WO2006040644A2 - Processes for the preparation of substituted thiochroman derivatives - Google Patents

Processes for the preparation of substituted thiochroman derivatives Download PDF

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WO2006040644A2
WO2006040644A2 PCT/IB2005/003016 IB2005003016W WO2006040644A2 WO 2006040644 A2 WO2006040644 A2 WO 2006040644A2 IB 2005003016 W IB2005003016 W IB 2005003016W WO 2006040644 A2 WO2006040644 A2 WO 2006040644A2
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formula
compound
hydrogen
acid
derivative
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PCT/IB2005/003016
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French (fr)
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WO2006040644A3 (en
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Jayachandra Suresh Babu
Chandra Has Khanduri
Jigar Bhaskarbhai Shah
Gajanan Jijaba Chavan
Ram Chander Aryan
Yatendra Kumar
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Ranbaxy Laboratories 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 field of the invention relates to processes for the preparation of substituted thiochroman derivatives of Formula I,
  • A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl;
  • n is an integer having a value between 0 to 5;
  • B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH 2 OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR 3 or a ketal derivative thereof, wherein R 3 is Ci -5 alkyl, cycloalkyl or alkenyl. More particularly, it relates to a process for the preparation of tazarotene of Formula III.
  • the invention also relates to a novel polymorphic form of tazarotene designated as Form A of tazarotene and process for producing it.
  • the invention also relates to pharmaceutical compositions that include the Form A of tazarotene and use of said compositions for treating stable plaque psoriasis and facial acne vulgaris.
  • Substituted thiochroman derivatives of Formula I are members of topically used acetylenic class of retinoids which are indicated for the topical treatment of patients with stable plaque psoriasis of up to 20% body surface area involvement and for the topical treatment of patients with facial acne vulgaris of mild to moderate severity.
  • Tazarotene is a prominent member belonging to this class of retinoids, and is commercially available in the market as Tazorac® gel and Avage® cream for topical use. Chemically, tazarotene is ethyl 6-[2-(4,4-dimetylthiochroman-6-yl)ethynyl]nicotinate of Formula III.
  • U.S. Patent No. 5,089,509 discloses a method for the preparation of tazarotene, wherein the tazarotene is isolated as a yellow solid by flash chromatography.
  • Several processes have been reported for the preparation of intermediates required for the preparation of the compound of Formula I for example, in Journal of Medicinal Chemistry 1984, 27, 1516; Journal of American Chemical Society 1974, 94, 9158; Chemical Letters 1976, 523; Journal of Organic Chemistry 1966, 31, 413; and Journal of Chemical Society, Chemical Communication, 1981, 237.
  • the inventors have found that the prior art approach for the preparation of thiochroman derivatives of Formula I is not suitable from a commercial point of view because the processes are lengthy requiring isolation of several intermediates, use of toxic reagents such as isoprene bromide and yields are low.
  • the present invention provides processes which are simple, cost-effective and easily scalable. The yield and purity of the product is greatly improved when made by the processes of the present invention.
  • Form A of tazarotene may have the X-ray diffraction pattern of Figure 1 , differential scanning calorimetry plot of Figure 2, and infrared spectrum of Figure 3.
  • composition that includes a therapeutically effective amount of the Form A of tazarotene; and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • a method for treating stable plaque psoriasis and facial acne vulgaris in a warm-blooded animal comprising providing the warm-blooded animal a pharmaceutical composition that includes the Form A of tazarotene.
  • Figure 1 is an X-ray powder diffraction pattern of Form A of tazarotene.
  • Figure 2 is a differential scanning calorimetry plot of Form A of tazarotene.
  • Figure 3 is an infrared spectrum of Form A of tazarotene.
  • the inventors have developed a process for the preparation of substituted thiochroman derivatives of Formula I,
  • A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl;
  • n is an integer having a value between 0 to 5; and
  • B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH 2 OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR 3 or a ketal derivative thereof, wherein R 3 is C 1 - S alkyl, cycloalkyl or alkenyl, the process comprising: a) treating a thiophenol derivative of Formula IV,
  • the compound of Formula IV may be dissolved in an organic solvent and treated with isoprene of Formula V in the presence of an acid catalyst.
  • the organic solvent includes one or more of aromatic hydrocarbons and halogenated aliphatic hydrocarbons.
  • the acid catalyst can be a Lewis acid or a non-Lewis acid. Examples of the acid catalysts include sulfuric acid, methane sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, nitric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chlorosulfonic acid and amberlite sulfonic acid resin.
  • the reaction of the compound of Formula IV with a compound of Formula V may be exothermic and may require cooling.
  • the substituted thiochroman derivative may be isolated by a technique which includes for example, distillation, distillation under vacuum, cooling, extraction, filtration, filtration under vacuum, decantation and centrifugation. After the reaction is complete, the reaction mass may be poured into a mixture of crashed ice and water. The resultant mixture may be extracted with a water immiscible organic solvent and the organic extracts may be washed subsequently with water and aqueous alkali solution. The organic extracts may be concentrated under vacuum to dryness to get a compound of Formula I.
  • the compound of Formula I thus recovered may be further purified or additionally purified, by employing commonly practiced recrystallization techniques using solvent / antisolvent mixtures or may be purified by column chromatography.
  • the inventors also have developed a process for the preparation of substituted thiochroman derivatives of Formula Ia,
  • R 2 is hydrogen or lower alkyl
  • A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl
  • n is an integer having a value between 0 to 5
  • B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH 2 OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR 3 or a ketal derivative thereof, wherein R 3 is C ⁇ s alkyl, cycloalkyl or alkenyl, the process comprising: a) treating a thiophenol derivative of Formula IVa,
  • the compound of Formula IVa may be treated with isoprene of Formula V in the presence of an organic solvent containing an acid catalyst.
  • the organic solvent includes one or more of aromatic hydrocarbons or halogenated aliphatic hydrocarbons.
  • the acid catalyst can be a Lewis acid or a non-Lewis acid. Examples of acid catalysts include sulfuric acid, methane sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, nitric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chlorosulfonic acid and amberlite sulfonic acid resin.
  • reaction of the compound of Formula IVa with a compound of Formula V may be exothermic and may require cooling.
  • the substituted thiochroman derivative may be isolated by a technique which includes for example, distillation, distillation under vacuum, cooling, extraction, filtration, filtration under vacuum, decantation and centrifugation.
  • reaction mass may be poured into a mixture of crushed ice and water.
  • the resultant mixture may be extracted with a water immiscible organic solvent and the organic extracts may be washed subsequently with water and aqueous alkali solution.
  • the organic extracts may be concentrated under vacuum to dryness to get a compound of Formula Ib.
  • the compound of Formula Ib thus recovered may be further purified or additionally purified, by employing commonly practiced recrystallization techniques using solvent / antisolvent mixtures or may be purified by column chromatography.
  • the compound of Formula Ib may be reacted with a compound of Formula Ha at a temperature of from about 35° to about 75 0 C in the presence of an alkylamine, copper salt or palladium containing catalyst for a period of about 15 to 30 hours. After completion of the reaction, the reaction may be quenched with water and extracted with a water immiscible organic solvent. The organic layer may be concentrated under vacuum to get a residue, which may be further purified by crystallization or by column chromatography to get the substituted thiochroman derivative of Formula Ia.
  • the inventors also have developed a process for the preparation of substituted thiochroman derivatives of Formula Ia,
  • A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl;
  • n is an integer having a value between 0 to 5; and
  • B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH 2 OH or its ether or ester derivative thereof, - CHO or an acetal derivative thereof, or -COR 3 or a ketal derivative thereof, wherein R 3 is Ci -5 alkyl, cycloalkyl or alkenyl, the process comprising: a) treating a thiophenol derivative of Formula IVb,
  • the compound of Formula IVb may be treated with isoprene of Formula V in the presence of an organic solvent containing an acid catalyst.
  • the organic solvent may include one or more of aromatic hydrocarbons or halogenated aliphatic hydrocarbons.
  • the acid catalyst can be a Lewis acid or a non-Lewis acid and may include one or more of sulfuric acid, methane sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, nitric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chlorosulfonic acid and amberlite sulfonic acid resin.
  • the reaction may be exothermic and may require cooling. After the reaction is complete, the reaction mass may be poured into a mixture of crushed ice and water. The resultant mixture may be extracted with a water immiscible organic solvent and the organic extracts may be washed subsequently with water and aqueous alkali solution. The organic extracts may be concentrated under vacuum to dryness to get a compound of Formula Ic, which may optionally be purified by recrystallization or column chromatography.
  • the compound of Formula Ic may be reacted with a halogenating agent in the presence of an inert organic solvent to get a compound of Formula Id.
  • the halogenating agent include bromine, iodine, N-halosuccinimide, and the like.
  • the compound of Formula Id may be reacted with a compound of Formula Ha at a temperature of from about 35° to about 75 0 C in the presence of an alkylamine, copper salt or palladium containing catalyst for a period of about 15 to 30 hours. After completion of the reaction, the reaction may be quenched with water and extracted with a water immiscible organic solvent. The organic layer may be concentrated under vacuum to get a residue, which may further be purified by crystallization or by column chromatography to get substituted thiochroman derivative of Formula Ia.
  • the inventors also have developed a process for the preparation of tazarotene of Formula III,
  • FORMULA III the process comprising: a) reacting a compound of Formula IVc,
  • FORMULA III the process comprising: a) treating a thiophenol derivative of Formula IVd,
  • FORMULA III the process comprising: a) treating a thiophenol derivative of Formula IVe,
  • R 2 is hydrogen or lower alkyl
  • A is phenyl or heteroaryl selected from the group comprising of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl
  • n is an integer having a value between 0 to 5
  • B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH 2 OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR 3 or a ketal derivative thereof, wherein R 3 is Ci -5 alkyl, cycloalkyl or alkenyl.
  • R 2 is hydrogen
  • A is selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl
  • n is an integer having a value between 0 to 5
  • B is -COOH or a pharmaceutically acceptable salt or an ester thereof.
  • the inventors also have developed a process for the preparation of substituted thiochroman derivatives of Formula Ia,
  • R 2 is hydrogen or lower alkyl
  • A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl
  • n is an integer having a value between 0 to 5
  • B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH 2 OH or its ether or ester derivative thereof, - CHO or an acetal derivative thereof, or -COR 3 or a ketal derivative thereof, wherein R 3 is C i- 5 alkyl, cycloalkyl or alkenyl; the process comprising: a) cyclizing a thiophenol derivative of Formula VI,
  • the compound of Formula VI may be cyclized in the presence of Lewis acids.
  • the Lewis acid may comprise one or more of halides of aluminium, boron, tin, titanium, or iron for example, titanium chloride, aluminium chloride and boron trifluoride.
  • the reaction may also be carried out in the presence of non-Lewis acids.
  • non-Lewis acids include sulfuric acid, methane sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, nitric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chlorosulfonic acid or amberlite sulfonic acid resin.
  • the compound of Formula Ia may further be purified by column chromatography.
  • the inventors also have developed a process for the preparation of compounds of Formula VI,
  • R 2 is hydrogen or lower alkyl
  • A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl
  • n is an integer having a value between 0 to 5
  • B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH 2 OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR 3 or a ketal derivative thereof, wherein R 3 is C 1 - 5 alkyl, cycloalkyl or alkenyl; the process comprising: a) treating a compound of Formula VII,
  • A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl;
  • n is an integer having a value between 0 to 5; and
  • B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH 2 OH or its ether or ester derivative thereof, - CHO or an acetal derivative thereof, or -COR 3 or a ketal derivative thereof wherein R 3 is Ci-5 alkyl, cycloalkyl or alkenyl; the process comprising: a) treating a compound of Formula VII,
  • FORMULA lie wherein X is halogen or a leaving group and A, B and n are as defined above, to get a compound of Formula VI, FORMULAVI wherein R 2 is hydrogen or lower alkyl, and A, B and n are as defined above; d) cyclizing the compound of Formula VI in the presence of an organic solvent optionally containing an acid; and e) isolating the compound of Formula Ia.
  • the compound of Formula VII may be treated with a trialkylsilylacetylene in the presence of a palladium catalyst and copper halide to get a compound of Formula IX.
  • the reaction may be carried out in the presence of a base, which can also be used as a solvent.
  • the palladium catalyst may be any suitable Pd(O) or Pd(II) containing catalyst.
  • the compound of Formula IX may be desilylated by using an organic or inorganic base in the presence of an organic solvent.
  • the organic solvent may be one or more of alcohols, ketones, hydrocarbons, halogenated hydrocarbons, ethers and esters.
  • a mixture of an aqueous solution containing an inorganic base and an alkanol can be used as a reaction medium.
  • the desilylated compound of Formula X may be treated with a compound of Formula Hc in the presence of palladium catalyst and copper halide to get a compound of Formula VT.
  • the palladium catalyst may be any suitable Pd(O) or Pd(II) containing catalyst.
  • the compound of Formula VI can be further purified by column chromatography.
  • the compound of Formula VI may be cyclized in the presence of an acid.
  • the acid can be a Lewis acid and includes one or more of halides of aluminium, boron, tin, titanium or iron.
  • the acid can also be a non-Lewis acid.
  • non- Lewis acids examples include concentrated sulfuric acid, methane sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, nitric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chlorosulfonic acid and amberlite sulfonic acid resin.
  • the cyclization may be carried out in the presence of an organic solvent for example, alcohols, ketones, hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitroalkanes, ethers and esters.
  • the reaction can be carried out in non-aqueous conditions and at a temperature of 4O 0 C or less.
  • a base can also be added to the reaction mixture at a temperature less than 2O 0 C before isolating the compound of Formula Ia. The addition of base helps in neutralizing the acid present in the reaction mixture.
  • the compound of Formula Ia may be isolated from the reaction mixture by layer separation.
  • the inventors also have found a novel polymorphic form designated as Form A of tazarotene.
  • the Form A is characterized by its X-ray diffraction pattern as shown in Figure 1, differential scanning calorimetry plot as shown in Figure 2, and infrared spectrum as shown in figure 3.
  • Form A of tazarotene may be characterized by X-ray diffraction peaks at about 10.36, 13.71, 15.16, 15.31, 16.37, 18.47, 20.81, 21.84, 23.14, 23.97', 24.34, 25.02 and 25.12 ⁇ 0.2 degrees two-theta values.
  • the novel polymorphic Form A may be characterized by DSC endothermic peak at 97°-110°C.
  • the inventors also have developed a process for the preparation of the polymorphic Form A of tazarotene, by obtaining a solution of tazarotene in one or more organic solvents; adding a second organic solvent to the solution; and isolating the Form A of tazarotene by the removal of solvents.
  • the inventors also have developed pharmaceutical compositions that contain the Form A of tazarotene, in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and/or excipients.
  • the solution of tazarotene may be obtained by is dissolving tazarotene in one or more organic solvents.
  • organic solvents include acetone, methyl ethyl ketone, acetonitrile, C 1-4 alkanol or mixtures thereof.
  • the solution of tazarotene in a solvent can be obtained by dissolving, slurrying, stirring or a combination thereof.
  • the solvent may be heated to obtain a solution. It may be heated at a temperature from about 40° to about 100 0 C for example, from about 50° to about 8O 0 C.
  • the solution may be filtered to remove undissolved solids.
  • the solution may be concentrated under vacuum before adding a second organic solvent.
  • the second organic solvent includes one or more of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, C 2-7 ethers, C 3-I o cycloalkanes or mixtures thereof.
  • the reaction mixture may be further stirred and cooled at a temperature from about 2O 0 C or less.
  • Removing the solvents may include, for example, one or more of filtration, filtration under vacuum, decantation and centrifugation.
  • the process may include further forming of the product so obtained into a finished dosage form.
  • the resultant solid may be separated by filtration and washed with same or a different organic solvent.
  • the process may include further drying of the product obtained.
  • the solid so obtained may be further or additionally dried to achieve the desired moisture values.
  • the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • the resulting Form A of tazarotene is obtained as pure white crystals and is free from coloring impurities.
  • the tazarotene may be prepared by any of the methods known in the art including those described in U.S. Patent No. 5,089,509 and can be used as a starting material.
  • the resulting Form A of tazarotene may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc.
  • the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
  • compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration.
  • the oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs.
  • Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.
  • the Form A of tazarotene can be administered for the treatment of stable plaque psoriasis and facial acne vulgaris, in a warm-blooded animal.
  • a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
  • X-ray powder diffraction patterns of the samples were recorded using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A
  • Example 1 Preparation of 4.4-dimethylthiochroman To a mixture of thiophenol (20 g) and methanesulfonic acid (28 g) in toluene (60 ml), isoprene (21 g) was added. The reaction mixture was stirred at ambient temperature for 5 hours and then cooled to 10 0 C followed by the addition of crushed ice (100 g). The resultant mass was extracted with ether and ether extracts were washed with water followed by 5% aqueous sodium hydroxide solution and finally with water. The organic layer was concentrated under vacuum to get title compound as yellow oil.
  • Example 2 Preparation of 4,4-dimethyl-6-bromothiochroman To a mixture of 4-bromothiophenol (20 g), methanesulfonic acid (28 g) in toluene (60 ml), isoprene (20 g) was added. The reaction mass mixture stirred at ambient temperature for 5 hours and then cooled to 10 0 C followed by the addition of crushed ice (100 g). The resultant mass was extracted with ether and ether extracts were washed with water followed by 5% aqueous sodium hydroxide solution and finally with water. The organic layer was concentrated under vacuum to get title compound as yellow oil, which was recrystallized from hexane to get white to off-white crystals of the title compound.
  • Example 3 Preparation of 4,4-dimethyl-6-bromothiochroman A mixture of 4,4-dimethylthiochroman (14 g) and iron filings (0.2 g) suspended in methylene chloride (120 ml) was cooled to 3 0 C. Bromine (13 g) was added to the reaction mass over about 3 hours while maintaining the temperature below 8 0 C. After the bromine addition was complete, the reaction mixture was stirred for 30 minutes and then a solution of sodium bicarbonate (9 g in 50 ml water) was added to the reaction mixture with vigorous stirring. The layers were separated and the aqueous layer was extracted with methylene chloride (30 ml). The combined organic extracts were washed with water (2 x 20 ml), dried over sodium sulfate and evaporated to give crude yellow oil, which was recrystallized from hexane to get white to off-white crystals of the title compound.
  • the reaction mixture was heated at 80° to 85°C for 18 h and cooled to 25 0 C, followed by the addition of 50% ethyl acetate in hexane (360 ml) and stirring for 30 minutes.
  • the reaction mixture was filtered through celite bed and washed the filtrate with water.
  • the organic layer was evaporated to get brown colored solid material which was purified by column chromatography using 15% ethyl acetate in hexane to get the title compound.
  • Ethyl 6-[ ⁇ 4-((3-methylbut-2-en-l-yl)thio)phenyl ⁇ ethynyl]nicotinate (0.5 g ) was dissolved in dichloromethane (25 ml) and cooled to O 0 C. Titanium chloride (1.6 g) in dichloromethane (25 ml) was added slowly at about 5°C, then the temperature was raised to 25 0 C and stirred for 12 h. It was followed by the addition of water and the pH was adjusted to basic condition with triethylamine. The precipitated solids were filtered through celite bed. The layers were separated and the organic layer was evaporated to get the title compound.
  • Example 8 Preparation of tazarotene Using the procedure set forth in Example 7, dichloromethane was replaced with nitromethane (1 L) to obtain the title compound.
  • Example 9 Preparation of tazarotene Using the procedure set forth in Example 7, methane sulphonic acid was replaced with concentrated sulfuric acid (1 Kg) to obtain the title compound.
  • Example 10 Preparation of tazarotene Using the procedure set forth in Example 7, methane sulphonic acid was replaced with triflic acid (1 Kg) to obtain the title compound.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
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Abstract

The invention relates to processes for the preparation of substituted thiochroman derivatives of Formula (I), wherein R2 is hydrogen or lower alkyl; R1 is hydrogen, halogen, a leaving group or a group of Formula (II), wherein A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2oH or its ether or ester derivative thereof, -CHO or and acetal derivative thereof, or -COR3 or ketal derivative thereof, wherein R3 is C1-5 alkyl, cycloalkyl or alkenyl. More particularly, it relates to a process for the preparation of tazarotene of Formula (III). The Invention also relates to a novel polymrophic form of tazarotene designated as Form A of tazarotene and process for producing it. The invention also relates to pharmaceutical compositions that include the Form A of tazarotene and use of said composition for treating stable plaque psoriasis and facial acne vulgaris.

Description

PROCESSES FOR THE PREPARATION OF SUBSTITUTED THIOCHROMAN
DERIVATIVES
Field of the Invention
The field of the invention relates to processes for the preparation of substituted thiochroman derivatives of Formula I,
Figure imgf000003_0001
FORMULA I wherein R2 is hydrogen or lower alkyl; Ri is hydrogen, halogen, a leaving group or a group of Formula II, = A— (CH2)n — B
FORMULA II wherein A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is Ci-5 alkyl, cycloalkyl or alkenyl. More particularly, it relates to a process for the preparation of tazarotene of Formula III.
Figure imgf000003_0002
FORMULA III The invention also relates to a novel polymorphic form of tazarotene designated as Form A of tazarotene and process for producing it. The invention also relates to pharmaceutical compositions that include the Form A of tazarotene and use of said compositions for treating stable plaque psoriasis and facial acne vulgaris.
Background of the Invention
Substituted thiochroman derivatives of Formula I are members of topically used acetylenic class of retinoids which are indicated for the topical treatment of patients with stable plaque psoriasis of up to 20% body surface area involvement and for the topical treatment of patients with facial acne vulgaris of mild to moderate severity. Tazarotene is a prominent member belonging to this class of retinoids, and is commercially available in the market as Tazorac® gel and Avage® cream for topical use. Chemically, tazarotene is ethyl 6-[2-(4,4-dimetylthiochroman-6-yl)ethynyl]nicotinate of Formula III.
Several processes have been reported for the preparation of substituted thiochroman derivatives of Formula I for example, in U.S. Patent Nos. 5,420,295;
5,519,150; International Publication No. WO 95/19973 (PCT) and European Patent No. 0 740 665.
U.S. Patent No. 5,089,509 discloses a method for the preparation of tazarotene, wherein the tazarotene is isolated as a yellow solid by flash chromatography. Several processes have been reported for the preparation of intermediates required for the preparation of the compound of Formula I for example, in Journal of Medicinal Chemistry 1984, 27, 1516; Journal of American Chemical Society 1974, 94, 9158; Chemical Letters 1976, 523; Journal of Organic Chemistry 1966, 31, 413; and Journal of Chemical Society, Chemical Communication, 1981, 237. The inventors have found that the prior art approach for the preparation of thiochroman derivatives of Formula I is not suitable from a commercial point of view because the processes are lengthy requiring isolation of several intermediates, use of toxic reagents such as isoprene bromide and yields are low. The present invention provides processes which are simple, cost-effective and easily scalable. The yield and purity of the product is greatly improved when made by the processes of the present invention.
Summary of the Invention
In one general aspect there are provided processes for the preparation of substituted thiochroman derivatives of Formula I.
In another general aspect there are provided processes for the preparation tazarotene of Formula III.
In another aspect there are provided compounds of Formula VI,
Figure imgf000005_0001
FORMULA VI and a process for producing the compounds of Formula VI.
In another aspect there is provided a novel polymorphic form designated as Form A of tazarotene. The Form A of tazarotene may have the X-ray diffraction pattern of Figure 1 , differential scanning calorimetry plot of Figure 2, and infrared spectrum of Figure 3.
In another general aspect there is provided a process for the preparation of polymorphic Form A of tazarotene.
In another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of the Form A of tazarotene; and one or more pharmaceutically acceptable carriers, excipients or diluents.
In another aspect there is provided a method for treating stable plaque psoriasis and facial acne vulgaris in a warm-blooded animal, the method comprising providing the warm-blooded animal a pharmaceutical composition that includes the Form A of tazarotene.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.
Description of the Drawings
Figure 1 is an X-ray powder diffraction pattern of Form A of tazarotene. Figure 2 is a differential scanning calorimetry plot of Form A of tazarotene. Figure 3 is an infrared spectrum of Form A of tazarotene. Detailed Description of the Invention
The inventors have developed a process for the preparation of substituted thiochroman derivatives of Formula I,
Figure imgf000006_0001
FORMULA I wherein R2 is hydrogen or lower alkyl; Ri is hydrogen, halogen, a leaving group or a group of Formula II, = A— (CH2)n — B
FORMULA II wherein A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is C1-S alkyl, cycloalkyl or alkenyl, the process comprising: a) treating a thiophenol derivative of Formula IV,
Figure imgf000007_0001
FORMULA IV wherein R2 is hydrogen or lower alkyl; R] is hydrogen, halogen, a leaving group or a group of Formula II, == A — (CH2)Ii — B
FORMULA II wherein A, B and n are as defined above, with a compound of Formula V,
Figure imgf000007_0002
FORMULA V in the presence of an acid catalyst; and b) isolating the substituted thiochroman derivative of Formula I.
The compound of Formula IV may be dissolved in an organic solvent and treated with isoprene of Formula V in the presence of an acid catalyst. The organic solvent includes one or more of aromatic hydrocarbons and halogenated aliphatic hydrocarbons. The acid catalyst can be a Lewis acid or a non-Lewis acid. Examples of the acid catalysts include sulfuric acid, methane sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, nitric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chlorosulfonic acid and amberlite sulfonic acid resin. The reaction of the compound of Formula IV with a compound of Formula V may be exothermic and may require cooling.
The substituted thiochroman derivative may be isolated by a technique which includes for example, distillation, distillation under vacuum, cooling, extraction, filtration, filtration under vacuum, decantation and centrifugation. After the reaction is complete, the reaction mass may be poured into a mixture of crashed ice and water. The resultant mixture may be extracted with a water immiscible organic solvent and the organic extracts may be washed subsequently with water and aqueous alkali solution. The organic extracts may be concentrated under vacuum to dryness to get a compound of Formula I.
The compound of Formula I thus recovered may be further purified or additionally purified, by employing commonly practiced recrystallization techniques using solvent / antisolvent mixtures or may be purified by column chromatography.
The inventors also have developed a process for the preparation of substituted thiochroman derivatives of Formula Ia,
Figure imgf000008_0001
FORMULA Ia wherein R2 is hydrogen or lower alkyl; Rj is a group of Formula II, = A— (CH2)n — B FORMULA II wherein A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is Cμs alkyl, cycloalkyl or alkenyl, the process comprising: a) treating a thiophenol derivative of Formula IVa,
Figure imgf000009_0001
FORMULA IVa wherein R2 is hydrogen or lower alkyl; Ri is halogen or a leaving group, with a compound of Formula V,
Figure imgf000009_0002
FORMULA V in the presence of an acid catalyst to get a compound of Formula Ib,
Figure imgf000009_0003
FORMULA Ib wherein Ri is halogen or a leaving group and R2 is hydrogen or lower alkyl; b) reacting the compound of Formula Ib with a compound of Formula Ha,
≡≡ A— (CH2)Ii-B
FORMULA Ha wherein A, B and n are as defined above; and c) isolating the substituted thiochroman derivative of Formula Ia.
The compound of Formula IVa may be treated with isoprene of Formula V in the presence of an organic solvent containing an acid catalyst. The organic solvent includes one or more of aromatic hydrocarbons or halogenated aliphatic hydrocarbons. The acid catalyst can be a Lewis acid or a non-Lewis acid. Examples of acid catalysts include sulfuric acid, methane sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, nitric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chlorosulfonic acid and amberlite sulfonic acid resin.
The reaction of the compound of Formula IVa with a compound of Formula V may be exothermic and may require cooling.
The substituted thiochroman derivative may be isolated by a technique which includes for example, distillation, distillation under vacuum, cooling, extraction, filtration, filtration under vacuum, decantation and centrifugation.
After the reaction is complete, the reaction mass may be poured into a mixture of crushed ice and water. The resultant mixture may be extracted with a water immiscible organic solvent and the organic extracts may be washed subsequently with water and aqueous alkali solution. The organic extracts may be concentrated under vacuum to dryness to get a compound of Formula Ib.
The compound of Formula Ib thus recovered may be further purified or additionally purified, by employing commonly practiced recrystallization techniques using solvent / antisolvent mixtures or may be purified by column chromatography.
The compound of Formula Ib may be reacted with a compound of Formula Ha at a temperature of from about 35° to about 750C in the presence of an alkylamine, copper salt or palladium containing catalyst for a period of about 15 to 30 hours. After completion of the reaction, the reaction may be quenched with water and extracted with a water immiscible organic solvent. The organic layer may be concentrated under vacuum to get a residue, which may be further purified by crystallization or by column chromatography to get the substituted thiochroman derivative of Formula Ia.
The inventors also have developed a process for the preparation of substituted thiochroman derivatives of Formula Ia,
Figure imgf000010_0001
FORMULAIa wherein R2 is hydrogen or lower alkyl; Ri a group of Formula II = A— (CH2)n — B
FORMULA II wherein, A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, - CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is Ci-5 alkyl, cycloalkyl or alkenyl, the process comprising: a) treating a thiophenol derivative of Formula IVb,
Figure imgf000011_0001
FORMULA IVb wherein R2 is hydrogen or lower alkyl; Ri is hydrogen, with a compound of Formula V,
Figure imgf000011_0002
FORMULA V in the presence of an acid catalyst to get a compound of Formula Ic,
Figure imgf000011_0003
FORMULA Ic wherein Ri is hydrogen and R2 is hydrogen or lower alkyl; b) reacting the compound of Formula Ic with a halogenating agent to get a compound of Formula Id,
Figure imgf000012_0001
FORMULA Id wherein Ri is halogen and R2 is hydrogen or lower alkyl; c) reacting the compound of Formula Id with a compound of Formula Ha, ^ A — (CH2)n — B
FORMULA Ha wherein A, B and n are as defined above; and d) isolating the substituted thiochroman derivative of Formula Ia.
The compound of Formula IVb may be treated with isoprene of Formula V in the presence of an organic solvent containing an acid catalyst. The organic solvent may include one or more of aromatic hydrocarbons or halogenated aliphatic hydrocarbons. The acid catalyst can be a Lewis acid or a non-Lewis acid and may include one or more of sulfuric acid, methane sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, nitric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chlorosulfonic acid and amberlite sulfonic acid resin. The reaction may be exothermic and may require cooling. After the reaction is complete, the reaction mass may be poured into a mixture of crushed ice and water. The resultant mixture may be extracted with a water immiscible organic solvent and the organic extracts may be washed subsequently with water and aqueous alkali solution. The organic extracts may be concentrated under vacuum to dryness to get a compound of Formula Ic, which may optionally be purified by recrystallization or column chromatography.
The compound of Formula Ic may be reacted with a halogenating agent in the presence of an inert organic solvent to get a compound of Formula Id. Examples of the halogenating agent include bromine, iodine, N-halosuccinimide, and the like. The compound of Formula Id may be reacted with a compound of Formula Ha at a temperature of from about 35° to about 750C in the presence of an alkylamine, copper salt or palladium containing catalyst for a period of about 15 to 30 hours. After completion of the reaction, the reaction may be quenched with water and extracted with a water immiscible organic solvent. The organic layer may be concentrated under vacuum to get a residue, which may further be purified by crystallization or by column chromatography to get substituted thiochroman derivative of Formula Ia.
The inventors also have developed a process for the preparation of tazarotene of Formula III,
Figure imgf000013_0001
FORMULA III the process comprising: a) reacting a compound of Formula IVc,
Figure imgf000013_0002
FORMULA IVc with a compound of Formula V,
Figure imgf000014_0001
FORMULAV in the presence of an acid catalyst; and b) isolating the tazarotene of Formula III. In another aspect there is provided a process for the preparation of tazarotene of
Formula III,
Figure imgf000014_0002
FORMULA III the process comprising: a) treating a thiophenol derivative of Formula IVd,
Figure imgf000014_0003
FORMULA IVd wherein R2 is hydrogen; Ri is halogen or a leaving group, with a compound of Formula V,
Figure imgf000014_0004
FORMULA V in the presence of an acid catalyst to get a compound of Formula Ie,
Figure imgf000015_0001
FORMULA Ie wherein R1 is halogen or a leaving group and R2 is hydrogen; b) reacting a compound of Formula Ie with a compound of Formula lib; and
Figure imgf000015_0002
FORMULA lib c) isolating the tazarotene of Formula III.
In another aspect there is provided a process for the preparation of tazarotene of Formula III,
Figure imgf000015_0003
FORMULA III the process comprising: a) treating a thiophenol derivative of Formula IVe,
Figure imgf000016_0001
FORMULA IVe with a compound of Formula V,
Figure imgf000016_0002
FORMULA V in the presence of an acid catalyst to get a compound of Formula If;
Figure imgf000016_0003
FORMULA If b) reacting the compound of Formula If with a halogenating agent to get a compound of Formula Ig,
Figure imgf000016_0004
FORMULA Ig wherein X is halogen; c) reacting the compound of Formula Ig with a compound of Formula lib; and
Figure imgf000017_0001
FORMULA πb d) isolating the tazarotene of Formula III.
In another aspect there are provided compounds having the structure of Formula
VI,
Figure imgf000017_0002
FORMULA VI wherein R2 is hydrogen or lower alkyl; A is phenyl or heteroaryl selected from the group comprising of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is Ci-5 alkyl, cycloalkyl or alkenyl.
In particular, there are provided the compounds of Formula VI, wherein R2 is hydrogen, A is selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; B is -COOH or a pharmaceutically acceptable salt or an ester thereof.
The inventors also have developed a process for the preparation of substituted thiochroman derivatives of Formula Ia,
Figure imgf000018_0001
FORMULA Ia wherein R2 is hydrogen or lower alkyl; Ri is a group of Formula II, = A— (CH2)n — B FORMULA II wherein, A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, - CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is C i-5 alkyl, cycloalkyl or alkenyl; the process comprising: a) cyclizing a thiophenol derivative of Formula VI,
Figure imgf000018_0002
FORMULA VI wherein R2 is hydrogen or lower alkyl, and A, B and n are as defined above; and b) isolating the compound of Formula Ia.
The compound of Formula VI may be cyclized in the presence of Lewis acids. The Lewis acid may comprise one or more of halides of aluminium, boron, tin, titanium, or iron for example, titanium chloride, aluminium chloride and boron trifluoride. The reaction may also be carried out in the presence of non-Lewis acids. Examples of non-Lewis acids include sulfuric acid, methane sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, nitric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chlorosulfonic acid or amberlite sulfonic acid resin. The compound of Formula Ia may further be purified by column chromatography.
The inventors also have developed a process for the preparation of compounds of Formula VI,
Figure imgf000019_0001
FORMULA VI wherein R2 is hydrogen or lower alkyl; A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is C1-5 alkyl, cycloalkyl or alkenyl; the process comprising: a) treating a compound of Formula VII,
Figure imgf000019_0002
FORMULAVII wherein X is halogen or a leaving group and R2 is hydrogen or lower alkyl, with a compound of Formula VIII,
Figure imgf000020_0001
FORMULA VIII wherein R4 is C1-S alkyl, to get a compound of Formula IX,
Figure imgf000020_0002
FORMULA IX wherein R2 is hydrogen or lower alkyl and R4 is C1-S alkyl; b) desilylating the compound of Formula IX to get a compound of Formula X,
Figure imgf000020_0003
FORMULA X wherein R2 is hydrogen or lower alkyl; c) treating the compound of Formula X with a compound of Formula Hc,
X — A— (CH2)n — B FORMULA IIc wherein X is halogen or a leaving group and A, B and n are as defined above; and d) isolating the compound of Formula VI.
In another aspect there is provided a process for the preparation of substituted thiochroman derivatives of Formula Ia,
Figure imgf000021_0001
FORMULA Ia wherein R2 is hydrogen or lower alkyl; Ri is a group of Formula II, = A— (CH2)n — B
FORMULA II wherein, A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, - CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof wherein R3 is Ci-5 alkyl, cycloalkyl or alkenyl; the process comprising: a) treating a compound of Formula VII,
Figure imgf000021_0002
FORMULA VII wherein X is halogen or a leaving group and R2 is hydrogen or lower alkyl, with a compound of Formula VIII,
Figure imgf000022_0001
FORMULA VIII wherein R4 is C1-5 alkyl, to get a compound of Formula IX,
Figure imgf000022_0002
FORMULA IX wherein R2 is hydrogen or lower alkyl and R4 is C1-S alkyl; b) desilylating the compound of Formula IX to get a compound of Formula X,
Figure imgf000022_0003
FORMULA X wherein R2 is hydrogen or lower alkyl; c) treating the compound of Formula X with a compound of Formula Hc,
X A— (CH2)Ii — B
FORMULA lie wherein X is halogen or a leaving group and A, B and n are as defined above, to get a compound of Formula VI,
Figure imgf000023_0001
FORMULAVI wherein R2 is hydrogen or lower alkyl, and A, B and n are as defined above; d) cyclizing the compound of Formula VI in the presence of an organic solvent optionally containing an acid; and e) isolating the compound of Formula Ia.
The compound of Formula VII may be treated with a trialkylsilylacetylene in the presence of a palladium catalyst and copper halide to get a compound of Formula IX. The reaction may be carried out in the presence of a base, which can also be used as a solvent. The palladium catalyst may be any suitable Pd(O) or Pd(II) containing catalyst.
The compound of Formula IX may be desilylated by using an organic or inorganic base in the presence of an organic solvent. The organic solvent may be one or more of alcohols, ketones, hydrocarbons, halogenated hydrocarbons, ethers and esters. In particular, a mixture of an aqueous solution containing an inorganic base and an alkanol can be used as a reaction medium.
The desilylated compound of Formula X may be treated with a compound of Formula Hc in the presence of palladium catalyst and copper halide to get a compound of Formula VT. The palladium catalyst may be any suitable Pd(O) or Pd(II) containing catalyst. The compound of Formula VI can be further purified by column chromatography. The compound of Formula VI may be cyclized in the presence of an acid. The acid can be a Lewis acid and includes one or more of halides of aluminium, boron, tin, titanium or iron. The acid can also be a non-Lewis acid. Examples of non- Lewis acids include concentrated sulfuric acid, methane sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, nitric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chlorosulfonic acid and amberlite sulfonic acid resin. The cyclization may be carried out in the presence of an organic solvent for example, alcohols, ketones, hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitroalkanes, ethers and esters. The reaction can be carried out in non-aqueous conditions and at a temperature of 4O0C or less. A base can also be added to the reaction mixture at a temperature less than 2O0C before isolating the compound of Formula Ia. The addition of base helps in neutralizing the acid present in the reaction mixture. The compound of Formula Ia may be isolated from the reaction mixture by layer separation. The inventors also have found a novel polymorphic form designated as Form A of tazarotene. The Form A is characterized by its X-ray diffraction pattern as shown in Figure 1, differential scanning calorimetry plot as shown in Figure 2, and infrared spectrum as shown in figure 3.
In general, the Form A of tazarotene may be characterized by X-ray diffraction peaks at about 10.36, 13.71, 15.16, 15.31, 16.37, 18.47, 20.81, 21.84, 23.14, 23.97', 24.34, 25.02 and 25.12 ± 0.2 degrees two-theta values. It may be further characterized by X-ray diffraction peaks at about 11.13, 12.28, 14.56, 14.74, 17.48, 18.87, 19.20, 20.25, 20.42, 21.37, 21.50, 22.32, 22.86, 26.16, 26.73, 27.00, 27.62, 28.52, 28.60, 29.37, 30.16, 30.83, 31.24, 32.01, 32.44, 32.96, 33.57, 34.10, 34.72, 35.00, 35.44, 36.35, 37.86, 38.32, 38.71 and 39.53 ± 0.2 degrees two-theta values.
The novel polymorphic Form A may be characterized by DSC endothermic peak at 97°-110°C.
The inventors also have developed a process for the preparation of the polymorphic Form A of tazarotene, by obtaining a solution of tazarotene in one or more organic solvents; adding a second organic solvent to the solution; and isolating the Form A of tazarotene by the removal of solvents. The inventors also have developed pharmaceutical compositions that contain the Form A of tazarotene, in admixture with one or more solid or liquid pharmaceutical diluents, carriers, and/or excipients. In general, the solution of tazarotene may be obtained by is dissolving tazarotene in one or more organic solvents. Examples of organic solvents include acetone, methyl ethyl ketone, acetonitrile, C1-4 alkanol or mixtures thereof.
The solution of tazarotene in a solvent can be obtained by dissolving, slurrying, stirring or a combination thereof. The solvent may be heated to obtain a solution. It may be heated at a temperature from about 40° to about 1000C for example, from about 50° to about 8O0C. The solution may be filtered to remove undissolved solids. The solution may be concentrated under vacuum before adding a second organic solvent. The second organic solvent includes one or more of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, C2-7 ethers, C3-Io cycloalkanes or mixtures thereof.
The reaction mixture may be further stirred and cooled at a temperature from about 2O0C or less. Removing the solvents may include, for example, one or more of filtration, filtration under vacuum, decantation and centrifugation. The process may include further forming of the product so obtained into a finished dosage form. The resultant solid may be separated by filtration and washed with same or a different organic solvent.
The process may include further drying of the product obtained.
The solid so obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier. The resulting Form A of tazarotene is obtained as pure white crystals and is free from coloring impurities.
The tazarotene may be prepared by any of the methods known in the art including those described in U.S. Patent No. 5,089,509 and can be used as a starting material.
The resulting Form A of tazarotene may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
The compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration. The oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs. Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.
The Form A of tazarotene can be administered for the treatment of stable plaque psoriasis and facial acne vulgaris, in a warm-blooded animal.
For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Methods
X-ray powder diffraction patterns of the samples were recorded using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A
Infrared spectra of the samples were recorded using instrument: Perkin Elmer, 16 PC, SCAN: lβscans, 4.0 cm"1, according to the USP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method. Differential scanning calorimetry thermograms were recorded using DSC821 e,
Mettler Toledo, Sample weight: 3-5 mg, Temperature range: 50-350° C, Heating rate: 20° C/min, Nitrogen 80.0 mL/min, Number of holes in the crucible: 1
Example 1: Preparation of 4.4-dimethylthiochroman To a mixture of thiophenol (20 g) and methanesulfonic acid (28 g) in toluene (60 ml), isoprene (21 g) was added. The reaction mixture was stirred at ambient temperature for 5 hours and then cooled to 100C followed by the addition of crushed ice (100 g). The resultant mass was extracted with ether and ether extracts were washed with water followed by 5% aqueous sodium hydroxide solution and finally with water. The organic layer was concentrated under vacuum to get title compound as yellow oil.
Yield: 23.8 g
Example 2: Preparation of 4,4-dimethyl-6-bromothiochroman To a mixture of 4-bromothiophenol (20 g), methanesulfonic acid (28 g) in toluene (60 ml), isoprene (20 g) was added. The reaction mass mixture stirred at ambient temperature for 5 hours and then cooled to 100C followed by the addition of crushed ice (100 g). The resultant mass was extracted with ether and ether extracts were washed with water followed by 5% aqueous sodium hydroxide solution and finally with water. The organic layer was concentrated under vacuum to get title compound as yellow oil, which was recrystallized from hexane to get white to off-white crystals of the title compound.
Yield: 27.2 g
Example 3: Preparation of 4,4-dimethyl-6-bromothiochroman A mixture of 4,4-dimethylthiochroman (14 g) and iron filings (0.2 g) suspended in methylene chloride (120 ml) was cooled to 30C. Bromine (13 g) was added to the reaction mass over about 3 hours while maintaining the temperature below 80C. After the bromine addition was complete, the reaction mixture was stirred for 30 minutes and then a solution of sodium bicarbonate (9 g in 50 ml water) was added to the reaction mixture with vigorous stirring. The layers were separated and the aqueous layer was extracted with methylene chloride (30 ml). The combined organic extracts were washed with water (2 x 20 ml), dried over sodium sulfate and evaporated to give crude yellow oil, which was recrystallized from hexane to get white to off-white crystals of the title compound.
Yield: 14 g.
Example 4: Preparation of ethyl 6-ethvnylnicotinate
A mixture of ethyl 6-iodonicotinate (10 g) in triethylamine (100 ml) was degassed under nitrogen and then successively added cuprous iodide (0.68 g), tetrakis(triphenylphosphine)palladium (2.32 g) and trimethylsilylacerylene (5.2 ml). The mixture was stirred for 2 hours followed by the addition of water and extracted with ethyl acetate. The solvent was evaporated under vacuum and the resultant residue was dissolved in THF (50 ml). A solution of tetrabutylammonium fluoride in THF (40 ml, IM) was added drop-wise to this mass and stirred for 2 h. The mass was finally treated with ammonium chloride solution and extracted with ethyl acetate. The organic layer was concentrated to dryness to get a residue, which was purified by chromatography to get the title compound as a solid.
Yield: 3.9 g
Example 5: Preparation of ethyl 6-r2-r4,4-dimethylthiochroman-6-yl)ethvnyllnicotinate (tazarotene)
A mixture of ethyl 6-ethynylnicotinate (10 g), 4,4-dimethyl-6-bromothiochroman (14.9 g) and triethylamine (100 ml) was degassed under nitrogen followed by the addition of a mixture of cuprous iodide (14.2 g) and bis(triphenylphosphine)palladium (II) chloride (2.8 g). The reaction mixture was heated to 550C and stirred for 20 hours at 55° to 6O0C. The reaction mixture was cooled to 250C, quenched with water and extracted with ether. The ether extracts were combined and washed with brine solution. The ethereal extracts were concentrated under vacuum and the residue was purified by chromatography to give the title compound as a white solid. Yield: 20% w/w
Example 6: Preparation of tazarotene a) Preparation of 4-bromophenyl 3-methylbut-2-en-l-yl sulfide
A solution of 4-bromothiophenol (15 g; 0.079 mol) and sodium hydroxide (3.17 g; 0.079 mol) in acetone (60 ml) was heated at reflux for 0.5 h followed by drop wise addition of a solution of l-bromo-3-methyl-2-butene (11.72 g; 0.079 mol) in acetone (20 ml). The reaction mixture was heated at reflux for a further 1.5 h, cooled to 250C and the solvent was removed in vacuum. The residue was taken up in water and extracted with ethyl acetate. The ethyl acetate extracts were combined and washed successively with water and sodium chloride solution. The organic layer was concentrated in vacuum to give the title compound as pale yellow oil.
Yield: 100 % w/w 1HNMR (CDCl3, δ): 1.57 (3H, s), 1.70 (3 H, s), 3.50 (2H, d, J~7.6Hz), 5.26 (IH, t, J~7.6Hz), 7.17 (2H, d, J~8.4Hz), 7.37 (2H, d, J~8.4Hz).
b) Preparation of trimethyl[{4-((3-methylbut-2-en-l-yl)thio)phenyl}ethynyl]silane
A mixture of 4-bromophenyl-3-methylbut-2-en-l-yl sulfide (68 g; 0.265 mol) and trimethylsilylacetylene (32 g; 0.326 mol) in triethylamine (100 ml) was degassed under argon for 15 minutes, followed by the addition of cuprous iodide (3.55 g; 0.186 mol) and tetrakis(triphenyl phosphine)palladium (14.3 g; 0.012 mol). The reaction mixture was heated at 90°C for 7 h and then cooled to 250C. Hexane (700 ml) was added to the reaction mixture and stirred for 30 minutes followed by filtration through celite bed and washing with water. The organic layer was then evaporated to get the title compound as dark brown oil.
Yield: 73 g
1HNMR (CDCl3, δ): 0.24 (9H, s), 3.52 (2H, t, J~7.5Hz), 5.27 (IH, t, J~7.5Hz), 7.11 - 7.39 (4H, m).
c) Preparation of 4-ethynylphenyl 3-methylbut-2-en-l-yl sulfide
A mixture of trimethyl[{4-((3-methylbut-2-en-l-yl)thio) phenyl} ethynyl]silane (73 g; 0.265 mol) and 1 N aqueous potassium hydroxide solution (170 ml) in isopropyl alcohol (550 ml) for 5 h at 250C. Completion of the reaction was monitored by thin layer chromatography, followed by filtration through celite bed and washing with isopropyl alcohol (50 ml). The reaction mixture was concentrated under vacuum, followed by the addition of water (220 ml) to the residue and extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to get the title compound. Yield: 40 g
1HNMR (CDCl3, δ): 1.62 (3H, s), 1.71 (3H, s), 3.07 (IH, s), 3.54 (2H, d, J~7.6Hz), 5.28 (IH, t, J~7.6Hz), 7.22 (2H, d, J~8.2Hz), 7.37 (2H, d, J~8.2Hz). d) Preparation of ethyl 6-[{4-((3-methylbut-2-en-l-yl)thio)phenyl}ethynyl]nicotinate A reaction mixture of 4-ethynyl-phenyl-3-methylbut-2-en-l-ylsulfϊde (72 g; 0.356 mol), ethyl 6-chloronicotinate (126 g; 0.679 mol) and triethylamine (360 ml) was degassed with argon for 15 minutes, followed by the addition of tetrakis(triphenyl phosphine)palladium (20.9 g; 0.018 mol) and copper (I) iodide (7.2 g; 0.038 mol). The reaction mixture was heated at 80° to 85°C for 18 h and cooled to 250C, followed by the addition of 50% ethyl acetate in hexane (360 ml) and stirring for 30 minutes. The reaction mixture was filtered through celite bed and washed the filtrate with water. The organic layer was evaporated to get brown colored solid material which was purified by column chromatography using 15% ethyl acetate in hexane to get the title compound.
Yield: 35.3 g 1HNMR (CDCl3, δ): 1.62 (3H, s), 1.71 (3H, s), 3.07 (IH, s), 3.54 (2H, d, J~7.6Hz), 5.28 (IH, t, J~7.6Hz), 7.22 (2H, d, J~8.2Hz), 7.37 (2H, d, J~8.2Hz).
e) Preparation of ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate (tazarotene)
Ethyl 6-[{4-((3-methylbut-2-en-l-yl)thio)phenyl}ethynyl]nicotinate (0.5 g ) was dissolved in dichloromethane (25 ml) and cooled to O0C. Titanium chloride (1.6 g) in dichloromethane (25 ml) was added slowly at about 5°C, then the temperature was raised to 250C and stirred for 12 h. It was followed by the addition of water and the pH was adjusted to basic condition with triethylamine. The precipitated solids were filtered through celite bed. The layers were separated and the organic layer was evaporated to get the title compound.
Yield: 67% w/w
1HNMR (CDCl3, δ): 1.34 (6H, s), 1.42 (3H, t, J~6.9Hz), 1.96 (2H, t, J~6 Hz), 3.05 (2H, t, J~6 Hz), 4.45 (2H, q, J~7.3Hz), 7.08 (IH, d, J~8.2Hz), 7.26 (IH, d, J~8.2Hz), 7.57 (IH, d, J~8.1Hz), 7.62 (IH, s), 8.27 (IH, d, r8.1Hz), 9.19 (IH, s). Example 7: Preparation of tazarotene
A solution of ethyl 6-[{4-((3-methylbut-2-en-l-yl)thio)phenyl}ethynyl]nicotinate (100 g) in dichloromethane (1 L) was added into a mixture of methane sulphonic acid (1 Kg) and dichloromethane (1 L) at 250C. The reaction mixture was stirred for 5 minutes, followed by quenching with ethyl acetate (6 L). The reaction mixture was cooled to 100C, followed by the addition of water (1 L) and the pH was adjusted to neutral using 15% sodium hydroxide solution at 10° to 150C. The layers were separated and the organic layer was evaporated under vacuum to get brown colored gummy solid (100 g). The solid so obtained was purified by column chromatography (15% ethyl acetate in haxanes) and crystallized using ethyl acetate to get the title compound.
Yield: 33 % w/w HPLC Purity: 99%
Example 8: Preparation of tazarotene Using the procedure set forth in Example 7, dichloromethane was replaced with nitromethane (1 L) to obtain the title compound.
Yield: 68.12 % w/w
Example 9: Preparation of tazarotene Using the procedure set forth in Example 7, methane sulphonic acid was replaced with concentrated sulfuric acid (1 Kg) to obtain the title compound.
Yield: 54.39 % w/w
Example 10: Preparation of tazarotene Using the procedure set forth in Example 7, methane sulphonic acid was replaced with triflic acid (1 Kg) to obtain the title compound.
Yield: 48.25 % w/w Example 11: Preparation of tazarotene
Ethyl 6-[{4-((3-methylbut-2-en-l-yl)thio)phenyl}ethynyl]nicotinate (100 g) was added into a slurry of aluminium chloride (0.4 Kg) and dichloromethane (1 L) at 250C. The reaction mixture was stirred for 5 minutes and quenched with ethyl acetate (6 L). The reaction mixture was cooled to 100C, followed by the addition of water (1 L) and the pH was adjusted to neutral using 15% sodium hydroxide solution at 10° to 150C. The reaction mixture so obtained was filtered through celite bed and the layers were separated. The organic layer was evaporated under vacuum and purified by column chromatography (15% ethyl acetate in haxanes) to get the title compound. Yield: 45 % w/w
Example 12: Preparation of tazarotene
Using the procedure set forth in Example 11, aluminium chloride was replaced with boron trifluoride etherate (0.4 Kg) to obtain the title compound. Yield: 33.80 % w/w
Example 13: Preparation of tazarotene
Using the procedure set forth in Example 11, aluminium chloride was replaced with boron trifluoride dihydrate (0.4 Kg) to obtain the title compound. Yield: 74.50 % w/w
Example 14: Preparation of Form A of tazarotene
Crude tazarotene (5 g) was dissolved in acetone (15 ml) at 45° to 5O0C. The solution so obtained was charged with activated charcoal (0.25 g) and stirred for 30 minutes at 45° to 500C. The solution was filtered through celite bed and washed with acetone (5 ml). The filtered solution was distilled under vacuum to obtain the volume of 10 ml of acetone followed by the addition of hexanes (20 ml). The reaction mixture was cooled to 250C and stirred for 30 minutes. The reaction mixture was further cooled to 100C and stirred for 1 hour. The reaction mass was filtered and washed with hexanes (10 ml). The solid was dried under vacuum at ambient temperature to get 3.7 g of title compound as white crystalline powder.
Yield: 3.7 g HPLC purity: 99%
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

We Claim: 1. A process for the preparation of substituted thiochroman derivatives of Formula I,
Figure imgf000034_0001
FORMULA I wherein R2 is hydrogen or lower alkyl, Ri is hydrogen, halogen, a leaving group or a group of Formula II, = A-(CH2)Ii — B
FORMULA II wherein A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is Ci-5 alkyl, cycloalkyl or alkenyl, the process comprising: a) treating a thiophenol derivative of Formula IV,
Figure imgf000034_0002
FORMULA IV wherein R2 is hydrogen or lower alkyl; Ri is hydrogen, halogen, a leaving group or a group of Formula II, ≡≡≡ A— (CH2)n — B FORMULA II wherein A, B and n are as defined above, with a compound of Formula V,
Figure imgf000035_0001
FORMULA V in the presence of an acid catalyst; and b) isolating the substituted thiochroman derivative of Formula I.
2. The process of claim 1 , wherein the acid catalyst comprises one or more of sulfuric acid, methane sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, nitric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifiuoroacetic acid, chlorosulfonic acid and amberlite sulfonic acid resin.
3. A process for the preparation of substituted thiochroman derivatives of Formula Ia,
Figure imgf000035_0002
FORMULA Ia wherein R2 is hydrogen or lower alkyl, Ri is a group of Formula II, == A — (CH2)n — B
FORMULA II wherein A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is Q-5 alkyl, cycloalkyl or alkenyl, the process comprising: a) treating a thiophenol derivative of Formula IVa,
Figure imgf000036_0001
FORMULA IVa wherein R2 is hydrogen or lower alkyl; Ri is halogen or a leaving group, with a compound of Formula V,
Figure imgf000036_0002
FORMULA V in the presence of an acid catalyst to get a compound of Formula Ib,
Figure imgf000036_0003
FORMULA Ib wherein Ri is halogen or a leaving group and R2 is hydrogen or lower alkyl; b) reacting the compound of Formula Ib with a compound of Formula Ha, ^ A — (CH2)Ii- B FORMULA IIa wherein A, B and n are as defined above; and c) isolating the substituted thiochroman derivative of Formula Ia.
4. The process of claim 3, wherein the step b) is carried out in the presence of a palladium catalyst or a copper salt.
5. A process for the preparation of substituted thiochroman derivatives of Formula Ia,
Figure imgf000037_0001
FORMULA Ia wherein R2 is hydrogen or lower alkyl; Ri a group of Formula II, = A— (CH2)n — B
FORMULA II wherein A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is Ci-S alkyl, cycloalkyl or alkenyl, the process comprising: a) treating a thiophenol derivative of Formula IVb,
Figure imgf000037_0002
FORMULA IVb wherein R2 is hydrogen or lower alkyl; Rj is hydrogen, with a compound of Formula V,
Figure imgf000037_0003
FORMULA V in the presence of an acid catalyst to get a compound of Formula Ic,
Figure imgf000038_0001
FORMULA Ic wherein Ri is hydrogen and R2 is hydrogen or lower alkyl; b) reacting the compound of Formula Ic with a halogenating agent to get a compound of Formula Id,
Figure imgf000038_0002
FORMULA Id wherein Ri is halogen and R2 is hydrogen or lower alkyl; c) reacting the compound of Formula Id with a compound of Formula Ha, ≡≡≡ A— (CH2)n— B FORMULA Ha wherein A, B and n are as defined above; and d) isolating the substituted thiochroman derivative of Formula Ia.
6. The process of claim 5, wherein the halogenating agent comprises one or more of bromine, iodine and N-halosuccinimide.
7. A process for the preparation of tazarotene of Formula III,
Figure imgf000039_0001
FORMULA III the process comprising: a) reacting a compound of Formula IVc,
Figure imgf000039_0002
FORMULA IVc with a compound of Formula V,
Figure imgf000039_0003
FORMULA V in the presence of an acid catalyst; and b) isolating the tazarotene of Formula III.
8. A process for the preparation of tazarotene of Formula III,
Figure imgf000040_0001
FORMULA III the process comprising: a) treating a thiophenol derivative of Formula IVd,
Figure imgf000040_0002
FORMULA IVd wherein R2 is hydrogen; Ri is halogen or a leaving group, with a compound of Formula V,
Figure imgf000040_0003
FORMULA V in the presence of an acid catalyst to get a compound of Formula Ie,
FORMULA Ie wherein Ri is halogen or a leaving group and R2 is hydrogen; b) reacting the compound of Formula Ie with a compound of Formula lib; and
Figure imgf000041_0001
FORMULA Hb c) isolating the tazarotene of Formula III.
9. A process for the preparation of tazarotene of Formula III,
Figure imgf000041_0002
FORMULA III the process comprising: a) treating a thiophenol derivative of Formula IVe,
Figure imgf000041_0003
FORMULA IVe with a compound of Formula V,
Figure imgf000041_0004
FORMULA V in the presence of an acid catalyst to get a compound of Formula If;
Figure imgf000042_0001
FORMULA If b) reacting the compound of Formula If with a halogenating agent to get a compound of Formula Ig,
Figure imgf000042_0002
FORMULA Ig wherein X is halogen; c) reacting the compound of Formula Ig with a compound of Formula lib; and
Figure imgf000042_0003
FORMULA IIb d) isolating the tazarotene of Formula III.
10. Compounds having the structure of Formula VI,
Figure imgf000043_0001
FORMULA VI wherein R2 is hydrogen or lower alkyl; A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is Ci-5 alkyl, cycloalkyl or alkenyl.
11. The compound of claim 10, having the structure of Formula Via.
Figure imgf000043_0002
FORMULAVIa
12. A process for the preparation of substituted thiochroman derivatives of Formula Ia,
Figure imgf000043_0003
FORMULA Ia wherein R2 is hydrogen or lower alkyl; Ri is a group of Formula II, === A— (CH2)n— B FORMULA II wherein A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is C1-S alkyl, cycloalkyl or alkenyl; the process comprising: a) cyclizing a thiophenol derivative of Formula VI,
Figure imgf000044_0001
FORMULA VI wherein R2 is hydrogen or lower alkyl, and A, B and n are as defined above; and b) isolating the compound of Formula Ia. 13. The process of claim 12, wherein the step a) is carried out in the presence of a Lewis acid comprising one or more of halides of aluminium, boron, tin, titanium, or iron. 14. The process of claim 13, wherein the Lewis acid is titanium chloride, aluminium chloride or boron trifluoride. 15. The process of claim 12, wherein the step a) is carried out in the presence of a non- Lewis acid comprising one or more of sulfuric acid, methane sulfonic acid, camphor sulfonic acid, trifluoromethane sulfonic acid, nitric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chlorosulfonic acid or amberlite sulfonic acid resin. 16. The process of claims 12, wherein the compound of Formula Ia is tazarotene. 17. . The process of claims 12, further comprising purification of the compound of Formula Ia by column chromatography. 18. A process for the preparation of compounds of Formula VI,
Figure imgf000045_0001
FORMULA VI wherein R2 is hydrogen or lower alkyl; A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is C1-S alkyl, cycloalkyl or alkenyl; the process comprising: a) treating a compound of Formula VII,
Figure imgf000045_0002
FORMULA VII wherein X is halogen or a leaving group and R2 is hydrogen or lower alkyl, with a compound of Formula VIII,
Figure imgf000046_0001
FORMULA VIII wherein R4 is Ci-5 alkyl, to get a compound of Formula IX,
Figure imgf000046_0002
FORMULA IX wherein R2 is hydrogen or lower alkyl and R4 is Ci-5 alkyl; b) desilylating the compound of Formula IX to get a compound of Formula X,
Figure imgf000046_0003
FORMULA X wherein R2 is hydrogen or lower alkyl; c) treating the compound of Formula X with a compound of Formula Hc, x A— (CH2)n— B FORMULA lie wherein X is halogen or a leaving group and A, B and n are as defined above; and d) isolating the compound of Formula VI. 19. The process of claim 18, wherein the compound of Formula VIII is trimethylsilylacetylene. 20. The process of claim 18, wherein the desilylation is carried out in the presence of an organic or inorganic base. 21. The process of claim 18, wherein the step a) is carried out in the presence of a palladium catalyst. 22. The process of claim 18, wherein the step c) is carried out in the presence of a palladium catalyst. 23. A process for the preparation of substituted thiochroman derivatives of Formula Ia,
Figure imgf000047_0001
FORMULA Ia wherein R2 is hydrogen or lower alkyl; Ri is a group of Formula II, ΞΞ^≡ A— (CH2)n — B FORMULA II wherein A is phenyl or heteroaryl selected from the group consisting of pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; n is an integer having a value between 0 to 5; and B is hydrogen, -COOH or its pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or its ether or ester derivative thereof, -CHO or an acetal derivative thereof, or -COR3 or a ketal derivative thereof, wherein R3 is Ci-5 alkyl, cycloalkyl or alkenyl; the process comprising: a) treating a compound of Formula VII,
Figure imgf000048_0001
FORMULA VII wherein X is halogen or a leaving group and R2 is hydrogen or lower alkyl, with a compound of Formula VIII,
Figure imgf000048_0002
FORMULA VIII wherein R4 is Ci-5 alkyl, to get a compound of Formula IX,
Figure imgf000048_0003
FORMULA IX wherein R2 is hydrogen or lower alkyl and R4 is Ci-5 alkyl; b) desilylating the compound of Formula IX to get a compound of Formula X,
Figure imgf000049_0001
FORMULA X wherein R2 is hydrogen or lower alkyl; c) treating the compound of Formula X with a compound of Formula Hc, X A — (CH2)n — B FORMULA Hc wherein X is halogen or a leaving group and A, B and n are as defined above, to get a compound of Formula VI,
Figure imgf000049_0002
FORMULA VI wherein R2 is hydrogen or lower alkyl, and A, B and n are as defined above; d) cyclizing the compound of Formula VI in the presence of an organic solvent optionally containing an acid; and e) isolating the compound of Foπnula Ia. 24. The process of claim 23, wherein the step a) is carried out in the presence of an acid. 25. The process of claim 24, wherein the acid is a Lewis acid. 26. Polymorphic Form A of tazarotene. 27. The polymorphic Form A of claim 26, wherein the tazarotene has the X-ray diffraction pattern of Figure 1. 28. The polymorphic Form A of claim 26 having characteristic X-ray diffraction peaks at about 10.36,
13.71, 15.16, 15.31, 16.37, 18.47, 20.81, 21.84, 23.14, 23.97, 24.34, 25.02 and 25.12 ± 0.2 degrees two-theta values. 29. The polymorphic Form A of claim 28 further characterized by X-ray diffraction peaks at about 11.13, 12.28, 14.56,
14.74, 17.48, 18.87, 19.20, 20.25, 20.42, 21.37, 21.50, 22.32, 22.86, 26.16, 26.73, 27.00, 27.62, 28.52, 28.60, 29.37, 30.16, 30.83, 31.24, 32.01, 32.44, 32.96, 33.57, 34.10, 34.72, 35.00, 35.44, 36.35, 37.86, 38.32, 38.71 and 39.53 ± 0.2 degrees two-theta values. 30. The polymorphic Form A of claim 26, wherein the tazarotene has the differential scanning calorimetry plot of Figure 2 having a DSC thermogram, 31. The polymorphic Form A of claim 30 having characteristic endothermic peak at 97°-110°C. 32. The polymorphic Form A of claim 26, wherein the tazarotene has the infrared spectrum of Figure 3. 33. A process for the preparation of polymorphic Form A of tazarotene, the process comprising: a) obtaining a solution of tazarotene in one or more organic solvents; b) adding a second organic solvent to the solution; and c) isolating the Form A of tazarotene by the removal of the solvents. 34. The process of claim 33, wherein the organic solvent comprises one or more of acetone, methyl ethyl ketone, acetonitrile, C1-4 alkanol or mixtures thereof. 35. The process of claim 33, wherein the second organic solvent comprises one or more of aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, C2-7 ethers, C3-10 cycloalkanes or mixtures thereof. 36. The process of claim 33, wherein removing the solvents comprises one or more of filtration, filtration under vacuum, decantation and centrifugation. 37. A pharmaceutical composition comprising a therapeutically effective amount of polymorphic Form A of tazarotene; and one or more pharmaceutically acceptable carriers, excipients or diluents. 38. A method of treating stable plaque psoriasis and facial acne vulgaris in a warm- blooded animal, the method comprising providing a dosage form to the warm-blooded animal that includes Form A of tazarotene.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1700855A1 (en) * 2005-03-08 2006-09-13 SOLMAG S.p.A. A process for the preparation of tazarotene
US8586008B2 (en) 2003-01-24 2013-11-19 Stiefel West Coast, Llc Pharmaceutical foam
US8808716B2 (en) 2009-02-25 2014-08-19 Stiefel Research Australia Pty Ltd Topical foam composition
WO2015107542A3 (en) * 2013-12-13 2016-06-02 Sun Pharmaceutical Industries Limited Tazarotene with low dimer impurity for treating acne or psoriasis
CN105924425A (en) * 2016-04-29 2016-09-07 浙江师范大学 Preparation method of dihydrothiochroman derivative
EP3428155A4 (en) * 2016-03-11 2019-04-03 Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences Retinoid compound, preparation method therefor, intermediates thereof and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0436398A1 (en) * 1989-12-29 1991-07-10 Allergan, Inc. Acetylenes disubstituted with a heteroaromatic group and a substituted phenyl group having retinoid like activity
US5089509A (en) * 1988-09-15 1992-02-18 Allergan, Inc. Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity
US5202471A (en) * 1990-02-06 1993-04-13 Allergan, Inc. Alkyl, alkoxy and thioalkoxy substituted diphenyl acetylenes having retinoid like activity
EP0740665A1 (en) * 1994-01-19 1996-11-06 Allergan Process for preparing 4,4-dialkyl-6-halo-chromans or thiochromans useful as pharmaceutical intermediates

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5089509A (en) * 1988-09-15 1992-02-18 Allergan, Inc. Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity
EP0436398A1 (en) * 1989-12-29 1991-07-10 Allergan, Inc. Acetylenes disubstituted with a heteroaromatic group and a substituted phenyl group having retinoid like activity
US5202471A (en) * 1990-02-06 1993-04-13 Allergan, Inc. Alkyl, alkoxy and thioalkoxy substituted diphenyl acetylenes having retinoid like activity
EP0740665A1 (en) * 1994-01-19 1996-11-06 Allergan Process for preparing 4,4-dialkyl-6-halo-chromans or thiochromans useful as pharmaceutical intermediates

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8586008B2 (en) 2003-01-24 2013-11-19 Stiefel West Coast, Llc Pharmaceutical foam
US9486394B2 (en) 2003-01-24 2016-11-08 Stiefel West Coast, Llc Pharmaceutical foam
EP1700855A1 (en) * 2005-03-08 2006-09-13 SOLMAG S.p.A. A process for the preparation of tazarotene
US8808716B2 (en) 2009-02-25 2014-08-19 Stiefel Research Australia Pty Ltd Topical foam composition
US10568859B2 (en) 2009-02-25 2020-02-25 Mayne Pharma Llc Topical foam composition
US10688071B2 (en) 2009-02-25 2020-06-23 Mayne Pharma Llc Topical foam composition
WO2015107542A3 (en) * 2013-12-13 2016-06-02 Sun Pharmaceutical Industries Limited Tazarotene with low dimer impurity for treating acne or psoriasis
US9688667B2 (en) 2013-12-13 2017-06-27 Sun Pharmaceutical Industries Limited Tazarotene with low dimer impurity for treating acne or psoriasis
EP3428155A4 (en) * 2016-03-11 2019-04-03 Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences Retinoid compound, preparation method therefor, intermediates thereof and application thereof
US10556879B2 (en) 2016-03-11 2020-02-11 Shanghai Institute Of Organic Chemistry, Chinese Acadmeny Of Sciences Retinoid compound, preparation method therefor, intermediates thereof and application thereof
CN105924425A (en) * 2016-04-29 2016-09-07 浙江师范大学 Preparation method of dihydrothiochroman derivative

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