SU496733A3 - Method for preparing benzodiazepine derivatives - Google Patents

Description

(54) METHOD FOR PRODUCING BENZODIAZEPINL DERIVATIVES

The invention relates to a new method of pulsing benzodiazepine derivatives of the formula in which R "is identical or personal, is a hydrogen atom, lower alkyl,; lower alkoxy, halo, oxy, nitro or cyano, aiyl, trifluoromethyl, actnyl, acylaminogroup, / f -mono- (lower alkyl) -, Qg-amino group, N -di- (lower alkyl) G and amino group acyloxy group, carboxyl, alzhoxycarbonyl, carbamoyl, N-mono- (nor 1th alkyl) -carbamoyl, N -di -Neei an1; kil) carbamoyl, lower alkylthio group, 25 lower alkylsulfinyl group or nye; sha alkylsul phonil group; R is a hydrogen atom, lower alkyl, cycloalkyl, aralkyl, arid or phenacyl; c: hydrogen atom or lower alkyl; o A is straight or branched alkylon; Y is an atom of oxygen or sulfur. These compounds have physically logically active properties. A method of producing benzodiazepine derivatives of the formula 1 is known, which consists in the fact that compounds of the general formula. O 11 - - S where R - R have the indicated meanings. Q is an acidic residue, is reacted with a derivative of a primary amine of the formula H N N-A-UN, where A and Y have the indicated values when heated. The yield of the target products 2 O-7O%. The purpose of the invention is to increase the yield of target products. For this compound of the formulas I .. HSTC 14 l C M-A-un in which R J-R ,, A and Y have the same meaning as,. or mixtures of these compounds are subjected to a reactive carboxylic acid derivative of the formula HOOC-GH-Q in which R has the indicated meaning P - acid radical of the reactive ester, In formula L, the O group, i.e. the acid relative to the radical of the reactive atjwpa The acid radical of such ethers as esters of halo-hydrofluoric acids, E (}, isry of superacids and phosphoric acid; representatives of similar radical acids are added, for example, chlorine, bromine,; yodol, / -toluenesulfonyloxy, methanesulfonyloxy, diphenylphosphor, This radical can be used as a reactive carbonic acid derivative of the formula U can be used acid halides and anhydrides, as well as other carboxylic acid derivatives. The reaction should be carried out in the presence of an acid neutralizing agent and an inert organic solvent, which can be used any organic solvent that does not affect the reaction. These include hydrocarbons like benzene, toluene; or KS11OLOL; cyclic ethers, such as dioxane or tetrahydrofuran; esters of organic acids, such as ethyloacetate, amyl acetate or butyl acetate; halogenated hydrocarbons, such as chloro-zoform, dichloroethane or carbon tetrachloride, acetonitrile, dimethylformamide, dimethyl sulfoxide, etc. The reaction should be carried out in the presence of an acid binding agent (neutralizing agent), which can be organic and inorganic bases; of the organic bases, for example, aliphatic, aromatic or heterocyclic tertiary amines, for example trimethylamine, triethylamine, tributylamine, dimethylaniline, f4-methylmorpholine, N-methylpiperidine, M, -dimethylphenyzine, pyridine, picoline or chinine, pyridine, picoline or chinine, chidrin, chidridine, M, -dimethylphenylamine, pyridine, picoline or chinine, pyridine, picoline or chinine, M, -dimethylphenidine, pyridine, picoline or chinin, pyridine, choline, or chinine, choline, M, -dimethylphenylacetate, pyridine, picoline or chinine, choline, choline, chromium, pyridine, pyridine, choline or choline, can be used CG inorganic bases can be used, for example, alkali metal bases, for example hydroxides,. alkali metals such as caustic soda, lithium or potassium; alkali metal carbonates or bicarbonates, for example sodium carbonate, potassium carbonate, sodium or potassium bicarbonate, alkali metal salts and carboxylic acid salts, sodium and potassium acetates, etc. In the process, the solution of the compound of formula C or II or their salts in organic a neutralizing agent (acid) and, if desired, a catalyst, such as sodium iodide, are added to the solvent. In the resulting mixture, while stirring slowly, a reactive carboxylic acid derivative, preferably soluble in the withdrawn solvent, is added dropwise in a more than equimolar amount. The reaction mixture in the process of pouring in order to eliminate side reactions. preferably maintained at a temperature below room temperature. The reaction usually ends quickly. At the end of the inflow, the reaction mixture can be maintained at a temperature from room temperature to the boiling point of the solvent until the reaction is complete. At the end of the reaction, the target product can be isolated from the reaction mixture by conventional methods, for example, by adding water to the reaction mixture, extracting with benzene, toluene or ether, drying the extract and then removing | the solvent, after which the crude Nro, the product can be subjected to purification by conventional means, for example, by recrystallization or chromatography. . The compounds of the formulas I and O a used as starting materials are tautomeric and in different ratios, depending on the nature. . substituents, i.e.; Y and A, and storage conditions, e.g., temperature or solvent. Almost all coi unities of the formula T | represent; oily substances that become crystalline on standing or: treated with an organic solvent. The resulting crystalline substances can be transformed into vacuum oil distillation. mainly from Compound of formula C I Compounds of formulas D) and On or their mixture can be obtained by reacting 2-aminobenzophenone derivative with amines. Getting the original material. 2- (5-Chloro-2-aminophenyl) -2-phenyl-5-m-tnloksazolidii. A mixture of 11.8 g of 5-chloro-2-aminobenzo-zofenone and 12.0 g of isopropanolamine heated JB for 4 hours at 17 ° -18 ° C, the excess isopropanolamine was distilled off under vacuum, and the residue was distilled under vacuum. The oily substance obtained contains mainly 2- (5-chloro-2-aminophenyl) -2-phenyl-5-methyloxazolidine, boiling Tfi 159-162 ° / 5. 1O%: C 66, 5.93; Calculated, N 9.70; C1 12.28 Found%: C 66.7; H 5.93; N 9.52; C112.56. In a similar way, the following oxazolidine derivatives can be obtained from the corresponding benzophenone amines; 2- (3,5-dimethyl-2-aminophenyl) -2-phenyl-5-methyloxazolidine (m.p., 164-17O ° / -3 / 2 U mm Hg. Art.); 2- (5-chloro-2-aminophenyl) -2-phenyloxazolidine (bp 191-194 ° / 8 mm Hg, cent.); 2- {5-chromo-2-aminophenyl) -2-phenyl-5-methylcacazolidine (t. Bale, 179-182 ° / -4 / 8,110 mm Hg; st); 2- (5-chloro-2-amino-noyl) -2- (chlorophenyl) -5-methyloxazolidine (bp 189-193 ° / 8 1 O mm Hg); 2- (5-chloro-2-amiuyufenpl) -2- (2-chlo-fonil) -oxazolidi11 (kip. 193-194 / / 6 10 mm Hg); 2- (5-chloro-2-aminfeiyl) -2- (2-. Chloro-nyl) -5-methyloxazolidine (kip. 183-184 ° / 4, 4. 10 mm Hg, cent.); 2- (3,5-dimethyl-2-aminophoyl) -2-.l enioxyazolidine (kip. 174-177 /,. 1, -4. / 1 1O mm Hg. /; 2- (2- amino-5-chloro-Of- (2-chlorofspyl) -benzylideneamino) -ethanol, A mixture of 10.6 g of 5-chloro-ami11o-o-chlorobenzophenor and 9.8 g of 2-amh) ethanol narpcv are 5 hours at 170-180, cooled, an excess of 2-aminoethanol is distilled off under vacuum, the residue is re-installed from benzene and the expected product is obtained in the form of crystals, melting at 121-1123 ° C. Similarly, from the corresponding benzophenones and amines, various benzylideneamioethanol derivatives of the formula Aa-O Example 1 can be obtained. 7-Chloro-5-phenyl- (5,4) 5-methyloxazolidino-2, 3, 4, 5-tgragrahydro-1H-1 , 4-benzodiazepinone-2. To a solution of 16 g of 2- (5-chloro-2-minos-nyl) -2-phenyl-5-methyloxazolidine, 8 g of pyridine is poured into 180 ml of dioxane while cooling with a mixture of ice-water and porosmeshivanie. To the resulting solution was added dropwise 12.2 g of bromoacetyl bromide. When making the reagent, the TOMnej reaction mixture is kept below 20. The smog is then transferred for 3 hours at room temperature, 2OO ml of toluene and 2OO ml of water are added and shaken. The organic layer is separated from the aqueous, dried over anhydrous sodium sulfate and the solvent is distilled off. The residue is recrystallized from ethanol and the desired product is obtained in a yield of 85%, melting at 186.5-188 ° C. f EXAMPLE 2. 7-Chloro-5-41eyl- (5,4-}}) oxazolidino-2, 3, 4, 5-tetrahydro-1H-1, 4-benzodiazepinone-2. Analogously to Example 1, but using 2- (5-chloro-2-aminophenyl) -2 - (}) enyloxazolidine and triethylamine instead of 2- (5-chloro-, 2-aminophenyl) -. 2-phenyl-5-methyloxazole - Dina and pyridine receive the target product with so pl. 175-176 C and 89% yield. EXAMPLE 3: 7,9-Dimethyl-5-fe1 {il- (5,4-b) -5-methyloxazolidino-2, 3,4, 5-tetrahydro-1 H-1,4 -6oH3onHa3enwnon -2 Analogously to Example 1, but using 2- (3,5-dimethyl-2-aminophonyl) -2-phenyl-5-methyl-oxaolidine and bromoacetic anhydride instead of 2- {5-chloro-. -2 aminophenyl) 2-phenyl-5-methyloxazolidine and bromoacetyl bromide, get the product with so pl. 272-273 ° C and yield, 61%. PRI me R 4. 7-Bromo-.5-phenyl- (5,4-b) -5-methyloxazolidino-2, 3, 4, 5--. -tetrapidro-1H-1,4-benzodiazepinone. Analogously to example 1, but using 2- (5-bromo-2-aminophenyl) 2-phenyl-5-methyoxazolidine and sodium carbonate instead of 2- {5-chloro-2-aminophenyl) -2-phenyl-5-methyloxazolidine and pyridine receive a product with t. pl, 180,5-182 and b} 85% ,. Example 5, 7-Bromo-4- (2 chlorophenyl) -5,4- 1}) -methyloxaolidino-2, 3, 4, 5-tetrahydro-1H-1,4-benzodiazepinone-2, Described in example 1 , but using 2- (5-bromo-2-aminophenyl-2- (2-chlorophenyl) -5-methyloxazolidine instead of 2- (5-hz) p-2-aminophenyl) -2-phenyl-.5-methyl xaeolidine, the product is obtained with t, pl. 196-198 C and a yield of 86%. Example 6. 7-chloro-5- (2-chloro-nyl) - (5,4-b) -oxazolidino-2, 3, 4, 5-tetrahydro 1H-1,4-benzodiaaepinon-2, Analogous to example 1, but using 2- (5-h1yur-2-aminophenyl) -2- (2-chlorophenyl) -oxazoyl and instead of 2- (5-chloro-2-amino-neyl) -L-pheny-5-methyloxazolidine, the product is obtained with t. pl, 2O1-2O4-C (decomposition) in a yield of 83%. Example 7. 7-Chloro-5- (2-chlorof & nn) - (5,4- 4) - etx1-oxazolidino-2,3, 4 5-tetragi fo-1 H-1, idnazedinone ,. Analogously to example 1, but using 2- (5- "Yor, -2-aminophenyl) -2- {2-chlorophen-5- etigao ::: azolidine instead of 2- (5-chloro - 2-" minophenyl) -2 -phenyl.l-3-mnloksazolidntl, 1st learn a product with t pl. 19O-192-4i; Sh yield of 85%, PRI me R 8, 3, 7, 9-Trimethyl-5-f8 wcgl- (5.4-. 5 j., 3, 4, 5 tetrahydro-1H-. -1.4 -be zodiazelinone-2. Described in diet 1 by the method, but using 2- (3,5-dimethyl-2-aminophenyl) -2-phenyloxazolidine and (X-bromopropionyl chloride instead of 2- (5-chloro-2-aminfeiyl) - -2-phenyl-5-methyloxazolidine and bromoacetyl bromide, a product is obtained with m, pl, 21S 221 ° C and a yield of 85%, Example 9, 7-Chloro-5-phenyl- (5.4- - B) -5-methylcososolidino-2, 3, 4, 5-tetrahydro-1H-1, 4-benzodiazepinone-2, In a solution of 5.8 g of 2- (2-amino-5-chloro-d-phenylbenzylideneamino) -1 -methylete-iola B.8O ml of dioxane is poured, 3.8 gT of pyridine. the mixture is stirred and cooled to 6aFie with a mixture of water and ice, then 4.5 g of bromoacetyl bromide are added dropwise (the temperature is kept below 15 ° C), then stirred for 3 hours at room temperature. After the reaction is completed, the reaction mixture is poured into the mixture water with ice and kstragiruyut dichloromethane.The extract is passed through with water, dried over anhydrous sodium sulfate, then the solvent is distilled Ute, The residue is recrystallized from ethanol, to obtain a product with mp, 186188 ° C and a yield of 82%, Example 10, 7,9-Dimethyl -5-phenyl "(5,4- 5) -5-methyloxazolidino-2,3,4,5-those trahydro-, 4-benzodiazepinone-2. Analogously to Example 9, but using 2- - (2-amino-3,5-dimethyl- of - (- phenylbenzylideneamino) - 1-methylethanol and bromoacetyl chloride instead of 2- (2-amino-5-chloro-Of-phenylbenzylideneamino A) -2-methylethanol and bromoacetyl bromide get the target product with t, pl. 272-273 C (decomposition) and a yield of 85%, Example 11, 7-Chloro-5- (2-chlorophenyl) - (5,4- b) - okkazazolidino-2,3,4,5- -Tetrahydro-1 f, 4-benzodiazepinone-2, In a solution of 5.6 g of 2-2-amino-5 chlorine - Of - (2 chlorophenyl) -benzylidene-amino-ethiol and HE ml of dioxane is added with 2.3 g of carbonate carbon dioxide while stirring and cooling on a bath with a mixture of water and ice. 8.1 g of bromoacetyl bromide is dropped in. The temperature of the reaction mixture during the addition process is kept below 15 ° C. The mixture is stirred for 3 hours at room temperature. Upon completion of the reaction, the reaction mixture is poured into ice-water and extracted with dichloromethane. dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue is recrystallized from ethanol to give the product with m, mp, (decomposition) and a 95% yield, Example 12, 7-Chloro-5-phenyl- (5.4-b) - thiazolidino 2, 3, 4,5-tetrahydro-1H-1, 4 benzodiases yepinon-2, Described in example 2 by the method, but using 2- (2-amino-5-chloro-c} -phenyl-benzylideneamino) -ethyl mercaptan instead of-2-amino-5-chloro-cf - (2-chlorophenyl) - benzo, imino-ethanol, get the product with t, mp, 241-243 ° C and yield 93%, Example 13. 7-.Chloro-9-methyl-5-phenyl ™ 55F 6) -5-methyloxazolidino-2, 3, 4, 5-.tetrahydro-1H, -1,4-.benzodiase pinon-2, o: Described in iif ) iiMepo 9 by the method, but using 2- (2 amnno-3-methyl-5-chloro-a-phenylbenoylideneamino) -1-methylethanol instead of 2- (2-amino-5-chloro-C (-phenylbenzylideneamino) -1- methyl ethanol and triethylamine instead of pyridine, a product is obtained with a melting point of 253-25evC and a yield of 86%. Example 14. 7,8-Dichloro-5-phenyl- (5,4-b) -methyloxazolidino-2,3, 4, 5 -tetrahydro-1H-1,4-benzodiazepinone-2. Described in Example II using n- 2- (2-amino-4,5-dichloro-a- (phenylbenzylideneamino) -1-methylethanol instead of 2- 2-amino -5's lor- 0 (- (2-chlorophenyl) -benzylideneamino-ethanol) gives the product with mp 195-197 ° C and the yield. Example 15. 7-Bromo-1-ethyl-5- -phenyl- (5,4- i) -oxazolidino-2, 3, 4, 5- -tetrahydro-1H-1,4-benzodiazepinone-2. Described in Example 11, but using 2- (2-ethylamino-5-bromo-Qf-phenylbenzylideneamino) -ethanol and potassium carbonate instead of 2- 2-amino-5-chloro-0 (- (2-chlorophenyl) -benzylideneamino-ethyl and sodium carbonate receive the product with so pl. 136-138 ° C and a yield of 94%. Example 16. 7-Chloro-5-phenyl- (5,4-b) -oxazolidino-2, 3, 4, 5-tetI rahidro-1H-1,4-benzodiazepinone-2. As described in Example 11, but using 2- (2-.amino-5-chloro (L-phenylbenzylideneamino) -ethanol instead of 2- 2-amine-5-chloro-d- (2-chlorophenyl) -benzylidendenamq-ethanol, a product is obtained with mp 175-176 ° C and a yield of 92%. Example 17. 7-Chloro-3-methyl-5-phenyl- (5,4-b) -oxazolidino-2, 3.4, 5- tetrahydro-1H-1, 4g-benzodiaz1pinyun-2. Described in the example by the method, but using 2- (2 amino-5-chloro (j (-phenylbenzylideneamino) -ethanol and 0-bromopropionyl chloride instead of 2- | 2-amino-5- chloro-o (- - (2-chlorophenyl) -benzylideneamino-ethanol and bromoacetyl bromide, get the product with mp. 2O5-207 ° C and yield 92%. Example 18. 7 -Chloro-5-o tolyl- (5,4- 5) -5-methyloxazolidino-2,3,4,5-tetrahydro-1H-1, 4-benzidiazepinone-2. Described in Example 8, but using 2- f2-amino-5-chloro-C - (O-tolyl) -benzylideneamino-methyl ethanol and triethylamine instead of 2- (2-amino-5-chloro-Of-phenylbenzylidene-amino) -1-methylethanol and pyridine, a product is obtained with mp 205. C (decomposition) and a yield of 84%. Example 19. 7-Chloro-5- (2-chlorophenyl) - (5,4-b) -5-methyl-oxazolidino-2, 3, 4, 5 -tetrahydro-1H-1,4-benzodiazepinone-2. D; In the 11 way described in the winner, but: using 2- 2-amino-5-chloro-of - {2-chloro-phenyl) -benzplidenaminoJ-1-methyl-ethanol and: potash instead of 2-amins -5-chloro-I - {2 | -chlorophenyl) -benzylideneamino-ethanol and sodium carbonate, get the product with so pl. 192 C (decomposition) and 95% yield. ; Example 20. 7-Chloro-1-methyl-5-4-alkyl-5,4-5-oxazolidino-2,3,4, 5-tetrahydro-1H-1, 4-benzodiazepinone-2. . By the method described in Example 11, but using 2- (2-methylamino-5-chloro-C (; - phenyl benzyl id enamino) -ethanol instead of 242-amino-5-chloro-.0 - (2-chlorophenyl) -benzylideneamino - ethanol, a product is obtained with a melting point of 181-183 ° C. and a yield of 93%. Example 21. 7-Bromo-5- (2-chlorophenyl) - (5,4-i) -oxazolidino-2,3,4, 5: -tetrahydro-1H-1,4-benzodiazepinone-2. Described in example 11 using the method, but using 2-: 2-amino-5-bromo-c (- (2- -chlorophenyl) -benzolidenamino-ethanol and bromoacetyl chloride instead of 2- 2-amino-5-, chloro-c - (2-chlorophenyl) -benzylideneamino-ethanol and bromoacetyl bromide, get the product with T.iui. 2O7 (decomposition) and you Example 22. 7-Bromo-5- (2-chloro-phenyl) - (5,4-i) -i5-methyloxazolidino--2, 3, 4, 5 (-tetrahydro-1H-1,4-benzodiazepinone- 2. Described in Example 11, but using 2-f .2-amino-5-bromo-c (- (2- -chlorophenyl) -benzylideneamino -1-methyl-eta-. NOL instead of 2- 2-amino-5- chlorine-Of- (2I-chlorophenyl) -benzylideneamino-ethanol, I get a product with mp 196-197 ° C (expansion) and a yield of 93%. Example 23. 7-Chlorophenyl- (5 , B) -tetrahydro-2H-1, 3-oxazipo-2, 3, i 4, 5-tetrahydro-1H-1,4-.benzodiazepinone-2. Described in Example 11, but using 3- (2-amino-5-chloro-Of-phenyl-benzylideneamino) -. N-propanol and bromoacetyl chloride instead of 2- 2-amino-5-chloro-c (: - (2- chlorophenylbenzylidene amino-ethanol and i bromoacetyl bromide, a product is obtained with mp 22O-222 C and a yield of 93%. Example 24. 7-Nitro-5-phenyl- (5,4- - i) -oxazolidino-2, 3, 4, 5-tetrahydro-1H-1,4-benzodiazepinone-2. Described in Example 9 by the method, but using 2- (2-amino-5-nitro-Cf-phenylbenzylideneamino) ethanol and bromoacetyl chloride instead of 2- ( 2-amino-5-chloro-o (-phenylbenzylideneamino) -1-methylene ethanol and bromoacetyl bromide, get about BCCH with m. mp, 218-22O C (decomposition) and 84% yield.

eleven

Example 25. 7-.Chloro-5- (4-nitro. Phenyl) (5,4-. B) -5-methyloxazolidino- i -2, 3, 4, 5-tetrahydro-1H-1,4-. Benaodiazepinone-2,.

By the method described in example 11, but using amino-5-chloro-o (- (4-nitrophenyl) -benzydimoJ -1.methylMeTBHoh instead of 2-2-amino-5-chloro-Of -. {2-chlorophenyl) - benzylidene J-ethanol; get the product with so pl. 193-195 ° C and: yield 82%.

P. P and meper 26, 7-. Chloro-5 (2-JpTop. Fvnil) - (5,4-i) -oxaolidino-2,3, 4, 5-tetrahydro-1 Hl, 4-bvdzodiazepinon- 2

i As described in Example 9, using 2-2-amino-5-chloro-o (- (a-fluorofvnil) -benzylideneamino; 1-ethanol, triethylamine and bromoacetyl chloride instead) 2- (2-mino-5-chloro) Cf-phenylbenzylideneamino) -1-methylethanol, pyridine and bromoacetyl bromide, get the product with t, PL, 181-183 C and a yield of 83%.

Example27. 7-Chloro-1-4) vnac 5-phenyl (5,4-b) methyloxazolidino-2, 3,4, 5-tetrahydrOt. 1H-1,4-benzdiae pinon-2 .I

As described in Example 11, but using 2- (2C) enacyl-amino-5-chloro (-phenyl-6-silyl-amino) -1-methyleth- | NOL, potash and bromoacetyl chloride instead

. 2-f 2-amino-5-chloro-o (- (2-chlorophenyl) benzylideneamino-ethanol, sodium carbonate and bromoacetyl bromide, a product is obtained with mp 175-176 ° C and a yield of 95%.

Example 28. 7-Chloro-1-6 vnayl “phenyl-B, 4-. (B) 5-mtiloksazolidino-2, 3, 4, 5-tetragyro-1H-.1,4-benzodi-1 azepinoH.

Described in example 11 is a way but; using 2- (2-benzylamino-8-x or-fl-phenylbenzylidene (E) -1-methylethanol d bromoacetyl chloride instead of 2-amHo-5-a-chloro-Of- (2-chlorophenyl) - "bvnailidbnami-. but-ethanol and bromoacetyl bromind, and the product is m.p. 154-15BS and 95% yield.

Example 29. 6-phenyl- (5,4- $) -5-methyloxazolidino-2, 3, 4, 5-tetragyro. -1H-1,4-benzodiaopinone-2 ...

In the manner described in Example 9, but using 2- (2-amino-d -phenylbenzyl- and Denamino) -1-methylethanol instead of -amino-5-chloro. 0 (-phenylbenzylidene-, but) -1-methylethanol, receive the product with t, pl. 174-176 ° C and a yield of 84%,

Example 30, 7-Chloro-5-phenyl- (5,4-i,) -. 4-methyloxazolidino-2, 3, 4, 5-tetragndro-1H-1, 4-.b © nzindiazepinone-2,

12

By the method described in Example 9, but using 2 (2-amino 5-chloro-0 (-phenylbenzylideneamino)) - 2. 2. methyL9thanol instead of 2 "- {2-amino-5-chloro-phenylbenzylidene amino) -1 -methyl ethanol, get the product with so pl. 126-127 ° C and a yield of 83%,

Example 7-Chloro-5-phenyl- (5.4 5) -4-methyloxazolidino-2, 3, 4, 5.. -tetrahydro-1H-1,4-benzodiazepinone-2. Described in example 9, but

using 2- (2-amino-5-chloro-Of-phenyl; benzylideneamino) -2-methylethanol and tosyl xylacetyl bromide instead of 2- (2-amino-5, -chloro-d-phenylbenzylideneamino) -1-methyl-, I ethanol and bromoacetyl bromide, get the product with so pl. 12 6-12 7 With and a yield of 82%, With m er32. 7-Bromo-5-phenyl- (5,4 -i i) -4-mtiloksazolidino 2, 3,4,5-tetrahydro H-1,4-benzodiazepinone-2. As described in Example 9, but using 2 -. (2-amino-5-bromo-Of-phenylbenzylideneamino) -2-methylethanol instead of 2- (2-amino-5-chloro-o (-phenylbenzylideneamino) -1 "-methylethanol , get the product with t, PL, 126-127 ° C and a yield of 81%.

Example of 7-Nitro-5-feiyl- (5,4-b) -4-1Letyloxazolidino-2,3,4, 5-tetrahydro-1H-1,4-benzodiazepinone-2,

By the method described in Example 9, but using 2- (2-amino-5-nitro Of-phenylbenzolidenamino) -2-m9-TL-ethanol b & 2- (2-amino-5-chloro-Qf-phenylbenzylideneamino) -1-methyl benzene, get the product with so pl. 182-183 0 and yield 82%. Example 34 7-Chloro-5- (2-chloro-.

fvil) - (5,4-b) -4-methyloxazolidino-2, 3,4, 5-.tetrahydro-1H-1,4-benzodiazepinone-2,

Using the method described in Example 11, but using 2-f2-amino-5-chloro-Of - (2-chlorophenyl) benzylidene amino-3-2-methylethanol instead of 2- 2-amino-5-chloro-0 - (2- chlorophenyl) -benzylidenemino-Ji-ethanol, a product is obtained with a mp of 172-175 ° C and a yield of 96%. |

Example 35 7-Bromo-5- (2-chlorophenyl) - (5,4-fc) -4-methyloxazolidino-2, 3, 4, 5-tetrahydro-1H-1,4-benzodia:, zepinone-2.

Using the method described in Example 9, but using 2-f2-amino-5-bromo-{2-chlorophenyl-benzylidene-amine 9} -2-methylethanol instead of 2- (2-amino-5-chloro-Of-phenylbenzylndenamino) -1- Methyl ethanol get the product with so pl. 182-184 ° C, and a yield of 83%,

Claims (2)

Example 36, 9-Methyl-7-Chloro "5-phenyl- (5,4-b) 5-methyloxazolidino-2,3,4,5-tetrahydro-1H-1,4-benzodiaz I pinon-2 . A mixture of 4.4 g of 3-methyl-5-chloro-2-aminobenzophenone and 3.2 g of isopropanol amino is gently heated at a low I boiling (with reflux condenser) for 1 hour. at one o'clock. After distilling off an excess of isopropanolamino under vacuum, an oily residue containing mainly 12- (3-methyl-5-chloro-2-aminophenyl) -2-phenyl-5-methyloxazolidine is added 200 ml of toluene and 3 g of pyridine. 5.8 g of bromoacetyl bromide was added dropwise with stirring to the resulting solution, cooled with a mixture of water and ice, while maintaining the temperature below J10 °. The mixture is then stirred for 3 hours at room temperature. After this, 20 O ml of toluene and 200 ml of agitation are added. The top organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off. The residue is recrystallized from ethanol to give 2-65 g of crystalline product with mp. 25 ° -153 ° C and yield 82%. Example 37. 7,9-Dimethyl-5-fe; NIL- (5,4-6) -5-methyloxazolidino--2,3,4,5-tetrahydro-1H-1,4-benzodiazepinone-. Using the method described in example 36, but using 3,5-dimethyl “2-amino-benzophenone and bromoacetic anhydride instead of 3-methyl-5-chloro-2-aminobenzophenone and bromapetyl bromide, a product with m.p. 271.5-273 ° C and a yield of 81%. Example38. 7-Chloro-5-phenyl- (5,4; - b) - zhazazolidino-2,3,4,5-tetrahydroi-1H-1, 4-benzodiazepinone-2. As described in Example 36, but using 5-chloro-2-aminobenzophenone, 2-α-aminoethanol and triethylamine instead of 3-methyl-5-chloro-2-aminobenzophenone, isoprop-. nolamine and pyridine, get the product with so pl. 175-176 ° C and a yield of 82%. Note 39. 7-Chloro-5-phenyl- (5.4 -. Jj) -5-methyloxazolidino-2,3,4,5-tetra hydro-1H-1,4-benzo diazepinone-2. Described in example 36, by loading 5-chloro-2-aminobenzophenone instead of 3-methyl-5-chloro-2-aminobenzophenone, get the product with so pl. 186.5-188 ° C and a yield of 83%. Example 40, 7-Bromo-5-phenyl- (5, - b) -oxazolidino-2,3,4,5-tetrahydro-1H-1, 4-.benzodiazepi} yn-2, Described in Example 36, but Using 5-bromo-2-aminobenzophenone and 2-aminoethanol instead of 3-methyl-5-chloro-2-aminobenzophenone and isopropanolamine, a product with m.p. 189-191 ° С in a yield of 84%. Example 41. 7-Bromo-5-phenyl- (5,4-b) -5-methyloxazolidino-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinone-2. Using the method described in Example 36, but using 5-bromo-2-aminobenzophenone and carbon, instead of 3-methyl-5-chloro-2-aminobenzo-phenone and pyridine, a product is obtained with a melting point of 180.5-182 ° C and a yield of 94%. Example 42 7-Chloro-5-phenyl- (5,4-b) tetrahydro2H-1,3-oxazino-2, 3,4,5-tetrahydro-1H-1,4-benzolyazepinon-2. By the method described in example 36, but I using 5-chloro-2-aminobenzophenone and 3-amino through NOL instead of 3-methyl-5-chlori-2-aminobenzophenone and isopropanolamine, a product with m.p. 221-223 C and 82% yield. Example 43,7-Nitro-5-phenyl; .- (5,4-b) oxazolidino-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinol-2. By the method described in npHNe e 36, but: using 5-nitro-2-aminobenzophenone, 2-α-aminoethanol and triethylamine instead of 3-methyl-5-chloro-2-aminobenzophenone, isopropanolamine and pyridine, a product with m, m, p 217-221 ° C and a yield of 83%. EXAMPLE 44 7-Chloro-1-methyl-5- | - (2-chlorophenyl) - (5,4-b) -oxazolidino-2, 3,4,5-tetrahydro-1H-1 , 4-6 enzodiazepinone-2. As described in example 36, but using I 5-chloro-2-methylthylamino-o-chloroben-: zofenone and 2-, aminoethanol instead of 3-me. ., tyl-5-chloro 2-aminobenz | phenone and isopro-; panolamine, get the product with so pl. D56-158 ° C and a yield of 82%, Example 45. 7-chloro-1-ethyl-5-fe; NIL- (5,4-b) -5-methyloxazolide 1-2, i 3,4,5-tetrahydro -1 H-1,4-.benzodiazepinone- -2. Described in example 36 by the method, but using 5-chloro-2-ethdaminamine-benzofen., Non and triethylamine instead of 3-methyl-5-chloro-2-aminobenzophenone and pyridine get the product with so pl. 158-16 ° C and a yield of 83%. Example 46: 7-Chloro-1-ethyl-phenyl- (5,4-b) -5-methyloxazolidino-2; 3, 4,5-. Tetrahydro- 1 H-1,4-benzodiazepinone-2. Described in Example 36, but; Using 5-chloro-2-ethylaminobenzophenone,; triethylamine and tosyloxy-acetyl bromide instead of 3-methyl-5-chloro-2-aminobenzophenone, pyridine and broacetyl bromide, a product with m.p. 15 & -16 ° C and yield 84%. Example 47. 7-Chloro-5- (2UTOLYL) - (5,4-fe) -5-methyloxazolidino-2,3,4-. 5-tetragndro-1H-1,4-.benzodiazepinone-2 By the method described in Example 36, but using 5 chloro-amino-o-methylbenzophenone instead of 3-methyl-5-chloro-2-aminobenophenone, the product is obtained with t. pl. 203205 (decomposition) and a yield of 81%. P p i. meper 48. 7-Chloro-5- (4-nitrophenyl) -, 4-b) -5-methyloxazolidino--2,3,4,5-tetrahydro-1H-1, 4 benzodiazepi nvn-2. Using the method described in Example 36, but using 5-chloro-2-amino-fi-nitrobenyophenone and bromoacetyl chloride instead of 3-metnn-5-HLOR-2-aminobenzophenone and bromo-methyl bromide, a product with m.p. 193-1950S and 82% yield. PRI me R 49. 7-Chloro-5- {2-fluorophenyl) - | 5,4-J,) 5-methyloxaeolidino 2,3 4,5-tetrahydro-1H-1,4-benzodiazepinone-2 Described in Example 36 by the method, but using 5-chloro-2-amino-o-}) torbenzofe-. NOL instead of 3-methyl-5-chloro-2-aminobenzophenone, a product is obtained with a melting point of 197-199 ° C. and a yield of 84%. Example 50. 7-Chloro-5- (2-fluorophenyl) - (5,4-b) -oxazolidino-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinone-2. By the method described in Example 36, but using 5-chloro-2-amino-o-fluorobenzophenone and 2-amino but ethanol instead of 3-methyl-5-chloro-2-aminobenzophenone and isopropanol. amine, pspuchayut product with t. pl. 181183 ° C and a yield of 83%. Example51. 7-Bromo-5 -. (2-chloro. Fensch |) - (5,4-b) -oxazolidino 2,3,4,5-te1rahydro .1 H-1,4-benzodiazepinone-2. By the method described in example 36, but using 5 - bromo-2-amino-o-chlorobenzofvio and 2-aminoethanol instead of 3-methyl-5-5-5Sor-2-amino6eisophenone and isopropanolamine, a product with m.p. 205 2p7-C (decomposition) and yield 82%. Example 52. 7 bromo-4- (2-chloro phene e) - (5,4-b) -5-methyloxazolidino-2, 3,4,5-tetrahydro-1 H-1,4-benzodiazepn. Non-2 . By the method described in Example 36, but using 5-bromo-2 amino-o-chlorobenzophenone instead of 3-methyl-5-HLOR-.2-aminobenzophenone, a product with m.p. 196-198 ° C (decomposition) and 85% yield. Example53. 7,8-Dichloro-5-phenyl - (5,4-b) -5-methyloxazolidino-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinone 2. By the method described in Example 36, but using 4 , 5-dichloro-ampnobenzo4) enone, sodium carbonate and bromoacetyl chloride together-methyl-5-chloro-2-aminobenzophenone, pyriine and bromoacetyl bromide, get a product with mp. 196-197.5 ° C and a yield of 94%, Example 54 7-Chloro-5- (2-chloroenyl) - (5,4-b) -oxazolidino-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinone-2. By the method described in Example 36, but using 5-chloro-2-amino-o-chlorobenzof non and 2-aminoethanol instead of 3-methyl-5-chloro-2-aminobeneophenone and isopropanolamine, a product with m.p. O1204 ° C (decomposition) and yield 83%. Example55. 7-Chloro- (2-chlorophenyl) (5,4-b) -5-methyloxazolidino-2,3,4,5-, -tetrahydro-1H-1,4-benzodiazepinone-2. Described in example 36 by the method, but using 5-chloro-2-amino-o-chlorobenzof © - non instead of 3-methyl-5-chloro-2-amino-benzophenone, get the product with so pl. 19CU and 82% yield. Example.,. 56. 7,9-Dichloro-5-phenyl- (5,4-b) -5-methyloxazolidino-2,3,4,5-tetrahydro-1H-1, 4-benzodiazepinone-2. Using the method described in example 36, but using 3,5-dichloro-2-aminobenzophenium and sodium carbonate; instead of 3-methyl-5-chloro-2-aminobenzophenone and pyridine, a product with m.p. 226-228 0 and 95% yield. Example 57, 3,7,9-Trimethyl-5-phenyl- (5,4-b) -oxazolidino-2,3,4,5-tetrahydro-1H-1, 4-benzodiazepinone-2. As described in Example 36, using 3,5-dimethyl-2-aminobenzophenone, 2-aminoethanol, and o (-bromopropoyloylchloride in the place of 3-methyl-5-chloro-2 -amy-6-homophene. | On, isopropanolamine and bromapethyl bromide, yes, product Art.Sh1.218-22l C and yield 81%. Example 58. 7-Chloro-3-ethyl-5-fe-HHH- (5j4-b) -oxazolidino-2,3,4,5-tetrahydro- 1H-1, 4-.benzodiazepinone-2. Described in Example 36 using the method, but using 5-chloro-2-aminobenzophenone, 2-aminoethanol and d-bromo-n-butyl chloride instead of 3 methyl-5-chloro-2-aminobenzophenone , isopropanolamine and bromoacetyl bromide, get the product with mp 183-184 ° C and out odes 82%. Example 59. 7-Chloro-5-phenyl- (5,4-b) -thiazolidino-.2,3,4,5-tetrahydro-1H-1, 4-benzodiazepinone-2. Described in Example 36 using the method, but using 5-chloro-2- "aminobenzophenone and 2-mercaptoethylamine instead of 3-methyl-5-chloro--2-aminobenzophenone and isopropanolamine, a product is obtained with mp 241-243 ° C and a yield of 83%. Example 60, 7-Chloro-1-benzyl-5-phenyl- (5,4-b) -5-.methyloxazolidino-2, 3,4,5-tetrahydro-1H-1,4-benzidiazepinone-2 in example 36 by the method, but using 5-chloro-2-benzylaminobenzophenone instead of 3-methyl-5-chloro-aminobenzophenone, semi-dry the product with m, 154-157 ° C and a yield of 85%. For example, 61, 7-Chloro-1- {ft-chlorobenzyl) -5-phenyl- (5.4 b) -5-methyloxazolidino- .2,3,4,5-tetrahydro-1H-1,4-1,4 benzodiazepinone- .2. Using the method described in example 36, but using 5-chloro-2- (P-chlorobenzene) -amj nobenzophenone and triethylamine instead of 3-methyl 5-. Chloro-2-aminobenzophenone and pyridine, a product is obtained with mp 162-163.5 C and 78% yield, Example 62 „7-Chloro-5-phenyl - (5,4-5) -4-methyloxazolidino-2,3,4,5-i-tetrahydro-1H-1,4-benzodiazepinone-2 . As described in Example 36, but using 5-chloro-2-aminobenzophenone and 2-; -amino-n-propanol instead of 3-methyl-az-chloro-j "2-aminobeneophenol and isopropanolamine, a product with m, mp, 126-127 G and a yield of 86% is obtained. Example 7-Chloro-5-phenyl- {5,4-L) -4-methyloxazolidino-2,3,4,5-tetrahydro-1H-1,4 benzodiazepinone-2, i Described in Example 36, but using 5 -chloro-2-aminobenzophenone, 21 -amino-n-propanol and tosyloxy acetyl bromide instead of 3-methyl-5-chloro-2-aminobenzophenone, isopropanolamine and bromoacetyl bromide, i get the product with m, pl. 126-127 ° C and. 78% yield. Example 64. 7-Bromo-.5-phenyl (5,4-) -. 4-methyloxazolidino-2,3,4,5 ". Tetrahydro-1H-1,4-benzodiazepinone-2. : Described in Example 36, but using 5-bromo-2-aminobenzophenone and 2-α-amino-n-propanol instead of 3-methyl-5-chloro; -2-aminobenzophenone and isopropanolamine, a product with m.p. 126-127 C and 82% yield. Example 65 7-Nitro-.5-phenyl- (5.4 b) -4-.methyloxazolidino-2,3,4,5-tetrahydro 1H-114-benzodiazepinone-2 In the procedure described in Example 36, but using 5-.nitro-2-.aminobenzo |) enone and 2 1 aminopropanol instead of 3-methyl 5-chloro-2- | -aminobenzophenone and isopropanolamine, get the product with. t, pl. 182-183-C and a yield of 81%. “EXAMPLE 66, 7-Chloro-5 (2-chlorophenyl) - (5,4-b) —4-methyl-oxazolidino-2,3, 4j5-tetrahydro-.1H-1,4-.benzodiazepinone-2. By the method described in example 36, but using 5 chloro- “2-mino-o-chlorobenzophenone and 2-amino-n-propanol instead of 3-methyl-5 chloro-2 .aminobenzophenone and isopropanolamine, a product with m, pl. 172- .175 ° C and a yield of 83%. Example 76. 7-Bromo-5- (2-chlorophenyl) - (5,4-b) -4-methyloxazolidino-2, 3,4,5-tetrahydro-1H-1,4. -Benzodiazepinone-2. Using the method described in Example 36, but using 5.-bromo-2-2-amino-o-chlorobenzophenone and 2-amino-n-propanol instead of 3-amp-5. Chloro-2-.aminobenzophenone and nolamine isoprop, product with mp, 182184 С and yield 84%. The claims of the invention, 1. The method of obtaining benzo | diaz derivatives of the formula of the formula - "3 identical or different - hydrogen atom or lower alkyl, lower alkoxy group, halo, oxy group, nitro or cyano group, acyl, trifluoro; methyl, amino, acylamino, N-mono- (lower alkyl) aminogroup,. I-di- (lower alkyl) amino group, acyloxy group, carboxyl.-alkoxycarbonyl, car- yamoyl, N-mono- (lower alkyl) carbamoyl, N-di- (lower allyl) carbamoyl, lower alkylthio group, lower alHylsulfinyl, or lower alkylsulfonyl; R is a hydrogen atom, lower alkyl, cycloalkyl, aralkyl or phenacyl; C is a hydrogen atom or a lower al-A — straight or branched alkyl — an oxygen or sulfur atom, characterized in that. for the purpose of increasing the yield of the target product, compounds of the formulas in which f ' is R, A, and I 4 the indicated values, or a mixture of these compounds through i interaction with the reactive derivative of the compound of the formula HOOG-CH-Q 5 where R - have the indicated value ; I 5 P -. a reactive acidic residue, and the target product is isolated by advanced methods ..; 2. The method according to claim 1, wherein the interaction is carried out in an inert organic solvent medium in the presence of an acid binding agent. Priority on the grounds: from 12/24/68 as a source use the compounds of the formulas H dated 17.О4.69 as starting materials the compounds of the formulas (a and I