SU1056904A3 - Process for preparing derivatives of 1,4-diazepine - Google Patents

Abstract

A method for producing 1,4-diazepine derivatives with the general formula dvd R,. Xf is chlorine, bromine or C ;, is C2 j: al-where R is kil; 2 - hydrogen, chlorine, bromine, methyl, C „C cycloalkyl, tetrahydropyranyl, methylamine, ethyl: amine or diethylamine; R is fluorine or chlorine radical, characterized in that, in order to increase, yield and expand the assortment of the target product, the compound of the general formula where these values are f Hal is halogen, is reacted with hydroxylamine hydrochloride in the presence of potassium iodide and N, fi flHH3onpo-: with pilethylamine in organic S solvent at the boiling point (L nor the reaction mixture and the compound obtained with the general formula v RiHf W rt-M-Tj CH-lk co and o have the indicated values. where they are reacted with thionyl chloride or iodide 2- rum-1-methyl-4: ib pyridyl and 1,5-diazabicyclo 4,3,0 non-5-ene at a temperature .komnatnoy in an organic solvent.

Description

The invention relates to a process for the preparation of known derivatives of diazepine, in particular, to a process for the preparation of derivatives of 1,4-diazep &amp; on the general formula P M) wi Y6 where R is chlorine, bromine or alkyl Cc-C R ,, is hydrogen, chlorine, bromine, methyl cycloalkyl with 3 or b C-atoms, tetrahydropyranyl, meth amine, ethylamine or diethylamine; RJ-fluorine or chlorine with valuable pharmacological properties l and 2. A known method for producing .1,4-diazepine derivatives of general formula l), where R. - has the indicated value; methylamine, ethylamine and diethylamine; fluorine and chlorine, by reacting a compound of the general formula </ BR> where R and R: t have the indicated meanings; Hal is halogen, with the appropriate amine l. The disadvantage of this method is that the yield of the desired product is only 58-61%. The closest to the invention: according to the achieved positive effect, is the method of obtaining 1,4-diazepine derivatives of the general formula (I, where R is chlorine, bromine or alkyl R2 is hydrogen, methyl, cycloalkyl with 3 or 6 carbon atoms, genus, tetrahydropyranyl ; Rj is fluorine and chlorine, by reacting a compound of the general formula. $ N: where R has the indicated values X-mercapto, fine, alkox alkylthio and halogen, with the compound of general formula R - CO - NH - NH2, where R has the specified value 2J. A disadvantage of the known method is that the yield of the desired product is At most 75%. The aim of the invention is to increase the yield of the target product and to expand the range of 1,4-diazepines, ... The goal is achieved according to the method of obtaining 1,4-diazepine derivatives of the general formula (1, consisting in that the compound of the general formula RzY if CH2-H1g is -CJH-Hali where they have the indicated meanings: On 1 - halo, react with hydroxylamine hydrochloride in the presence of potassium iodine and N, M-diisopropylethylamine in an organic solvent at the boiling point of the reaction mixture and obtain The compound of the general formula vvH LX cn, wherein these Ryi-Rj values are indicated, is reacted with thionyl chloride or 2-bromo-1-methylpyridinium iodide and 1,5-diazabicyclo, 3, oZnon-5-enom at room temperature in medium organic solvent. The essential differences of the proposed method are the use of new starting reagents in certain parameters mentioned above. The proposed method is based on the well-known condensation reaction with hydroxylamine hydrochloride, which is carried out in the presence of potassium carbonate at the boiling point of the solvent mixture in an organic solvent medium. In contrast to the above method, the condensation reaction in the proposed method is carried out in the presence of potassium iodide and N, N-diisopropylethylamine, which ensures the yield of the target product.

Example 1. 8-Bromo-6- (O-chlorophenyl) -methyl-4H-sim.-triazolo-3, 4-c-thieno-2, 4-diazepine.

a) 8-Bromo-b- (o-chlorophenyl) -5-hydroxy 1-methyl-4H, bH-sym-triazolo-3,4, -c-thieno-2,3-e -1, 4-diazepine .

30 g (0.06 mol) 3-methyl-4-3- (0-chlorophenyl-bromomethyl) -5-bromothienyl (2) -5-chloromethyl-1,2, 4-triazole, together with 10.1 g (0, 06 mol of potassium iodide, 116 g (o, 89 mol) of N, N-diisopropylethylamine and 32.4 g (0.47 mol) of hydroxylamine hydrochloride in 1000 m of methanol are heated under reflux for 2.5 h. Then the solvent is distilled off from the insoluble product, the solvent is distilled off, the residue is taken up in methylene chloride, washed with water, the methylene chloride phase is dried, evaporated and the residue is recrystallized from ethanol. The yield of 8-bromo-6- (-0-chlorophenyl) -5-hydroxy-g1-methyl -4H, 6H-sim. -triazolose, 4-c -thieno-2, 3rd e -1, 4-diazepine 22.3 g (90.3% of theoretical). M.p. 215-217s.

b) Target product. 7.5 g (0.018 mol) of 8-bromo-6- (o-chlorophenyl) -5-hydroxy-1-methyl-4n, bH-sim.-triazolo-3, 4, -s2-thieno-2, 3 4-diazepine is stirred with 10.2 g (0.06 mol of thionyl chloride in 240 ml of methylene chloride at room temperature for 2 hours. Water is then added with cooling, the methylene chloride phase is separated, washed with dilute ammonia and the residue is recrystallized from ethanol.

The yield of 8-bromo-6- (O-chlorophenyl) -i-methyl-4H-sim. -Triazolo-, -cj-thieno-2 ,, 4-diisepin 6.72 g (95% of the theoretical). T. pl. 208-210 ° C.

Example 2. 1,8-Dibromo-6- (o-chlorophenyl) -411-sim.-triazolo-3, 4-c-thieno, 3-eJ -1, 4-diazepine.

a) 1, 8-Dibrom-6- (o-chlorophenyl) -5-OXI-4H, 6H-SIM. -triazolo-3, 4-c-thieno - {2, 3-el-1,4-diazepine. 16 g (0.02G mol) 3-bromo-4- 3- (o-chloro-phenyl-bromomethyl) -5-bromothienyl (2) -5-bromomethyl-1, 2,4-triazole (m.p. 146- 148 ° C) together with 4.3 g (O, 026 mol of potassium iodide, 51.2 g (0.40 mol) of N, N-diisopropylethyl.min and 14, 3 g (6.21 mol) of hydroxylamine hydrochloride in 530 (l) 7 methanol is heated under reflux for 5 h. Then the insoluble product is sucked off, the solvent is distilled off in vacuum at 40 ° C, the residue is taken up in methylene chloride, the prog / is dried, the methylene chloride phase is dried, evaporated and the residue is recrystallized from ethyl acetate The yield of the target product was 11.3 g (90.8% of the theoretical), mp 188-190s.

b) Target product. 5 g (0.011 mol) of 1,8-dibromo-6- (o-chlorophenyl) -5-hydroxy-4H, 6H-SIM. -Triazolo- 3, 4-c-thieno-2, 4-diazepine for 1 h at room temperature is stirred 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 non-5-ene in 370 ml methylene chloride. Then the organic phase is washed with an aqueous solution of sodium thiosulfate and water, dried, evaporated and the residue is recrystallized from methanol. The yield of 1,8-dibromo-6- (o-chlorophenyl) -4H-SIM.-triazolo-3, 4-c-thieno - {2,3, 4-diazepine 4.6 g (90.1% of theoretical ), T. pl. 209-2 10 ° C.

; Example 3. 8-Bromo-6- (o-chlorophenyl) -1-cyclohexyl-4H-sim. -triazolo- (3, 4-c) - thieno- (2,3-e} -1, 4-diazepine.

a) 8-Bromo-5-hydroxy-6- (o-chlorophenyl) -1-cyclohexyl-4H-sim. -triazo- (3,4-c) -thieno (2,3-e) -1, 4 - diazepine. 15 g (0.0266 mol) 4-15-bromo-3- (a-bromo-2-chlorobenzyl) -2-tnenyl-3-chloromethyl-4H-1, 2,4-triazole with 3.2, g of iodide potassium (0.0192 mol), 37 g (0.286 mol) of N, N-diisopropylethylamine and 10.7 g (0.154 mol) of hydroxylamine hydrochloride in 430 ml of methanol are heated under reflux for 5 h. After 2 hours of reaction, the compound crystallizes out. Upon completion of the reaction, the mixture is cooled to 15 ° C and further stirred for 1 hour. Then the reaction mixture is sucked off and washed with cold methanol. The solution is concentrated under vacuum, 200 ml of methylene chloride are added, and the mixture is filtered with suction.

After insoluble and extracted three times with 150 ml of water each time. The organic phase, after drying over Nan 50, is concentrated and, with the help of 30 ml of acetone, brought to crystallization. The yield of 11.6 g (90.8% of theoretical. So pl. 261-263s.

b) Target product, 2 g

(0.00417 mol) 8-bromo-5-hydroxy-6- (o-chlorofeyl) -1-cyclohexyl-4H-sim.-triazo (3,4-с) -thieno - (2, 3-e) -1,4-diazepine with 2.8 g (0.023 mol) of thionyl chloride in 80 ml of methylene chloride is stirred for 90. minutes at room temperature. Water is then added to the residue of the hydrochloride and the phases are separated. The organic phase is washed with diluted ammonia, dried and concentrated to dryness in vacuo at 30 ° C. The residue is recrystallized from ethanol.

The output of 1.75 g (0,00378 mol), 90,8% of theoretical. M.p. 190-192S.

Example 4, 8-Bromo-b- (0-xnophenyl) 1-tetrahydropyranyl- (4) -4H-sym. -Triazolo- (3,4-c) -1; yeno- (2,3-e) -1 , 4-diazepine.

a) 8-Bromo-5-hydroxy-b - (. o-chlorophenyl) -1-tetrahydropyranyl- (2) -4H-sym, g-triazolo-3, 4-c} -thieno-2,3-e - 1, 4-diazepine. 25 g (0.0442 mol) 4-5-6-6-3 - (. CI-bromo-2-6enznl) -2-thienyl-3-chloromethyl-4H-1, 2,4-triaol with 7.3 g ( 0.044 mol) of potassium iodide, .87.5 g (0.67 mol) of M, M-diisopropylethylamine and 17 g (0.245 mol of hydroxylactin hydrochloride in 600 ml of methanol is heated under reflux for 7 hours; after the end of the reaction, cooled to room temperature The solvent is distilled off in vacuo, the residue is taken up in methylene chloride and taken up in water. The organic phase is separated, dried over and in vacuo it is concentrated to dryness. The residue is dissolved in, 50 ml-acetonitrile and, after cooling, it is removed. istoshlizovyvayut. Yield 19.3 g (0.04 mol), 90.7% of theory. T mp, 249-251 0

b) Target product, 2 g (0.00415 mol) 8-bromo-5-hydroxy-6- (0 chlorophenyl) -1-tetrahydropyranyl- (2) -4H-sim, -triazolo- (3,4-s) -thieno- (2,3-e) -1,4-diazepine with 2.8 g (0.023 mole) of thionyl chloride in 80 ml of methylene chloride is stirred for 2 hours at 15 ° C. Then, after cooling, add water, the organic phase is separated and extracted with diluted ammonia. Organic phase after

drying over Na2SO; j sucked off and concentrated to dryness in vacuo. The residue is recrystallized from dimethyl 1-1 amide.

Yield 1.8 g (0.003.88 mol), 92.8% of the theoretical. T, pl, 257-258 C.

Similarly receive 1,4-diaeepine derivatives, listed in the table

The significance of the reaction. condensation in the presence of potassium iodide and H, H-diisopropylethylamine instead of potassium carbonate is confirmed by example 16,

-. Example 16, Example 1a is repeated, with the difference that instead of 0.0.6 mol of potassium iodide and 0.89 mol of N, n-diisopropylethylamine, 0.95 mol of carbonate, potassium is used. 17.7 g (71.7% of theoretical) of 8-bromo-6- (o-chlorophenyl) -5-hydroxy-1-methyl-4H, 6H-sym, -triazolo- Gz, 4-s - are obtained. thieno (2,3-е1-1,4-diazepine, T, pl, 215-2170С,

A comparison of the data on the yield of the intermediate compound of the proposed method, given in Examples 1a and 16, indicates that the yield of the intermediate compound can be increased by 25.9% compared with the performance of the condensation reaction in the presence of potassium iodide and m, M-DiI isopropylethylamine. condensation reactions under local conditions, t, e, in the presence of potassium carbonate (the yield of example 16 is taken as 100%), due to which it is possible to obtain the desired product with an increased yield.

CH "

Vg

5 6 7.

se

CH, j

SNS

Vg

h ..

CH

-WITH

Vg

93.5

208-210 92.8 204-206 93.2 208-210 92.7 144-146 94.6 212-214

Continued table. one

Claims (1)

METHOD FOR PRODUCING PRODUCTION- NEW 1,4 · -DIAZEPINE of the general formula where R ^ is chloro, bromo or C ₄ -C ₂ is al- ¹ kil; , ^p 2 - hydrogen, chlorine, bromine, methyl, ^c 3 ~ ^c 6-cycloalkyl, tetrahydropyranyl, methylamine, ethylamine or diethylamine; R ^ is fluorine or a chloro radical, characterized in that, in order to increase, yield and expand the assortment of the target product, a compound of the general formula wherein R ^ -Rj have the indicated meanings; On) - halogen, is reacted with hydroxylamine hydrochloride__ in the presence of potassium iodide and 'N, * K-diisopropylethylamine in an organic solvent at the boiling point of the reaction mixture and the resulting compound of the general formula where R ₄ -R3 have the indicated meanings, are reacted with thionyl chloride or iodide 2-bromo-1-methylpyridinium and 1,5-diazabicyclo [4.3.0] non-5-ene at room temperature in an organic 'solvent.'