WO2002020498A2

WO2002020498A2 - An improved process for the preparation of 3,4-dihydro-1,4-benzothiazine

Info

Publication number: WO2002020498A2
Application number: PCT/IB2001/001615
Authority: WO
Inventors: Chandrasekhar Batchu; Om Reddy Gaddam; Rabin Bera
Original assignee: Dr Reddys Research Foundation
Current assignee: Dr Reddys Research Foundation
Priority date: 2000-09-04
Filing date: 2001-09-03
Publication date: 2002-03-14
Anticipated expiration: 2003-03-04
Also published as: WO2002020498A3; AU2001282403A1

Abstract

A process for the preparation of 3,4-dihydro-1,4-benozthiazine of the formula (1) which comprises, condensing of 2-aminothiophenol with dihaloethane of formula (11) wherein X represents halogen atom in presence of organic base and relatively non polar solvent at a temperature in the range of 40-80 °C followed by cyclization and formation of organic salt as by product and isolating the compound of formula (1) by conventional methods.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF 3,4-DIHYDRO-

1,4-BENZOTHIAZLNE

Field of the invention

The present invention relates to an improved process for the preparation of 3,4-dihydro-l,4-benzothiazine of the formula (1).

The first synthesis of dihydrobenzothiazine was reported by Gulvenor (CA.

43, 7420 e) in the year 1949. After its first report however, the chemistry of the benzothiazine laid dormant for nearly half a century. Only during the last 5 years this class of compounds have aroused renewed interest, as evidenced by the discovery of a biologically active novel antidiabetic compounds.

3,4-Dihydro-l,4-benzothiazine of the formula (1) is an important intermediate / starting material for the preparation of [3,4-dihydro-l,4-benzothiazin- 4-yl]ethylmethane sulphonate of the formula (2) which in turn is a starting material for the preparation of several pharmaceutically active substances.

The classical method for preparation of 3,4-dihydro-l,4-benzothiazine, based upon Gulvenor (J. Chem. Soc, 278, 1949) synthesis of dihydrobenzothiazines is reaction of o-aminothiophenol (3) with ethylene oxide (4) in ethanol and potassium hydroxide under reflux conditions. The reaction is shown in Scheme- 1 below:

Scheme-1

Raffaello and Giuseppe (Gazz. Chim. ital. 81, 735, 1951) has described another method for the preparation of dihydrobenzothiazine from 2- mercaptoethanol of the formula (6) and o-chloronitrobenzene of the formula (5) using sodium and ethanol to form 2-nitrophenyl mercaptoethanol of the formula (7), which was cyclised under Nascent hydrogen evaluation generated by Tin and HC1. The reaction is shown in Scheme-2 below:

τΛ^s

(5) (6) (7) C¹)

Scheme-2

Cymerman-Craia & Rogers (Australian J. Chem. 8, 252, 1955) has reported the synthesis of 3,4-dihydro-l,4-benzothiazine of the formula (1) and a number of substituted diphenylamines, phenothiazine and phenoselenezines for testing antihelmintic properties by a process which involves : i). reducing o-nitrophenyl disulftde of the formula (8) with H S to give o- aminophenyldisulfide of the formula (9) which on further reduction with lithium aluminium hydride (LAH) yields o-aminothiophenol of the formula (3). ii). condensation of o-aminothiophenol of the formula (3) with bromoacetic acid gave- 3,4-dihydro-3-oxo-l,4-benzothiazine of the formula (10) which on refluxing with LAH in Et₂O yields 3,4-dihydro-l,4-benzothiazine of the formula (1). The reaction is shown in Scheme-3 below:

(11)

Scheme-3

Watanabe, Masanovi [(JP 02,264,768 (1990)] have reported the synthesis of

3,4-dihydro-l,4-benzothizne (1) by reacting 2-aminothiophenol (3) with 1,2- dihalogenated ethane (11) in an alcoholic solvent in presence of alkali metal carbonate and alkali metal iodide by single step cyclization. The reaction is shown in Scheme-4 below:

Scheme-4

The following disadvantages have been observed during the scale up of the above process for the preparation of the compound of the formula (1). 1. The above processes for the preparation of 3,4-dihydro-l,4-benzothiazine are very tedious and laborious.

2. The preparation starting from o-nitrothiophenol or its corresponding dimer involves use of toxic gases such as H₂S.

3. • The reduction process either by metal / HC1, which generates lot of effluents or by pyrophoric reagents such as LAH, is difficult to scale up.

4. The formation of high amounts of dimer 2-aminophenyl disulfide in protic media such as alcohol with hard bases like sodium carbonate resulting in low yield of the desired product.

5. Ether was used for both reaction and extraction, which is a low boiling, highly inflammable solvent and has a poor recovery for recycling. For all practical commercial purposes it is no more used.

The present invention is based on our finding that the condensation of 2- aminothiophenol in polar protic solvent such as methanol, ethanol, isopropanol did not occur as this has favored the dimerization process. Similarly, the condensation of 2-aminothiophenol in polar aprotic solvents such as dimethyl formamide (DMF), N-methyl pyrrolidine (NMP) did not occur as this also favored the dimerization process. Temperatures more than 80 °C and lower than 40 °C also affects the reaction and facilitates the dimerization process.

Given the importance for the development of a simple, efficient and commercially practicable process for the preparation of the compound of the formula (1), we directed our research towards the development of ai r improved process for the preparation of 3,4-dihydro-l,4-benozthiazine of formula (1).

Accordingly, the main objective of the present invention is to provide an improved process for the preparation of 3,4-dihydro-l,4-benozthiazine of the formula (1).

According to a process of the present invention the compound of formula (1)

is prepared by a process which comprises : i). condensation of 2-aminothiophenol (3)

with dihaloethane of formula (11)

wherein X represents halogen atom such as chlorine, bromine, idoine or fluorine in presence of organic base and relatively non polar solvent at a temperature in the range of 40-80 °C followed by cyclization and formation of organic salt as by product and ii). isolating the compound of formula (1) by conventional methods.

This reaction is assumed to proceed through an intermediate uncyclized 2- aminophenyl-2-haloethyl sulfϊde. The reaction is solvent and temperature specific. The organic bases used for condensation are selected from diisopropylamine (DIP A), triethylamine, tributylamine, and the like. The non-polar solvent such as ethyl acetate, isopropyl acetate, butyl acetate, DMF and the like are used.

The amounts of 2-aminothiophenol and ethyl acetate or DMF used are very specific. A ratio of 1 : 4 is used. Further increase in solvent volume may slow down the reaction rate.

Preferred ratio of 2-aminothiphenol and triethylamine is 1 : 1.5 - 1.75. Any further decrease in the ratio affects the yield of the product and dimerization may take place.

The mode of addition of base to the substrate is also very important as this may lead to dimerization of the 2-aminothiophenol. The preferred way of performing the reaction is addition of triethylamine to a mixture of 2- aminothiophenol and 1,2-dibromoethane in ethylacetate.

Ethyl acetate and DMF are found to be most suitable solvents for condensation as these gave better results in terms of yields. These solvents not only addresses the problem of dimerization of the 2-aminothiophenol but also compatible with the triethylamine and ecofriendly solvents.

The work up involves direct filtration of the organic salt by-product and thus circumventing the tedious work up such as quenching of LAH and extraction of aqueous solution with solvents.

The details of the process of the present invention is described in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example - 1

Preparation of 3,4-dihydro-l,4-benzothiazine

2- Aminothiophenol (500 g), 1,2-dibromoethane (902 g, ~ 414 ml) and ethyl acetate (2 L) were taken in a 5 L 4 necked round bottom flask fitted with a mechanical stirrer, reflux condenser. The reaction mixture was slowly heated to a temperature of 55 to 65 °C under stirring and triethylamine (707 g ~968 ml) was added under nitrogen atmosphere dropwise in about 2-3 hours. As reaction progresses, the precipitation of triethylamine hydrobromide salt increases and maintained gentle reflux temperature for 10-12 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and ethyl acetate (1 L) was added for dilution of the reaction mass and ease of filtration. The precipitated solid triethylamine hydrobromide was separated by filtration. The ethyl acetate layer was washed with water (3 x 2 L), dried over Na₂SO₄ and concentrated on rotavapour water bath at 60-70 °C under reduced pressure. The residual crude oil was distilled under high vacuum to yield the 3,4- dihydro-l,4-benzothiazine of the formula (1) appeared as pale yellow liquid, (weight 400 g, yield 66 %, b.p (1.5 mm) 144 °C, m.p. 38 °C, purity 96-97 % by HPLC).

Example - 2

Preparation of 3,4-dihydro-l,4-benzothiazine

2-Aminothiophenol (50 g), 1,2-dichloroethane (47.5 g, ~ 38 ml) and DMF (200 ml) were taken in a 500 ml 4 necked round bottom flask fitted with a mechanical stirrer and reflux condenser. The reaction mixture was slowly heated to a temperature of 55 to 65 °C under stirring and triethylamine (70.7 g, -96.8 ml) was added under nitrogen atmosphere dropwise in about 2-3 hours. As reaction progresses, the precipitation of triethylamine hydrochloride salt increases and maintained gentle reflux temperature for 10-12 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and ethyl acetate (1 L) was added for dilution of the reaction mass and ease of filtration. The precipitated solid triethylamine hydrochloride was separated by filtration. The ethyl acetate layer was washed with water (3 x 200 ml), dried over Na₂SO₄ and concentrated on rotavapour water bath at 60-70 °C under reduced pressure. The residual dark orange colored crude oil was distilled under high vacuum to yield the 3,4-dihydro-l,4-benzothiazine appeared as pale yellow liquid, (weight 24 g, yield 40 %, b.p (1.5 mm) 144 °C, m.p. 38 °C, purity 96 % by HPLC).

Example - 3

Preparation of 3,4-dihydro-l,4-benzothiazine

2-Aminothiophenol (50 g), l-bromo-2-chloroethane (68.6 g, ~ 40 ml) and DMF (200 ml) were taken in a 500 ml 4 necked round bottom flask fitted with a mechanical stirrer and reflux condenser. The reaction mixture was slowly heated to a temperature of 55 to 65 °C under stirring and triethylamine (70.7 g, 96.8 ml) was added under nitrogen atmosphere dropwise in about 2-3 hours. As reaction progresses, the precipitation of triethylamine salt increases and maintained gentle reflux temperature for 10-12 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and ethyl acetate (1 L) was added for dilution of the reaction mass and ease of filtration. The precipitated solid triethylamine salt was separated by filtration. The ethyl acetate layer was washed with water (3 x 200 ml), dried over Na₂SO₄ and concentrated on rotavapour water bath at 60-70 °C under reduced pressure. The residual dark orange colored crude oil was distilled under high vacuum to yield the 3,4-dihydro-l,4-benzothiazine appeared as pale yellow liquid, (weight 30 g, yield 50 %, b.p (1.5 mm) 144 °C, m.p. 38 °C, purity 96 % by HPLC). The following are the advantages of the present invention :

1. A convenient synthesis of the compound of the formula (1) has been developed without extraction.

2. The process is very simple and efficient with safe operation.

3. The use of ethyl acetate as medium has addressed the problem of dimerization of the 2-aminothiophenol, thus improving the overall yield and purity of the product.

Claims

Claims : l.A process for the preparation of 3,4-dihydro-l,4-benozthiazine of the formula (1).

which comprises, i). condensing the 2-aminothiophenol of the formula (3)

with dihaloethane of formula (11)

wherein X represents halogen atom in the presence of organic base and relatively non polar solvents at a temperature in the range of 40-80 °C followed by cyclization and formation of organic salt as by product and ii). isolating the compound of formula (1) by conventional methods.

2. The process as claimed in claim 1, wherein the organic base used for condensation is selected from diisopropylamine, triethylamine or tributylamine.

3. The process as claimed in claims 1 and 2, wherein the non-polar solvent used is selected from ethyl acetate, isopropyl acetate, butyl acetate or DMF.

4. The process as claimed in claims 1 to 3, wherein the amount of 2- aminothiophenol and ethyl acetate or DMF used is in the ratio of 1 : 4.

5. The process as claimed in claims 1 to 4, wherein the amount of 2- aminothiphenol and triethylamine used is in the ration of 1 : 1.5 - 1.75.

6. The process for the preparation of 3,4-dihydro-l,4-benozthiazine of the formula (1) substantially as herein described with reference to the examples.