HU193042B - New process for preparing 1,2,4-triazoline-3/2h/-t-hione derivatives - Google Patents

Abstract

1,2,4-triazolin-3(2H)-thione derivs. of formula (I) are obtd by reacting a thiosemicarbazide of general formula R1NHNHC(:S)NH2 (II) with an acide-halide of formula R2COX (III) at 5-140 deg.C by themselves or in presence of a water immiscible solvent, opt. in the presence of an acid-binding agent. The reaction mixt. is subsequently cooled and mixed with stirring with the aq. soln. of an alkali metal hydroxide. After phase sepn. the prod. is sepd. from the aq. phase by the addition of acid. - In the formulae R1 and R2 are independently unsubstd. phenyl, or phenyl substd. with one or more alkyl, alkenyl or alkoxy gps. having 1-4C with halogen, trifluoromethyl or nitro gps., with alkyl-thio, alkyl-sulphinyl or alkoxy-sulphonyl gps. having 1-4C or furyl, thienyl or pyridyl qps. X = halogen.

Description

The present invention relates to an improved process for the preparation of 1,5-diaryl-1,2,4-triazoline-3 [2H] -thione derivatives of general formula 1 and their tautomeric forms. These compounds are important intermediates that are novel with significant anti-inflammatory and antirheumatic effects

1.5-diaryl-3- (alkylthio) -1,2,4-triazole derivatives (published application T / 37765).

In principle, a number of methods known in the art can be used to prepare compounds of Formula I, which are summarized below:

1. Barnikow et al. (Zeitschrift für Chemie, 20.55 and 97 (1980)) reacted phenylhydrazine with N-phenylbenzimidoyl isothiocyanates or N-arylsulfonylbenzimidoyl isothiocyanates, in addition to the expected 1,5-diaryl derivative. 1,3-diaryl derivatives (more than 30%) are also formed.

2. Pohloudek-Fabini et al., Pharm. Zentralh., 107, 736 (1968); CA 70; 77,870 m (1969)] with benzoyl isothiocyanate and phenylhydrazine to give a mixture of 1,5- and 1,3-diphenyl derivatives.

3. Sgarbi [Chim. Ind./Milán, 48, 18 (1966); CA 64, 9727 d (1966)] for the reaction of the benzoylthiourea derivative with phenylhydrazine

A mixture of 1.5- and 1,3-diphenyl isomers was obtained.

4. Masuda et al., Chem. Pharm. Bull., 27, 1683 (1979); CA 92, 76410d (1980)], react the N-acylaminodrhodanides with hydrazine, then diazotize the resulting mesonic ionic 4-aminothiazolium salt and finally reduce it with lithium aluminum hydride.

5. Fromm and Trnka [L. Ann. Chem., 442, 150 (1925)] and Cawkill et al. (J. Chem. Soc., Perkin Trans. 1, 1979, 724), the 1-benzoyl-1-phenylthiosemicarbazide obtained by the reaction of phenylthiosemicarbazide and benzoyl chloride cyclized to an 1,5-diphenyl derivative in aqueous-alkaline solution.

The disadvantages of the known procedures discussed above can be summarized as follows:

the. The major disadvantage of the 1-3 synthesis pathways is clearly that the reaction leads to a mixture of the two structural isomers (1,5- and 1,3-diphenyl) in which the proportion of undesirable 1,3-diphenyl derivatives is high. Separation of such mixtures causes difficulties and further losses due to the high melting point and poor solubility of the isomers. Thus, these processes are not suitable for industrial implementation.

b. / Process 4 describes a complex synthesis pathway from hard-to-access starting materials, and furthermore involves a step-by-step reduction of lithium aluminum hydride, which is difficult to accomplish, and is therefore not suitable for intermediate synthesis.

c. / Process 5 seems to be the simplest since the two step reaction sequence does not lead to the formation of isomers. However, this reaction is not clearly favorable either: in the first step, 1-benzoyl-1-phenylthiosemicarbazide is synthesized and no 2 yields are given for this step, the second step, hot aqueous-basic cyclization (also in modified form ) yields only 34% of the final product. Therefore, due to the low production, this reaction sequence is not suitable for industrial synthesis.

SUMMARY OF THE INVENTION It is an object of the present invention to overcome the drawbacks of the known processes by providing a novel process for the preparation of compounds of formula I which is economical, industrially available and provides a high purity product in high yield.

The invention is based on the following discovery: when the arylthiosemicarbazides, which can be obtained in a simple manner and in good yields, are reacted with aroyl halides at 5 to 140 ° C, either alone or in a solvent, in the presence of acid-sensitive substituents, with good production we get directly to the expected target product.

This finding is also surprising for a professional. Namely, substituted thiosemicarbosides are often cyclized to 1,3,4-thiadiazoles under acidic conditions, e.g. in the presence of phosphoric acid, Soc., 1949, 1163, in the presence of acetyl chloride, Chem. Bér., 89, 1534 (1956)]. In addition to the synthesis of compounds containing an acid-sensitive alkoxy group, the reaction according to the invention is carried out under strongly acidic conditions, since the reaction liberates the hydrochloric acid. However, surprisingly, the reaction proceeds only in the desired direction.

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of 1,5-diaryl-1,2,4-triazoline-3 [2H]

R 1 and R ² each independently represent an unsubstituted phenyl group or a max. Phenyl substituted with one or two halogen atoms, alkyl or alkoxy group containing 4 carbon atoms, a trifluoromethyl, nitromethylthio or methylsulfonyl group, and R ^{2 is} thienyl or pyridyl, starting from arylthiosemicarbazides, consisting of a thiosemicarbazide of formula II, wherein R 'is as defined above, with an acid halide of formula III, wherein R ² is as defined above, and X is a halogen atom,

The reaction is carried out alone or in an aprotic, non-polar solvent, optionally in the presence of an acid scavenger, at a temperature of 5-14 ° C. The reaction mixture is cooled and mixed with the final product is precipitated.

Apart from the compounds of the Formula I compounds prepared by this invention wherein R ^l and R ² is a phenyl group are new.

In a preferred embodiment of the process according to the invention, a thiosemicarbazide of formula II is obtained in an equimolar amount with an acid chloride of the formula III, respectively. acid chloride

In an excess of 5 to 10%, the reaction is carried out at 80-100 ° C in an organic solvent, preferably benzene.

The use of an acid scavenger is generally not required, but for acid sensitive groups (e.g. methoxy), the use of an acid scavenger, e.g. potassium carbonate or pyridine, which may also be used as a solvent, but in such cases the reaction is conveniently carried out at a temperature of 20-25 ° C.

The alkaline treatment is carried out by adding a 4 to 20% aqueous solution of 1 to 1.2 moles of an alkali metal hydroxide, preferably sodium hydroxide, to the cooled solution, preferably at 20 to 40 ° C, so that the pH of the aqueous portion is Above 7.5, preferably 8-9, the organic and aqueous phases are separated. The aqueous solution is acidified with dilute mineral acid, preferably 10% hydrochloric acid, at room temperature to pH 3-4, and the precipitated precipitate is filtered off and recrystallized if desired.

One of the thiosemicarbazides of formula II is known in the art [e.g. phenylthiosemicarbazide, Chem. Bér., 28, 2081 (1895), p-tolylthiosemicarbazide, Gazette, 28, II. 560], others can be prepared in a simple manner by reaction of the appropriate hydrazinium salt with an alkali or ammonium rhodanide in a known manner (e.g., J. Indian Chem. Soc., 5, 653, C.Z. 1929, 1.1110).

The acid halides of formula III are known compounds or are readily adjustable from the corresponding carboxylic acids (A. J. Vogel, Practical Organic Chemistry, Longmans, 1956, p. 791).

The advantages of the process of the invention over the methods described in the literature are as follows:

a./ readily available arylthiosemicarbazides and aroyl halides can be easily obtained in good yields to the final product of formula I,

b. / the reaction does not employ a high temperature aqueous-alkaline treatment which leads to the formation of disulfide and results in a large reduction of the yields,

c. / the reaction is selective, contrary to the procedure described in most literature, only to the desired 1,5-diaryl derivative,

d. / Due to the above-mentioned advantages of the process, it allows continuous industrial scale production.

In order to carry out the process according to the invention, the following examples are given.

Example 1: 1,5-Bis (Phenyl) -1,2,4-thiazoline-3 [2H] -thione

6.4 g (38 mmol) of phenylthiosemicarbazide in 100 ml of abs. A mixture of benzene and 5.9 g (41.8 mmol) of benzo2θl chloride was heated under reflux for 90 minutes under nitrogen. A mixture of 54 ml of sodium hydroxide solution (1.8 g, 45 mmol of sodium hydroxide) and 18 ml of methanol was added dropwise to the mixture cooled to 50 ° C over a period of 15 minutes, and the solution was stirred at 50 ° C for a further 15 minutes. The two phases are separated and the aqueous phase is acidified with 70 ml of 10% hydrochloric acid. After cooling, the desired precipitate is filtered off, washed with water and dried. The crude product (9.4 g-98%) was recrystallized from alcohol.

Yield: 8.2 g (85.5%), m.p. 191-192 ° C / Office: 188-189 ° C

Example 2: 1,5-bis (4-Chlorophenyl) -1,2,4-triazole ³⁵ h-3 tH-thione

Method A: 5.5 g (27.3 mmol) of 1- (4-chlorophenyl) thiosemicarbazide, 5.0 g (28.6 mmol)

A mixture of 4-chlorobenzoyl chloride and 70 ml of benzene was stirred at 80-90 ° C until gas evolution ceased (about 90 minutes). The mixture, cooled to 30-40 ° C, was stirred with 36 ml of aqueous sodium hydroxide solution (1.2 g, 30 mmol of sodium hydroxide) and 12 ml of methanol, after 15 minutes the two phases were separated and the aqueous phase was separated. with cooling - acidified to pH 3-4 with 10% hydrochloric acid. The precipitate was filtered off, washed with cold water and dried. Yield:

7.45 g (84.5%, of alcohol), m.p. 119-122 ° C.

⁵⁰ Following the procedure of Example 2, Method A, the following compounds were prepared:

Example song R · R ² Yield· % M.p. Third 2-chlorophenyl 2-chlorophenyl 77 139-142 4th 4-chlorophenyl 2-fluorophenyl 74.5 146-149 5th 4-chlorophenyl 2-thienyl 82.5 159-162 6th 2-chlorophenyl 2-thienyl 71 148-151 7th 2-chlorophenyl 2-fluorophenyl 81.5 134-7 8th 4-chlorophenyl 3,4-dichlorophenyl 83.5 143-144 9th 4-phenyl-flur 2-thienyl 78 176-180 10th phenyl 4-chlorophenyl 79 139-140 11th 4-chlorophenyl 2-methyl ester-phenyl 78 168-169

-3193042 continued

Example song R R ² Yield 7th Op ' 12th 4-chlorophenyl 4-methylthiophenyl 90 230-232 13th 3-trifluoromethylphenyl 4-chlorophenyl 89 131-134 14th 3-trifluoromethylphenyl 4-fluorophenyl 50 135-137 15th 4-fluorophenyl 4-fluorophenyl 79 150-152 16th 3-chlorophenyl 4-fluorophenyl 75 159-160 17th 4-chlorophenyl 4-fluorophenyl 83 172-174 18th 4-chlorophenyl 4-methylphenyl 80.5 152-154 19th 4-fluorophenyl 4-trifluoromethylphenyl 85 140-142 20th 4-nitrophenyl 4-chlorophenyl 83 171-173 21st 4-bromophenyl 4-chlorophenyl 83.5 143-4 22nd 3-trifluoromethylphenyl 2-methylthio-phenyl 79 124-6 23rd 4-fluorophenyl 2-methylthio-phenyl 67 144-7 24th 4 metilszul- sulfonyl-phenyl 4-chlorophenyl 82 158-160 25th 4-fluorophenyl 4-chlorophenyl 75.5 148-150 26th 4-fluorophenyl 2-methylsulfonyl-phenyl 73 226-8 27th 4-chlorophenyl 4-nitrophenyl 75 116-8

Method B 5.5 g (27.3 mmol) of 1- (4-chlorophenyl) thiosemicarbazide and 5.0 g (28.6 mmol)

The mixture of 4-chlorobenzoyl chloride is heated at 90-95 ° C. After cooling, the mixture was diluted with 70 ml of benzene, following the procedure of Example 1, Method A. Yield: 6.6 g (75%), m.p. 118-120 ° G.

Example 28: 1- (4-Chlorophenyl) -5- (2-chlorophenyl) -1,2,4-triazoline-3- [2H] -thione 2.0 g (10 mmol) 1- ( To a mixture of 4-chlorophenyl) thiosemicarbazide, 10 ml of benzene and 1.6 g (11.5 mmol) of calcined potassium carbonate in 20 minutes, with stirring, 1.75 g (10 mmol) of 2-chlorobenzoyl chloride in 10 ml benzene solution was added dropwise and the reaction mixture was refluxed for 1 hour. In the following, the procedure of Example 1 is followed. Yield: 2.65 g (82.5%), m.p. 182-185 ° C.

Example 29 1,5-Bis (4-Methoxyphenyl) -1,2,4-50

-triazolin-3 [2H] -tion

A mixture of 1- (4-methoxyphenyl) thiosemicarbazide (2.0 g, 10 mmol), pyridine (0.88 g, 11 mmol) and dioxane (20 mL) at 0-5 ° C (1.7 g, 10 mmol) was stirred. A solution of 4-methoxybenzoyl chloride in 10 ml of dioxane was added dropwise over 20 minutes. Stirring is continued for 5 hours at 20-25 ° C. After cooling, 12 ml of 4% aqueous sodium hydroxide solution was added dropwise with stirring, and the reaction mixture was extracted with benzene (3 x 30 ml) after 15 minutes, after which the aqueous solution was acidified with 20% hydrochloric acid. The precipitate was filtered off, washed with cold water and dried. Yield:

1.95 g (62%), m.p. 172-175 ° C (from alcohol). Following the procedure of Example 29, the following compounds were prepared.

Example song R ¹ R ² Yield 7th M.p. 30th 4-chlorophenyl 4-methoxyphenyl 56 175-178 31st 4-methoxyphenyl 4-chlorophenyl 64 69-72 32nd 4-methoxyphenyl 4-fluorophenyl 65.5 73-75 33rd 4-fluorophenyl 4-methoxyphenyl 67 193-196 34th 4-> chlorophenyl 4-pyridyl 57 oil* 35th 3-trifluoromethylphenyl 4-fluorophenyl 71.5 135-137

\ _ IR (nujol): 1310 cm * ¹ . ancestor

-4193042

Claims (7)

PATENT CLAIMS A process for the preparation of 1,5-diaryl-1 2,4-Triazoline-3 [2H] -thione derivatives - wherein R ¹ and R ² each independently represent an unsubstituted phenyl group or a max. Alkyl or alkoxy group having 4 carbon atoms, one or two halogen atoms, a trifluoromethyl, nitro, methylthio or methylsulfonyl-substituted phenyl, and R ² is thienyl or pyridyl group may be - from the corresponding aryl starting from thiosemicarbazides, characterized in that a thiosemicarbazide of formula II, wherein R 'is as defined above, with an acid halide of formula III, wherein R ² is as defined above and X is halogen, alone or in the form of an aprotic, in a non-polar solvent, optionally in the presence of an acid scavenger, the reaction mixture is optionally cooled and mixed with an aqueous solution of an alkali metal hydroxide, optionally separating the phases and precipitating the final product from the aqueous phase by adding acid. 2. A process according to claim 1 wherein the acid halide of formula III is acid chloride. Process according to claim 1 or 2, characterized in that the thiosemicarbazides 10 and the acid chlorides are carried out at a temperature of 80-100 ° C. 4. A process according to any one of claims 1 to 3, wherein the solvent is benzene. ₁₅ 5. The process of claim 1 wherein the acid scavenger is anhydrous pyridine or potassium carbonate. 6. A process according to any one of claims 1 to 4 Process 20, wherein the aqueous solution of the alkali metal hydroxide is an aqueous solution of sodium hydroxide. 7. Process according to any one of claims 1 to 3, characterized in that the final product is precipitated with dilute mineral acid.