CS215141B2 - Method of making the substituted 6-aryl-4h-s-triazolo-+l3,4-c+p-thieno+l2,3-e+p-1,4-diazepines - Google Patents

Description

The present invention relates to a process for the manufacture of substituted 6-aryl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazeipines.

The compounds of formula (I) below, as well as their preparation from compounds of formula (II), are known from Liebigs Annalen der Chemie 1978, pp. 1257-1265. This work describes the conversion of starting materials of formula (II) to the resulting products of formula (I). according to the following scheme:

Hal _from liquid ammonia

-: ———-->

melKanol i

However, this process has been shown to have some disadvantages.

A very high excess of liquid ammonia (ratio of compound of formula I: liquid ammonia = 1: 180) must be used to achieve good yields of the products of formula (IIa). Due to aggressiveness (mucosal irritation) and toxicity of readily volatile ammonia [boiling point —33.4 ° C; MAC value (maximum allowable concentration in the workplace) = 35 mgZm ³ ] all work must be carried out in a gas-tight manner, which requires the use of autoclaves and gas-tight lines. After reaction with ammonia, the reaction mixture must be purged with air in special washing machines installed for reasons of health and protection of the environment. For further processing, which is carried out in a mixing apparatus, it is again necessary to use washing machines installed separately for this purpose.

All of the processes described above are therefore very time-consuming and expensive.

SUMMARY OF THE INVENTION It is an object of the present invention to simplify, cheaper and adapt the process for producing the above compounds to meet increasingly stringent environmental protection requirements.

Accordingly, the present invention provides an improved process for the preparation of compounds of Formula I,

in which

R1 represents a chlorine atom, a bromine atom or an alkyl group having 1 or 2 carbon atoms,

R 3 represents a hydrogen, chlorine or bromine atom, a methyl group, a C 3 -C 6 cycloalkyl group, a tetrahydropyranyl group or a radical of formula

R3 ^ř /

- N \

R 5 "wherein each of R 3‘ and R 3 ", which may be the same or different, each represents a hydrogen atom, a methyl or ethyl group, and

R 1 represents a fluorine, chlorine or bromine atom and their physiologically acceptable acid-addition salts, characterized in that the dihalide of the formula II,

in which

R1, R3 and Rd are as defined above, reacted with hydroxylamine and the hydroxylamine derivative of formula III thus formed,

in which

R 1, R 2 and R 1 are as defined above, treated with a water cleavage agent, and the product obtained is converted into its physiologically acceptable acid addition salt in a conventional manner.

The process according to the invention proceeds according to the following reaction scheme:

(!)

Reaction of the dihalide of formula II with hydroxylamine. is carried out at a temperature between 20 and 150 ° C in organic solvents, for example lower alcohols such as methanol or ¹ ethanol or isopropanol, with the addition of potassium iodide and a hardly alkylable base such as N, N-diisopropylethylamine, dicyclohexylethylamine or 4- hydroxy-2,2,6,6-tetramethylpiperidine as a hydrogen halide acceptor. In this reaction the obtained hydroxylamine derivative of formula III with elimination of water which is converted to the final product of Formula I. ¹

The hydroxylamine derivative is dissolved in an organic solvent such as methylene chloride, chloroform, ethylene chloride or chlorobenzene, and the like. at a temperature between 20 ° C and 150 ° C, it is treated with a water splitting agent such as thionyl chloride; Methanesulfonic acid chloride, 2-bromo (optionally Z-chloro-N-methylpyridinium iodide or dicyclohexylcarbodiimide) Especially gentle cleavage of the water is achieved by using thionyl chloride, since the reaction takes place at room temperature.

The resulting compounds of formula (I) can be converted into physiologically acceptable acid addition salts in a conventional manner. Acids suitable for the preparation of salts are, for example, hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, tartaric acid, formic acid, salicylic acid. methanesulfone or toluenesulfone and the like.

The preparation of the compounds of the formula II which are used as starting materials is known and is carried out, for example, as described in Belgian patent specification 844 170. It is based on the triazolo-thienooxazepine of the formula IV,

in which

R 1, R 3 and R 4 are as defined above, wherein the oxazepine ring is cleaved at the oxygen atom and to the resulting compound of formula V,

in which

R 1, R 3 and R 1 are as defined above, treated with a phosphorus or sulfur halide.

The reaction time required to carry out the novel process according to the invention is only half of the working time required in the known autoclave process, using expensive absorption of large amounts of ammonia. Since also the investment costs are considerably higher known method brings a new method according to the invention about 35 ^l% savings in manufacturing costs.

The resulting products of formula (I), as well as their acid addition salts, exhibit significant anticonvulsant, sedative, anxiolytic and autiagressive effects in a dose range of 0.1 to 3 mg / kg at very low toxicity.

The invention is illustrated in more detail by the following non-limiting examples.

He did

8-Bromo-6- (o-chlorophenyl) -1-methyl-4H-s-totol [3,4-c-thieno [2,3-e] -1,4-diazepine

a) 8-Bromo-6- (o-chlorophenyl) -5-hydroxy-1-methyl-4H, 6H-s-triazolo [3,4-c] thieno] 2,3-e] -1,4 -diazepine g (0.06 mol) of 3'-methyl-4- [3- (o-chlorophenylbromomethyl) -5-bromo-2-thienyl] -5-chloromethyl-1,2,4-triazole was added together with 10.1 g (0.06 mol) of potassium iodide, 116 g (0.89 mol) of N, N-diisopropylethylamine and 32.4 g (0.47 mol) of hydroxylamine hydrochloride in 1000 ml of methanol were heated for 2.5 hours The insoluble materials are filtered off with suction, the solvent is distilled off and the residue is taken up in methylene chloride, the solution is washed with water, the methylene chloride phase is dried, evaporated and the residue is recrystallized from ethanol.

22.3 g (90.3% of theory) of 8-bromo-6- (o-chlorophenyl) -5-hydroxy-1-methyl-4H, 6H-s-triazolo] 3,4-c] thieno are obtained. Mp 215-217 ° C; 2,3-e] -1,4-diazepine.

b) The title compound

7.5 g (0.018 mol) of 8-bromo-6-chlorophenyl) -5-hydroxy-1-methyl-4H, 6H-thiazolo [3,4-c] thieno [2, 3-e] -1,4-diazepine together with

10.2 g (0.086 mol) of thionyl chloride in 240 ml of methylene chloride are stirred at room temperature for 2 hours, water is added to the reaction mixture with cooling, the methylene chloride phase is separated, washed with dilute ammonia, the organic phase is dried, evaporated and recrystallized from ethanol.

6.55 g (92.6% of theory) of 8-bromo-6- (o-chlorophenyl) -1-methyl-4H-s-triazolo [3,4-c] thieno [2] are obtained. 208 DEG-210 DEG C. 3-e] 11,4-diazzepine.

In further experiments, yields between 89 and 95% of theory are obtained.

EXAMPLE 2 1,8-Dibromo-ϋ- [o-chloro-1-phenyl) -4,14-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine

a) 1,81D1-bromo-6- (o-chlorophenyl) 15H-hydroxy-4H, 6H-ss-thiazolo] 3,4-c] thieno [2,3-e] -1,4-diazepiin g (0.026 m- ol) 3-bram-4- [3- ^(oC hlorfenyllbro ^ι mméthyl) -5-brm ^ R ^ - ^ - U ^ phenyl] -5lbroml methyl-l, 2,4-triazole (m.p. 146-148 ° C) together with 4.3 g (0.026 mol) of potassium iodide, 51.2 g (0.40 mol) of N, N-diisopropylethylamine and 14.3 g (0.21 mol) of hydroxylamine hydrochloride in 530 ml of methanol for 5 hours The insoluble material is filtered off with suction, the solvent is distilled off under vacuum at 40 DEG C., the residue is taken up in methylene chloride, the solution is washed with water, the methylene chloride phase is dried and evaporated and the residue is recrystallized from ethyl acetate.

The yield of the title compound, melting at 188-190 ° C, was 10.9 g (87.8% of theory).

b) The title compound g (0.011 mol) 1,8-dibromo-6- (o-chlorophenyl) -5-hydroxy-4H, 6H-s-triazolo [3,4-c] thieno] -2,3-e ] -1,4-diazepiin together with 3.5 g (0.012 mol) of 2-bromo-1-methylpyridinium iodide and 2.8 g (0.023 mol) of 1,5-diazabicyclo [4.3.0-] - of non-5-ene in 370 ml of methylene chloride was stirred at room temperature for 1 hour. The organic phase is washed with sodium thiosulphate solution and water, dried and, after evaporation, the residue is recrystallized from methanol.

1,8-dl-bromo-6- (o-chlorophenyl) -4H1S-triazolo [3,4-c] thieno [-2,3-e] -1,4-diazepine, melting at 209 to 210 Deň: 32 ° C. Yield: 4.3 g (85.1% of theory).

In an analogous manner to the foregoing examples, the following resultant compounds were obtained: 21141

Ri

R3

R4 intermediate (III) final product (I) melting point (° C) melting point (° C)

Br CH3 Cl Cl CH3 Cl Br CH3 F C2H5 CH3 Cl Br Cl Br O Cl Br Cl Br H Cl Br Cl Cl Br Br CH3 \ Cl Br N— / CH3 Cl

215 - - 217 208 - - · 210 194 - - 196 204 - - 206 188 - - 191 208 - - 210 158 - - -161 144 - - 146 261 - - 263 190 - - 192

249 - - 251 257 - - 258 224 - - 226 212 - - 214 195 - - 198 216 - - 218 186 - - 188 161 - - 162 188 - - 190 209 - - 210

162-163

166-168

Br

C2H5 \

N— Cl /

C2H5

208-210

143-145

Br

H \

N— Cl /

C2H5

215-217

224-226

Claims (4)

object of the invention A process for the preparation of substituted 6-aryl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepines of the general formula I, 4) in which R1 represents a chlorine atom, a bromine atom or an alkyl group having 1 or 2 carbon atoms, R 3 represents a hydrogen, chlorine or bromine atom, a methyl group, a C 3 -C 8 cycloalkyl group, a tetrahydropyranyl group or a radical of formula wherein each of R 3 'and R 3', which may be the same or different, each represents a hydrogen atom, methyl or ethyl, and R4 represents a fluorine, chlorine or bromine, and their physiologically acceptable acid addition salts, characterized in that the dihalide of the general formula II, ·, ^R8 ~ y ^{n N -} Hal Hal _í CH- LJJ III) in icterim R1, R3 and R4 are as defined above, reacted with hydroxylamine and the hydroxylamine derivative of formula III thus formed, wherein R1, R3 and Rd are as defined above, treated with a water cleaving agent, and the product obtained is converted into its physiologically acceptable acid addition salt. 2. The process of claim 1 wherein the reaction is a compound of formula. II with hydroxylamine is carried out with the addition of potassium iodide and a hardly alkylable base. 3. The process according to claim 2, wherein těž, di-diisapropylethylamine, dicyclohexylethylamine or 4-hydroxy-2,2,6,6-tetramethylpiperidine is used as the poorly alkylable base. 4. The process of claim 1 wherein the water scavenger is thionyl chloride, methanesulfonic acid chloride, 2-bromo-N-methylpyridinium iodide, 2-chloro-N-methylpyrrolidinium iodide or dicyclohexylcarbodiimide.