United States Patent (19) 11 Patent Number: 4,612,378 Bosshard et al. (45) Date of Patent: Sep. 16, 1986 54) PROCESS FOR THE PREPARATION OF Primary Examiner-John Kight B-(BENZOTHIAZOLYLTHIO). AND Assistant Examiner-Garnette D. Draper B-(BENZIMIDAZOLYLTHIO)-CARBOXYIC Attorney, Agent, or Firm-Luther A. R. Hall ACDS 57 ABSTRACT (75) Inventors: Hans Bosshard, Basel; Hans Greuter, The reaction of 2-mercapto-benzothiazole or -benzimid Eiken, both of Switzerland azole with a 9-unsaturated carboxylic acids in a 73) Assignee: Ciba-Geigy Corporation, Ardsley, strongly acid reaction medium gives compounds of the N.Y. formula I (21) Appl. No.: 610,145 R I 22 Filed: May 14, 1984 R N R R2 (30) Foreign Application Priority Data N C-S-C-CH May 14, 1983 GB United Kingdom ................. 8313321 / X R3 COOH 51) Int. Cl............................................. C07D 277/70 R 52 U.S. Cl...... ... 548/170; 548/329 58 Field of Search ................................ 548/170, 329 R (56) References Cited in which X is sulfur or NH, each radical R indepen U.S. PATENT DOCUMENTS dently of one another is H, alkyl, halogenoalkyl, alkoxy, 2,725,364 11/1955 Dozzi .................................. 548/170 alkylthio, alkylsulfonyl, phenyl, alkylphenyl, phenylal 3,499,085 3/1970 Sasse et al. ... ... 548/329 kyl, cycloalkyl, halogen, NO2, CN, COOH, COOalkyl, 4,289,886 9/1981 D'Amico ............................. 548/170 OH or an amino or carbamyl group and R, R2 and R3 independently of one another are H, alkyl, halogenoal FOREIGN PATENT DOCUMENTS kyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, carboxyl 0204-183 11/1983 Japan ................................... 548/170 or unsubstituted or substituted aryl or aralkyl, or Rand 149785 9/1962 U.S.S.R. .............................. 548/127 R2 together are straight-chain or branched alkylene, OTHER PUBLICATIONS which can be substituted by 1 or 2 carboxyl groups. F. B. Zienty et al, J. Org. Chem. 27, 3140 (1962). 11 Claims, No Drawings 4,612,378 1. 2 PROCESS FOR THE PREPARATION OF R II B-(BENZOTHIAZOLYLTHIO)- AND R (3-(BENZIMIDAZOLYLTHIO-CARBOXYLIC N ACDS N C-SH / The present invention relates to a process for the X preparation of aliphatic or cycloaliphatic carboxylic R R acids which are substituted in the 6-position by a heter 10 ocyclic mercapto radical, which comprises reacting an afé-unsaturated carboxylic acid with a heterocyclic with an unsaturated carboxylic acid of the formula III mercaptan in a strongly acid medium. The addition of mercaptains onto af3-unsaturated R1 R2 III acids is known in principle. However, it is usually car 15 R3-C-C-COOH ried out in a basic medium or using basic catalysts. It is assumed that the first step in this reaction, consists of or an anhydride thereof, in a strongly acid medium. addition of the mercaptide anion onto the 3-carbon An alkyl radical R in formulae I and II can be atom of the carboxylic acid. F. B. Zienty et al. (J. Org. straight-chain or branched alkyl and is preferably C1-C12-alkyl, for example methyl, ethyl, propyl, isopro Chem. 27 (1962), 3140) described the addition of various pyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, thiols onto maleic anhydride under basic catalysis. nonyl, decyl or dodecyl. A halogenoalkyl radical R is These authors comment that the addition under free preferably C1-C4-halogenoalkyl, for example chloro radical catalysis gives only moderate yields, and that methyl, mono-, di- or tri-fluoromethyl, trichloromethyl Lewis acids have no catalysing effect. 25 or 2-chloroethyl. An alkoxy or alkylthio radical R pref. U.S. Pat. No. 2,725,364 mentions that maleic acid or erably has 1-4 carbon atoms and can be, for example, fumaric acid can be added onto 2-mercaptobenzo methoxy, ethoxy, isopropoxy, methylthio, propylthio thiazole at 30°-60° C. in aqueous-alkaline solution, but or tert.-butylthio. An alkylsulfonyl radical R is prefera no experimental details are given. 30 bly C1-C12-alkylsulfonyl and can be, for example, meth However, attempts to add o,6-unsaturated carbox yisulfonyl, tert.-butylsulfonyl, n-octylsulfonyl or n ylic acids, in particular maleic acid and fumaric acid, dodecylsulfonyl. onto 2-mercaptobenzothiazole in an alkaline-aqueous A cycloalkyl radical R preferably contains 5-8 car medium at 45-50 C. have shown that no addition bon atoms. Examples are cyclopentyl, cyclohexyl and 35 cyclooctyl. An alkylphenyl or phenylalkyl radical R occurs within 100 hours. Surprisingly, however, it has preferably has 7-12 carbon atoms and can be, for exam been found that the addition proceeds smoothly in a ple, tolyl, xylyl, ethylphenyl, tert-butylphenyl, benzyl, strongly acid medium and the corresponding 6-benzo 1- or 2-phenylethyl or a,a-dimethylbenzyl. A thiazolyl-2-mercaptocarboxylic acids are formed in -COOalkyl radical R is preferably -COO(C1-C4 high yield and purity. The same applies to addition onto alkyl), for example methoxycarbonyl, ethoxycarbonyl 2-mercaptobenzimidazole. or butoxycarbonyl. A primary, secondary or tertiary The invention thus relates to a process for the prepa amino group or carbamyl group R is preferably such a ration of compounds of the formula I group with up to 20 carbon atoms, for example -NH2, -NHCH3, -NH-C4H9, -NH-phenyl, -NH-cy 45 clohexyl, -NCCH3)2, -N(C2H5)2, -N(i-C3H7)2, R I -N(CH2CH2OH)2, -NCC4H9)2, -NCC8H17)2, R -N(CH)3-phenyl, -N(CH3)-benzyl, piperidino, mor N R1 R2 N pholino, -CONH2, -CONHCH3, -CONHphenyl, C-S-C-CH -CONCCH3)2, -CONC6H13)2, morpholinocarbonyl / or piperidinocarbonyl. X R3 COOH 50 R A compound of the formula II in which at least two of the substituents R are hydrogen, in particular com R pounds of the formula II in which one substituent R is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, halogen or in which X is sulfur or NH, each radical R indepen 55 -COOH and the other three substituents R are hydro dently of the others is hydrogen, alkyl, halogenoalkyl, gen, are preferably used. alkoxy, alkylthio, alkylsulfonyl, phenyl, alkylphenyl, Compounds of the formula II in which X is sulfur are phenylalkyl, cycloalkyl, halogen, -NO2, -CN, preferably used, and the corresponding 6-(benzo -COOH, -COOalkyl, -OH or a primary, secondary thiazol-2-ylthio) carboxylic acids are thereby obtained. or tertiary amino or carbamyl group and R, R2 and R3 60 An alkyl substituent R, R2 or R3 in formulae I and III independently of one another are hydrogen, alkyl, halo can be straight-chain or branched alkyl, in particular with 1-12 carbon atoms. Examples are methyl, ethyl, genoalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, n-pen carboxyl or unsubstituted or substituted aryl or aralkyl, tyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl and or R and R2 together are a direct bond or straight-chain 65 dodecyl. A halogenoalkyl or hydroxyalkyl radical R, or branched alkylene, which can be substituted by 1 or R2 or R3 preferably has 1-4 carbon atoms. Examples are 2 carboxyl groups, by reaction of a mercaptan of the hydroxymethyl, 1- or 2-hydroxyethyl, 1-, 2- or 3 formula II hydroxypropyl, 3-hydroxybutyl, chloromethyl, mono-, 4,612,378 3 4. di- or tri-fluoromethyl, bromomethyl, 2-chloroethyl, zimidazole, 7-hydroxy-2-mercapto-benzimidazole, 6 3-chloropropyl and 2-chlorobutyl. amino-, 5-dimethylamino-, 4-piperidino-, 5-methylcar An alkoxyalkyl radical R, R2 or R3 can be, in partic bamyl- Ot 5-diethylcarbamyl-2-mercapto-ben ular, C2-C10-alkoxyalkyl, for example methoxymethyl, zimidazole, 4-bromo-5-n-hexyl-2-mercapto-ben 1- or 2-methoxyethyl, ethoxymethyl, 2-butoxyethyl or zimidazole, 5-nitro-6-n-propyl-2-mercaptoben octyloxymethyl. A carboxyalkyl radical R, R2 or R3 zimidazole, 4,5,6-triethyl-2-mercapto-benzimidazole can be, in particular, C2-C12-carboxyalkyl, for example and 4,5-dimethyl-7-propoxy-2-mercapto-ben carboxymethyl, 1- or 2-carboxyethyl, 2- or 3-carboxy zimidazole. propyl, 1- or 4-carboxybutyl or 6-carboxyhexyl. A sub Examples of unsaturated carboxylic acids of the for stituted aryl or aralkyl radical R, R2 or R3 can be, in 10 mula III are: acrylic acid, methacrylic acid, crotonic particular, phenyl or benzyl which is substituted by acid, 2,3- or 3,3-dimethylacrylic acid, propiolic acid, halogen, nitro, alkyl, hydroxyl, alkoxy or carboxyl, for phenylpropiolic acid, maleic acid, fumaric acid, acety example 4-chlorophenyl, 3-nitrophenyl, tolyl, xylyl, lene dicarboxylic acid, itaconic acid, cyclohexene-1,2- 4-tert.-butylphenyl, 4-hydroxyphenyl, 3-methoxyphe dicarboxylic acid, 3-methylcyclohexene-1,2-dicarboxy nyl, 3- or 4-carboxyphenyl, 4-fluorobenzyl or 4-methyl 15 benzyl. lic acid, ethylenetetracarboxylic acid, mesaconic acid, A straight-chain or branched alkylene radical of R glutaconic acid, aconitic acid, citraconic acid, a and R2 together forms, together with the carbon atoms methyleneglutaric acid, a-methyleneadipic acid, a to which R1 and R2 are bonded, a cycloalkane ring, ethylidene-adipic acid, propylene-1,3-dicarboxylic acid, preferably a cyclopentane or cyclohexane ring, which 20 1-butene-1,4-dicarboxylic acid, 1-butene-2,3,4-tricar can be substituted by alkyl groups, preferably C1-C4 boxylic acid, 2-pentenoic acid, 2-hexenoic acid, 2 alkyl groups, or by one or two carboxyl groups. octenoic acid, 2-decenoic acid, 2-undecenoic acid, 2 Preferably, R, R2 and R3 independently of one an dodecenoic acid, 2-octadecenoic acid, cinnamic acid, other are hydrogen, C1-C8-alkyl, C2-C8-carboxyalkyl, a-phenylacrylic acid, a-phenylcrotonic acid, g-ben carboxyl or phenyl, or R1 and R2 together are tri-or 25 Zylacrylic acid, benzylidenemalonic acid, a-methylcin tetra-methylene. Particularly preferably, at least two of namic acid, 4-chlorocinnamic acid and 3-nitrocinnamic the substituents R, R2 and R3 are hydrogen. acid. The mercaptans of the formula II are known com Instead of the carboxylic acid, it is also possible to use pounds or they can be prepared analogously to known anhydrides thereof.