DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10; rule 13)

“INDUSTRIAL METHOD FOR PRODUCING 2-BUTYL-1,2-BENZISOTHIAZOL-3-ONE”

Hikal Limited, an Indian Company of 3A & 3B, International Biotech Park, Hinjewadi, Pune – 411 057, India

The following specification describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to an industrial method for the preparation of 2-Butyl-1,2-benzisothiazol-3-one of formula (I) in an environment friendly and commercially viable manner with high yield and high chemical purity.

BACKGROUND OF THE INVENTION
2-Butyl-1,2-benzisothiazol-3-one (BBIT) is a derivates of Benzisothiazolinone (BIT) which belongs to the class of isothiazolinones used as a biocide. It is used as a biocide in the European Economic Area and Switzerland for material preservation such as films, fibers, leather, rubber, or polymers, construction materials, cutting fluids.

The derivative of Benzisothiazolinone is first disclosed in U.S. Pat No.4,093,730 as spermicidal vaginal compositions comprising the derivatives of 1,2-benzisothiazole.

The Chinese publication no. CN102807532A described the preparation of 2-Butyl-1,2-benzisothiazol-3-one by forming sodium or potassium salt of BIT and then reacting with bromobutane. The drawback of this method is that N-alkylation does not proceed with good yield and purity.

The U.S. Pat. No. 4,871,754 describes that N-substituted 1,2-benzothiazoline-3-ones can be prepared with high selectivity by using lithium salt of BIT with appropriate alkylating agent. Further, the U.S. Patent No. 8,884,024 B1 describes the preparation of N-substituted 1,2-benzisothiazolin-3-one including (BBIT)by reacting the lithium, potassium or sodium of 1,2-benzisothiazolin-3-one with a straight chain or branched alkyl or benzyl halide in presence of solvents. The major drawback of this process is the use of expensive, lithium hydroxide monohydrate and long reaction time such as 18-23 hours. The process yet requires further purification since it only provides up to 95% purity, moreover it has failed to provide the removal of impurities.

The U. S. patent No. 5,633,384 is disclosed the preparation of 2-methylsulfanyl-benzonitrileby reacting ortho-chloro benzonitrile with sodium thiamethoxide in presence of tetra-n-butylammonium bromide and monochlorobenzene.

The research article Chemische Berichte, 1915, vol. 48, p. 1247 disclosed general process for the preparation of 2-methylsulfanyl-benzoic acid by reacting with potassium hydroxide.

The Chinese patent CN107602501 describes the preparation of precursor intermediate of BBIT. Thus, the N-butyl-2-methylsulfanyl benzamide was prepared from 2-methylsulfanyl benzoic acid using acid chloride followed by coupling with n-butyl amine in presence of base. Similarly, another Chinese patent CN103664817 is disclosed the preparation of 2-Butyl-1,2-benzisothiazol-3-one from 2-methylsulfanyl benzoic acid. The 2-Methylsulfanyl benzoic acid is reacted with thionyl chloride in chlorobenzene followed by coupling with n-butyl amine in presence of TEA, which is further cyclized using bromine in presence of aq. sodium carbonate. The drawback of process is the use corrosive, toxic bromine liquid. The process does not disclose the purity of desired compound and it may silent on removal of impurities.

The European Journal of Organic Chemistry; vol. 2018; no. 40; (2018); p. 5520-5523 disclosed the preparation of BBIT by reacting N-butyl-2-methyl sulfanyl-benzamide with Selectfluor in presence of acetonitrile, at 80°C for 12 hours in seal tube.

The above prior arts have certain disadvantages such as usage of expensive reagent for example LiOH, corrosive and toxic reagent for examplebromine, involve long reaction time in cyclization step 6-12 hours, and over all long cycle time. Thus, achieving the desired compound using economic, easily available solvents, catalyst; recyclization and reuse of solvents; easy isolation and purification methods to remove reaction impurities; and to achieve acceptable regulatory standard of N-butyl-1,2-benzisothiazolin-3-one formula (I) in less no of steps, in less cycle time remains a need. Therefore, the present inventors have come-up with an improved process which involveseasily available key starting material ortho-chlorobenzonitrile, non-use or minimum use of solvents, catalyst; recyclization of solvents and sequential reaction such as thioalkylation, hydrolysis, chlorination, alkylation and cyclization in less number of steps (2 steps). The process further involves unique isolation or purification technique to remove reaction impurities and further increase yield and purity of N-butyl-1,2-benzisothiazolin-3-one in 5-7 hours cyclization time.

SUMMARY OF THE INVENTION

In one aspect of present invention provides an industrial method for the preparation of 2-Butyl-1,2-benzisothiazol-3-one (BBIT) of formula (I), comprising:

a) obtaining 2-(methylthio)benzoic acid formula (IV) by first thiomethylating ortho-chloro benzonitrile formula (II)using thioalkyl metal salt in presence or absence of catalyst, in suitable solvent followed byhydrolys is using a base and acidification in presence of an acid;
b) obtaining a 2-Butyl-1,2-benzisothiazol-3-one formula (I) by converting 2-(methylthio)benzoic acid formula (IV) into its corresponding acid chloride using suitable chlorinating agent in presence or absence of catalyst in a solvent, followed by coupling with appropriate alkyl amine in presence or absence of base which is cyclized in presence of cyclizing agent.
In one embodiment, the improved method for the preparation of 2-Butyl-1,2-benzisothiazol-3-one resulting HPLC purity more than 95%.

In another aspect of present invention provides an industrial method for the preparation of 2-Butyl-1,2-benzisothiazol-3-one of formula (I)comprising the steps of:

a) obtaining 2-(methylthio)benzoic acid formula (IV) by first thiomethylating ortho-chloro benzonitrile formula (II)using thioalkyl metal salt in presence or absence of catalyst, in suitable solvent followed by hydrolysis using a base and acidification in presence of an acid;
b) obtaining a 2-Butyl-1,2-benzisothiazol-3-one formula (I) by converting 2-(methylthio)benzoic acid formula (IV) into its corresponding acid chloride using suitable chlorinating agent in presence or absence of catalyst in a solvent, followed by coupling with appropriate alkyl amine in presence or absence of base which is cyclized in presence of cyclizing agent;
c) treating 2-Butyl-1,2-benzisothiazol-3-one formula (I) in basic medium to obtain pure BBIT.
In one embodiment, the improved method for the preparation of 2-Butyl-1,2-benzisothiazol-3-one resulting HPLC purity more than 97%.

In one embodiment, the improved method for the preparation of 2-Butyl-1,2-benzisothiazol-3-one resulting HPLC purity more than 99%.

In one embodiment, the improved method for the preparation of 2-Butyl-1,2-benzisothiazol-3-one resulting a single unknown impurity is less than 0.5%.

In one embodiment, the improved method for the preparation of 2-Butyl-1,2-benzisothiazol-3-one resulting a single unknown impurity less than 0.1%.

In certain embodiments, wherein purification of 2-Butyl-1,2-benzisothiazol-3-one (I) comprises treating a crude 2-Butyl-1,2-benzisothiazol-3-one of step (c) with base, heating and maintaining; separating and further distillation under vacuum to obtain pure 2-Butyl-1,2-benzisothiazol-3-one formula (I) with HPLC purity greater than 99% and assay greater than 98%.

In certain embodiment, wherein the base used for purification is selected from organic or inorganic bases.

In certain embodiment where2-Butyl-1,2-benzisothiazol-3-one (I) is obtained after the purification meets “standard specification”; where the “standard specification” is meeting HPLC purity greater than 99%; single unknown impurity less than 0.1%; assay purity greater than 98% with colorless to pale yellow. In certain embodiment where2-Butyl-1,2-benzisothiazol-3-one (I) is obtained with around 77% yield on input basis of ortho-chloro toluene formula (II).

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

In one of the embodiment of present invention, wherein an industrial method for the preparation 2-Butyl-1,2-benzisothiazol-3-oneformula (I),is obtained in less number of step (2 steps) with or without isolating 2-(methylthio) benzonitrile (III),2-(methylthio)benzoyl chloride formula (V)and N-butyl-2-(methylthio) benzamide formula (VI) in economically feasible, environmentally viable manner.

In another embodiment of the present invention, wherein the said thioalkyl metal salt of step (a) is preferably selected from the group consisting of sodium thiomethoxide, potassium thiomethoxide, sodium thioethoxide, potassium thioethoxide and the like.

In another embodiment of the present invention, wherein unreacted thioalkyl metal salt is recovered by acidification, solvent extraction and treating with an alkali up to 14 to 18%.

In another embodiment of the present invention, wherein recovery and reuse of thioalkyl metal salt is achieved from mother liquor by dissolving methyl chloride gas in solvent, phase transfer catalysts, treating with sodium hydrosulfide, extracting with solvent and further treating with an alkali in 44 to 48%.

In another embodiment of the present invention, wherein overall recovery of thioalkyl metal salt in 58 to 60% from input of thioalkyl metal salt.

In another embodiment of the present invention, wherein the said catalyst in step (a) and (b) is preferably selected from sodium acetate, tetra butyl ammonium bromide (TBAB), tetra butyl ammonium chloride (TBAC), dimethyl formamide (DMF) and the like or mixture thereof.

In another embodiment, wherein the catalyst used in from 0.01 to 0.03 eq.

In another embodiments, wherein said solvent is selected from the group consisting of hydrocarbon solvents and chlorinated solvents.

In another embodiments, wherein said hydrocarbon solvent(s) is preferably selected from the group consisting benzene, toluene, xylene and the like or mixture of solvents thereof.

In another embodiments, wherein chlorinated solvent(s) is preferably selected from the group consisting of monochlorobenzene, ethylene dichloride, dichlorobenzene and the like or mixture of solvents thereof.

In another embodiments, wherein the reaction temperature for thiomethylation and hydrolysis is 25oC to 110oC.

In another embodiment of the present invention, wherein the said base in step (a), step (b) and step (c) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like.

In another embodiment of the present invention, wherein the said acid in step (a) is selected from hydrochloric acid, sulfuric acid, acetic acid and the like.
In another embodiment of the present invention, wherein the pH of step (a) after acidification is kept in 1 to 2.

In another embodiment of the present invention, wherein chlorination, alkylation and cyclization reactions are carried out at 0°C to 70°C.

In another embodiments, wherein the said chlorinating agent and cyclizing agent is selected from group consisting of thionyl chloride, sulfuryl chloride, Cl2 gas, N-chlorosuccinimide and the like.

In another embodiments, wherein chlorinating agent and cyclizing agent is used from 1.0 to 1.5 eq.

In another embodiments, wherein the said suitable alkyl amine used in step (b) is n-butyl amine.

In another embodiments, wherein n-butyl amine is used from 1.0 to 1.5 eq.

In another embodiments, wherein the base used in step (b) is selected from group consisting methyl amine, ethyl amine, propyl amine, isoproylamine 4-Quniolyl amine, trimethyl amine, triethyl amine and the like.

In another embodiments, wherein the cyclization step required 3 to 5 hours.

In another embodiment, wherein the resulting 2-Butyl-1,2-benzisothiazol-3-one formula (I) of step (b) may contains a sulfoxide impurity of formula (VII).

In another embodiment of the present invention, wherein the unreacted catalyst in process is recycled and reused.

In another embodiments, wherein the said base used in step (c) is commercially available inorganic base.

In another embodiments, wherein the inorganic base used in step (c) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like.

In another embodiments, wherein the inorganic base in step (c) is used from 0.1 to 0.3 eq.

In another embodiment of the present invention, wherein the solvents used in process are recovered and reused by distillation from the mother liquor.

The above process is illustrated in the following general synthetic scheme:

In yet another embodiment of the present invention, wherein the isolation and purification of 2-Butyl-1,2-benzisothiazol-3-oneformula (I) in step (c) is comprising of:
• treating reaction mixture containing crude BBIT (I) of step (b), with base, heating, adjusting pH to 9.0 ± 2.0, cooling, and concentrating organic layer under vacuum.
In yet another embodiment, wherein the resulting BBIT formula (I) of step (c) optionally distilled by using high vacuum distillation.

In yet another embodiment, wherein the high vacuum distillation is carried out at vapor temperature 140° to 160°C.

In still another embodiment of the present invention, wherein the pure compound of formula (I) is obtained in step (c) meets “standard specification” with higher chemical purity and greater yield.

The “standard specification” of compound of formula (I) mentioned in an embodiment is HPLC purity of compound of formula (I)more than 99%;single unknown impurity less than 0.1%; assay purity more than 98%.

The following examples serve to illustrate the invention, but they are not intended to limit it thereto:

EXPERIMENTAL

Example1: Preparation of 2-(methylthio)benzoic acid.

To mixture of ortho-chloro benzonitrile (1.0 eq) in monochlorobenzene (1.0 to 3.0 V), and catalytic amount of TBAB, an aqueous sodium thiomethoxide (25%w/w, 1.0 to 2.0 eq) was added at room temperature and heated for 1.0 to 3.0 hours. The reaction mixture was cooled to 60°C to 70°C and organic layer separated. The aqueous layer extracted with monochlorobenzene and combined organic layer containing 2-(methylthio) benzonitrile was heated inaqueous 25% NaOH (3.0 to 5.0 eq) for 8.0 to 10.0 hours. The reaction mixture was cooled to room temperature, diluted with water and acidified with aq. hydrochloric acid. The reaction mass was filtered and washed with water and dried under vacuum to obtain white to off-white color2-(methylthio) benzoic acid with 98 to 99% purity by HPLC and 95% molar yield.

Example 2: Preparation of 2-Butyl-1,2-benzisothiazol-3-one

The mixture of 2-(methylthio) benzoic acid (1.0 eq), in monochlorobenzene (6.0 to 10.0 V), catalytic amount of dimethylformamide was added and heated to the 50°C to 60°C. To above reaction mixture thionyl chloride was added for 1.0 hour and further heated to 60°C to 70°C for 2.0 to 4.0 hours. The unreacted thionyl chloride was removed and resulting reaction mass was added into a solution of triethyl amine (1.0 to 1.5 eq), monochlorobenzene (2.0 to 4.0V), n-butylamine at 20°C to 25°C for 1.0 hour and stirred for 2.0 hour. The reaction mixture was quenched by water and layers separated. The organic layer was washed with aqueous sodium bicarbonate and then with water. To the resulting pale light brownish yellow liquid, a solution of sulfuryl chloride in monochlorobenzene (1.0 to 3.0V) was added at 5°C to 10°Cand maintained for 3 to 5 hours. The reaction mixture was quenched by adding water and layers were separated. The organic layer was washed with saturated sodium bicarbonate solution, then with water to obtain yellow to orange liquid contains 2-Butyl-1,2-benzisothiazol-3-one with 94% purity by HPLC.

Example 3: Purification of 2-Butyl-1,2-benzisothiazol-3-one

The crude yellow liquid of 2-Butyl-1,2-benzisothiazol-3-one (with at least purity 90% by HPLC) was charged into an aqueous solution of sodium carbonate (~ 0.5 v) and heated to 70°C to 80°C for 3-4 hours. The reaction mixture was cooled, separated organic layer was concentrated and further distilled to obtain pure light pale-yellow color 2-Butyl-1,2-benzisothiazol-3-onewithat least purity 99% by HPLC, impurity less than 0.1% and assay more than 98%.
,CLAIMS:WE CLAIM:

1. A process for preparation of 2-Butyl-1,2-benzisothiazol-3-one (BBIT) of formula (I), comprising:

a) obtaining 2-(methylthio)benzoic acid formula (IV) bythiomethylating ortho-chloro benzonitrile formula (II) using thioalkyl metal salt in presence or absence of catalyst, in solvent followed by hydrolysis using a base and acidification in presence of an acid;
b) obtaining a 2-Butyl-1,2-benzisothiazol-3-one formula (I) by converting 2-(methylthio)benzoic acid formula (IV) into its corresponding acid chloride using chlorinating agent in presence or absence of catalyst in a solvent, followed by coupling with appropriate alkyl amine in presence or absence of base which is cyclized in presence of cyclizing agent.

2. The process as claimed in claim 1, which further comprises treating 2-Butyl-1,2-benzisothiazol-3-one formula (I) in basic medium to obtain pure BBIT.

3. The process as claimed in claim 1 or 2 wherein, compound of formula (I) is obtained with chemical purity greater than 95% and single unknown impurity less than 0.1%.

4. The process as claimed in claim 1 wherein, said thioalkyl metal salt is selected from sodium thiomethoxide, potassium thiomethoxide, sodium thioethoxide, and potassium thioethoxide.

5. The process as claimed in claim 1 wherein, said catalyst is selected from sodium acetate, tetra butyl ammonium bromide (TBAB), tetra butyl ammonium chloride (TBAC), and dimethyl formamide (DMF).

6. The process as claimed in claim 1 wherein, said solvent is selected from hydrocarbon solvents and chlorinated solvents.

7. The process as claimed in claim 1wherein, said base used in step (a) isinorganic base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate potassium carbonate, potassium bicarbonate, and in step (b) is organic base selected from methyl amine, ethyl amine, propyl amine, isoproylamine 4-Quniolyl amine, trimethyl amine, triethyl amine, and said alkyl amine is n-butyl amine.

8. The process as claimed in claim 1 wherein, said acid is selected from hydrochloric acid, sulfuric acid, and acetic acid.

9. The process as claimed in claim 1 wherein, said chlorinating agent, cyclizing agent is selected from thionyl chloride, sulfuryl chloride, Cl2 gas, and N-chlorosuccinimide.

10. The process as claimed in claim 2 wherein, said basic medium isinorganic base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate potassium carbonate, and potassium bicarbonate.