PROCESS OF PREPARING 2-(PHENYLIMINO)-1,3-THIAZOLIDIN-4-ONES

Abstract

The present invention relates to a method for preparing 2-(phenylimino)-1,3-thiazolidin-4-ones of the general formula (I).

##STR00001##

in which Y.sup.1, Y.sup.2, R.sup.1, R.sup.2 and R.sup.3 are as defined in the description.

Claims

1. A Method for preparing 2-(phenylimino)-1,3-thiazolidin-4-ones of formula (I) ##STR00009## in which Y.sup.1 and Y.sup.2 are independently fluorine, chlorine or hydrogen, R.sup.1 and R.sup.2 are independently hydrogen, C.sub.1-C.sub.12 alkyl, C.sub.1-C.sub.12 haloalkyl, cyano, halogen or nitro, and R.sup.3 is optionally substituted C.sub.6-C.sub.10 aryl, C.sub.1-C.sub.12 alkyl or C.sub.1-C.sub.12 haloalkyl, in which the substituents are selected from halogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl, cyano, nitro, hydroxy, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl and C.sub.1-C.sub.6 haloalkoxy, comprising reacting an aniline of formula (IV) ##STR00010## in which Y.sup.1, Y.sup.2, R.sup.1 and R.sup.2 are as defined above, in the presence of an acetic acid derivative of formula (III) ##STR00011## in which X is bromine, chlorine, OSO.sub.2Me, OSO.sub.2Ph, OSO.sub.2(4-Me-Ph) or OSO.sub.2CF.sub.3, and W is OH or an O(C.sub.1-C.sub.6 alkyl) radical, and in the presence of a base, with an isothiocyanate of formula (V) ##STR00012## in which R.sup.3 is as defined above, initially to form a thiourea of formula (II) ##STR00013## in which Y.sup.1, Y.sup.2, R.sup.1, R.sup.2 and R.sup.3 are as defined above, which is then converted into a compound of formula (I), with the acetic acid derivative of formula (III) being initially present in the reaction mixture prior to the addition to the reaction mixture of at least one of the compounds of formulas (IV) and (V).

2. The method according to claim 1, wherein the compound of formula (I) is in the form of the Z-isomer or a mixture of the E- and Z-isomers in which the proportion of the Z-isomer is greater than 50% based on the total amount of the E- and Z-isomers in the mixture.

3. The Method according to claim 1, X is bromine or chlorine, Y.sup.1 and Y.sup.2 are independently fluorine, chlorine or hydrogen, W is an O(C.sub.1-C.sub.6 alkyl) radical, R.sup.1 and R.sup.2 are independently fluorine, chlorine, C.sub.1-C.sub.3 alkyl or hydrogen and R.sup.3 is optionally substituted phenyl, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl, in which the substituents are selected from halogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.10 cycloalkyl, cyano, nitro, hydroxy, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl and C.sub.1-C.sub.6 haloalkoxy.

4. The Method according to claim 1, wherein X is bromine or chlorine, Y.sup.1 and Y.sup.2 are independently fluorine or hydrogen, W is an O(C.sub.1-C.sub.6 alkyl) radical, R.sup.1 and R.sup.2 are independently fluorine, chlorine, hydrogen or methyl and R.sup.3 is C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl.

5. The Method according to claim 1, wherein X is bromine or chlorine, Y.sup.1 and Y.sup.2 are fluorine, W is an OCH.sub.3 or OC.sub.2H.sub.5 radical, R.sup.1 and R.sup.2 are independently fluorine, hydrogen or methyl and R.sup.3 is C.sub.1-C.sub.6 haloalkyl.

6. The Method according to claim 1, wherein X is bromine or chlorine, Y.sup.1 and Y.sup.2 are fluorine, W is OCH.sub.3, R.sup.1 is methyl, R.sup.2 is fluorine and R.sup.3 is CH.sub.2CF.sub.3.

7. The Method according to claim 1, wherein conversion of the aniline of formula (IV) into the compound of formula (I) takes place in the presence of a diluent selected from tetrahydrofuran (THF), dioxane, diethyl ether, methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME), 2-methyl-THF, acetonitrile (ACN), acetone, butyronitrile, ethyl acetate, isopropyl acetate, butyl acetate, pentyl acetate, methyl isobutyl ketone, ethylene carbonate, propylene carbonate, N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), sulfolane, tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride (dichloromethane, DCM), dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, 1,2-dichloroethane, toluene, ortho-xylene, meta-xylene, para-xylene, ethylbenzene, mesitylene, chlorobenzene, 1,2-dichlorobenzene, anisole, n-pentane, n-hexane, n-heptane, n-octane, 1,2,4-trimethylpentane (isooctane), petroleum ether 40/55, special boiling point spirit 80/110, cyclohexane, methylcyclohexane and mixtures thereof.

8. The method according to claim 1, wherein the isothiocyanate of formula (V) is present in a molar ratio from 0.95:1 to 2:1 based on the aniline of formula (IV).

9. The method according to claim 1, wherein the base is an organic base selected from trimethylamine, triethylamine, tributylamine and ethyldiisopropylamine, or that the base is an inorganic base selected from potassium acetate, sodium acetate, lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, caesium carbonate, calcium carbonate and magnesium carbonate.

10. The method according to claim 1, wherein the base is used in a molar ratio from 0.8:1 to 3:1 based on the aniline of formula (IV).

11. The method according to claim 1, wherein the acetic acid derivative of formula (III) is present in a molar ratio from 0.9:1 to 2:1 based on the aniline of formula (IV).

12. The method according to claim 7, wherein the diluent is selected from toluene, ortho-xylene, meta-xylene, para-xylene, ethylbenzene, chlorobenzene and a mixture of said diluents and/or the base potassium carbonate.

13. The method according to claim 1, wherein the method is carried out at a temperature between −20 and 150° C.

Description

EXAMPLES

Example 1: Synthesis of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one in toluene

[0038] A reaction vessel was charged with 648.8 g of toluene, 153.9 g [1.09 mol] of 1,1,1-trifluoro-2-isothiocyanatoethane, 170.3 g [1.23 mol] of potassium carbonate and 165.9 g [1.09 mol] of methyl bromoacetate. The reaction mixture was heated to 50° C. with stirring. At this temperature, a solution of 235.8 g [0.986 mol] of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline in 235.8 g of toluene was added dropwise, with continued stirring, over a period of 30 minutes. The reaction mixture was then stirred at 50° C. for 7 hours, cooled to 20° C. over a period of 2 hours, and stirred at 20° C. for a further 12 hours. The reaction mixture was a readily stirrable suspension throughout this time. For workup, the reaction mixture was metered into 672.8 g of water with stirring. The reaction vessel was rinsed afterwards with 259.5 g of toluene and the rinse liquid was likewise metered into the water. The upper, organic phase was separated off and stirred with 270 g of hydrochloric acid (16%). Renewed phase separation afforded 1523.3 g of organic phase, which was shown by quantitative HPLC analysis against a reference standard to contain 26.0% (w/w) of the target compound (396.1 g, corresponding to a yield of 95.6% of theory).

Example 2: Synthesis of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one in methylcyclohexane

[0039] A reaction vessel was charged with 100 ml of methylcyclohexane (MCH), 7.76 g [55 mmol] of 1,1,1-trifluoro-2-isothiocyanatoethane, 8.41 g [55 mmol] of methyl bromoacetate and 8.6 g [62.5 mmol] of potassium carbonate. The mixture was heated to 50° C. and 11.9 g [50 mmol] of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline was added dropwise at this temperature, with stirring, and stirring at 50° C. was continued for 24 hours. Minor depositions of a sticky solid during the reaction did not adversely affect the stirrability of the reaction mixture. At the end of this time, a reddish, readily stirrable suspension was present. This was cooled to room temperature and then stirred with 100 ml of 1 N hydrochloric acid, after which the phases were separated and the organic phase was concentrated. This afforded 10 g of product having a purity by HPLC of 80.3%, corresponding to a yield of 38.2% of theory. The aqueous phase was then extracted with three 100 ml portions of MCH. The combined organic phases were concentrated. This afforded 9.8 g of product having a purity by HPLC of 71.8%, corresponding to a yield of 33.5% of theory. The overall yield was accordingly 71.7% of theory.

Example 3: Synthesis of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one in xylene

[0040] A reaction vessel was charged with 17.2 g of a technical xylene mixture and 5.18 g [37.5 mmol, 1.5 equiv.] of potassium carbonate. 4.21 g [27.5 mmol, 1.1 equiv.] of methyl bromoacetate was added, rinsing afterwards with 2.15 g of xylene. 3.91 g [27.5 mmol, 1.1 equiv.] of 1,1,1-trifluoro-2-isothiocyanatoethane was added dropwise, rinsing afterwards with 2.15 g of xylene. The reaction mixture was heated to 50° C. with stirring. At this temperature, 6.16 g [25.0 mmol, 1.0 equiv.] of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline was added dropwise, with stirring, over a period of 30 minutes. The reaction mixture was then stirred at 50° C. for 6.5 hours, with the conversion checked at regular intervals by HPLC. The reaction mixture was a readily stirrable suspension throughout this time. For workup, the reaction mixture was cooled to room temperature and 15 g of water was added. The mixture was transferred to a separating funnel, rinsing afterwards with 3 ml of xylene. Phase separation afforded 35.1 g of a dark brown xylene solution, which was shown by quantitative HPLC analysis against a reference standard to contain 29.0% (w/w) of the title compound (10.18 g, corresponding to a yield of 96.9% of theory).

Example 4: Synthesis of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one in chlorobenzene

[0041] A reaction vessel was charged with 22.1 g of chlorobenzene and 5.18 g [37.5 mmol, 1.5 equiv.] of potassium carbonate. 4.21 g [27.5 mmol, 1.1 equiv.] of methyl bromoacetate was added, rinsing afterwards with 2.15 g of chlorobenzene. 3.91 g [27.5 mmol, 1.1 equiv.] of 1,1,1-trifluoro-2-isothiocyanatoethane was added dropwise, rinsing afterwards with 2.8 g of chlorobenzene. The reaction mixture was heated to 50° C. with stirring. At this temperature, 6.16 g [25.0 mmol, 1.0 equiv.] of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline was added dropwise, with stirring, over a period of 30 minutes. The reaction mixture was then stirred at 50° C. for 6.5 hours, with the conversion checked at regular intervals by HPLC. The reaction mixture was a readily stirrable suspension throughout this time. For workup, the reaction mixture was cooled to room temperature and 15 g of water was added. The mixture was transferred to a separating funnel, rinsing afterwards with 3 ml of chlorobenzene. Phase separation afforded 42.1 g of a dark brown chlorobenzene solution, which was shown by quantitative HPLC analysis against a reference standard to contain 23.5% (w/w) of the title compound (9.89 g, corresponding to a yield of 94.1% of theory).

Comparative Examples

Comparative example 1: Synthesis of 1-{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}-3-(2,2,2-trifluoroethyl)thiourea in toluene

[0042] 5.0 g of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline [20.9 mmol, 1.0 equiv.] was added to 30 ml of toluene and to this was added dropwise, at room temperature, 3.2 g of 1,1,1-trifluoro-2-isothiocyanatoethane [23.0 mmol, 1.1 equiv.]. The reaction mixture was stirred at room temperature for 3 hours, resulting in the formation from the original solution of a very thick, poorly stirrable suspension. Monitoring of the reaction indicated only about 85% conversion. The reaction mixture was heated to 50° C. in order to make it partially stirrable again. After 3 hours at 50° C., complete conversion still had not been achieved, consequently the reaction mixture was heated to 70° C. Complete conversion was still not achieved even after 3 hours at 70° C. (HPLC monitoring of the reaction indicated that 0.9% of the aniline was still present). The reaction mixture was cooled to 5° C. and the very thick, pasty suspension transferred to a suction filter as thoroughly as possible and the solid isolated. The solid obtained was washed with cold MTBE and dried under reduced pressure. This afforded 5.1 g of the target product as a beige solid (61% of theory). Concentration of the filtrate gave a further 2.2 g of a brown solid, which had a target product content of approx. 60% (17% of theory). The poor isolated yield is due in part also to the relatively large losses during transfer of the very thick suspension to the suction filter.

Comparative example 2: Synthesis of 1-{2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}-3-(2,2,2-trifluoroethyl)thiourea in methylcyclohexane

[0043] A reaction vessel was charged with 77 ml of methylcyclohexane (MCH) and 11.9 g [50 mmol] of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline. This was heated to 50° C. and 8.1 g [57.5 mmol] of 1,1,1-trifluoro-2-isothiocyanatoethane was added dropwise at this temperature, with stirring, over a period of approx. 5 minutes. After a few minutes the target product began to precipitate out, causing the reaction mixture to become a thick, unstirrable paste. Even the addition of a further 80 ml of methylcyclohexane did not make the mixture stirrable again. The reaction mixture was cooled to 20° C. and rinsed out of the reaction vessel with large amounts of MCH. The solid was filtered off with suction, washed with MCH and dried. This afforded 18.55 g of product having a purity by HPLC analysis of 98.5% (a/a), corresponding to a yield of 96% of theory. Thus, although the yield is very good, the extremely pasty consistency of the reaction mixture makes the methodology unworkable on an industrial scale.

Comparative example 3: Synthesis of (2Z)-2-({2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]phenyl}imino)-3-(2,2,2-trifluoroethyl)-1,3-thiazolidin-4-one in toluene

[0044] 7.1 g of 1,1,1-trifluoro-2-isothiocyanatoethane [95%, 48.0 mmol, 1.2 equiv.] was dissolved in 40 ml of toluene and stirred (400 rpm) with 9.57 g of 2-fluoro-4-methyl-5-[(2,2,2-trifluoroethyl)sulfanyl]aniline (40.0 mmol, 1.1 equiv.) for 30 min at 20° C., resulting in the formation from the yellowish solution of a suspension containing a white solid. After 1 hour the suspension was no longer stirrable, but monitoring of the reaction by HPLC analyses of the suspension indicated only about 65% conversion. A further 10 ml of toluene was added, the stirring speed was increased to 600 rpm and the reaction mixture was heated to 40° C., as a result of which the mixture became moderately stirrable again. After 3 hours at 40° C. (HPLC monitoring of the reaction showed approx. 87% conversion), 8.3 g of solid potassium carbonate [60.0 mmol, 1.5 equiv.] was added. After a further 30 min, 8.0 g of methyl 2-bromoacetate [52.0 mmol, 1.3 equiv.] was added at 40° C. over a period of 1 hour and the reaction mixture was stirred at 40° C. for 20 hours, resulting in the formation of a suspension of potassium bromide and potassium carbonate in a toluene solution of the target product that was once again readily stirrable. HPLC monitoring of the reaction at this point showed complete conversion of the aniline and only traces of the intermediate thiourea. The reaction mixture was cooled to 20° C., stirred at 20° C. for a further 17 hours and filtered. The solid was washed with a little toluene and the combined filtrates concentrated to 66.8 g of a reddish brown toluene solution, which was shown by HPLC against an external standard to contain 21.1% of the target product (84% of theory) and neither aniline nor the thiourea intermediate.