The present invention is directed to a process for preparation of substituted thiochroman derivatives of Formula I,
(FORMULA REMOVED)

FORMULA I
wherein R1 is hydrogen or lower alkyl; A is phenyl or heteroaryl selected from the group comprising of pyridynyl, 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 II.
(FORMULA REMOVED)

FORMULA II
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, US Patent No. 5,519,150, PCT Patent Application WO 95/19973 and European Patent No. 0,740,665 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 provide 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 novel and industrially scalable process for preparation of substituted thiochroman derivatives of Formula I in the presence of distinct acids. By employing the present process, the yield and purity of the product is improved.
A first 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 pyridynyl, 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 a Lewis acid selected from a group comprising of halides of aluminium, boron, tin and iron.
b) isolating a compound of Formula I from the reaction mixture 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 pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; n is an integer having a value between 0 to 5; B is hydrogen, -COOH or pharmaceuticallt 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 a non-Lewis acid selected from a group comprising of 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.
b) isolating a compound of Formula I from the reaction mixture thereof.
The compound of Formula III is cyclized in the presence of an acid. The acid can be a Lewis acid selected from a group comprising of halides of aluminium, boron, tin and iron. The acid can also be a non-Lewis acid selected from a group comprising of 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 takes place in the presence of an organic solvent selected from a group comprising of 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 40°C or less. A base can also be added to the reaction mixture at a temperature less than 20°C before isolating the compound of Formula I. The addition of base helps in neutralizing the acid present in the reaction mixture. 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 solution of ethyl 6-[{4-((3-methylbut-2-en-1-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 ambient temperature. The reaction mixture was stirred for 5 minutes, followed by quenching with ethyl acetate (6 L) at ambient temperature. The reaction mixture was cooled to 10°C, followed by the addition of water (1 L) and the pH was adjusted to neutral using 15% sodium hydroxide solution at 10-15°C. 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 % Purity: 99%
EXAMPLE 2
PREPARATION OF TAZAROTENE
Using the procedure set forth in Example 1, dichloromethane was replaced with nitromethane (1 L) to obtain the title compound.
Yield: 68.12 %
EXAMPLE 3
PREPARATION OF TAZAROTENE
Using the procedure set forth in Example 1, methane sulphonic acid was replaced with concentrated sulfuric acid (1 Kg) to obtain the title compound.
Yield: 54.39 %
EXAMPLE 4
PREPARATION OF TAZAROTENE
Using the procedure set forth in Example 1, methane sulphonic acid was replaced with triflic acid (1 Kg) to obtain the title compound.
Yield: 48.25 %
EXAMPLE 5
PREPARATION OF TAZAROTENE
Ethyl 6-[{4-((3-methylbut-2-en-1-yl)thio)phenyl}ethynyl]nicotinate (100 g) was added into a slurry of aluminium chloride (0.4 Kg) and dichloromethane (1 L) at ambient
temperature. The reaction mixture was stirred for 5 minutes and quenched with ethyl acetate (6 L) at room temperature. The reaction mixture was cooled to 10°C, followed by the addition of water (1 L) and the pH was adjusted to neutral using 15% sodium hydroxide solution at 10-15°C. 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 %
EXAMPLE 6
PREPARATION OF TAZAROTENE
Using the procedure set forth in Example 5, aluminium chloride was replaced with boron trifluoride etherate (0.4 Kg) to obtain the title compound.
Yield: 33.80 %
EXAMPLE 7
PREPARATION OF TAZAROTENE
Using the procedure set forth in Example 5, aluminium chloride was replaced with boron trifluoride dihydrate (0.4 Kg) to obtain the title compound.
Yield: 74.50 %

WE CLAIM:
1. 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 pyridynyl, 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 REMOVED0

wherein R1, A, B and n are as defined above, in the presence of a Lewis acid selected from a group comprising of halides of aluminium, boron, tin and iron.
b) isolating the compound of Formula I from the reaction mixture thereof. 2. 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 pyridynyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and oxazolyl; n is an integer having a value between 0 to 5; B is hydrogen, -COOH or pharmaceuticall 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 a non-Lewis acid selected from a group comprising of 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.
b) isolating the compound of Formula I from the reaction mixture thereof.
3. A process as claimed in claims 1 and 2, wherein the compound of Formula I is tazarotene.
4. A process as claimed in claims 1 and 2, wherein step a) is carried out in the presence
of an organic solvent selected from a group comprising of alcohols, ketones, hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitroalkanes, ethers and esters.
5. A process as claimed in claims 1 and 2, wherein step a) is carried out in nonaqueous
medium.
6. A process as claimed in claims 1 and 2, wherein step a) is carried out at a temperature of 40°C or less.
7. A process as claimed in claims 1 and 2, wherein step a) is followed by neutralization
of the reaction mixture.
8. A process as claimed in claim 6, wherein neutralization is carried out at a
temperature of 20°C or less.

9. A process as claimed in claims 1 and 2, wherein step b) comprises purification of the compound of Formula I by column chromatography.
10. A process as claimed in claim 9, wherein column chromatography is carried out in a solvent system comprising ethyl acetate and hexanes.