United States Patent (10) Patent No.: US 9,334.248 B2 Dai (45) Date of Patent: May 10, 2016

USOO9334248B2

(12) United States Patent (10) Patent No.: US 9,334.248 B2 Dai (45) Date of Patent: May 10, 2016

(54) SYNTHETIC METHOD FOR THE FOREIGN PATENT DOCUMENTS PREPARATION OF 1, CN 102491955. A 6, 2012 2-BENZSOTHAZOLN-3-ONE CN 103130738 A 6, 2013 CN 103.145638 A 6, 2013 (71) Applicant: Shouguang Syntech Fine Chemical CN 10342.9579 A 12/2013 Co., Ltd., Yangkou Town (CN) CN 10396.5132 9, 2014 EP 0702008 A2 3, 1996 (72) Inventor: Mingben Dai, Yangkou Town (CN) EP 2687519 A1 1, 2014 EP 268752O A1 1, 2014 JP 2002O88072 A 3, 2002 (73) Assignee: Shouguang Syntech Fine Chemical JP 2013O43881 A 3, 2013 Co., Ltd. (CN) JP 2013 043882. A 3, 2013 WO WO-2012/127996 A1 * 9, 2012 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 0 days. Chemical Abstracts Registry No. 110502-29-9, indexed in the Reg istry file on STN CAS Online Oct. 3, 1987.* (21) Appl. No.: 14/719,825 Chemical Abstracts Registry No. 1160509-17-0, indexed in the Reg istry file on STN CAS Online Jun. 30, 2009.* (22) Filed: May 22, 2015 Chemical Abstracts Registry No. 859791-22-3, indexed in the Reg istry file on STN CAS Online Aug. 12, 2005.* (65) Prior Publication Data Node et al Tetrahedron Letters, 42, 2001, pp. 9207-9210.* Butanethiol, ChemSpider, date not available.* US 2015/033691.0 A1 Nov. 26, 2015 Pentanethiol, ChemSpider, date not available.* Hexanethiol, ChemSpider, date not available.* European Search Report for EP 14181603.3-1452 mailed Oct. 10, Related U.S. Application Data 2014. (60) Provisional application No. 62/039,442, filed on Aug. * cited by examiner 20, 2014. Primaryy Examiner — Laura L. Stockton (51) Int. Cl. (74) Attorney, Agent, or Firm — Drinker Biddle & Reath C07D 275/04 (2006.01) LLP (52) U.S. Cl. CPC ...... C07D 275/04 (2013.01) (57) ABSTRACT (58) Field of Classification Search The present invention relates to a method for producing a USPC ...... 548/209 1,2-benzisothiazolin-3-one compound (I) by reacting a 2-ha See application file for complete search history. lobenzonitrile compound (II) with a thiol compound (III) to form an intermediate (IV) and Subsequently reacting the (56) References Cited intermediate (IV) with a halogenation agent in the presence of water to form a reaction mixture (RM), comprising the 12 U.S. PATENT DOCUMENTS benzisothiazolin-3-one compound (I) and a halide compound 4,736,040 A 4, 1988 Tonne et al. (V). 8,802,862 B2 8/2014 Hiyama et al. 2013/0345434 A1* 12/2013 Kanda et al...... 548,209 13 Claims, No Drawings US 9,334,248 B2 1. 2 SYNTHETIC METHOD FOR THE R" is selected from the group consisting of hydrogen, PREPARATION OF 1, unsubstituted or at least monosubstituted C-Co-alkyl, OR, 2-BENZSOTHAZOLIN-3-ONE C(O)OR, F, Cl, Br, I and NO, wherein the Substituents are selected from the group con This patent application claims the benefit of U.S. provi sisting of F, Cl, Br, I, OH, NH and Cs-Co-aryl, sional patent application Ser. No. U.S. 62/039,442, filed on wherein Aug. 20, 2014 and CN patent application Ser. No. CN R is selected from the group consisting of hydrogen, 10396.5132, filed on May 26, 2014, incorporated in their unsubstituted or at least monosubstituted C-Co-alkyl entirety herein by reference. and unsubstituted or at least monosubstituted Cs-Co 10 aryl, The present invention relates to a method for producing a wherein the Substituents are selected from the group con 1.2-benzisothiazolin-3-one compound (I) by reacting a 2-ha sisting of F, Cl, Br, I, OH, NH, C-Co-alkyl and lobenzonitrile compound (II) with a thiol compound (III) to Cs-Co-aryl; form an intermediate (IV) and Subsequently reacting the comprising the steps intermediate (IV) with a halogenation agent in the presence of 15 a) reacting a 2-halobenzonitrile compound of the general water to form a reaction mixture (RM), comprising the 12 formula (II) benzisothiazolin-3-one compound (I) and a halide compound (V). 1,2-benzisothiazolin-3-one compounds (I), especially 1.2- (II) benzisothiazolin-3-one (BIT) itself, are of high industrial rel 21 CN, evance as they are high efficient fungicides. Furthermore, R-- 1,2-benzisothiazolin-3-one compounds (I) inhibit the growth of microorganisms like bacteria, fungi, mold and mildew. N X 1.2-benzisothiazolin-3-one compounds (I) are typically used as a preservative in emulsion paints, varnishes, adhesives, 25 wherein Washing agents and paper pulps. X is selected from the group consisting of F, Cl, Brand I; Various methods for the production of 1,2-benzisothiazo with a thiol compound of the general formula (III) lin-3-ones are described in the state of the art. For example, U.S. Pat. No. 4,736,040 describes a method R SH (III), for the preparation of 1,2-benzisothiazolin-3-ones by react 30 wherein ing 2,2'-dithiobenzamides with an oxygenation agent in the R is selected from the group consisting of unsubstituted or presence of an aqueous alkaline medium. The 2,2'-dithioben at least monosubstituted Cs-Co-alkyl, unsubstituted or at Zamides are prepared by nitrosation of anthranilamides and least monosubstituted Cs-Co-aryl and unsubstituted or at Subsequently reacting the thus obtained product with Sulfur least monosubstituted C-Co-aralkyl, dioxide in the presence of a catalyst. This method for the 35 wherein the Substituents are selected from the group con preparation of 1,2-benzisothiazolin-3-ones is both, time-con sisting of F, Cl, Br, I, OH, NH, C, -Co-alkyl and OR, Suming and costly as many reaction steps are necessary. wherein A more simple method for the preparation of 1,2-ben R" is hydrogen or C1-Co-alkyl: Zisothiazolin-3-ones is described in EP 2 687 519. In the in the presence of at least one base (B) to form an interme method according to EP 2687519 first a 2-halobenzonitrile is 40 reacted with an alkylthiol having from 1 to 4 carbon atoms to diate of the general formula (IV) give a 2-(alkylthio)benzonitrile. The 2-(alkylthio)benzoni trile is Subsequently reacted with a halogenation agent in the (IV) presence of water to give the 1,2-benzisothiazolin-3-one. CN With this method a recycling of intermediate products 45 obtained during the preparation of the 1,2-benzisothiazolin 3-one is almost impossible. This makes the method very costly. SR3, The object underlying the present invention is therefore to provide an improved method for producing a 12-benzisothia 50 b) reacting the intermediate of the general formula (IV) Zolin-3-one. The method should not have the above men obtained in step a) with a halogenation agent in the presence tioned disadvantages of the prior art or have them only to a of water to form a reaction mixture (RM), comprising the significantly less extend. The method should be carried out 1,2-benzisothiazolin-3-one of the general formula (I) and a more simply, saver and more cost efficient than those halide compound of the general formula (V) described in the state of the art. 55 This object is solved by a method for producing a 12 R XI (V), benzisothiazolin-3-one compound of the general formula (I) wherein X' is C1 or Br. It has surprisingly been found that the thiol compound (III), (I) 60 which has from 5 to 30 carbon atoms can be used for the O preparation of a 12-benzisothiazolin-3-one starting from a N 2-halobenzonitrile compound. The use of a thiol compound having from 5 to 30 carbon R!-H 21 NS NH. atoms is advantageous as these thiols are semivolatile and 65 have only a light odor. As these thiols are semivolatile, safety and environmental problems can be reduced compared to the wherein methods described in the state of the art. US 9,334,248 B2 3 4 Moreover, the halide compound (V) obtained in step b) as trile, 2-chloro-3-nitrobenzonitrile, 4-methoxycarbonyl-2- well is semivolatile and furthermore it is non-solubleinwater. chlorobenzonitrile, 4-carboxy-2-chlorobenzonitrile and 2,4- This makes it possible, in one embodiment of the present dichlorobenzonitrile. invention, to separate the halide compound (V) from the In a particularly preferred embodiment, the 2-halobenzoni 1.2-benzisothiazolin-3-one compound (I) and Subsequently trile compound (II) selected from the group consisting of to react the halide compound (V) with a sulfide compound to 2-chlorobenzonitrile and 2-bromobenzonitrile. give the thiol compound (III) having from 5 to 30 carbon Within the context of the present invention, definitions atoms. This thiol compound (III) can be recycled to step a). such as C-Co-alkyl as for example defined above informula This makes the method according to the present invention (II) for R' mean that this substituent (radical) is an alkyl very economical and highly cost efficient. 10 radical with a carbon atom number from 1 to 10. Step a) Within the context of the present invention, definitions In step a) of the present invention a 2-halobenzonitrile Such as C-C-alkyl as for example defined above in formula compound (II) is reacted with a thiol compound (III) in the (II) for R' mean that this substituent (radical) is an alkyl radical with a carbon atom number from 1 to 4. presence of at least one base (B) to forman intermediate (IV). 15 A 2-halobenzonitrile compound (II) within the context of Within the context of the present invention, definitions the present invention means precisely one 2-halobenzonitrile such as Cs-Co-alkyl as for example defined below informula compound (II) and also a mixture of two or more 2-haloben (III) for R mean that this substituent (radical) is an alkyl Zonitrile compounds (II). radical with a carbon atom number from 5 to 30. A thiol compound (III) within the context of the present The alkyl radical may be linear or branched and also invention means precisely one thiol compound (III) and also optionally cyclic. Alkyl radicals which have both a cyclic component and also a linear component likewise fall under a mixture of two or more thiol compounds (III). this definition. According to the present invention a 2-halobenzonitrile Examples of C-Co-alkyl are methyl, ethyl, n-propyl, sec compound (II) is used. propyl. n-butyl, sec-butyl, isobutyl, 2-ethylhexyl, tert-butyl 25 (tert-bu?t-Bu), pentyl, hexyl, heptyl, cyclohexyl, octyl, nonyl and decyl. Examples of C-C-alkyl are methyl, ethyl, n-pro (II) CN, pyl, Sec-propyl. n-butyl, sec-butyl, isobutyl and tert-butyl (tert-bu?t-Bu). Examples of Cs-Co-alkyl are pentyl, hexyl, heptyl, cyclohexyl, octyl, nonyl, decyl, undecyl, dodecyl and 30 octadecyl. Within the context of the present invention, the term “aryl'. as for example defined above for the radical R in formula (II) wherein means that the Substituent (radical) is an aromatic. The aro R" is selected from the group consisting of hydrogen, matic may be a monocyclic, bicyclic or optionally polycyclic unsubstituted or at least monosubstituted OR, C(O)OR. F. 35 aromatic. In the case of polycyclic aromatics, individual Cl, Br, I and NO, cycles can optionally be completely or partially Saturated. wherein the Substituents are selected from the group con Preferred examples of aryl are phenyl, naphthyl or anthracyl, sisting of F, Cl, Br, I, OH, NH and Cs-Co-aryl, in particular phenyl. wherein The 2-halobenzonitrile compound (II) can be prepared by R is selected from the group consisting of hydrogen, 40 any method known to the skilled person. unsubstituted or at least monosubstituted C-Co-alkyl According to the present invention the 2-halobenzonitrile and unsubstituted or at least monosubstituted Cs-Co compound (II) is reacted with a thiol (III) aryl, R SH (III), wherein the Substituents are selected from the group con 45 sisting of F, Cl, Br, I, OH, NH, C-Co-alkyl and wherein Cs-Co-aryl; R is selected from the group consisting of unsubstituted or X is selected from the group consisting of F, Cl, Brand I. at least monosubstituted Cs-Co-alkyl, unsubstituted or at In a preferred embodiment of the present invention a 2-ha least monosubstituted Cs-Co-aryl and unsubstituted or at lobenzonitrile compound (II) is used, wherein the substitu 50 least monosubstituted Co-Co-aralkyl, ents have the following meanings: wherein the Substituents are selected from the group con R" is selected from the group consisting of hydrogen, sisting of F, Cl, Br, I, OH, NH, C, -Co-alkyl and OR, C-C-alkyl, OR, C(O)CR, Cl, Br, I and NO, wherein wherein R" is hydrogen or C1-Co-alkyl. R is hydrogen or C1-C4-alkyl; 55 In a preferred embodiment a thiol compound (III) is used, X is C1 or Br. wherein the Substituents have the following meanings: In a particularly preferred embodiment of the present R is selected from the group consisting of unsubstituted or invention a 2-halobenzonitrile compound (II) is used, at least monosubstituted C-C2-alkyl, unsubstituted or at wherein the Substituents have the following meanings: least monosubstituted Cs-Ca-aryl and unsubstituted or at R" is selected from the group consisting of hydrogen, 60 least monosubstituted C7-Cs-aralkyl, methyl, ethyl, tert-butyl, methoxy, carboxy, methoxy carbo wherein the Substituents are selected from the group con nyl, ethoxy carbonyl, propoxy carbonyl, Cl and NO; sisting of F, Cl, Br, I, OH, NH, C, -Cs-alkyl and OR, X is C1 or Br. wherein Preferably the 2-halobenzonitrile compound (II) is R" is hydrogen or C-C-alkyl. selected from the group consisting of 2-chlorobenzonitrile, 65 In a particularly preferred embodiment a thiol compound 2-bromobenzonitrile, 3-methyl-2-chlorobenzonitrile, 5-tert (III) is used, wherein the substituents have the following butyl-2-chlorobenzonitrile, 4-methoxy-2-chlorobenzoni meanings: US 9,334,248 B2 5 6 R is unsubstituted or at least monosubstituted Cs-C2- wherein alkyl or unsubstituted or at least monosubstituted C7-Cs- R" is selected from the group consisting of hydrogen, aralkyl, unsubstituted or at least monosubstituted C-Co-alkyl, OR, wherein the Substituents are selected from the group con- C(O)OR, F, Cl, Br, I and NO, sisting of F, Cl, Br, I, C-C-alkyl and OR, 5 wherein the Substituents are selected from the group con wherein sisting of F, Cl, Br, I, OH, NH and Cs-Co-aryl, R is C-C-alkyl. wherein Inafurther particularly preferred embodimentathiolcom- R2 is selected from the group consisting of hydrogen, pound (III) is used, wherein the substituents have the follow- unsubstituted or at least monosubstituted C-Co-alkyl 1ng mean1ngs: 10 and unsubstituted or at least monosubstituted Cs-Co R is unsubstituted or at least monosubstituted Cs-C2- aryl, "Skein the Substituents are selected from the group con wherein the Substituents are selected from the group con sisting of F, Cl, Br, I, C-C-alkyl and OR, g of E. Cl, Br, I, OH, NH, C-Co-alkyl and wherein 15 5-O-o-aryl R" is C-C-alkyl. R is selected from the group consisting of unsubstituted or Particular preference is given to a thiol compound of the at least monosubstituted Cs-Co-alkyl, unsubstituted or at general formula (III) selected from the group consisting of least monosubstituted Cs-Co-aryl and unsubstituted or at n-octadecanethiol, n-octanethiol, n-dodecanethiol, 2-tert-bu least monosubstituted Co-Co-aralkyl, tyl-benzylmercaptan, 3-tert-butyl-benzylmercaptain and 20 wherein the Substituents are selected from the group con 4-tert-butyl-benzylmercaptan. sisting of F, Cl, Br, I, OH, NH, C, -Co-alkyl and OR, Within the context of the present invention, the term wherein “aralkyl”, as for example defined above for the radical R in R" is hydrogen or C1-Co-alkyl. formula (III), means that the substituent is an alkyl radical that In a preferred embodiment of the present invention an is in turn substituted with an aryl radical. In other words, the 25 intermediate (IV) is formed, where the Substituents have the term “aralkyl describes an alkylene that is substituted with following meanings: an aryl radical. The aryl radical may be for example an arylas R" is selected from the group consisting of hydrogen, per the above definitions. C-C-alkyl, OR, C(O)OR, C1, Br, I and NO, Methods for the preparation of a thiol compound (III) are wherein known to the skilled person. 30 R is hydrogen or C-C-alkyl: According to the present invention step a), the reaction of R is selected from the group consisting of unsubstituted or the 2-halobenzonitrile compound (II) with the thiol com- at least monosubstituted Cs-C-alkyl, unsubstituted or at pound (III), is carried out in the presence of at least one base least monosubstituted C-C-aryl and unsubstituted or at (B). least monosubstituted C7-Cs-aralkyl, Suitable at least one bases (B), that can be used in step a) of 35 wherein the Substituents are selected from the group con the present invention, are known to the skilled person. sisting of F, Cl, Br, I, OH, NH, C-C-alkyl and OR, At least one base (B) within the context of the present wherein invention means precisely one base and also a mixture of two R" is hydrogen or C-C-alkyl. or more bases. Preferably the at least one base (B) comprises In a particularly preferred embodiment of the present a base selected from the group consisting of metal hydrox- 40 invention an intermediate (IV) is formed, where the substitu ides, metal carbonates and metal alkoholates. Particularly ents have the following meanings: preferably the at least one base (B) comprises a base selected R" is selected from the group consisting of hydrogen, from the group consisting of alkali metal hydroxides, alkali methyl, ethyl, tert-butyl, methoxy, carboxy, methoxy carbo metal carbonates and alkali metal alkoholates. More prefer- nyl, ethoxy carbonyl, propoxy carbonyl, Cl and NO; ably the at least one base (B) comprises a base selected from 45 R is unsubstituted or at least monosubstituted Cs-C22 the group consisting of sodium hydroxide, potassium hydrox- alkyl or unsubstituted or at least monosubstituted C7-C8 ide, Sodium carbonate, potassium carbonate, sodium methy- aralkyl, late and sodium ethylate. Most preferably the at least one base wherein the Substituents are selected from the group con (B) comprises sodium hydroxide. sisting of F, Cl, Br, I, C-C-alkyl and OR, In a further preferred embodiment of the present invention, 50 wherein the at least one base (B) is sodium hydroxide. In a most R" is C-C-alkyl. preferred embodiment of the present invention, the at least It is known to the skilled person that R' and R in formula one base (B2) is a solution of 20 to 50% by weight of sodium (IV) is the same R' and R as stated above for formula (II). hydroxide in water, based on the total amount of sodium Consequently, R and R in formula (IV) and in formula (II) hydroxide and water. 55 have the same meanings and preferences. During the reaction of the 2-halobenzonitrile compound Furthermore, it is known to the skilled person that R and (II) with the thiol compound (III) in the presence of the at least R" in formula (IV) is the same R and R as stated above for one base (B) an intermediate (IV) is formed formula (III). Consequently, RandR' informula (IV) and in formula (III) have the same meanings and preferences. 60 In step a) the molar ratio of the 2-halobenzonitrile com (IV) pound (II) to the thiol compound (III) is usually in the range 21 CN of from 1:0.8 to 1:3, preferably of from 1:1 to 1:3 and par ticularly preferably of from 1:1 to 1:1.2. The molar ratio of the 2-halobenzonitrile compound (II) to SR3, 65 the at least one base (B) is generally in the range of from 1:0.8 to 1:3.5 preferably of from 1:0.8 to 1:1.5 and particularly preferably of from 1:1.03 to 1:1.2. US 9,334,248 B2 7 8 In one embodiment of the present invention step a) is The weight ratio of the aqueous solvent to the organic carried out under an inertgas atmosphere. Suitable inert gases solvent is usually in the range of from 1:0.5 to 1:10, if a are known to the skilled person. Preferred inert gases are for heterogeneous solvent system is used in step a). example nitrogen or argon. The molar ratio of the 2-halobenzonitril compound (II) to In one embodiment of the present invention step a) is the organic solvent is preferably in the range of from 1:0 to 1:4 carried out in the presence of a heterogeneous solvent system. and particularly preferably of from 1:0 to 1:1. A heterogeneous solvent system within the present invention In one embodiment of the present invention step a) is means that at least one aqueous solvent and at least one carried out in the presence of a heterogeneous solvent system organic solvent, are used, which are immiscible in each other. and furthermore at least one phase transfer catalyst is used. 10 Preferably the at least one phase transfer catalyst is Consequently a heterogeneous solvent system means that two selected from the group consisting of quaternary ammonium liquid phases are present. salts, quaternary phosphonium salts and crown ethers. Another object of the present invention is therefore a Another object of the present invention is therefore a method, wherein step a) is carried out in the presence of a method, wherein step a) is carried out in the presence of at heterogeneous solvent system, comprising an aqueous sol 15 least one phase transfer catalyst selected from the group con vent and an organic solvent. sisting of quaternary ammonium salts, quaternary phospho An organic solvent within the present invention means nium salts and crown ethers. precisely one organic solvent and also mixtures of two or Suitable quaternary ammonium salts are known to the more organic solvents. skilled person. For example, the quaternary ammonia Salt can An aqueous solvent within the present invention means a be selected from the group consisting of benzyltriethylam Solvent that comprises water and optionally at least one fur monium bromide, benzyltriethylammonium chloride, ben ther solvent that is miscible with water. In a preferred embodi Zyltrimethylammonium bromide, benzyltrimethylammo ment the aqueous solvent comprises at least 70% by weight, nium chloride, hexadecyltriethylammonium bromide, in particular at least 80% by weight and more preferably at hexadecyltriethylammonium chloride, hexadecyltrimethy least 90% by weight of water based on the total amount of the 25 lammonium bromide, hexadecyltrimethylammonium chlo aqueous solvent. In a particularly preferred embodiment the ride, dodecyltrimethylammonium bromide, dodecyltrim aqueous solvent consists of water. ethylammonium chloride, octyltriethylammonium bromide, Suitable organic solvents that can be comprised in the octyltriethylammonium chloride, tetra-butylammonium bro heterogeneous solvent system are known to the skilled per mide, tetra-butylammonium chloride, tetraethylammonium 30 bromide, tetraethylammonium chloride, trioctylmethylam son. Preferably, the organic solvent comprised in the hetero monium bromide, trioctylmethylammonium chloride, trieth geneous solvent system is at least one organic solvent ylphenylammonium bromide and triethylphenylammonium selected from the group consisting of benzene, toluene, chloride. Xylenes, aryl halides and Cs-Ca-alkanes. Preferably the quaternary ammonium salt is selected from Another object of the present invention is therefore a 35 the group consisting of hexadecyltrimethylammonium bro method, wherein the organic Solvent comprised in the hetero mide, hexadecyltrimethylammonium chloride, dodecyltrim geneous solvent system in step a) is selected from the group ethylammonium bromide, dodecyltrimethylammonium consisting of benzene, toluene, Xylenes, aryl halides and chloride, octyltriethylammonium bromide, tetra-butylammo Cs-Ca-alkanes. nium bromide, tetra-butylammonium chloride, triethylphe Xylenes comprise 1,2-dimethylbenzene, 1,3-dimethylben 40 nylammonium bromide and triethylphenylammonium chlo Zene and 1,4-dimethylbenzene. ride. Suitable aryl halides are known to the skilled person. Pre Suitable quaternary phosphonium salts are known to the ferred aryl halides within the present invention are selected skilled person. Preferably the quaternary phosphonium salt is from the group consisting of chlorobenzene, 1,2-dichlo selected from the group consisting of hexadecyltriethylphos robenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene and 45 phonium bromide, hexadecyltriethylphosphonium chloride, mixtures thereof. hexadecyltributylphosphonium bromide, hexadecyltribu Cs-Ca-alkanes are alkanes having a carbon atom number tylphosphonium chloride, tetra-butylphosphonium bromide, offrom 5 to 14. The alkanes can be linear or branched and also tetra-butylphosphonium chloride, trioctylethylphosphonium optionally cyclic. Alkanes which have both a cyclic compo bromide, trioctylethylphosphonium chloride, tetraphe nent and also a linear component likewise fall under this 50 nylphosphonium bromide, tetraphenylphosphonium chlo definition. Preferred Cs-Ca-alkanes are selected from the ride, hexadecyltrimethylphosphonium chloride and hexade group consisting of n-hexane, n-heptane, cyclohexane and cyltrimethylphosphonium bromide. methylcyclohexane. Particularly preferably the quaternary phosphonium salt is In a further preferred embodiment the organic solvent com selected from the group consisting of tetra-butylphospho prised in the heterogeneous solvent system in which step a) is 55 nium bromide, tetra-butylphosphonium chloride and hexade carried out comprises at least one organic solvent selected cyltrimethylphosphonium chloride. from the group consisting of benzene, toluene, Xylenes, Suitable crown ethers are known to the skilled person. n-hexane, n-heptane, cyclohexane, methyl cyclohexane, Preferably the crown ether is selected from the group consist chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene ing of 18-crown-6, dibenzo-18-crown-6, benzo-18-crown-6 and 1,4-dichlorobenzene. 60 and dicyclohexyl-18-crown-6. In a particularly preferred embodiment, the organic solvent Particularly preferably the crown ether is selected from the comprises chlorobenzene. Preferably the organic solvent group consisting of 18-crown-6, dibenzo-18-crown-6 and comprises at least 70% by weight, in particular at least 80% dicyclohexyl-18-crown-6. by weight and more preferably at least 90% by weight of Therefore, in a particularly preferred embodiment step a) is chlorobenzene based on the total amount of the organic Sol 65 carried out in the presence of at least one phase transfer vent. Most preferably, the organic solvent consists of chlo catalyst selected from the group consisting of hexadecyltri robenzene. methylammonium bromide, hexadecyltrimethylammonium US 9,334,248 B2 9 10 chloride, dodecyltrimethylammonium bromide, dodecyltri In another preferred embodiment, step a) is carried out in methylammonium chloride, octyltriethylammonium bro the presence of a homogeneous solvent system and at a pres mide, tetra-butylammonium bromide, tetra-butylammonium sure of from 0.1 to 100000 bar, particularly preferably from chloride, triethylphenylammonium bromide, triethylpheny 100 to 10000 bar. lammonium chloride, tetrabutylphosphonium bromide, tet In another preferred embodiment step a) is carried out in rabutylphosphonium chloride, hexadecyltrimethylphospho the presence of a homogeneous solvent system and the reac nium chloride, 18-crown-6, dibenzo-18-crown-6 and tion time is in the range of from 1 to 10 hours. dicyclohexyl-18-crown-6. In step a) the intermediate (IV) is formed. In a most preferred embodiment step a) is carried out in the In one embodiment of the present invention the intermedi presence of at least one phase transfer catalyst selected from 10 ate (IV) is isolated after step a) and before step b). the group consisting of tetra-butylammonium bromide and Methods to isolate the intermediate (IV) are known to the tetra-butylammonium chloride. skilled person. For example, the intermediate (IV) can be The weight ratio of the phase transfer catalyst to the 2-ha isolated by crystallization or by phase separation. lobenzonitrile compound (II) is normally in the range of from 15 Preferably, the intermediate (IV) is isolated by phase sepa 0.02:1 to 0.4:1, preferably of from 0.05:1 to 0.15:1. ration. If a heterogeneous solvent system is used in step a), the In a further embodiment of the present invention step b) temperature during step a) depends on the heterogeneous directly follows step a) without isolating the intermediate Solvent system. Usually, the temperature in step a) is below (IV). the boiling temperature of the heterogeneous solvent system It is known to the skilled person that in step a) during the at the pressure at which step a) is carried out and above the reaction of the 2-halobenzonitrile compound (II) with the melting temperature of the heterogeneous solvent system at thiol compound (III) not only the intermediate (IV) is formed, the pressure at which step a) is carried out. but also by-products are formed. Typical by-products formed In one embodiment of the present invention step a) is in step a) are for example hydrogen halides. carried out in the presence of a heterogeneous solvent system 25 Step b) and the reaction temperature is in the range of from 20 to 120° In step b) the intermediate (IV) obtained in step a) is C., preferably of from 30 to 100° C. and more preferably of reacted with a halogenation agent in the presence of water to from 50 to 75° C. form a reaction mixture (RM). Step a) can be carried out at any pressure. It can be carried Within the present invention "a halogenation agent’ means out at positive pressure as well as at negative pressure. In a 30 precisely one halogenation agent but also a mixture of two or preferred embodiment, Stepa) is carried out in the presence of more halogenation agents. a heterogeneous solvent system and at a pressure of from 0.1 Suitable halogenation agents are known to the skilled per to 100000 bar, particularly preferably from 100 to 10000bar. son. Preferably, the halogenation agent is selected from the In another preferred embodiment of the present invention group consisting of chlorine, bromine, Sulfuryl chloride and step a) is carried out in the presence of a heterogeneous 35 sulfuryl bromide. Solvent system and the reaction time is in the range of from Another object of the present invention is therefore a 0.5 to 40 hours, preferably of from 0.5 to 25 hours and method, wherein in step b) the halogenation agent is selected particularly preferably of from 2 to 12 hours. from the group consisting of chlorine, bromine, Sulfuryl chlo In another preferred embodiment of the present invention ride and sulfuryl bromide. Stepa) is carried out in the presence of a homogeneous solvent 40 Sulfuryl chloride and chlorine are particularly preferred as system. A homogeneous solvent system means that at least halogenation agent. one solvent is used. If two or more solvents are used then the In one embodiment of the present invention the chlorine two or more solvents are fully miscible. Consequently, a used as a halogenation agent is generated in-situ by oxidizing homogeneous solvent system means that only one liquid a chloride. The bromine as well can be generated in-situ by phase is present. 45 oxidizing a bromide. Methods to oxidize a chloride and/or a In one embodiment step a) is carried out in the presence of bromide are known to the skilled person. a homogeneous solvent system comprising at least one polar In one embodiment of the present invention the halogena aprotic solvent. tion agent and the water are added gradually and simulta Another object of the present invention is therefore a neously to the intermediate (IV). method, wherein step a) is carried out in the presence of a 50 In another embodiment the water is already present when homogeneous solvent system, comprising at least one polar the halogenation agent is added to the intermediate (IV). aprotic solvent. The molar ratio of the halogenation agent to the interme Preferably, the at least one polar aprotic solvent is selected diate (IV) is usually in a range of from 0.8:1 to 3:1, preferably from the group consisting of N-methylpyrrolidone, dimethyl of from 1:1 to 1.5:1. sulfoxide, N,N-dimethylformamide, N,N-diethylformamide 55 The molar ratio of the water to the intermediate (IV) is and N-ethyl pyrrolidone. usually in the range of from 1:1 to 5:1, preferably of from 1:1 If a homogeneous solvent system is used in step a), the to 3:1. temperature during step a) depends on the homogeneous sol Step b) is usually carried out in the presence of a solvent. vent system. Usually, the temperature in step a) is below the Suitable solvents are known to the skilled person. Preferably boiling temperature of the homogeneous solvent system at 60 the solvent is inert to the reaction carried out in step b). the pressure at which step a) is carried out and above the In a preferred embodiment step b) is carried out in the melting temperature of the homogeneous solvent system at presence of an organic solvent. Suitable organic solvents in the pressure at which step a) is carried out. which step b) can be carried out are known to the skilled In a further preferred embodiment step a) is carried out in person. Preferably, the organic solvent in which step b) is the presence of a homogeneous solvent system and the reac 65 carried out is at least one organic solvent selected from the tion temperature is in the range of from 0 to 200° C., prefer group consisting of benzene, toluene, Xylenes, aryl halides, ably of from 30 to 150° C. Cs-Ca-alkanes and alkyl halides. US 9,334,248 B2 11 12 Another object of the present invention is therefore a wherein the Substituents are selected from the group con method wherein step b) is carried out in the presence of an sisting of F, Cl, Br, I, OH, NH, C-Co-alkyl and organic solvent and the organic Solvent is selected from the Cs-Co-aryl. group consisting of benzene, toluene, Xylenes, aryl halides, In a preferred embodiment of the present invention the Cs-Ca-alkanes, and alkyl halides. 5 reaction mixture (RM) obtained in step b) comprises the Xylenes comprise 1,2-dimethylbenzene, 1,3-dimethylben 1,2-benzisothiazolin-3-one compound (I), wherein the sub Zene and 1,4-dimethylbenzene. stituents have the following meanings: Suitable aryl halides are known to the skilled person. Pre R" is selected from the group consisting of hydrogen, ferred aryl halides within the present invention are selected C-C-alkyl, OR, C(O)CR, Cl, Br, I and NO, from the group consisting of chlorobenzene, 1,2-dichlo 10 wherein robenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene and mixtures thereof. R is hydrogen or C-C-alkyl. Suitable alkyl halides are as well known to the skilled In a particularly preferred embodiment of the present person. Within the present invention preferred alkyl halides invention the reaction mixture (RM) obtained in step b) com are selected from the group consisting of chloroform (IU 15 prises the 1,2-benzisothiazolin-3-one compound (I), wherein PAC-name: Trichlormethane) and 1,2-dichlorethane. the Substituents have the following meanings: Cs-Ca-alkanes are alkanes having a carbon atom number R" is selected from the group consisting of hydrogen, offrom 5 to 14. The alkanes can be linear or branched and also methyl, ethyl, tert-butyl, methoxy, carboxy, methoxy carbo optionally cyclic. Alkanes which have both a cyclic compo nyl, ethoxy carbonyl, propoxy carbonyl, Cl and NO. nent and also a linear component likewise fall under this Preferably the reaction mixture (RM) obtained in step b) definition. Preferred C-C-alkanes are selected from the comprises the 1,2-benzisothiazolin-3-one compound (I) group consisting of n-hexane, n-heptane, cyclohexane and selected from the group consisting of 1,2-benzisothiazolin methylcyclohexane. 3-one (BIT), 3-methyl-1,2-benzisothiazolin-3-one, 5-tert-bu In a further preferred embodiment the organic solvent in tyl-1,2-benzisothiazolin-3-one, 4-methoxy-1,2-benzisothia which step b) is carried out comprises at least one organic 25 Zolin-3-one, 3-nitro 1,2-benzisothiazolin-3-one, Solvent selected from the group consisting of benzene, tolu 4-methoxycarbonyl-1,2-benzisothiazolin-3-one, 4-carboxy ene, Xylenes, n-hexane, n-heptane, cyclohexane, methyl 1,2-benzisothiazolin-3-one and 4-chloro-1,2-benzisothiazo cyclohexane, chlorobenzene, 1,2-dichlorobenzene, 1.3- lin-3-one. dichlorobenzene, 1,4-dichlorobenzene, chloroform (IUPAC In an especially preferred embodiment, the reaction mix name: Trichlormethane) and 1,2-dichlorethane. 30 If an organic solvent is used in step b), the reaction tem ture (RM) obtained in step b) comprises the 1,2-benzisothia perature in stepb) depends on the organic solvent. Usually the Zolin-3-one compound (I) and the 1,2-benzisothiazolin-3-one reaction temperature in step b) is below the boiling tempera compound (I) comprises 1,2-benzisothiazolin-3-one (BIT). ture of the organic solvent at the pressure at which step b) is It is known to the skilled person, that R' and R in formula carried out and above the melting temperature of the organic 35 (I) is the same R' and R as stated above for formula (II) and solvent at the pressure at which step b) is carried out. also for formula (IV). Consequently, RandR informula (I), Step b) is preferably carried out at a temperature in the in formula (II) and in formula (IV) have the same meanings range of from 0 to 50° C., particularly preferably of from 10 and preferences. to 40° C. Furthermore, the reaction mixture (RM) comprises the The reaction time in step b) is preferably in the range of 40 halide compound (V) from 1 to 20 hours and particularly preferably in the range of from 4 to 12 hours. R XI (V), In step b) the reaction mixture (RM) is formed, which wherein comprises the 1,2-benzisothiazolin-3-one compound (I) and R is selected from the group consisting of unsubstituted or the halide compound (V). 45 at least monosubstituted Cs-Co-alkyl, unsubstituted or at The reaction mixture (RM) comprises the 1,2-benzisothia least monosubstituted Cs-Co-aryl and unsubstituted or at Zolin-3-one compound (I) least monosubstituted C-Co-aralkyl, wherein the Substituents are selected from the group con sisting of F, Cl, Br, I, OH, NH, C, -Co-alkyl and OR, 50 wherein O (I) R" is hydrogen or C1-Co-alkyl: X is C1 or Br. RI 1N NH, In a preferred embodiment the reaction mixture (RM) com 21 s/ prises the halide compound (V), wherein the substituents 55 have the following meanings: R is selected from the group consisting of unsubstituted or wherein at least monosubstituted C-C2-alkyl, unsubstituted or at R" is selected from the group consisting of hydrogen, least monosubstituted Cs-Ca-aryl and unsubstituted or at unsubstituted or at least monosubstituted C-Co-alkyl, OR, least monosubstituted C7-Cs-aralkyl, C(O)CR, F, Cl, Br, I and NO, 60 wherein the Substituents are selected from the group con wherein the Substituents are selected from the group con sisting of F, Cl, Br, I, OH, NH, C-C-alkyl and OR, sisting of F, Cl, Br, I, OH, NH and Cs-Co-aryl, wherein wherein R" is hydrogen or C-C-alkyl: R is selected from the group consisting of hydrogen, X' is C1 or Br. unsubstituted or at least monosubstituted C-Co-alkyl 65 In a particularly preferred embodiment the reaction mix and unsubstituted or at least monosubstituted Cs-Co ture (RM) comprises the halide compound (V), wherein the aryl, Substituents have the following meanings: US 9,334,248 B2 13 14 R is unsubstituted or at least monosubstituted Cs-C2 hydroxide. In a further preferred embodiment of the present alkyl or unsubstituted or at least monosubstituted C7-Cs invention, the second base (B2) is sodium hydroxide. In a aralkyl, most preferred embodiment of the present invention, the sec wherein the Substituents are selected from the group con ond base (B2) is a solution of 20 to 50% by weight of sodium sisting of F, Cl, Br, I, C-Cs-alkyl and OR, hydroxide in water, based on the total amount of sodium wherein hydroxide and water. R is C-C-alkyl: An object of the present invention is therefore a method X' is C1 or Br. wherein the second base (B2) is selected from the group In a further particularly preferred embodiment the reaction consisting of metal hydroxides, metal carbonates and metal mixture (RM) comprises the halide compound (V), wherein 10 the Substituents have the following meanings: alkoholates. R is unsubstituted or at least monosubstituted Cs-C2 Another object of the present invention is therefore a alkyl, method wherein the base (B) and optionally the second base wherein the Substituents are selected from the group con (B2) are independent of each other selected from the group sisting of F, Cl, Br, I, C-C-alkyl and OR, 15 consisting of metal hydroxides, metal carbonates and metal wherein alkoholates. R" is C-C-alkyl; The molar ratio of the 1,2-benzisothiazolin-3-one com X' is C1 or Br. pound (I) to the second base (B2) added in step c) is in one Particularly preferably the reaction mixture (RM) com embodiment of the present invention in the range of from 1:1 prises a halide compound (V) selected from the group con to 1:3. sisting of n-octadecylchlorid, n-octadecylbromid, n-octyl The second base (B2) in step c) is preferably added in an chlorid, n-octylbromid, dodecylchloride, docecylbromide, amount so that the pH-value of the first phase obtained in step 2-tert-butyl-benzylchloride, 2-tert-butyl-benzylbromide, c) is in the range of from 8 to 11, preferably of from 9 to 10. 3-tert-butyl-benzylchloride, 3-tert-butyl-benzylbromide, The molar ratio of the 1,2-benzisothiazolin-3-one com 4-tert-butyl-benzylchloride and 4-tert-butyl-benzylbromide. 25 pound (I) to the water added in step c) is in one embodiment It is known to the skilled person that the meaning of the of the present invention in the range of from 1:1 to 1:8. substituent X" in formula (V) depends on the halogenation preferably from 1:2 to 1:4. agent used in step b). If chlorine or sulfuryl chloride is used as The person skilled in the art knows, that when adding water halogenation agent, then X" is C1. If bromine or sulfuryl and the second base (B2) in step c) to the reaction mixture bromide is used as halogenation agent, then X is Br. 30 (RM) at least part of the 1,2-benzisothiazolin-3-one com Furthermore, it is known to the skilled person that R and pound (I) is deprotonated to give a 1,2-benzisothiazolin-3- R" in formula (V) is the same Rand Ras stated above for one compound metal salt. This 1,2-benzisothiazolin-3-one formula (III) and formula (IV). Consequently, R and R in compound metal salt is soluble in water. formula (V), in formula (III) and in formula (IV) have the In step c) two phases are obtained. The first phase is an same meanings and preferences. 35 aqueous phase, comprising the 1,2-benzisothiazolin-3-one After step b) the 1,2-benzisothiazolin-3-one compound (I) compound metal salt and water. The second phase is an is usually separated from the reaction mixture (RM) formed organic phase, comprising the halide compound (V). in step b). Methods to separate the 1,2-benzisothiazolin-3- If an organic Solvent is used in step b) this organic Solvent one compound (I) from the reaction mixture (RM) are known is as well comprised in the second phase obtained in Step c). to the skilled person. 40 In one embodiment of the present invention step c) is In one embodiment of the present invention step b) is carried out at a temperature in the range of from 40 to 100° C. followed by the following steps: preferably of from 60 to 80° C. and a reaction time in the c) adding water and a second base (B2) to the reaction range of from 0.5 to 4 hours, preferably of from 0.5 to 2 hours. mixture (RM) obtained in step b) to give a first phase, com In a further embodiment of the present invention step c) is prising the 1,2-benzisothiazolin-3-one compound (I) and a 45 carried out at a temperature in the range of from 0 to 40°C., second phase comprising the halide compound (V), preferably of from 10 to 30° C. and a reaction time of from 1 d) separating the first phase from the second phase. to 4 hours, preferably of from 1 to 2 hours. Another object of the present invention is therefore a In step d) the first phase is separated from the second phase. method wherein step b) is followed by the following steps: Methods for the separation of the first phase from the second c) adding water and a second base (B2) to the reaction 50 phase are known to the skilled person. The separation for mixture (RM) obtained in step b) to give a first phase, com example, can take place in a phase separation vessel. prising the 1,2-benzisothioazolin-3-one compound (I) and a In one embodiment of the present invention, after the sepa second phase, comprising the halide compound (V), ration in step d) an acid is added to the first phase. Suitable d) separating the first phase from the second phase. acids are known to the skilled person. For example, the acid A second base (B2) within the context of the present 55 can be selected from the group consisting of hydrochloric invention means precisely one second base and also a mixture acid, Sulfuric acid, nitric acid, acetic acid, oxalic acid, citric of two or more second bases. acid, methanesulfonic acid and mixtures thereof. Particularly Preferably the second base (B2) comprises a base selected preferred, the acid is an aqueous solution of 30% by weight of from the group consisting of metal hydroxides, metal carbon hydrochloric acid. ates and metal alkoholates. Particularly preferably the second 60 The pH-value of the first phase during the addition of the base (B2) comprises a base selected from the group consist acid preferably drops to a value in the range of from 1 to 6, ing of alkali metal hydroxides, alkali metal carbonates and particularly preferably from 3 to 4. alkali metal alkoholates. More preferably the second base When adding acid to the aqueous phase the 1,2-ben (B2) comprises a base selected from the group consisting of Zisothiazolin-3-one compound metal salt is neutralized and Sodium hydroxide, potassium hydroxide, sodium carbonate, 65 the 1,2-benzisothiazolin-3-one compound (I) precipitates and potassium carbonate, Sodium methylate and sodium ethylate. forms crystals. The thus obtained crystals of the 1,2-ben Most preferably the second base (B2) comprises sodium Zisothiazolin-3-one compound (I) can be separated from the US 9,334,248 B2 15 16 water and optionally further solvents comprised in the first sil R. C18HPLC-Column having a pore size of 100 A and a phase by any method known to the skilled person, for particle size of 7um was used. The length of the column was example, by filtration. 250 mm, the inside diameter 4.6 mm. As mobile phase a In a preferred embodiment step d) is followed by step e) in 1:1-mixture of deionized water and methanol was used. 100 which the halide compound (V) comprised in the second 5 phase is reacted with a sulfide compound to give a thiol mg of the 1,2-benzisothiazolin-3-one (I) were dissolved in the compound (III). mobile phase to give a total of 25 ml of the sample. The flow Another object of the present invention is therefore a rate was 0.8 ml/min at a temperature of 25°C. The injection method, wherein step d) is followed by step e), in which the volume was 20 ul, the run time 20 min. halide compound (V) comprised in the second phase is reacted with a sulfide compound to give a thiol compound 10 Example 1 (III). Suitable sulfide compounds are known to the skilled per Under nitrogen atmosphere, 100 g of chlorobenzene, 100 g son. Preferably the sulfide compound in step e) is selected of 2-chlorobenzonitrile (II), 219 g of n-octanethiol (III) and 4 from the group consisting of thiourea, metal bisulfide and g of tetra-butylammonium bromide are added into a 1000 ml metal sufide. More preferably, the sulfide compound in stepe) 15 four-necked flask with a stirrer, a thermometer, a dropping is selected from the group consisting of thiourea, alkaline funnel and a condenser. At a temperature in the range of from metal bisulfide and alkaline metal sulfide. Particularly pref 65 to 70° C. according to step a), 98.7 g of a 32% by weight erably the sulfide compound in step e) is selected from the sodium hydroxide solution in water are added dropwise. After group consisting of thiourea, sodium bisulfide and sodium the completion of the dropwise addition, the mixture is fur sulfide. In a further preferred embodiment, the sulfide com ther reacted for 4 hours. The mixture is separated into an pound is solution of 20 to 70% by weight of sodium bisulfide aqueous layer and an organic layer. The organic layer com in water, based on the total weight of the sodium bisulfide and prises 2-(octadecylthio)benzonitrile (IV) (381 g). the water. According to stepb) 381 g of the organic layer, comprising Another object of the present invention is therefore the 2-(octadecylthio)benzonitrile (IV) obtained in step a), 100 g method wherein the sulfide compound in step e) is selected 25 from the group consisting of thiourea, a metal bisulfide and a of chlorobenzene and 32 g of water are added into a 1000 ml metal sulfide. four-necked flask with a stirrer, a thermometer and a con The molar ratio of the halide compound of the general denser. At a temperature in the range of from 20 to 30°C., 53 formula (V) to the sulfide compound is preferably in the range g chlorine are blown into the mixture over a period of 2 hours. of from 1:1 to 1:3, particularly from 1:1.1 to 1:2. The mixture is further heated to a temperature in the range of Step e) is preferably carried out in the presence of a het 30 from 60 to 65° C. and then allowed to further react for 1 h. erogeneous solvent system. Concerning the heterogeneous During the reaction the reaction mixture (RM) is formed. Solvent system the same embodiments and preferences as After completion of the reaction the reaction mixture (RM) is described above for the heterogeneous solvent system in cooled to a temperature in the range of from 20 to 30° C. and which step a) can be carried out hold true. Preferably, in step according to step c) 200 g of water are added to the reaction e) a phase transfer catalyst is used. Concerning the phase 35 mixture (RM). A 32% by weight sodium hydroxide solution transfer catalyst the embodiments and preferences described is added dropwise to the reaction mixture (RM) to give a above for the phase transfer catalyst used in step a) hold true pH-value in the range of from 9 to 10. The mixture is heated as well. to a temperature in the range of from 60 to 65° C. and accord Another object of the present invention is therefore the ing to step d) separated into a first phase and a second phase. method wherein step c) is carried out in the presence of a 40 The first phase is cooled to a temperature in the range of from heterogeneous solvent system, comprising an aqueous sol 20 to 30° C. A 31% by weight hydrochloric acid solution is vent and an organic solvent. added dropwise to the first phase to give a pH-value in the Step e) is preferably carried out at a temperature in the range of from 3 to 4. Crystals of 1,2-benzisothiazolin-3-one range of from 30 to 90° C. preferably of from 45 to 75° C. precipitate. The precipitated crystals are collected by filtra The reaction time in step e) usually is in the range of from 2 to 25 hours preferably of from 5 to 15 hours. 45 tion, washed with water, and dried to obtain 1,2-benzisothia In a particular preferred embodiment the thiol compound Zolin-3-one (I) (102 g, HPLCD99%), the yield to 2-chlo (III) obtained in step e) is recycled to step a). robenzonitrile (II) is 93.5%. Another object of the present invention is therefore a The second phase (420 g) is distilled to obtain 1-chlorooc method wherein the thiol compound (III) obtained in step e) tadecane (V) (210 g). 210 g of the 1-chlorooctadecane (V), is recycled to step a). 50 200 g of chlorobenzene, 180g of a 32% by weight sodium In one embodiment of the present invention the thiol com bisulfide solution in water and 6 g of tetra-butylammonium pound (III) obtained in step e) is recycled to step a) without bromide are added into a 1000 ml four-necked flask with a any further separation and the heterogeneous solvent system stirrer, athermometeranda condenser. At a temperature in the used in step e) is as well recycled to step a) and can be used range of from 65 to 70° C., the mixture is reacted for 16h. The therein. 55 mixture is separated into an aqueous layer and an organic The recycling of at least the thiol compound (III) obtained layer. The organic layer is n-octadecanethiol (III) (405 g). in step e) to step a) makes the present invention highly cost efficient and time saving. Example 2 Furthermore, the thiol compound (III) has a high molecular weight and therefore a low volatility and a light odor. This 60 Under nitrogen atmosphere, 100 g of chlorobenzene, 100 g reduces the safety and environmental problems in compari of 2-chlorobenzonitrile (II), 112 g of n-octanethiol (III) and 4 son to the methods described in the state of the art. g of tetra-butylammonium bromide are added into a 500 ml four-necked flask with a stirrer, a thermometer, a dropping EXAMPLES funnel and a condenser. At a temperature in the range of from 65 65 to 70° C. according to step a), 98 g of a 32% by weight For the HPLC-measurements (high performance liquid sodium hydroxide solution in water are added dropwise. After chromatography) a FULI 2000 HPLC-system with a Kroma the completion of the dropwise addition, the mixture is fur US 9,334,248 B2 17 18 ther reacted for 4 hours. The mixture is separated into an ing to step d) separated into a first phase and a second phase. aqueous layer and an organic layer. The organic layer com The first phase is cooled to a temperature in the range of from prises 2-(octylthio)benzonitrile (IV) (279 g). 20 to 30° C. A 31% by weight hydrochloric acid solution is According to stepb) 279 g of the organic layer, comprising added dropwise to the first phase to give a pH-value in the the 2-(octylthio)benzonitrile (IV) obtained in step a), 200g of 5 range of from 3 to 4. Crystals of 1,2-benzisothiazolin-3-one chlorobenzene and 32 g of water are added into a 1000 ml (I) precipitate. The precipitated crystals are collected by fil four-necked flask with a stirrer, a thermometer and a con tration, washed with water, and dried to obtain 1,2-ben denser. At a temperature in the range of from 20 to 30°C., 54 Zisothiazolin-3-one (I) (100 g, HPLCD99%), the yield to g chlorine are blown into the mixture over a period of 2 hours. 2-chlorobenzonitrile (II) is 91.7%. The mixture is further heated to a temperature in the range of 10 The second phase (450 g) is distilled to obtain 1-chloro from 60 to 65° C. and then allowed to further react for 1 h. dodecane (V) (145g). 145g of the 1-chlorododecane (V), 100 During the reaction the reaction mixture (RM) is formed. After completion of the reaction the reaction mixture (RM) is g of chlorobenzene, 160 g of a 32% by weight sodium bisul cooled to a temperature in the range of from 20 to 30° C. and fide solution in water and 4 g of tetra-butylammonium bro according to step c) 200 g of water are added to the reaction 15 mide are added into a 1000 ml four-necked flask with a stirrer, mixture (RM). A 32% by weight sodium hydroxide solution athermometer and a condenser. At a temperature in the range is added dropwise to the reaction mixture (RM) to give a of from 65 to 70° C., the mixture is reacted for 12 h. The pH-value in the range of from 9 to 10. The mixture is heated mixture is separated into an aqueous layer and an organic to a temperature in the range of from 60 to 65° C. and accord layer. The organic layer is n-dodecanethiol (III) (240 g). ing to step d) separated into a first phase and a second phase. The first phase is cooled to a temperature in the range of from Example 4 20 to 30° C. A 31% by weight hydrochloric acid solution is added dropwise to the first phase to give a pH-value in the Under nitrogen atmosphere, 100 g of chlorobenzene, 100 g range of from 3 to 4. Crystals of 1,2-benzisothiazolin-3-one of 2-chlorobenzonitrile (II), 240 g of the n-dodecanethiol (III) (I) precipitate. The precipitated crystals are collected by fil 25 obtained in example 3, 24 g of n-dodecanethiol (III) and 4 g of tration, washed with water, and dried to obtain 1,2-ben tetra-butylammonium bromide are added into a 500 ml four Zisothiazolin-3-one (I) (103 g, HPLCD99%), the yield to necked flask with a stirrer, a thermometer, a dropping funnel 2-chlorobenzonitrile (II) is 94.5%. and a condenser. At a temperature in the range of from 50 to The second phase (310 g) is distilled to obtain 1-chlorooc 55° C. according to step a), 98 g of a 32% by weight sodium tane (V) (100 g). 100g of the 1-chlorooctadecane (V), 200 g 30 hydroxide solution in water are added dropwise. After the of chlorobenzene, 167 g of a 32% by weight sodium bisulfide completion of the dropwise addition, the mixture is further solution in water and 4 g of tetra-butylammonium bromide reacted for 4 hours. The mixture is separated into an aqueous are added into a 1000 ml four-necked flask with a stirrer, a layer and an organic layer. The organic layer comprises thermometerand a condenser. At a temperature in the range of 2-(dodecylthio)benzonitrile (IV) (315 g). from 65 to 70° C., the mixture is reacted for 12h. The mixture 35 According to stepb)315g of the organic layer, comprising is separated into an aqueous layer and an organic layer. The the 2-(dodecylthio)benzonitrile (IV) obtained in step a), 200 organic layer is n-octanethiol (Ill) (196 g). g of chlorobenzene and 40g of water are added into a 1000 ml four-necked flask with a stirrer, a thermometer and a con Example 3 denser. 40 At a temperature in the range of from 20 to 30° C., 54 g Under nitrogen atmosphere, 100g of chlorobenzene, 100 g chlorine are blown into the mixture over a period of 2 hours. of 2-chlorobenzonitrile (II), 154 g of n-dodecanethiol (Ill) The mixture is further heated to a temperature in the range of and 4 g of tetra-butylammonium bromide are added into a 500 from 60 to 65° C. and then allowed to further react for 1 h. ml four-necked flask with a stirrer, athermometer, a dropping During the reaction the reaction mixture (RM) is formed. funnel and a condenser. At a temperature in the range of from 45 After completion of the reaction the reaction mixture (RM) is 65 to 70° C. according to step a), 98 g of a 32% by weight cooled to a temperature in the range of from 20 to 30° C. and sodium hydroxide solution in water are added dropwise. After according to step c) 200 g of water are added to the reaction the completion of the dropwise addition, the mixture is fur mixture (RM). A 32% by weight sodium hydroxide solution ther reacted for 4 hours. The mixture is separated into an is added dropwise to the reaction mixture (RM) to give a aqueous layer and an organic layer. The organic layer com 50 pH-value in the range of from 9 to 10. The mixture is heated prises 2-(dodecylthio)benzonitrile (IV) (320 g). to a temperature in the range of from 60 to 65° C. and accord According to stepb)320g of the organic layer, comprising ing to step d) separated into a first phase and a second phase. the 2-(dodecylthio)benzonitrile (IV) obtained in step a), 200 The first phase is cooled to a temperature in the range of from g of chlorobenzene and 30 g of water are added into a 1000 ml 20 to 30° C. A 31% by weight hydrochloric acid solution is four-necked flask with a stirrer, a thermometer and a con 55 added dropwise to the first phase to give a pH-value in the denser. At a temperature in the range of from 20 to 30°C., 54 range of from 3 to 4. Crystals of 1,2-benzisothiazolin-3-one g chlorine are blown into the mixture over a period of 2 hours. (I) precipitate. The precipitated crystals are collected by fil The mixture is further heated to a temperature in the range of tration, washed with water, and dried to obtain 1,2-ben from 60 to 65° C. and then allowed to further react for 1 h. Zisothiazolin-3-one (I) (101 g, HPLCD99%), the yield to During the reaction the reaction mixture (RM) is formed. 60 2-chlorobenzonitrile (II) is 92.7%. After completion of the reaction the reaction mixture (RM) is The second phase (450 g) is distilled to obtain 1-chloro cooled to a temperature in the range of from 20 to 30° C. and dodecane (V) (148 g). 148g of the n-chlorododecane (V), 100 according to step c) 200 g of water are added to the reaction g of chlorobenzene, 160 g of a 32% by weight sodium bisul mixture (RM). A 32% by weight sodium hydroxide solution fide solution in water and 4 g of tetra-butylammonium bro is added dropwise to the reaction mixture (RM) to give a 65 mide are added into a 1000 ml four-necked flask with a stirrer, pH-value in the range of from 9 to 10. The mixture is heated athermometer and a condenser. At a temperature in the range to a temperature in the range of from 60 to 65° C. and accord of from 65 to 70° C., the mixture is reacted for 12 h. The US 9,334,248 B2 19 20 mixture is separated into an aqueous layer and an organic wherein the Substituents are selected from the group con layer. The organic layer is n-dodecanethiol (III) (241 g). sisting of F, Cl, Br, I, OH, NH, and C-C-aryl, wherein Example 5 R is selected from the group consisting of hydrogen, unsubstituted or at least monosubstituted C-Co-alkyl Under nitrogen atmosphere, 100g of chlorobenzene, 100 g and unsubstituted or at least monosubstituted Cs-Co of 2-chlorobenzonitrile (II), 154 g of n-dodecanethiol (III) aryl, and 4 g of tetra-2-butylammonium bromide are added into a wherein the Substituents are selected from the group con 500 ml four-necked flask with a stirrer, a thermometer, a sisting of F, Cl, Br, I, OH, NH, C-Co-alkyl and dropping funnel and a condenser. At a temperature in the 10 Cs-Co-aryl; range of from 65 to 70° C. according to step a), 98 g of a 32% comprising the steps by weight sodium hydroxide solution in water are added a) reacting a 2-halobenzonitrile compound of formula (II) dropwise. After the completion of the dropwise addition, the mixture is further reacted for 4 hours. The mixture is sepa rated into an aqueous layer and an organic layer. The organic 15 layer comprises 2-(dodecylthio)benzonitrile (IV) (320 g). CN (II) According to stepb)320g of the organic layer, comprising 21 s the 2-(dodecylthio)benzonitrile (IV) obtained in step a), 200 R-- g of chlorobenzene and 30 g of water are added into a 1000 ml N X four-necked flask with a stirrer, a thermometer and a con denser. At a temperature in the range of from 20 to 30°C., 100 wherein g sulfuryl chloride are added dropwise to the mixture over a X is selected from the group consisting of F, Cl, Brand I; period of 2 hours. The mixture is further heated to a tempera with a thiol compound of formula (III) ture in the range of from 60 to 65° C. and then allowed to further react for 1 h. During the reaction the reaction mixture 25 R SH (III), (RM) is formed. After completion of the reaction the reaction wherein mixture (RM) is cooled to a temperature in the range of from R is selected from the group consisting of unsubstituted or 20 to 30° C. and according to step c) 200g of water are added at least monosubstituted Cs-Co-alkyl, unsubstituted or to the reaction mixture (RM). A 32% by weight sodium at least monosubstituted Cs-Co-aryl and unsubstituted hydroxide solution is added dropwise to the reaction mixture 30 or at least monosubstituted C-C-aralkyl, (RM) to give a pH-value in the range of from 9 to 10. The wherein the substituents are selected from the group con mixture is heated to a temperature in the range of from 60 to sisting of F, Cl, Br, I, OH, NH, C, -Co-alkyl and OR, 65°C. and according to step d) separated into a first phase and wherein a second phase. The first phase is cooled to a temperature in R" is hydrogen or C1-Co-alkyl; the range of from 20 to 30°C. A 31% by weight hydrochloric 35 acid solution is added dropwise to the first phase to give a in the presence of at least one base (B) to form an interme pH-value in the range of from 3 to 4. Crystals of 1,2-ben diate of formula (IV) Zisothiazolin-3-one (I) precipitate. The precipitated crystals are collected by filtration, washed with water, and dried to (IV) obtain 1,2-benzisothiazolin-3-one (I) (106 g, HPLC-99%), 40 CN the yield to 2-chlorobenzonitrile (II) is 97.2%. The second phase (445 g) is distilled to obtain n-chloro dodecane (V) (143 g). 143 g of then-chlorododecane (V), 100 g of chlorobenzene, 180g of a 32% by weight sodium bisul fide solution in water and 4 g of tetra-butylammonium bro 45 mide are added into a 1000 ml four-necked flask with a stirrer, and athermometer and a condenser. At a temperature in the range b) reacting the intermediate of formula (IV) obtained in of from 65 to 70° C., the mixture is reacted for 12 h. The step a) with a halogenation agent in the presence of water mixture is separated into an aqueous layer and an organic to form a reaction mixture (RM), comprising the 12 layer. The organic layer is n-dodecanethiol (III) (244 g). 50 benzisothiazolin-3-one of formula (I) and a halide com pound of formula (V) The invention claimed is: 1. A method for producing a 12-benzisothiazolin-3-one R3 XI (V), compound of formula (I) wherein 55 X' is C1 or Br. 2. The method according to claim 1, wherein in step b) the (I) halogenation agent is selected from the group consisting of O chlorine, bromine, sulfuryl chloride and sulfuryl bromide. 3. The method according to claim 1, wherein step b) is RI 1N NH, 60 carried out in the presence of an organic solvent and the 21 s/ organic solvent is selected from the group consisting of ben Zene, toluene, Xylenes, aryl halides, Cs-Ca-alkanes, and alkyl halides. wherein 4. The method according to claim 1, wherein step b) is R" is selected from the group consisting of hydrogen, 65 followed by the following steps: unsubstituted or at least monosubstituted C-Co-alkyl, c) adding water and a second base (B2) to the reaction OR, C(O)OR, F, Cl, Br, I and NO, mixture (RM) obtained in step b) to give a first phase, US 9,334,248 B2 21 22 comprising the 1,2-benzisothioazolin-3-one compound 9. The method according to claim 4, wherein step c) is (I) and a second phase, comprising the halide compound carried out in the presence of a heterogeneous solvent system, (V), and comprising an aqueous solvent and an organic solvent. 10. The method according to claim 1, wherein step a) is d) separating the first phase from the second phase. carried out in the presence of a heterogeneous solvent system, 5. The method according to claim 4, wherein step d) is comprising an aqueous solvent and an organic solvent. followed by step e), in which the halide compound (V) com 11. The method according to claim 10, wherein the organic prised in the second phase is reacted with a Sulfide compound Solvent comprised in the heterogeneous solvent system in to give a thiol compound (III). step a) is selected from the group consisting of benzene, toluene, xylenes, aryl halides and Cs-Ca-alkanes. 6. The method according to claim 5, wherein the thiol 10 12. The method according to claim 10, wherein step a) is compound (III) obtained in step e) is recycled to step a). carried out in the presence of at least one phase transfer 7. The method according to claim 1, wherein the base (B) catalyst selected from the group consisting of quaternary and optionally the second base (B2) are independent of each ammonium salts, quaternary phosphonium salts and crown other selected from the group consisting of metal hydroxides, ethers. metal carbonates and metal alkoholates. 15 13. The method according to claim 1, wherein step a) is 8. The method according to claim 5, wherein the sulfide carried out in the presence of a homogeneous solvent system, compound in step e) is selected from the group consisting of comprising at least one polar aprotic solvent. thiourea, a metal bisulfide and a metal sulfide. k k k k k