figure imgf000008_0002
Formula 1 comprising
(a) cyclizing phenyl-3-methylbut-2-enylsulfide, a compound of formula 6 in presence of an acid selected from sulfuric acid or p-toluenesulfonic acid, to yield, 4,4- dimethylthiochroman, a compound of formula 2;
Figure imgf000009_0001
Formula 6 Formula 2
(b) acetylating the compound of formula 2 to 4,4 -dimethyl-6-acetylthiochroman, a compound of formula 3;
Figure imgf000009_0002
Formula 3
(c) (i) reacting the compound of formula 3 with hydrazine; (ii) reacting resultant product of step (i) with iodine; (iii) converting the resultant product of step (ii) to 4,4-dimethyl-6-ethynyl thiochroman, a compound of formula 4 and
Figure imgf000009_0003
Formula 4
(d) reacting the compound of formula 4 with ethyl-6-halonicotinate, a compound of formula 5,
Figure imgf000010_0001
Formula 5 wherein X is Cl or Br, in presence of cuprous halide, a transition metal , and inorganic base in an organic solvent.
In the process of the present invention, ρhenyl-3-methylbut-2-enylsulfide, a compound of formula 6 is cyclized in the presence of an acid selected from sulfuric acid or p- toluenesulfonic acid, to yield 4,4-dimethyl thiochroman, a compound of formula 2.
Figure imgf000010_0002
Formula 2
The cyclization may be advantageously carried out in aliphatic or aromatic hydrocarbon solvents such as hexane, heptane, toluene, xylene and the like at a temperature of about 20 to HO0C, for about 1 to 24 hours depending on the reagent chosen, to effect the cyclization. The process of the present invention thus avoids use of moisture sensitive reagent like phosphoric acid used in the prior art process for preparation of compound of formula 2.
The resultant 4,4-dimethylthiochroman, a compound of formula 2 may be acetylated to 4,4-dimethyl-6-acetylthiochroman, a compound of formula 3, by any process known in the art, for example, as in United States Patent No. 5,089,509 which is incorporated herein by reference only.
Figure imgf000011_0001
The 4,4-dimethyl-6-acetylthiochroman, compound of formula 3, obtained by following the process of the present invention is reacted with hydrazine to prepare a hydrazone derivative of compound of formula 3. The hydrazone derivative of compound of formula 3 is further reacted with iodine and the resultant product is subjected to dehydrohalogenating conditions to obtain 4,4-dimethyl-6-ethynylthiochroman, a compound of formula 4.
Figure imgf000011_0002
Formula 4
If desired the hydrazone derivative of compound of formula 3 may be isolated. The reaction of hydrazone derivative of compound of formula 3 with iodine may be carried out in presence of a suitable base, for example an amine base in solvent.
The amine base may be selected from triethylamine, tributylamine and the like and the solvent may be selected from alcohols such as methanol, ethanol and the like; haloalkanes such as dichloromethane, ethylene dichloride and the like; haloaromatic such as monohalobenzene and the like; nitriles such as acetonitrile and the like; ethers such as tetrahydrofuran, diethylether and the like; sulfoxides such as dimethylsulfoxide and the like; and amides such as dimethylformamide and the like. This process may be carried out under ambient conditions at about 20 to 350C for a period of about 1-5 hours. The resultant product may or may not be isolated before subjecting to further transformation. The resultant product is subjected to dehydrohalogenation conditions, such as treatment with a suitable base, for example, potassium hydroxide in an alcoholic solvent. The alcoholic solvent may be selected from methanol, ethanol and the like. The process may be carried out at reflux temperature of the solvent, preferably about 50 to 1000C for about 5 to 10 hours.
The compound of formula 4, 4,4-dimethyl-6-ethynylthiochroman, obtained by following the process of the present invention is reacted with halosubstituted heteroaromatic compound, a compound of formula 5
Figure imgf000012_0001
Formula 5 wherein X is Cl or Br to give a compound of formula 1 , The reaction of compound of formula 4 with compound of formula 5 may be carried out in presence of transition metal, copper halide and inorganic base in an organic solvent.
The term transition metal as used herein refers to metal or its complex. The transition metal may be preferably selected from palladium, platinum and nickel.
Palladium complex may be selected from bis(triphenylphosphine) dichloropalladium [PdCl2(PPh3)2], tetrakis(triρhenylphosphine)palladium [(Ph3P)4Pd], bis(dibenzylideneacetone)ρalladium [(dba^Pd] (or tris(dibenzylideneacetone) dipalladium (O)), (bisimidazole)Pd(Me)Cl, Pd (PhCN)2Ci2/P(t-bu)3, Pd/P(T-bu)3 palladium polyfluorophenyl complex and the like; platinum polyfluorophenyl complex, Pt(hfac)2, [Pt(hfac)(Pme3)2[hfac] and the like; Ni(PPh3)2Cl2, [Ni(TAA-sal)(H2O)]X wherein TAA-sal is schiff s base derived from tris-(2-aminoethyl)amine-TAA and salicylaldehyde-sal & X= Cl, NO3, [Ni(TAA-acac), (H2O)BPh4 wherein TAA-acac is scliiff s base derived from TAA and acetylacetone - acac, Ni(phen)(6,7-THIQ)C12.3H2O, Ni(bpy)(6,7-THIQ)C12.2H2O, Ni(en)(6,7-THIQ)C12.2H2O, Ni(nphen)(6,7-
THIQ)C12.3H2O, Ni(phen)(3,4-PHA)2C12.H2O5 Ni(bpy)(3, 4-PHA)2Cl2. H2O wherine phen=l,10 phenanthroline, bpy = 2s2'-bipyridine, en=ethylenediamine and nphen = 5- nitro- 1 , 10-phenanthroline, 2-hydroxo-3 -piperidine- 1 -yl-methyl-N,N' (bis-5- bromobenzylpropylenediimine) nickel(II) perchlorate, nickel(II) meso- tetraphenylporphine, ,5,10,15,20-tetraρhenyl-21H, 23H -porphine, nickel complex, nickel TPP, nickel(II)moφholinie-dithiocarbamate and the like.
The copper halide may be selected from cuprous chloride or cuprous iodide and the like.
The inorganic base may be selected from a group consisting of alkali metal carbonates or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and the like.
The organic solvent may be selected from aliphatic or aromatic hydrocarbons such as n- pentane, n-hexane, n-octane, cyclohexane, toluene and the like; ethers such as diethylether, tetrahydrofuran, dioxane and the like; amides such as dimethylformamide, dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the mixtures thereof. The reaction may be advantageously carried out at reflux temperature for about 1 to 8 hours.
The compound of formula 5, can be advantageously prepared by a process comprising reacting corresponding 6-halonicotinic acid with ethanol in the presence of carbonyldiimidazole. The reaction may be carried out at ambient temperature in the absence of additional base in a suitable solvent such as acetonitrile, dimethylacetamide, dimethyl formamide, N-methylpyrrolidine, dichloromethane and the like.
In a preferred embodiment 6-chloronicotinic acid is reacted with ethanol in presence of carbonyldiimidazole at ambient temperature for 2 hours in acetonitrile. Without wishing to be bound by theory it is proposed that the reaction of carbonyldϋmidazole with 6-chloronicotinic acid leads to the activation of the carboxylic acid of 6-chloronicotinic acid to form a compound of formula 7.
Figure imgf000014_0001
Formula 7
The compound of formula 7, is then converted to ethyl-6-chloronicotinate, a compound of formula 5, wherein X= Cl, by reacting with ethanol. The imidazole acts as a leaving group, hence the reaction requires no external base and can be performed under mild non- acidic conditions. Also the byproduct imidazole being water soluble it is easy to eliminate from the product. The process of the present invention has an advantage in that it avoids use of moisture sensitive agent like dicyclohexylcarbodiimide and does not yield the byproduct dicyclohexylurea associated with the use of dicyclohexylcarbodiimide. It also does not require additional base like dimethylaminopyridine used in the '509 patent.
In a typical workup after completion of the reaction, the reaction mixture may be subjected to filtration, followed by removal of the solvent to obtain a residue. The resultant residue may be subjected to crystallization. Advantageously the compound of formula 1 can be obtained in pure form by directly subjecting the resultant residue to recystallization with a solvent like heptane repeatedly if desired.
hi another embodiment the present invention provides a process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4- dimethylthiochroman-6-yl ethynyl] nicotinate, a compound of formula 1, comprising subjecting the compound of formula 1 to recrystallization with a mixture of acetic acid and water,
The recrystallization can be carried out by dissolving the compound of formula 1 in mixture of acetic acid and water, heating if required or dissolving the compound of formula 1 in acetic acid and then adding water as an antisolvent, and cooling to temperature below ambient or seeding with seed crystals to initiate crystallization, if desired.
The compound of formula 1, subjected to recrystallization may be prepared by any process known in the art. hi a preferred embodiment the compound of formula 1 is prepared by the process of the present invention and then subjected to recrystallization with a mixture of acetic acid and water.
Advantageously, for recrystallization acetic acid : water is used in the ratio of 5 : 95 to 95 : 5, preferably 25 : 75 to 75 : 25 volume/volume. In a preferred embodiment the compound of formula is recrystallized with acetic acid : water in the ratio of 40 : 60.
The recrystallization process of the present invention provides a compound of formula 1 with purity at least 99.8% as determined by HPLC.
The starting material, a compound of formula 6, phenyl-3-methylbut~2enylsulfide, used for the preparation of compound of formula 1, preferably may be prepared by addition of l-bromo-3-methyl-2-butene to thiophenol in presence of sodium hydroxide. The addition may be carried out in polar aprotic solvent or mixture of polar aprotic solvent and aromatic hydrocarbon solvent. The polar aprotic solvent may be selected from dimethylsulfoxide, dimethylformamide and the like. The aromatic hydrocarbon solvent may be selected from benzene, toluene and the like. The reaction is completed in about 20 to 25 hours at 60 to 650C as against 64 hours required by the process of the '509 patent.
According to another embodiment the present invention provides a process for preparation of 4,4-dimethyl-6-ethynylthiochroman, compound of formula 4
Figure imgf000016_0001
Formula 4 comprising
(i) reacting 4,4 -dimethyl-6-acetylthiochroman, a compound of foπnula 3 with hydrazine;
Figure imgf000016_0002
Formula 3
(ii) reacting the resultant product of step (i) with iodine and
(iii) converting the resultant product of step (ii) to a compound of formula 4,
The preparation of compound of foπnula 4, from compound of formula 3, may be carried out using solvent(s) selected from alcohol, haloalkanes such as dichloromethane, ethylene dichloride, haloaromatic such as monohalobenzene; nitriles such as acetonitrile, ethers such as tetrahydrofuran, diethylether and the like; sulfoxides such as dimethylsulfoxide and amides such as dimethylformamide. This process obviates the use of strong base. such as lithium diisopropylamide used in prior art. The process may be carried out at reflux temperature of the solvent, preferably about 50 to 1000C.
According to yet another embodiment the present invention provides a process for preparation of ethyl-6-[2-(4,4- dimethylthiochroman-6-yl)ethynyl]nicotinate, a compound of foπnula 1
Figure imgf000017_0001
Formula 1 comprising reacting 4,4-dimethyl-6- ethynylthiochroman, a compound of formula 4, with ethyl-6-halonicotinate, a compound of formula 5, wherein X is Cl or Br,
Figure imgf000017_0002
Formula 4 Formula 5 in presence of cuprous halide, a transition metal and inorganic base, in an organic solvent.
The invention is illustrated but not restricted by the description in the following examples.
EXAMPLES
Example 1
A] Preparation of phenyl-3-methylbut-2enylsulfide, compound of formula 6
A mixture of 175g (1.59 mol) of thiophenol and 63.5 g (1.59 mol) of NaOH in 1.22 L dimethylsulfoxide was heated to 60-650C for 1.5 hours and then treated drop wise with a solution of 237g (1.59 mol) of freshly distilled l-bromo-3-methyl-2-butene (ca 98% by GC) over a period of 45 mins. This solution was maintained for 20 hours (TLC control) at 60-650C. To the reaction mixture was added 1.25 L cold water ( ca. 5 0C) and the quenched mass extracted with dichloromethane. The product enriched dichloromethane is washed with aqueous NaOH followed by aqueous NaCl. The organic phase is next treated with anhydrous sodium sulfate and taken up for concentration in hi vacuo. The residue was further purified by distillation (70-75°C, < 0.5 mm) to give 194g of the title compound as pale yellow oil with purity > 98% by gas chromatography,
] Preparation of phenyI-3-methylbut-2enylsulfide, compound of formula 6
A mixture of 150 g (1.36 mol) of thiophenol and 68 g (1.7 mol) of NaOH in 300 ml dimethylsulfoxide and 750 ml toluene was heated to 60-650C for 1.5 hours and then treated drop wise with a solution of 158 ml (1.36 mol) of l-bromo-3-methyl-2-butene (ca 98% purity by GC) over a period of 45 mins. This solution was maintained for 1 hour (TLC control), at 60-700C. To the reaction mixture was added 750 ml D.M. water at 45 - 5O0C and cooled it to 25 - 3O0C. Separated out the toluene layer from the quenched mass and extracted the aq layer with toluene. The product-enriched organic layer was washed with aqueous NaOH followed by aqueous NaCl. The organic phase was next treated with anhydrous sodium sulfate and taken up for concentration in hi vacuo. The residue was further purified by distillation (70-75°C, < 0.5 mm) to give 165g of the title compound as pale yellow oil with purity > 98% by gas chromatography. Alternatively the product enriched Toluene layer could be directly taken for the next step reaction without purfication by high vacuum distillation.
Example 2
A] Preparation of 4,4-dimethylthiochroman, compound of formula 2
To a solution of 35Og (1.96 mol) of phenyl-3-methylbut-2-enylsulfide, compound of formula 6 in 1.750 L toluene was added 96.2g (0.98 mol) of sulfuric acid at 20-250C. The temperature was gradually raised to about 30-350C and stirred for 24 hours( GC control). To the reaction mixture was added 1.75 L water and stirred for 30 mins. The product enriched toluene phase was seperated and the aqueous layer was subjected to toluene extraction. The toluene phase was pooled and washed with aqueous NaOH, followed by aqueous NaCl. The product enriched toluene layer was dried over anhydrous sodium sulfate and subjected for concentration in hi vacuo and the residue further purified by distillation (82-850C, ca. 0.5 mm) to give 286g of the compound of formula 2 with purity > 98% by gas chromatography,
B] Preparation of 4,4-dimethylthiochroman, compound of formula 2
A 1125 ml of toluene layer (~ 225 g estimated, 1.26 mol) containing phenyl-3- methylbut-2-enylsulfide, compound of formula 6 as prepared in example IB was treated with 120 g of p-toluene sulphonic acid (0.63 mol) at 100 - HO0C for 1 hour (GC control). To the reaction mixture was added 1.125 L water at 25-30°Cand stirred for 30 mins. The product enriched toluene phase was separated and the aqueous layer was subjected to toluene extraction. The toluene phase was pooled and washed with aqueous NaOH, followed by aqueous NaCl. The product enriched toluene layer was dried over anhydrous sodium sulfate and subjected for concentration in hi vacuo and the residue further purified by distillation (82-850C, ca. 0.5 mm) to give 160 g of the compound of formula 2 with purity > 98% by gas chromatography. Example 3
Preparation of 4,4 DimethyI-6-acetyIthiochroman, compound of formula 3.
A solution of 100 g (0.56 mol) of 4,4-dimethyl thiochroman (from Example 2) and 112.2 g (0.84 mol) of anhydrous aluminum chloride in 500 ml dichloromethane was cooled to 10-150C and treated drop wise with 48.3 ml (0.70 mol) of acetyl chloride. The mixture was stirred at 10-150C for 3 hours (TLC control). The reaction mass was quenched in 500 ml 3N HCl solution at 5-100C. The organic layer was separated and the aqueous layer extracted with dichloromethane. The recovered organic fractions were combined and washed with 5% sodium bicarbonate solution, water, saturated NaCl solution and then dried (MgSO4), The solvent was removed in vacuo and the residual product taken up for the preparation of 4,4-dimethyl-6-ethynylthiochroman, compound of formula 4. Optionally the residue can be purified by distillation (15O0C, 0.7 mm) to give 75 g of the compound of formula 3 with purity > 98% by gas chromatography
Example 4
Preparation of 4,4-dimethyl-6-ethynylthiochroman, compound of formula 4.
25 g (0.11 mol) of 4,4-dimethyl-6-acetylthiochroman, compound of formula 3 was mixed with 27 g ( 0.54 moles) of Hydrazine hydrate(~80%) and 135 ml ( 0.96 moles) triethylamine & 250 ml ethanol, The reaction mixture was heated at reflux temperature and maintained for 5 hours with TLC control. Ethanol + triethylamine mixture was distilled off under vacuum to obtain a syrupy residue. 100 ml water was added followed by 100 ml dichloromethane to extract the product (hydrazone derivative) into organic layer. The organic layer was washed with water followed by Aq. NaCl. The dichloromethane was evaporated under vacuum to obtain a pale yellow syrupy mass.
The syrupy mass was dissolved in 500 ml tetrahydrofuran. To this was added 225 ml triethylamine and 65 g ( 0.25 moles) iodine and maintained for 2 hours at room temperature with TLC control. The reaction mass was concentrated to obtain thick syrupy mass. To the reaction mixture was added 250 ml dichloromethane followed by 125 ml 2NHC1. The organic layer was separated and washed with 250 ml sodium thiosulfate solution (5% w/v) followed by Aq1NaCl wash. The organic layer was concentrated and to the residue was added 300 ml ethanol followed by 59 g ( 1.05 moles) of potassium hydroxide. The reaction mixture was refiuxed for 8 hours with TLC control. The solvent was distilled off and to the residual mass was added 250 ml hexane and washed the product enriched hexane phase with 175 ml 6N HCl followed by water wash. The product enriched hexane phase was concentrated to obtain a thick residue which was then subjected to high vacuum distillation at 1000C at < 0.5mmhg, to obtain 12.5g compound of formula 4, 4,4-Dimethyl-6-ethynylthiochroman with purity > 98% by gas chromatography.
Example 5
Preparation of ethyl-6-halonicotinate, compound of formula 5
A mixture of 50g (0.317 mol) 6-halonicotinic acid, 500 ml acetonitrile and 56.6 g (0.35 mol) carbonyldiimidazole was stirred at ambient temperature for 2 hours ( TLC control until 6-halonicotinic acid is absent ). To this solution was added 52 ml (0.8 mol) ethanol and further stirred for 2 hours. ( TLC control for ester formation). The solvent was removed in vacuo and dissolved the residue in 1 L dichlromethane. This product enriched dichloromethane was washed with 2 % wt/vol aq,NaHCO3 followed by water. The organic layer dried over anhydrous sodium sulfate and concentrated in vacuo to yield 58g of the title compound with purity > 99% by gas chromatography.
Example 6
Preparation of ethyI-6-[2- (4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, compound of formula 1.
25 g (0.135 mol) of ethyl-6-halonicotinoate, was mixed with 30 g ( 0.148 moles) 4,4- Dimethyl-6-ethynylthiochrornan, 23.4g( 0.020 moles) tetrakistriphenylphosphine palladium , 55.85g (0.404 mol) anhydrous K2CO3 , 10.6 g ( 0.040 moles) triphenylphosphine , 1.33 g ( 0.052 moles ) cuprous iodide in 500 ml tetrahydrofuran. The reaction mixture was heated at reflux temperature and maintained for 5 hours with
HPLC control.
HPLC Analysis reveals
Ethyl 6-halonicotinoate — Nil 4,4-dimethyl- 6-ethynylthiochroman — Nil Compound of formula 1— 78.08 % Impurity — 9.16 %
The inorganic matter was filtered off and to the filtrate was added 50 g hyflo and 25 g Basic alumina (Mesh size = 100, pH = 9.5-10.0 of aq. Suspension). The solvent was distilled out completely under vacuum at 50° C to get a residual mass. To the residual mass was added 200 ml n-heptane and distill off the solvents under vacuum at 60° C. To this was added 500 ml n-heptane and the contents were heated at 80° C so as to extract the product and filter off hyflo + alumina in hot condition. The filtrate was collected and solvent was distilled off from the filtrate at 60° C to obtain a syrupy residual mass. To the residual mass was added 125-ml n-heptane and stirred for 16 hours at room temperature. The crude product was filtered off and wash the product cake with 25 ml n-heptane and suck dried. HPLC Analysis of the crude solid reveals 87.98 % by HPLC.
The crude product was further dried at 80° C for 30 minutes to obtain 40 g crude dry product. The crude product was suspended in 800 ml n-heptane and heated at 80° C to get almost clear solution. To the clear solution, was added 40 g hyflo, 20 g Basic alumina and 5 g activated charcoal and stirred at 80° C for further 30 minutes and hyflo + alumina + charcoal was filtered off in hot condition and washed the bed with 75 ml hot n- heptane. The product layer was cooled gradually to room temperature and stirred for 20 hours at room temperature. The crystallised product was filtered off and the product cake was washed with 25 ml n-heptane and suck dried. The product was dried at 80° C for 30 minutes to get a compound of formula 1 having purity 92.5% as determined by HPLC.
Purification of compound of formula 1 using acetic acid and water
44 g of the compound of formula 1 obtained above was dissolved in 375 ml of glacial acetic acid at 25-300C to obtain a clear solution. Gradually added 565 ml of D.M. Water at 25-300C and stirred it for 2 hours and further cooled it to 15-200C 300C and stirred it for 2 hours. Filtered the product and washed it with water followed by n-Heptane. Dried the product at 70-750C to get 29.1 g of the compound of formula 1 having purity 99.88% as determined by HPLC.
Comparative Example
Preparation of ethyl-6~[2- (4,4-dimethylthiochroman-6-yi)ethynyl]nicotinate, compound of formula 1.
To 1 g (0.005 mol) Ethyl 6-halonicotinoate, compound of formula 5 in 10 ml of dry tetrahydrofuran was added 0.19 g Pd (PPh3)2Cl2 , 0.0123 g (0.000065 mol) CuI, 0.036 g (0.00013 mol )PPh3 and 1.12 ml(0.008 mol) triethylamine at 25-3O0C5 followed by gradual addition of a solution of 1.64 g (0,008 mol) of 4,4-dimethyl- 6- ethynylthiochroman, compound of formula 4, in 10 ml tetrahydrofuran at the same temperature. The above reaction mixture is stirred for 24 hours at the same temperature. Concentrate the reaction mixture to obtain a residual mass. The reaction was monitored by HPLC. HPLC Analysis reveals
Ethyl 6-halonicotinoate — 31.39 % 4,4-dimethyl- 6-ethynylthiochroman — 12.24 % Product — 22.01 % Impurity — 4.08 %
The residue was treated with about 100 ml heptane under boiling conditions to extract the product. The product enriched heptane phase was washed with hot water, charcoalised and filtered. The filtrate was subjected to gradual cooling to yield compound of formula 1 having purity 70% as determined by HPLC.

Claims

We claim
1. A process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4- dimethylthiochroman-6-yl)ethynyl]nicotinate, a compound of formula 1,
Figure imgf000024_0001
Formula 1 comprising,
(a) cyclizing phenyl-3-methylbut-2-enylsulfϊde, a compound of formula 6, in presence of an acid selected from sulfuric acid or p-toluenesulfonic acid to yield 4,4-dimethyl thiocliroman, a compound of formula 2;
Figure imgf000024_0002
Formula 6 Formula 2
(b) acetylating the compound of formula 2, to 4,4 -dimethyl-6-acetylthiochroman, a compound of formula 3;
Figure imgf000024_0003
Formula 3
(C) (i) reacting the compound of formula 3 with hydrazine; (ii) reacting resultant product of step (i) with iodine; (iii) converting the resultant product of step (ii) to 4,4-dimethyl-6- ethynyl thiochroman, a compound of formula 4 and
Figure imgf000025_0001
Formula 4
(d) reacting the compound of formula 4 with ethyl-6-halonicotinate, a compound of formula 5,
Figure imgf000025_0002
Formula 5 wherein X is Cl or Br, in presence of cuprous halide, a transition metal and inorganic base in an organic solvent.
2. A process as claimed in claim 1, wherein phenyl-3-methylbut-2-enylsulfide, a compound of formula 6, is prepared by reacting l-bromo-3-methyl-2-butene with thiophenol in a polar aprotic solvent or mixture of polar aprotic solvent and aromatic hydrocarbon solvent.
3. A process as claimed in claim 1, wherein in step c (iii), the conversion is carried out by treatment with a base.
4.A process as claimed in claim 1, wherein in step d, the transition metal used is selected from nickel, platinum and palladium.
5.A process as claimed in claim 1, wherein in step d, the inorganic base is selected from a group consisting of alkali metal carbonates and alkaline earth metal carbonates.
6. A process for the preparation of 4,4-dimethyl-6- ethynylthiochroman, a compound of formula 4
Figure imgf000026_0001
Formula 4 comprising
(i) reacting 4,4 -dimethyl-6-acetylthiochroman, a compound of formula 3 with hydrazine;
Figure imgf000026_0002
Formula 3
(ii) reacting resultant product of step (i) with iodine and (iii) converting the resultant product of step (ii) to 4,4-dimethyl-6- ethynyl thiochroman, a compound of formula 4.
7. A process as claimed in claim 6, further comprising reacting the compound of formula 4 with a compound of formula 5,
Figure imgf000026_0003
Formula 5 wherein X is Cl or Br in presence of cuprous halide, a transition metal and inorganic base in an organic solvent to yield the acetylenic retinoid, the compound of formula 1 .
8. A process as claimed in claim 6, wherein in step (iii) the conversion is carried out by treatment with a base.
9. A process as claimed in claim 6, wherein the compound of formula 3
Figure imgf000027_0001
Formula 3 is prepared by a process comprising
(a) cyclizing phenyl-3-methylbut-2-enylsulfide, a compound of formula 6, in presence of an acid selected from sulfuric acid or p-toluenesulfonic acid to yield a compound of formula 2 and
Figure imgf000027_0002
Formula 6 Formula 2
(b) acetylating the compound of formula 2 to yield to 4,4 -dimethyl-6- acetylthiochroman a compound of formula 3.
10. A process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4- dimethylthiochroman-6-yl)ethynyl]nicotinate, a compound of formula 1,
Figure imgf000028_0001
Formula 1 comprising reacting 4,4-dimethyl-6- ethynylthiochroman, a compound of formula 4, with ethyl-6-halonicotinate, a compound of formula 5, wherein X is Cl or Br,
Figure imgf000028_0002
Formula 4 Formula 5 in presence of cuprous halide, a transition metal and inorganic base in an organic solvent.
11. A process as claimed in claim 10, wherein transition metal used is selected from nickel, platinum and palladium.
12. A process as claimed in claim 10, wherein the inorganic base is selected from a group consisting alkali metal carbonates and alkaline earth metal carbonates.
13. A process as claimed in claim 10, wherein the solvent used is tetrahydrofuran.
14. A process as claimed in claim 10, wherein the compound of formula 5 is prepared by a process comprising reacting corresponding 6-halonicotinic acid and ethanol in presence of carbonyldiimidazole.
15. A process for the preparation of acetylenic retinoid, ethyl-6-[2- (4,4-dimethyl thiochroman -6-yl ethynyljnicotinate, a compound of formula 1, comprising subjecting the compound of formula 1 to recrystallization with a mixture of acetic acid and water.
16. A process as claimed in claim 15 wherein the compound of formula 1 is obtained in at least 99.8% purity as determined by HPLC.
PCT/IN2005/000384 2004-11-30 2005-11-29 Process for the preparation of acetylenic retinoid WO2006059345A2 (en)

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US9788434B2 (en) 2013-09-24 2017-10-10 Lg Chem, Ltd. Preparation method for dry film solder resist and film laminate used therein
CN109081835A (en) * 2017-06-14 2018-12-25 重庆华邦胜凯制药有限公司 A kind of preparation method of the tazarotene without using cuprous iodide
CN109081835B (en) * 2017-06-14 2022-04-12 重庆华邦胜凯制药有限公司 Preparation method of tazarotene without using cuprous iodide

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