RELATED APPLICATION

This application claims the benefit to Indian provisional application no. 202021047473, filed on October 30, 2020, the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to an industrial method for the preparation of Benzisothiazolinone (BIT) of formula (I) in an environment friendly and commercially viable manner with high yield and high chemical purity.

BACKGROUND OF THE INVENTION

Benzisothiazolinone (BIT) also known as l,2-benzisothiazol-3(2H)-one belongs to the class of isothiazolinones is a used as a biocide. Benzisothiazolinone acts as microbicide and/or fungicide and widely used as a preservative in: emulsion paints, caulks, varnishes, adhesives, inks, and photographic processing solutions home cleaning and car care products; laundry detergents, stain removers and fabric softeners; industrial settings, for example in textile spin-finish solutions, leather processing solutions, preservation of fresh animal hides and skins; agriculture in pesticide formulations; gas and oil drilling in muds and packer fluids preservation.

The Benzisothiazolinone (BIT) is first disclosed in J. Chem. Soc., Trans., 1923,123, 3310-3315 and J. Chem. Soc., 1926,129, 92! -925. T e U.S. Patent No.5,633,384 discloses the synthesis of BIT starting from ortho-chlorobenzo nitrile using sodium thiamethoxide in presence of tetra-n-butylammonium bromide and monochlorobenzene and further carried-out chlorination and cyclization. The preparation of 2-chlorobenzotrichloride discloses in U.S. Patent No. 2,132,361from 2-chlorotoluene by chlorinating in presence of light of a mercury vapor lamp at 100 °C to 150°C. The patent is silent on purity, impurity profile and yield. Another reference, DE 2,139,779 discloses the preparation of 2-chlorobenzotrichloride from 2- chlorotoluene using chlorinating in diffuse daylight in presence of pyridine compound. The major drawback of this process is the use of corrosive, carcinogenic 2,4,6- triphenylpyridine compound and the process does not disclose the removal of impurities and reaction time. Another reference, CN101947468 discloses the preparation of composite catalyst and its application in chlorination of 2-chlorotoluene for the preparation of 2-chlorobenzotrichloride. However, the composite catalyst is expensive, and it is not easy to prepare. In yet another reference, CN108129255A discloses the device and its process of manufacturing ortho-chlorotrichlorotoluene from chlorination of ortho-chlorotoluene using mercury lamp, illumination initiator and compressed air at 10 to 120°C. The drawback of the process is involving benzoyl peroxide which generates free-radicals and explosive.

Orthro-chloro benzonitrile (OCBN) is prepared from benzo trichlorides using ammonium chloride [i. EP 441004; ii. JACS, 52, 2951 (1930)]. However, the drawback of the process involves elevated temperature conditions and it demands expensive temperature-controlled jacket and metal oxides or salts belong to the groups 8, 11, 12 and 13.

The aforesaid references did not disclose a process for the preparation of Benzisothiazolinone (BIT) in a single reference. Further the references did not provide an easy process to manufacture and from an easily available ortho-chlorotoluene. Additionally, these processes involve longer cycle time, unfriendly reaction conditions such as the use of expensive, carcinogenic reagents, expensive temperature controlled jacketed device. Thus, achieving the desired compound in a less number of steps (two steps), using economic solvents, catalyst; recyclization, reuse of solvent or catalyst; isolation or purification techniques to remove reaction impurities and to achieve acceptable regulatory standard of Benzisothiazolinone formula (I) remains a need. Therefore, the inventors of the present invention have come-up with an improved industrial process which involves sequential reaction such as photochlorination, benzonitrile preparation, thioalkylation and cyclization in two steps, minimum/no-use of solvents, friendly available reagents and reuse of solvents, reagents and isolation or purification technique to remove reaction impurities with increase yield and purity of B enziso thiazo lino ne .

SUMMARY OF THE INVENTION

In one aspect of present invention provides an industrial method for the preparation of Benzisothiazolinone (BIT) of formula (I), which comprises the steps: a) obtainingortho-chloro benzonitrile formula (V) by photo chlorination of orthochlorotoluene formula (II) in presence of light, with or without initiator followed by nitrilation using ammonium chloride, metal salts and with or without suitable catalystor solvent; b) obtaining Benzisothiazolinone (BIT) formula (I) by reacting ortho-chloro benzonitrile formula (V) with thioalkyl metal salt with or without catalyst, in presence or absence of solvent and further cyclization in presence of acid catalyst, using chlorinating agent followed by addition of a base.

In one embodiment, the industrial method for the preparation of Benzisothiazolinone (I) where the purity by HPLC is greater than 90%.

In another embodiment, the industrial method for the preparation of Benzisothiazolinone (I) where the purity by HPLC is greater than 90%; in this embodiment, Benzisothiazolinone (I) is obtained with more than 82% yield.

In another aspect of present invention provides an industrial method for the preparation of Benzisothiazolinone formula (I), which comprises the steps: a) obtaining ortho-chloro benzonitrile formula (V) by photochlorination of orthochloro toluene formula (II) in presence of light, with or without initiator followed by nitrilation using ammonium chloride, metal salts and with or without catalyst, or solvent; b) obtaining Benzisothiazolinone (BIT) formula (I) by reacting ortho-chloro benzonitrile formula (V) with thioalkyl metal salt with or without catalyst, in presence or absence of solvent and cyclization in presence of acid catalyst, using chlorinating agent followed by addition of a base; c) purifying Benzisothiazolinone formula (I).

In one embodiment, the industrial method for the preparation of Benzisothiazolinone (I) where the purity by HPLC is greater than 97%.

In another embodiment, the industrial method for the preparation of Benzisothiazolinone (I) where the purity by HPLC is greater than 99%.

In yet another embodiment, the industrial method for the preparation of Benzisothiazolinone (I) where the purity by HPLC is greater than 99% and a single unknown impurity is less than 0.5%, preferably less than 0.1%.

In another aspect of present invention provides an industrial method for the preparation of Benzisothiazolinone formula (I), which comprises the steps:

1) obtaining ortho-chlorobenzotrichloride formula (III) by photochlorination of ortho - chlorotoluene formula (II) in presence of light, with or without initiator;

2) obtaining ortho-chloro benzonitrile formula (V) by nitrilation of ortho-chloro benzotrichloride formula (III) using ammonium chloride, metal salts and with or without ortho-chloro benzo icacid formula (IV); where the said ortho-chloro benzoic acid formula (IV) is obtained by reacting a ortho-chloro benzo trichloride formula (III) in presence of acid catalyst;

3) obtaining 2-(methylthio) benzonitrile formula (VI) by reacting ortho-chloro benzonitrile formula (V) using thioalkyl metal salt, with or without catalyst, in presence or absence of solvent;

4) obtaining Benzisothiazolinone formula (I) by cyclising 2-(methylthio) benzonitrile formula (VI) with chlorinating agent, base, in presence of acid catalyst, with or without catalyst or solvent.

In an embodiment, wherein ortho-chloro benzo trichloride formula (III), 2- (methylthio)benzonitrile formula (VI) and ortho-chloro benzoic acid formula (IV)are proceeded directly into subsequent steps or isolated.

In certain embodiments, wherein purification of Benzisothiazolinone (I) comprises treating a crude compound of step (b) with alkali solution and adjusting pH of clear solution to the pH 4.0 ± 1.0; filtering, washing with a solvent to obtain pure compound with HPLC purity greater than 98 %.

In certain embodiment, wherein the solvent used for purification is selected from chlorinated solvent or hydrocarbon solvents.

In certain embodiment where Benzisothiazolinone (I) is obtained further to 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 80% and moisture content by KF is in range of 10 to 20%.

In certain embodiment where Benzisothiazolinone (I) is obtained with around 89% yield. 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.

The term “solvent” used herein, refer to one or more solvents.

In certain embodiment of the present invention, wherein step (a) involves the photochlorination and nitrilation reaction.

In certain embodiments, wherein photochlorination involves UV light of 350 to 500nm wave length at temperature from 60°C to 140°C.

In certain embodiments, wherein photochlorination reaction in step (a) is carried out by purging chlorine gas 3.5 to 4.0 equivalent.

In certain embodiments, wherein the said initiator in photochlorination in step (a) is selected from water, azobisisobutyronitrile (AIBN), dibenzoyl peroxide, sulfuric acid, formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, orthro- chloro benzoic acid and the like or mixture thereof.

In certain embodiments, wherein the suitable initiator is 0.1 to 7.0% w/w.

In certain embodiments, wherein the said metal salts in nitrilation is preferably selected from the groups 8, 11, 12 and 13.

In certain embodiments, wherein said metal salts is selected from zinc acetate, zinc chloride, copper (II) acetate, copper (II) chloride, nickel (II) chloride, iron chloride, and the like. In certain embodiments, wherein said metal salts is 0.001 to 0.003 equivalent.

In certain embodiments, wherein said catalyst for nitrilation is selected from formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, orthro- chlorobenzoic acid and the like or mixture thereof.

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

In certain embodiments, wherein the said solvent used in step (b) step (3) and step (4) is selected from hydrocarbon solvents, chlorinated solvents and the like.

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

In certain 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 certain embodiments, wherein the reaction temperature for photochlorination and nitrilation is 60°C to 200°C.

In certain embodiments, wherein the cycle time of photochlorination and nitrilation is 8 to 24 hours.

In certain embodiments, wherein compound ortho-chloro benzonitrile formula (V) is isolated by adding minimum amount of solvent, filtering, adjusting the pH 7 to 9 using alkali solution; and adding minimum amount of base and separating the organic layer.

In certain embodiment, wherein the said ortho-chloro benzonitrile (V) may be isolated by extraction in solvent or by simple distillation. In certain embodiments, wherein a preparation of ortho-chloro benzo trichloride formula (III) is achieved with GC purity greater than 97% and chemical assay greater than 95%, yield 90 to 94% and the content of ortho-chloro toluene (II) is less than 0.1%.

In certain embodiment, wherein said thioalkyl metal salt is preferably selected from the group consisting of sodium thiomethoxide, potassium thiomethoxide, sodium thioethoxide, potassium thioethoxide and the like.

In certain embodiment, wherein said catalyst is preferably selected from sodium acetate, tetra butyl ammonium bromide (TBAB), tetra butyl ammonium chloride (TBAC), and the like or mixture thereof.

In certain embodiment, wherein said acid catalyst in step (b) and step (4) is preferably selected from thionyl chloride, chlorine gas and the like.

In certain embodiment, wherein said chlorinating agent is selected from chlorine gas, sulfuryl chloride, thionyl chloride, iron chloride, methane sulfonyl chloride, tert-butyl hypochlorite, methoxy acetyl chloride, oxalyl chloride, A-chloro succinimide and the like.

In certain embodiment, wherein said base of step (b) is selected from group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like.

In certain embodiment, wherein unreacted thioalkyl metal salt from reaction mixture is recovered by acidification, solvent extraction and treating with an alkali up to 14 to 18%.

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

In certain embodiment, wherein overall recovery of thioalkyl metal salt is 58 to 60% from input of thioalkyl metal salt. In certain embodiment, wherein Benzisothiazolinone formula (I) is recovered from solvent mother liquor by concentration and filtration; and acid impurity is recovered from solvent mother liquor by acid base treatment.

In certain embodiment, wherein acid impurity is 2-(methylthio)benzoic acid.

In certain embodiment, wherein concentrated HC1 is prepared by scrubbing HC1 gas generated in step (a) into water and reused in process.

In certain embodiment, wherein the solvents are recovered and reused in process by distillation from the mother liquor.

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

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

EXPERIMENTAL

Example 1: Preparation of 2-chlorobenzotrichloride (III)

In presence of UV light, an ortho-chlorotoluene (1.72Kg) and AIBN(5.2 g) were added and reaction mixture was heated at 50°C to 70°C. The chlorine gas (4.3 Kg) purging was started and reaction mixture was heated at 140 to 150°C and chlorine gas purging was continued for 20 to 24 hours. After completion of reaction, the UV light and chlorine gas purging were stopped, and reaction mixture was cooled to room temperature. The air was purged for 2.0 hour and the compound 2- chlorobenzotrichloride was isolated as a clear pale-yellow liquid (2.95 Kg, 90% yield, GC Purity 97.05% and Assay Purity 94.92%w/w), LCMS:230.92 [M+H] ⁺

Example 2: Preparation of 2- Chlorobenzonitrile (V)

In presence of UV light, an ortho-chlorotoluene (0.5 Kg) and AIBN (2.5 g) were added and reaction mixture was heated at 50°C to 70°C. The chlorine gas purging was started, and reaction mixture was heated to 140°C to 150°C and the chlorine gas purging continued for 28 hours. After completion of reaction, the UV light was switched off and chlorine gas purging was stopped, and the reaction mixture was cooled to room temperature. The air was purged for 2.0 hour and to the reaction mixture ammonium chloride (232.4 g), ortho-chlorobenzoic acid (61.83 g), and zinc acetate (1.66 g) were added at room temperature. The reaction mixture was heated at 180°C to 200°C for 8.0 hours and 2-chlorobenzonitrile was isolated by high vacuum distillation with 78% yield and GC 99% purity.

Example 3: Preparation of ortho-chloro benzonitrile (V)

The 2-chlorobenzotrichloride (0.91 Kg), ammonium chloride (2.32 Kg), ortho-chloro benzoic acid (61.88 g) and zinc acetate (1.66g) were charged at room temperature. The reaction mixture was heated tol80°C to 200°C for 8.0 hours. The reaction mixture was cooled to room temperature and monochlorobenzene (0.1 to 0.3V) was added. The reaction mixture was filtered, and pH of reaction mass was adjusted to neutral pH using sodium carbonate. The organic layer was separated and neutralized with aqueous ammonia under stirring. The organic layer separated to obtain compound ortho-chloro benzonitrile (90% yield).

Example 4: Preparation of ortho-chloro benzonitrile (V)

The 2-chlorobenzotrichloride (0.5 Kg), ammonium chloride (139.58 Kg), water (2.75 g), sulfuric acid (0.5g) and zinc acetate (0.92 g) were charged at room temperature. The reaction mixture was heated to 180°C to 200°C for 16.0 hours. The reaction mixture was cooled to 60-70 °C and filtered reaction mass at the same temperature and collected unreacted solid ammonium chloride (33.0 g; assay 95.23% w/w; 23.6% recovery). Crude ortho-chloro benzonitrile (filtrate) 252 g (85% yield; GC Purity - 96.01). Example 5: Preparation of ortho-chloro benzonitrile (V)

In presence of UV light, an ortho-chlorotoluene (2.5 Kg) and AIBN (3.75 g, 0.15%) were added and reaction mixture was heated at 50°C to 70°C. The chlorine gas (7.2 Kg) purging was started and reaction mixture was heated at 140°C to 150°C and chlorine gas purging was maintained for 20 to 24 hours. After completion of reaction, the UV light was switched off and chlorine gas purging was stopped, and reaction mixture was cooled to room temperature. The air was purged for 2.0 hour and ammonium chloride (1.13 Kg), ortho-chlorobenzoic acid (299.6 g), and zinc acetate (8.1 g) were charged at room temperature. The reaction mixture was heated to 180°C to 200°C for 8.0 hours. The reaction mixture was cooled to room temperature and monochlorobenzene (1320 mL) was added. The reaction mixture was filtered, and pH of reaction mass was adjusted to neutral by using aqueous sodium carbonate. The organic layer was separated and neutralized with aqueous ammonia under stirring. The organic layer was separated to obtain compound ortho-chloro benzonitrile (84.63% yield).

Example 6: Preparation of 2-methylsulfanyl-benzonitrile (VI)

The ortho-chloro benzonitrile (100 g) monochlorobenzene (1.0V), tetra butyl ammonium bromide (0.017 eq), 25% sodium thiamethoxide (1.5 eq) were added at room temperature. The reaction mixture was heated to 90°C to 100°C for 2.0 to 4.0 hours. The reaction mixture was cooled to 60°C to 70°C and aqueous layer separated. The aqueous layer extracted with monochlorobenzene at 60°C to 70°C and separated the organic layer to obtain 2-methylsulfanyl -benzonitrile (323.3g) with HPLC purity 97.59%.

Example?: Preparation of Benzisothiazolinone (I)

The 2-methylsulfanyl-benzonitrile (323 g), monochlorobenzene (100g) concentrated hydrochloride (26.26 g) and water (15.54 g) were added at room temperature. The reaction mixture was heated to 40°C to 45°C and chlorine gas (56.92 g) was purged for 1.0 to 2.0 hours. The reaction mixture was heated to 60°C to 70°C for 2.0 to 4.0hour and aqueous sodium hydroxide solution (61 g) was added. The reaction mass was cooled to room temperature and pH of reaction mass was adjusted using aqueous sodium hydroxide. The reaction mass was filtered, washed with monochlorobenzene and water and dried under vacuum to obtain compound (I) (105 g,96% yield). Example 8: Preparation of Benzisothiazolinone (I)

The ortho-chloro benzonitrile (1.0 eq), monochlorobenzene (1.0V), tetra butyl ammonium bromide (0.017 eq), 25% sodium thiamethoxide (1.5 eq) were added at room temperature. The reaction mixture was heated to 90°C to 100°C for 2.0 to 4.0 hours. The reaction mixture was cooled to 60°C to 70°C and aqueous layer separated. The aqueous layer extracted with monochlorobenzene at 60°C to 70°C and organic layer separated to obtain 2-methyl sulfanyl benzonitrile with HPLC purity 97.59%. To organic layer, monochlorobenzene (1.0V), concentrated hydrochloric acid (0.3eq), water (1.2eq) were added and heated to 35°C to 45 °C. The chlorine gas was purged for 1.0 to 2.0 hours and reaction mixture was heated to 65°Cto 70°C for 2.0 to 4.0 hours. The aqueous NaOH solution (l.Oeq) was added for 30 minutes and cooled to 25°C to 30°C.The pH was adjusted to 4.0 ± 1.0 and maintained for 30 minutes. The reaction mixture was filtered, and wet cake was washed with monochlorobenzene, water and dried under vacuum to obtain Benzisothiazolinone (I) with 85% yield.

Example 9: Purification of Benzisothiazolinone (I)

The compound (I) was treated with water, basified with aqueous sodium hydroxide and heated at 40°C to 50°C for 0.5 to 1.0 hour. The reaction mass was filtered and cooled to room temperature and acidified with concentrated hydrochloride till pH 4 to 5. The reaction mass was filtered, washed with water and dried under vacuum to obtain white powder pure Benzisothiazolinone compound (83% yield, HPLC purity 99.98%, assay by HPLC 80%, Moisture content 15.56% and single unknown impurity less than 0.1%).

Example 10: Preparation of ortho-chloro benzoic acid (IV)

To a mixture of ortho-chloro benzonitrile (250 g) and water (562.5 g), concentrated hydrochloric acid (187.5 g) was added under stirring for 15 to 30 minutes and mixture was heated to 100°C to 110°C for 6 to 8 hours. The reaction mixture was cooled to room temperature and stirred for 1 to 2 hours. The precipitated solid was filtered, washed with water and dried under vacuum to get ortho-chloro benzoic acid compound (168 g, 98%, HPLC purity 99.79%).