Title of Invention

A NOVEL PROCESS FOR PREPARATION OF 4, 4-DIMETHYL-6-ETHYNYL THIOCHROMAN

Abstract A process for the preparation of 4,4-dimethyl-6-ethynylthiochroman comprising: (a) reacting 4,4-dimethyl-6-acetylthiochroman and an acid chloride in a solvent to form a |3-chloro vinylaldehyde intermediate, at a temperature range of -10°C to 35°C; and (b) reacting the P-chloro vinylaldehyde intermediate with an alkali metal hydroxide in a solvent to form the 4,4-dimethyl-6-ethynylthiochroman, at a temperature range of 20°C to 90°C.
Full Text FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10, rule 13)
"A PROCESS FOR THE PREPARATION OF 4,4-DIMETHYL-6-
ETHYNYLTHIOCHROMAN."
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road
Post Box No. 26511
Mumbai- 400 026, India
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED
ORGN
685/MUM/2003 11 JAN 2005

BACKGROUND OF THE INVENTION
Technical Field
The present invention generally relates to an improved process for the preparation of
intermediates for tazarotene. More specifically, the present invention relates to an improved
process for the preparation of the intermediate 4,4-dimethyl-6-ethynylthiochroman using a
Vilsmeier Haack reaction.
Description of the Related Art
The present invention is directed towards an improved process for the preparation of
intermediates of tazarotene (also known as ethyl-6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl])
of Formula I:

Tazarotene is a member of the acetylenic class of retinoids and is a prodrug that is converted to its active drug form, known as AGN 190299, in most biological systems by rapid deesterificaion of the cognate carboxylic acid of tazarotene. AGN 190299 binds to all three members of the retinoic acid receptor (RAR) family: RARa, RARp, RARy. AGN 190299 shows relative selectivity for the RARp and RARy and may modify gene expression. Tazarotene is used in the treatment of psoriasis and is commercially available under the trade name Tazorac .
A key intermediate in the preparation of tazarotene, 4,4-dimethyl-6-ethynylthiochroman (II), is prepared as shown in Scheme I:



11 6 .5
Thiophenol (1) and l-bromo-3-methyl-2-butene (2) are heated at reflux with sodium hydroxide in acetone resulting in phenyl-3-methylbut-2-enylsulfide (3). The phenyl-3-methylbut-2-enyl sulfide (3) is cyclized by refluxing with phosphorus pentoxide and phosphoric acid in benzene to yield 4,4-dimethylthiochroman (4). The 4,4-dimethylthiochroman (4) is reacted with acetyl chloride catalyzed by tin (IV) chloride (SnCl4) in benzene resulting in 4,4-dimethyl-6-acetylthiochroman (5). The 4,4-dimethyl-6-acetylthiochroman (5) is dehydrated with lithium diisopropylamide (LDA) and diethyl chlorophosphate in tetrahydrofuran (THF) results in the initial 6-ethenyl phosphonate intermediate (6). This intermediate undergoes further reaction with two equivalents of LDA to give 4,4-dimethyl-6-ethynylthiochroman (II).
The main disadvantages of this process include the use of reagents, such as LDA, which is moisture sensitive, expensive, pyrophoric, and difficult to handle on a commercial scale, and diethyl chlorophosphate, which is highly toxic and corrosive. The process is also time consuming and includes low temperatures in an inert atmosphere, which is difficult to achieve on a commercial scale.
Accordingly, there remains a need for an improved process for preparing 4,4-dimethyl-6-ethynylthiochroman that eliminates and reduces the drawbacks of the prior art in a convenient and cost efficient manner on a commercial scale.

SUMMARY OF THE INVENTION
One aspect of the present invention is the preparation of a key intermediate of tazarotene, 4,4-dimethyl-6-ethynylthiochroman, via a Vilsmeier Haack reaction. The Vilsmeier Haack reaction comprises reacting 4,4-dimethyl-6-acetylthiochroman with an acid chloride in a solvent to form a P-chloro vinylaldehyde intermediate. The P-chloro vinylaldehyde intermediate is then reacted with an alkali metal hydroxide to form 4,4-dimethyl-6-ethynylthiochroman.
The advantages of the present invention includes:
1) The process may be performed without the isolation and purification of intermediates after each step. The intermediates of the present invention are advantageously formed in a solvent which can be used in further steps of the synthesis.
2) Avoids the use of low temperatures (e.g., -78°C) which is expensive to work in on a commercial scale.
3) Avoids the use of reagents such as LDA, benzene, diethyl chlorophosphate and diethyl ether. Each of these reagents present various hazards which make them particularly difficult to handle when working in commercial quantities.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In one aspect of the present invention, 4,4-dimethyl-6-ethynylthiochroman can be prepared by a process including a Vilsmeier Haack reaction that forms a P-chloro vinylaldehyde intermediate. In a further aspect of the present invention, 4,4-dimethyl-6-acetylthiochroman (5) is reacted with an acid chloride in a solvent to form a Vilsmeier Haack reagent, P-chloro vinylaldehyde (7) as shown in scheme II:
Scheme II

5 7 II
The P-chloro vinylaldehyde intermediate (7) may be reacted with a hot alkali in an ether type solvent to produce 4,4-dimethyl-6-ethynylthiochroman (II).

In the process of the present invention, the Vilsmeier Haack reagent may be generated in one or more solvents such as, for example, formamide solvents (e.g., disubstituted formamide solvents), chlorinated alkane solvents and the like and mixtures thereof. The formamide solvents include, but are not limited to, dimethyl formamide, N-methyl formanilide, N-formyl piperidine, N-formyl morpholine, dimethyl acetamide, N-methyl pyrrolidone, N,N-dimethyl benzamide and the like and mixtures thereof with dimethyl formamide being preferred. The chlorinated alkane solvents include, but are not limited to, dichloromethane, chloroform, carbon tetrachloride and the like and mixtures thereof.
The acid chlorides for use in the process of the present invention are used to convert formamide derivatives. Any acid chloride may be used herein including, for example, phosphorous oxychloride (POCI3). In one embodiment of the present invention, the acid chloride is selected from the group consisting of phosphorous oxychloride, thionyl chloride, phosgene and oxalyl chloride. The acid chloride may be present in a ratio up to 1:3(w/v) with respect to 4,4-dimethyl-6-acetylthiochroman. The acid chloride may be added dropwise to the 4,4-dimethyl-6-acetylthiochroman in the solvent over a time period of from about 1 to about 2 hours at a temperature ranging from -10°C to 0°C. After addition of the acid chloride, the reaction time for the Vilsmeier Haack reaction may be about 4 to 10 hours, and the reaction temperature may range from -10°C to 35°C. When the Vilsmeier Haack reaction of the present invention is carried out at a temperature below about 10°C, the impurity profile is advantageously reduced.
The reaction may be carried out in one of two ways: (1) by adding the 4,4-dimethyl-6-acetylthiochroman to the solvent and then adding the acid chloride; or (2) by adding the acid chloride to the solvent and then adding the 4,4-dimethyl-6-acetylthiochroman.
Next, 4,4-dimethyl-6-ethynylthiochroman may be formed by adding an aqueous solution of alkali metal hydroxide to the Vilsmeier Haack reaction product at a temperature ranging from about 80°C to 90°C for up to 2 hrs . Useful alkali metal hydroxide include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide. The alkali metal hydroxide is ordinarily added in a molar ratio of 1:4 to 1:12 with respect to the p-chloro vinylaldehyde intermediate. It is particularly advantageous to carry out the reaction in an ether type solvent selected from the group consisting of dialkyl ether, dioxane, tetrahydrofuran and pyran for which the reaction time will ordinarily

lnge from 12 hours to 18 hours at 20°C to 40°C . The reaction mixture may be quenched with saturated ammonium chloride.
To prepare the starting material 4,4-dimethyl-6-acetylthiochroman, thiophenol may be reacted with a strong base in about equimolar amounts in ethylene dichloride (EDC) and methanol at reflux. The mixture of methanol and ethylene dichloride (1:1 v/v) may vary from about 1:12 w/v to about 1:15 w/v with respect to the thiophenol. The strong base is preferably an alkali metal hydroxide, such as, for example, sodium hydroxide. l-bromo-3-methyl-2-butene is added in about equimolar amounts and the reaction mixture may be refluxed for about 8 to about 12 hours to form phenyl-3-methylbut-2-enyl sulfide.
The phenyl-3-methylbut-2-enyl sulfide is present in the EDC layer and does not need to further purified or separated prior to reacting it with phosphorous pentoxide in the presence of phosphoric acid. The reaction is heated to reflux with stirring for about 8 to about 12 hours. This reaction closes the ring of the sulfide forming 4,4-dimethylthiochroman.
The 4,4-dimethylthiochroman is present in the EDC layer and also does not need to be further purified or separated prior to reacting it with acetyl chloride in the presence of aluminum chloride. The reaction mixture is stirred for about 30 minutes to about 3 hours at a temperature ranging from about -10°C to about 10°C. The reaction is quenched and the product is 4,4-dimethyl-6-acetylthiochroman which is present in the EDC layer. The product may be used without further purification to perform the Vilsmeier Haack reaction.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims.
EXAMPLE 1 Preparation of 3-[4,4-dimethylthiochroman-6-yl]-3-chloro-2-propene-1 -al
In a 500ml 4-necked round bottom flask fitted with a mechanical stirrer and a reflux
condenser, 6-acetyl-4,4-dimethylthio-chroman (22g) and dimethylformamide (38ml) are added at
a temperature in the range of from about 35°C to about 95°C under stirring. The reaction
mixture is then cooled to a temperature in the range of from about -5°C to about 0°C.
Phosphorus oxychloride (17.2g) is added to the reaction mixture dropwise over about 30
minutes. Following the addition of the phosphorous oxychloride, the reaction mixture is
maintained at a temperature in the range of from about 10°C to about 15°C for about 8 hours to


about 10 hours. After completion of the reaction as determined by TLC, the reaction mixture is added to cold water (100ml) at a temperature of from about 0°C to about 5°C containing sodium acetate (25g). The aqueous layer is extracted with dichloromethane (200ml x 3). The organic layer is washed with demineralized water (100ml x 3) until it becomes neutral.
The dichloromethane layer is concentrated on a rotavapor bath at a temperature in the range of from about 25°C to about 30°C under plant vacuum until no more drops are observed. The resulting residual oil is purified by flash chromatography with petroleum ether and ethyl acetate (9:1 mixture) resulting in a pale yellow oil, weighing 22g, yield of 82%, purity of 98% (HPLC). The IR (neat) shows the following stretching 2900cm"1 (C-H str), 2750cm"1 (C-H str), 1690cm"1 (-C=0 str), 1620cm"1 (-C=C-str), 760 cm"1 (-C=C-C1 str). The 1H-NMR (CDC13) using TMS as internal standard shows the following signals at 8 1.35 (6H,s) 1.92-1.98 (2H,m), 3.02-3.08 (2H,m), 5.5 (lH,s), 7.13 (lH,d 8.6 Hz), 7.58 (lH,dd,J 8.6Hz,2H), 7.99 (lH,d,J 2 Hz), 8.9 (s,lH). The CI mass shows m/z 266 (M+).
Preparation of 4,4-dimethyl-6-ethynylthiochroman
In a 250 ml 4-necked round bottom flask fitted with a mechanical stirrer and reflux condenser, water (41.3ml) and sodium hydroxide (5.22g, 0.1305M) are added and heated to a temperature in the range of from 80°C to 90°C. The reaction mixture is stirred, and a solution of 3-[4,4-dimethylthiochroman-6-yl]-3-chloro-2-propene-l-al (3.0gm, 0.0113 M) is added dropwise in 1,4-dioxane (52.2ml) under vigorous stirring. The reaction mixture is maintained at a temperature in the range of from 80°C to 90°C for 2 hours. After completion of the reaction as determined by TLC, the solvents are distilled off and the product is extracted with ether (15ml x 3). The ether layer is washed with brine (15ml x 3). The organic layer is dried over sodium sulfate, and the solvent is distilled off to get an oily residue. The resulting crude oil is distilled under high vacuum and the vapors are collected at a temperature of about 126°C/0.2mm as the main product. The main fraction appears as red viscous oil, which upon standing crystallized. Net wt 2.00 g, yield of 87.68%; m.p. in the range of from 69°C to 72°C, purity of 98% (HPLC). The IR (neat) shows the following absorptions: 3200 cm"1 (C-H-str), 2950 cm"1 (-C=C-H str), 2100 cm"1 (-C=C-). The 1H-NMR (CDC13), TMS as internal standard shows the following signals 8 1.35 (6H,s), 1.92-1.98 (2H,m), 3.02-3.08 (3H,m), 7.13 (lH,d 8.6 Hz), 7.58 (lH,dd,J 8.6Hz,2Hz), 7.99 (lH,d,J 2Hz). The CI/MS shows m/z 202 (M+).

EXAMPLE 2 Preparation of phenyl-3-methylbut-2-enyl sulfide
In a 5L 4-neck round bottom flask, methanol (1400 ml) and thiophenol (200 g) were added under stirring at a temperature ranging from about 25°C to about 35oC. Sodium hydroxide (powder LR grade) (73.60 g) and methanol (100ml) were added under stirring. The reaction mixture was left under a nitrogen atmosphere and stirred at room temperature (about 25°C to about 30°C) for an hour, l-bromo-3-methyl-2-butene (274 gm) was added to the reaction mixture and it was observed that the temperature rose to about 40°C. The reaction mixture was heated to reflux and maintained for about 12 hours. After completion of the reaction as determined by HPLC, the methanol was distilled out from reaction mixture under vacuum at a temperature below 60°C. Ethylene dichloride (1500 ml) and water (1000 ml) were added to the residue. The organic layer was separated and washed with a 5% sodium hydroxide (600 ml) solution, and then water (3 x 600 ml) until the pH was about 7. The organic layer was then washed with a brine solution (700 ml). The ethylene dichloride was distilled out until the moisture content was less than 0.1%.
Preparation of 4,4-dimethylthiochroman
In a 5L 4-neck round bottom flask, ethylene dichloride (1500 ml) was added to the phenyl-3-methylbut-2-enyl sulfide from the previous step. Phosphorous pentoxide (200 gm) was added to the reaction mixture at a temperature ranging from about 25°C to about 35°C under stirring. Ortho phosphoric acid (174 ml) was added carefully under nitrogen. The reaction mixture was heated to reflux, a temperature of about 80°C to about 90°C and maintained at that temperature for about 12 hours. After completion of the reaction as determined by HPLC, the reaction mass was cooled to a temperature ranging from about 25°C to about 35°C and water (2000 ml) was slowly added to the reaction mass. The organic layer was separated, and the aqueous layer was extracted with EDC (2L x 2). The organic layers were combined and washed with saturated sodium bicarbonate solution (2L x 2) and water (1.5L x 2) until the pH was about 7. This was followed by a washing with a brine solution (1.5L). The EDC layer was distilled out under reduced pressure below a temperature of about 70°C until the moisture content was less than 0.1%. EDC (2L) was added to the residue and taken for the next step without further purification
Preparation of 4,4-dimethyl-6-acetylthiochroman


In a 5L 4-neck round bottom flask, EDC (2L) was added to the 4,4-dimethylthiochroman from the previous step. The contents were stirred and cooled to a temperature of about -10°C. Aluminum chloride (252 g) was slowly added to the reaction mixture. Acetyl chloride (152.7 g) was added at a temperature ranging from about -10°C to about -5°C over about 1.5 hours. After the addition, the reaction mixture was maintained at a temperature ranging from about -5°C to about 0°C for about 2 hours. The reaction was monitored by TLC. [If the reaction is incomplete as determined by TLC, bring the reaction mixture to a temperature ranging from about 25°C to about 35°C under stirring for about 4 hours.] The reaction mixture was quenched with ice (4.87 kg) and hydrochloric acid (1.63L), and the reaction mass was stirred for about 30 minutes. EDC (2.5L) was added to the reaction mass. The layers were separated. The aqueous layer was extracted with MDC (2 x 2L). The organic layers were combined and washed with 5% sodium bicarbonate solution (2 x 2L) and water (2 x 2L) until the pH is about 7. This was followed by a washing with brine (1.5L). The EDC and MDC layer were distilled out under reduced pressure until the moisture content was less than about 0.1%. There was a residual volume of about 3L.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.
/'


WE CLAIM:
1. A process for the preparation of 4,4-dimethyl-6-ethynylthiochroman comprising:
(a) reacting 4,4-dimethyl-6-acetylthiochroman and an acid chloride in a solvent to form a
|3-chloro vinylaldehyde intermediate, at a temperature range of -10°C to 35°C; and
(b) reacting the P-chloro vinylaldehyde intermediate with an alkali metal hydroxide in a
solvent to form the 4,4-dimethyl-6-ethynylthiochroman, at a temperature range of 20°C to
90°C.
2. The process of claim 1, wherein the acid chloride is selected from the group consisting
of phosphorous oxychloride, thionyl chloride, phosgene and oxalyl chloride.
3. The process of claim 1, wherein the solvent used in step (a) is selected from the group consisting of formamide solvents; and chlorinated alkane solvents.
4. The process of claim 3, wherein the formamide solvents are selected from the group consisting of dimethyl formamide, N-methyl formanilide, N-formyl piperidine, N-formyl morpholine, dimethyl acetamide, N-methyl pyrrolidone and N,N-dimethyl benzamide.
5. The process of claim 1, wherein the alkali metal hydroxide is selected from the group consisting of potassium hydroxide and sodium hydroxide.
6. The process of claim 1, wherein the step (b) is carried out in solvent selected from water, dialkyl ether, dioxane, tetrahydrofuran and pyran.
7. The process of claim 6, wherein the solvent is preferably tetrahydrofuran. Dated this fifteenth (15th) day of September, 2005



Documents:

685-mum-2003-cancelled pages(11-01-2005).pdf

685-mum-2003-claims(granted)-(11-01-2005).doc

685-mum-2003-claims(granted)-(11-01-2005).pdf

685-mum-2003-correspondence(15-09-2005).pdf

685-mum-2003-correspondence(ipo)-(05-09-2005).pdf

685-mum-2003-form 1(07-04-2003).pdf

685-mum-2003-form 19(22-06-2004).pdf

685-mum-2003-form 2(granted)-(11-01-2005).doc

685-mum-2003-form 2(granted)-(11-01-2005).pdf

685-mum-2003-form 3(02-02-2005).pdf

685-mum-2003-form 3(09-08-2004).pdf

685-mum-2003-form 3(22-07-2005).pdf

685-mum-2003-form 5(22-06-2004).pdf


Patent Number 206342
Indian Patent Application Number 685/MUM/2003
PG Journal Number 28/2007
Publication Date 13-Jul-2007
Grant Date 25-Apr-2007
Date of Filing 07-Apr-2003
Name of Patentee GLENMARK PHARMACEUTICALS LIMITED
Applicant Address B/2, MAHALAXMI CHAMBERS, 22, BHULABHAI DESAI ROAD, POST BOX NO. 26511, MUMBAI,
Inventors:
# Inventor's Name Inventor's Address
1 BOBBA VENKTA SIVA KUMAR GLENMARK PHARMACEUTICALS LIMITED, B/2, MAHALAXMI CHAMBERS, 22, BHULABHAI DESAI ROAD, POST BOX NO. 26511, MUMBAI-400 026,
2 VISHVAS DATTATRAYA PATIL GLENMARK PHARMACEUTICALS LIMITED, B/2, MAHALAXMI CHAMBERS, 22, BHULABHAI DESAI ROAD, POST BOX NO. 26511, MUMBAI-400 026,
3 CHANGDEV NAMDEV RAUT GLENMARK PHARMACEUTICALS LIMITED, B/2, MAHALAXMI CHAMBERS, 22, BHULABHAI DESAI ROAD, POST BOX NO. 26511, MUMBAI-400 026,
4 SHEKHAR BHASKAR BHIRUD GLENMARK PHARMACEUTICALS LIMITED, B/2, MAHALAXMI CHAMBERS, 22, BHULABHAI DESAI ROAD, POST BOX NO. 26511, MUMBAI-400 026,
5 BATCHU CHANDRASEKHAR GLENMARK PHARMACEUTICALS LIMITED, B/2, MAHALAXMI CHAMBERS, 22, BHULABHAI DESAI ROAD, POST BOX NO. 26511, MUMBAI-400 026,
PCT International Classification Number C07D 335/06
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA