DESC:FIELD
The present disclosure relates to a process for the synthesis of benzothiazoles.
BACKGROUND
Benzothiazoles, represented by Formula I are fused member rings, which contain heterocycles bearing thiazole.

Benzothiazoles are thermally stable electron withdrawing moieties and are weak bases, having multiple applications in the industry such as in dyes, bioorganic, medicinal chemistry and drug discovery. They also find application as anti-oxidants and vulcanization accelerators. Benzothiazole moieties are part of compounds showing significant biological activities, for use as an antimicrobial, anticancer, anthelmintic, and anti-diabetic.
Substituted benzothiazoles are known to possess antimicrobial activity. Previously known processes for the synthesis of substituted benzothiazoles are multiple step processes with harsh reaction conditions. Benzothiazoles obtained from the conventional processes possess low yield and low purity.
Thus, there is felt a need to provide a simple and efficient process for the synthesis of benzothiazoles having comparatively high yield and high purity.
OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:
It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
An object of the present disclosure is to provide a process for the synthesis of benzothiazole.
Another object of the present disclosure is to provide benzothiazoles with comparatively high yield.
Still another object of the present disclosure is to provide benzothiazoles with comparatively high purity.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY:
The present disclosure relates to a process for synthesizing benzothiazole. The process comprises reacting N-arylthiourea and at least one fluid medium in the presence of at least one catalyst under stirring to obtain a first reaction mixture. The so obtained first reaction mixture undergoes chlorination by reacting it with a first chlorinating agent at a first predetermined temperature for a first predetermined time period under stirring to obtain a second reaction mixture. The second reaction mixture is heated to a second predetermined temperature and reacted with at least one second chlorinating agent at the second predetermined temperature for a second predetermined time period under stirring to obtain a third reaction mixture. To the third reaction mixture, water is added under stirring to obtain a biphasic system comprising an organic layer and an aqueous layer. The so obtained biphasic system is allowed to settle and the aqueous layer is separated from the organic layer. The separated aqueous layer is further treated with an alkaline solution under stirring while maintaining the pH in the range of 7 to 12 to obtain a precipitate. The so obtained precipitate is separated by filtration followed by washing it with water and drying to obtain the benzothiazole.
DETAILED DESCRIPTION
Conventional processes for the synthesis of benzothiazoles are associated with drawbacks such as low yield and low purity. The present disclosure envisages a process for the synthesis of benzothiazoles having high yield and high purity from N-arylthiourea.
The present disclosure provides a two stage chlorination process for the synthesis of benzothiazoles. The process comprises chlorination of N-arylthiourea with a first chlorinating agent in the presence of at least one catalyst, followed by controlled chlorination with at least one second chlorinating agent, and cyclization thereafter. The process of controlled chlorination with the second chlorinating agent prevents the formation of chlorinated impurities and results in comparatively high purity benzothiazole.
The process is hereinafter described in detail:
In a first step, a reaction vessel is charged with N-arylthiourea, at least one fluid medium and at least one catalyst while stirring to obtain a first reaction mixture. In the present disclosure N-arylthiourea can be at least one selected from the group consisting of N-phenylthiourea and derivatives thereof. In accordance with the embodiments of the present disclosure, the N-phenylthiourea can be 4-methoxyphenylthiourea, 4-methylphenylthiourea, and 3,4-dichlorophenylthiourea.
The fluid medium can be at least one selected from a group consisting of methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, trichloroethylene, tetrachloroethylene, chlorobenzene and ortho-dichlorobenzene. In an exemplary embodiment the fluid medium is ethylene chloride.
The ratio of the amount of N-arylthiourea to the amount of the fluid medium can be in the range of 1:1 to 1:12. In an exemplary embodiment the ratio of the amount of N-arylthiourea to the amount of the fluid medium is 1:5.1.
The catalyst can be at least one selected from a group consisting of bromine and iodine, typically bromine. The molar ratio of the amount of N-arylthiourea to the catalyst can be in the range of 1:0.01 to 1:1, typically 1:0.1.
In a second step, the so obtained first reaction mixture is chlorinated by reacting the first reaction reaction mixture with a first chlorinating agent at a first pre-determined temperature for a first pre-determined time period to obtain a second reaction mixture.
The first chlorinating agent can be chlorine gas. The molar ratio of N-arylthiourea to the first chlorinating agent can be in the range of 1:0.1 to 1:4, typically 1:1.24.
The first pre-determined temperature can be in the range of 10 °C to 30 °C, typically 20 °C. The first pre-determined time period can be in the range of 15 minutes to 50 minutes, typically 30 minutes.
In a third step, the so obtained second reaction mixture is further heated to a second pre-determined temperature followed by the addition of at least one second chlorinating agent at the second predetermined temperature in a second predetermined time period to obtain a third reaction mixture. The step of chlorination using at least one second chlorinating agent is a controlled chlorination reaction, because the second chlorination is carried out at lower temperature. It is observed that, if the second chlorination is carried out at high temperature, chlorinated impurities are generated in high amount.
The second chlorinating agent can be at least one selected from the group consisting of disulfur dichloride, thionyl chloride and sulfuryl chloride, typically sulfuryl chloride. The molar ratio of N-arylthiourea to the second chlorinating agent can be in the range of 1:0.1 to 1:4, typically 1:1. The second pre-determined temperature can be in the range of 35 °C to 70 °C, typically 55 °C. The second pre-determined time period can be in the range of 4 hours to 5 hours.
In the fourth step, water is added to the so obtained third reaction mixture while stirring at a third pre-determined temperature to obtain a biphasic mixture of two immiscible layers. The biphasic mixture comprises an organic solvent layer and an aqueous layer. The molar ratio of water to the second chlorinating agent can be in the range of 1:0.01 to 1:0.15, typically 1:0.07. The third pre-determined temperature can be in the range of 20 °C to 60 °C, typically 40 °C.
The so obtained biphasic mixture of two immiscible layers is allowed to settle and the aqueous layer is separated from the organic layer. The organic solvent layer is discarded and the separated aqueous layer is used in the fifth step of the process of the present disclosure.
In the fifth step, an alkaline solution is added to the aqueous layer obtained in the fourth step under stirring while maintaining the pH in the range of 7.0 to 12.0 to obtain a precipitate containing benzothiazole. In the present disclosure, the alkaline solution can be at least one selected from the group consisting of sodium hydroxide solution, potassium hydroxide solution, calcium hydroxide solution, magnesium hydroxide solution, and ammonia solution, typically ammonia solution. In an exemplary embodiment, the concentration of the ammonia solution can be in the range of 5 % to 20 %, typically 11.5 %.
The so obtained precipitate is filtered, washed with water, and dried to obtain benzothiazole.
In one embodiment, the benzothiazole can be methoxy substituted benzothiazole. In one embodiment of the present disclosure, the benzothiazole can be 6-Methoxy-2-Aminobenzothiazole.
In accordance with the embodiments of the present disclosure, the yield of benzothiazole can be greater than 85.0 %.
In accordance with the embodiments of the present disclosure, the purity of benzothiazole can be greater than 85 % and can be 99 %. The purity of benzothiazole can be determined by high pressure liquid chromatography (HPLC).
The benzothiazole obtained by the process of the present disclosure is free of chlorinated impurities. In the present disclosure, the formation of chlorinated impurities such as 5-chloro-6-methoxy-2-aminobenzothiazole, 7-chloro-6-methoxy-2-aminobenzothiazole and 5,7-dichloro-6-methoxy-2-aminobenzothiazole are prevented by controlling two factors, namely, the temperature of the reaction, especially the second predetermined temperature of the reaction and the addition of the second chlorinating agent. These two factors assist in obtaining benzothiazole of high purity.
The present disclosure is further described in light of the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to industrial scale.
Experimental details:
Experiment 1: Synthesis of 6-Methoxy-2-Aminobenzothiazole in accordance with the process of the present disclosure (represented by Formula II):
The 6-Methoxy-2-Aminobenzothiazole represented by Formula II was prepared by chlorination of 4-methoxyphenylthiourea represented by Formula III with chlorine (first chlorinating agent) in the presence of catalytic amounts of bromine, followed by controlled chlorination with sulfuryl chloride, (second chlorinating agent) and cyclization thereafter.

A reaction vessel was charged with 4-methoxyphenylthiourea represented by Formula III (100 grams), ethylene dichloride (EDC) (510 ml) and bromine (4.34 grams) while stirring to obtain a first reaction mixture. Chlorine gas (24 grams) was passed through the first reaction mixture at a temperature of 20 °C for a time period of 32 minutes to obtain a second reaction mixture. The second reaction mixture was then heated at a temperature of 55 °C, followed by addition of sulfuryl chloride (74 grams) for a time period of 4 hours to obtain a third reaction mixture. Further, water (0.7 liters) was added to the third reaction mixture whilst stirring at a temperature of 40 °C for a time period of 30 minutes to obtain a mixture of two immiscible layers containing an ethylene dichloride layer and an aqueous layer. The mixture of two immiscible layers was then allowed to settle to form two separate layers. The two immiscible layers were decanted and the ethylene dichloride layer was discarded. A precipitate containing 6-Methoxy-2-Aminobenzothiazole was obtained by adding ammonia solution (11.5 %) to the aqueous layer under stirring while maintaining the pH at 9.0. The precipitate containing 6-Methoxy-2-Aminobenzothiazole was filtered, washed with water, and dried at room temperature to obtain 6-Methoxy-2-Aminobenzothiazole represented by Formula II.
Experiments 2-5: Synthesis of 6-Methoxy-2-Aminobenzothiazole
Similar experiments, as described in experiment 1, were carried out by varying the amount of catalyst (bromine), the fluid medium, the amount of chlorine passed, and the amount of sulfuryl chloride. Experiments were also carried out in the absence of the catalyst, or the first chlorinating agent or the second chlorinating agent.
The results for experiments 1-5 are summarized in Table 1 below:

Table 1
Sr. No Starting material (100 gm) Fluid medium
(510 ml) Catalyst-Bromine at
25 oC First chlorinating agent:
Chlorine gas at
25 oC Second chlorinating agent: Sulfuryl chloride at 55oC Product
6-Methoxy-2-Aminobenzothiazole
1 4-methoxyphenyl thiourea Ethylene dichloride (EDC) 4.34 gm 24 gm 74 gm 91.5 g. of Product yield with 99% purity Mpt 166 oC;
No chlorinated impurities
2 4-methoxyphenyl thiourea Ethylene dichloride (EDC) 5.4 gm 48 gm -------- 10% unreacted starting material and 15-20% chlorinated impurities.
78 g of product with Mpt 152-153 oC
3 4-methoxyphenyl thiourea Ethylene dichloride (EDC) 4.34 gm 48 gm -------- 5% unreacted starting material and 20-25% chlorinated impurities.
82 g of product with Mpt 142-152 oC
4 4-methoxyphenyl thiourea Ortho-dichloro benzene (ODCB) 4.34 gm 24 gm 70 gm 2.5 % chlorinated impurities.
89 g of product with purity 97.5 %
Mpt 164 oC
5 4-methoxyphenyl thiourea Ethylene dichloride (EDC) ……… ……… 100 gm No chlorinated product
83 g of product with purity 98.8 %
Mpt 165-167 oC

It was found that the yield and purity of 6-Methoxy-2-Aminobenzothiazole obtained by the process of the present disclosure (Experiment 1) were 91.5 g and 99.0 % respectively. The melting point of 6-Methoxy-2-Aminobenzothiazole was found to be 166 °C.
It is also observed that, if the second chlorination is avoided in the process of preparation of 6-Methoxy-2-Aminobenzothiazole (Experiments 2 and 3), chlorinated impurities are generated in high amount. Further, if the reaction is carried out using ODCB (ortho-dichloro benzene) as a fluid medium, generation of chlorinated impurities is observed (Experiment 4). Still further, if the reaction is carried out using an excess amount of sulfuryl chloride (in the absence of the first chlorinating agent), less yield of the product is observed (Experiment 5).

The 6-Methoxy-2-Aminobenzothiazole obtained by the process of the present disclosure is found to be free of chlorinated impurities and can be used for preparing dyes.
TECHNICAL ADVANCEMENTS
The present disclosure described herein above has several technical advantages including, but not limited to, the realization of a process for the synthesis of benzothiazoles with comparatively;
• high yield; and
• high purity.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.
The numerical values given for various physical parameters, dimensions, and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary.
While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.\ ,CLAIMS:1. A process for synthesizing benzothiazole, said process comprising:
a. admixing N-arylthiourea and at least one fluid medium in the presence of at least one catalyst under stirring to obtain a first reaction mixture;
b. chlorinating said first reaction mixture by reacting it with a first chlorinating agent at a first predetermined temperature for a first predetermined time period under stirring to obtain a second reaction mixture;
c. heating said second reaction mixture at a second predetermined temperature followed by reacting it with at least one second chlorinating agent at the second predetermined temperature for a second predetermined time period under stirring to obtain a third reaction mixture;
d. adding water to said third reaction mixture at a third predetermined temperature under stirring to obtain a biphasic system comprising an organic layer and an aqueous layer;
e. separating said aqueous layer and adding an alkaline solution to said aqueous layer under stirring while maintaining the pH in the range of 7 to 12 to obtain a precipitate; and
f. filtering said precipitate followed by washing it with water and drying to obtain the benzothiazole.
2. The process as claimed in claim 1, wherein N-arylthiourea is at least one selected from the group consisting of N-phenylthiourea, 4-methyphenylthiourea, 4-methoxy phenylthiourea, and 3,4-dichlorophenylthiouera.
3. The process as claimed in claim 1, wherein the fluid medium is at least one selected from the group consisting of methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, trichloroethylene, tetrachloroethylene, chlorobenezene and ortho-dichlorobenzene; and the molar ratio of the amount of N-arylthiourea to the amount of fluid medium is in the range of 1:1 to 1:12.
4. The process as claimed in claim 1, wherein the catalyst is at least one selected from the group consisting of bromine and iodine; and the molar ratio of the amount of N-arylthiourea to the amount of catalyst is in the range of 1:0.01 to 1:1.
5. The process as claimed in claim 1, wherein the first chlorinating agent is chlorine gas and the second chlorinating agent is at least one selected from the group consisting of disulfur dichloride, thionyl chloride, and sulfuryl chloride.
6. The process as claimed in claim 1, wherein the molar ratio of the amount of N-arylthiourea to the amount of first chlorinating agent and the molar ratio of the amount of N-arylthiourea to the amount of second chlorinating agent is independently in the range of 1:0.1 to 1:4
7. The process as claimed in claim 1, wherein the first predetermined temperature is in the range of 10 oC to 30 oC, the second predetermined temperature is in the range of 35 oC to 70 oC and the third predetermined temperature is in the range of 20 oC to 60 oC.
8. The process as claimed in claim 1, wherein the first predetermined time period is in the range of 15 minutes to 50 minutes and the second predetermined time period is in the range of 4 hours to 5 hours.
9. The process as claimed in claim 1, wherein the alkaline solution is at least one selected from the group consisting of sodium hydroxide solution, potassium hydroxide solution, calcium hydroxide solution, magnesium hydroxide solution, and ammonia solution.
10. The process as claimed in claim 1, wherein the benzothiazole has a purity of at least 85%