The present invention is directed to a process for preparation of a substituted thiochroman derivative of Formula I,
(Formula Removed)
wherein R1 is hydrogen or lower alkyl; A is phenyl or heteroaryl selected from the group comprising of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; n is an integer having a value between 0 to 5; B is hydrogen, -COOH or pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative thereof, -CHO or an acetal derivative thereof, -COR2 or a ketal derivative thereof wherein R2 is C1-5 alkyl, cycloalkyl or alkenyl.
The present invention further provides a process for preparation of tazarotene of Formula

(Formula Removed)
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. Prominent member belonging to this class of retinoids is tazarotene, chemically known as ethyl 6-[2-(4,4-
dimetylthiochroman-6-yl)ethynyl]nicotinate of Formula II, which is commercially available in the market as Tazorac® Gel and Avage® Cream for topical use.
Several literature reports provide a method for preparation of substituted thiochromans of Formula I. The synthesis of especially tazarotene of Formula II is well described.
US Patent No. 5,420,295 and its equivalent US Patent No. 5,519,150, PCT Patent Application WO 95/19973 and European Patent No. 740665 provide a synthetic methodology for preparation of substituted thiochroman derivatives of Formula I. In addition US Patent No. 5,089,509 and US Patent No. 5,717,094 (Equivalents are PCT Patent Application WO 93/16068, WO 96/11686, EP 785782) provides a method for preparation of tazarotene like compounds.
Intermediates required for preparation of the compound of Formula I are reportedly prepared in Journal of Medicinal Chemistry 27, 1516 (1984); Journal of American Chemical Society 94, 9158 (1974); Chemical Letters 523 (1976); Journal of Organic Chemistry 31., 413 (1966); Journal of Chemical Society, Chemical Communication, 237 (1981).
The present inventors have developed a simple, cost-effective and easily scalable process for preparation of substituted thiochroman derivatives of Formula I.
A first aspect of the present invention provides a compound of Formula III,
(Formula Removed)
wherein R1 is hydrogen or lower alkyl; A is phenyl or heteroaryl selected from the group comprising of pyridinyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and
oxazolyl; n is an integer having a value between 0 to 5; B is hydrogen, -COOH or pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative thereof, -CHO or an acetal derivative thereof, -COR2 or a ketal derivative thereof wherein R2 is C1-5 alkyl, cycloalkyl or alkenyl.
Preferred are the compounds of Formula III, wherein R1 is hydrogen, A is selected from the group comprising of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; n is an integer having a value between 0 to 5; B is -COOH or pharmaceutically acceptable salt, ester or amide thereof.
A second aspect of the present invention provides a process for preparation of a compound of Formula I
(Formula Removed)
wherein R1 is hydrogen or lower alkyl; A is phenyl or heteroaryl selected from the group comprising of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; n is an integer having a value between 0 to 5; B is hydrogen, -COOH or pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative thereof, -CHO or an acetal derivative thereof, -COR2 or a ketal derivative thereof wherein R2 is C1-5 alkyl, cycloalkyl or alkenyl; which comprises of a) cyclizing a thiophenol derivative of Formula III
(Formula Removed)
wherein R1, A, B and n are as defined above, in the presence of an organic solvent
optionally containing a metal halide catalyst,
b) isolating a compound of Formula I from the reaction mixture thereof.
A third aspect of the present invention provides a process for the preparation of a compound of Formula III,

(Formula Removed)
wherein R1 is hydrogen or lower alkyl; wherein, A is phenyl or heteroaryl selected from the group comprising of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; n is an integer having a value between 0 to 5; B is hydrogen, -COOH or pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative thereof, -CHO or an acetal derivative thereof, -COR2 or a ketal derivative thereof wherein R2 is C1-5 alkyl, cycloalkyl or alkenyl; which comprises of a) treating a compound of Formula IV,
(Formula Removed)
wherein X is halogen or a leaving group and R1 is hydrogen or lower alkyl, with a compound of Formula V,
(Formula Removed)
wherein R3 is C1-5 alkyl, to get a compound of Formula VI,
(Formula Removed)
wherein R1 and R3 are as defined above,
b) desilylating the compound of Formula VI to get a compound of Formula VII,

(Formula Removed)
wherein R1 is as defined above,
c) treating the compound of Formula VII with a compound of Formula VIII,
(Formula Removed)
wherein X is halogen or a leaving group and A, B and n are as defined above;
d) isolating the compound of Formula III from the reaction mixture thereof.
A fourth aspect of the present invention provides a process for preparation of a compound of Formula I
(Formula Removed)
wherein R1 is hydrogen or lower alkyl; A is phenyl or heteroaryl selected from the group comprising of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; n is an integer having a value between 0 to 5; B is hydrogen, -COOH or pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative thereof, -CHO or an acetai derivative thereof, -COR2 or a ketal derivative thereof wherein R2 is C1-5 alkyl, cycloalkyl or alkenyl; which comprises of a) treating a compound of Formula IV,
(Formula Removed)
wherein X is halogen or a leaving group and R1 is hydrogen or lower alkyl, with a compound of Formula V,
(Formula Removed)
wherein R3 is C1-5 alkyl, to get a compound of Formula VI,
(Formula Removed)
wherein R1 and R3 are as defined above,
b) desilylating the compound of Formula VI to get a compound of Formula VII,
(Formula Removed)
wherein R1 is as defined above,
c) treating the compound of Formula VII with a compound of Formula VIII,
(Formula Removed)
wherein X is halogen or a leaving group and A, B and n are as defined above, to get a compound of Formula III,
(Formula Removed)
wherein R1, A, B and n are as defined above,
d) cyclizing the compound of Formula III in the presence of an organic solvent optionally containing a metal halide catalyst,
e) isolating the compound of Formula I from the reaction mixture thereof.
A compound of Formula IV is treated with a trialkylsilylacetylene in the presence of a palladium catalyst and copper halide to get a compound of Formula VI. The reaction is carried out in the presence of a base, which can also be used as a solvent. The palladium catalyst may be any suitable Pd(0) or Pd(ll) containing catalyst.
The compound of Formula VI is then desilylated by using an organic or inorganic base in the presence of an organic solvent selected from a group comprising of alcohols, ketones, hydrocarbons, halogenated hydrocarbons, ethers and esters. Preferably a mixture of an aqueous solution comprising an inorganic base and an alkanol can be used as a reaction medium.
The desilylated compound of Formula VII is further treated with a compound of Formula VIII in the presence of palladium catalyst and copper halide to get a compound of Formula III. The palladium catalyst may be any suitable Pd(0) or Pd(ll) containing catalyst. The compound of Formula III can be further purified by column chromatography. After chromatographic purification, the compound of Formula III is cyclized in the presence of an organic solvent selected from a group comprising of alcohols, ketones, hydrocarbons, halogenated hydrocarbons, ethers and esters. A metal halide can optionally be used as a catalyst. The metal halide may be selected from a group comprising of aluminum chloride, aluminum bromide, and chloride, boron trifluoride, boron trichloride, boron tribromide,
titanium chloride, titanium tetrabromide, stannic chloride, stannic bromide, bismuth trichloride and ferric chloride. The compound of Formula I is isolated from the reaction mixture by layer separation.
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.
EXAMPLE 1
PREPARATION OF TAZAROTENE
A) PREPARATION OF 4-BROMOPHENYL 3-METHYLBUT-2-EN-1-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 1-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 ambient temperature 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%
1HNMR (CDCI3, δ): 1.57 (3H, s), 1.70 (3H, s), 3.50 (2H, d, J~7.6Hz), 5.26 (1H, 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-1-
YL)THIO)PHENYL}ETHYNYL]SILANE
A mixture of 4-bromophenyl-3-methylbut-2-en-1-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 ambient temperature. 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 colored oil.
Yield: 100%
1HNMR (CDCI3, δ): 0.24 (9H, s), 3.52 (2H, t, J~7.5Hz), 5.27 (1H, t, J~7.5Hz), 7.11 - 7.39 (4H, m).
C) PREPARATION OF 4-ETHYNYLPHENYL 3-METHYLBUT-2-EN-1-YL SULFIDE
A mixture of trimethyl[{4-((3-methylbut-2-en-1-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 ambient temperature. 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: 93%
1HNMR (CDCI3, δ): 1.62 (3H, s), 1.71 (3H, s), 3.07 (1H, s), 3.54 (2H, d, J~7.6Hz), 5.28 (1H, 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-1-
YL)THIO)PHENYL}ETHYNYL]NICOTINATE
A reaction mixture of 4-ethynyl-phenyl-3-methylbut-2-en-1-ylsulfide (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 - 85°C for 18 h and cooled to ambient temperature, followed by the addition of 50% ethyl acetate in hexane (360 ml) and stirred 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 and purified by column chromatography using 15% ethyl acetate in hexane to get the title compound. Yield: 28.2%
1HNMR (CDCl3, δ): 1.62 (3H, s), 1.71 (3H, s), 3.07 (1H, s), 3.54 (2H, d, J~7.6Hz), 5.28 (1H, 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-1-yl)thio)phenyl}ethynyl]nicotinate (0.5 g, 0.0014 mol ) was dissolved in dichloromethane (25 ml) and cooled to 0°C. Titanium chloride (1.6 g, 0.0084mol) in Dichloromethane (25 ml) was added slowly at below 5°C, then the temperature was raised to ambient temperature and stirred for 12 h, 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%
1HNMR (CDCI3, 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 (1H, d, J~8.2Hz), 7.26 (1H, d, J~8.2Hz), 7.57 (1H, d, J~8.1Hz), 7.62 (1H, s), 8.27 (1H, d, J~8.1Hz), 9.19 (1H, s).

WE CLAIM:
1. A compound of Formula III,
(Formula Removed)
wherein Ri is hydrogen or lower alkyl; A is phenyl or heteroaryl selected from the group comprising of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; n is an integer having a value between 0 to 5; B is hydrogen, -COOH or pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative thereof, -CHO or an acetal derivative thereof, -COR2 or a ketal derivative thereof wherein R2 is C1.5 alkyl, cycloalkyl or alkenyl.
2. A compound as claimed in claim 1,
(Formula Removed)
3. A process for preparation of a compound of Formula I
(Formula Removed)
wherein R1 is hydrogen or lower alkyl; A is phenyl or heteroaryl selected from the group comprising of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; n is an integer having a value between 0 to 5; B is hydrogen, -COOH or pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative thereof, -CHO or an acetal derivative thereof, -COR2 or a ketal derivative thereof wherein R2 is C1-5 alkyl, cycloalkyl or alkenyl; which comprises of a) cyclizing a thiophenol derivative of Formula III
(Formula Removed)
wherein R1, A, B and n are as defined above, in the presence of an organic solvent optionally containing a metal halide catalyst, b) isolating substituted thiochroman derivative of Formula I from the reaction mixture thereof.
4. A process as claimed in claim 3, wherein the metal halide is selected from a group comprising of aluminum chloride, aluminum bromide, and chloride, boron trifluoride, boron trichloride, boron tribromide, titanium chloride, titanium tetrabromide, stannic chloride, stannic bromide, bismuth trichloride and ferric chloride.
5. A process for the preparation of a compound of Formula III,
(Formula Removed)
wherein Ri is hydrogen or lower alkyl; wherein, A is phenyl or heteroaryl selected from the group comprising of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; n is an integer having a value between 0 to 5; B is hydrogen, -COOH or pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative thereof, -CHO or an acetal derivative thereof, -COR2 or a ketal derivative thereof wherein R2 is C1-5 alkyl, cycloalkyl or alkenyl; which comprises of a) treating a compound of Formula IV,
(Formula Removed)
wherein X is halogen or a leaving group and R1 is hydrogen or lower alkyl, with a compound of Formula V,
(Formula Removed)
wherein R3 is C1-5 alkyl, to get a compound of Formula VI,

wherein R1 is hydrogen or lower alkyl and R3 is C1-5 alkyl, b) desilylating the compound of Formula VI to get a compound of Formula VII,
(Formula Removed)
wherein R1 is as defined above,
c) treating the compound of Formula VII with a compound of Formula VII,
(Formula Removed)
wherein X is halogen or a leaving group and A, B and n are as defined above;
d) isolating the compound of Formula III from the reaction mixture thereof.
6. A process as claimed in claim 5, wherein the compound of Formula V is
trimethylsilylacetylene.
7. A process according to claim 5, wherein desilylation is carried out in the presence of an organic or inorganic base.
8. A process for preparation of a compound of Formula I
(Formula Removed)
wherein R1 is hydrogen or lower alkyl; A is phenyl or heteroaryl selected from the group comprising of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; n is an integer having a value between 0 to 5; B is hydrogen, -COOH or pharmaceutically acceptable salt, ester or amide thereof, -CH2OH or an ether or ester derivative thereof, -CHO or an acetal derivative thereof, -COR2 or a ketal derivative thereof wherein R2 is C1-5 alkyl, cycloalkyl or alkenyl; which comprises of a) treating a compound of Formula IV,
(Formula Removed)
wherein X is halogen or a leaving group and R1 is hydrogen or lower alkyl, with a compound of Formula V,
(Formula Removed)
wherein R3 is C1-5 alkyl, to get a compound of Formula VI,
(Formula Removed)
wherein R1 is hydrogen or lower alkyl and R3 is C1-5 alkyl, b) desilylating the compound of Formula VI to get a compound of Formula VII,
(Formula Removed)
wherein R1 is as defined above, c) treating the compound of Formula VII with a compound of Formula VIII,
(Formula Removed)
wherein X is halogen or a leaving group and A, B and n are as defined above, to get a compound of Formula III,
(Formula Removed)
wherein R1, A, B and n are as defined above,
d) cyclizing the compound of Formula III in the presence of an organic solvent
optionally containing a metal halide catalyst,
e) isolating the compound of Formula I from the reaction mixture thereof.
9. A process as claimed in claim 8 wherein step a) and step c) is performed in presence of
palladium catalyst.
10. A process as claimed in claim 9 wherein copper halide is used along with palladium
catalyst.