PL125636B1 - Process for preparing substituted 6-aryl-4h-s-triazol/3,4-c/-thien-/2,3-e/-1,4-diazepines - Google Patents

Description

Published Patent: 1986 01 31 125636 Int. Cl. C07D 495/14 Inventor: Authorized by the patent: C.H. Boehringer Sohn, Ingelheim on the Rhine (Federal Republic of Germany) Preparation of substituted 6-aryl-4H-s-triazolo [3,4-c] -thieno- [2,3] -el, 4-diazepines. - the invention is a process for the preparation of substituted 6-aryl-4H-s-triazole-i [3,4-c] -thiene- and [2,3-e] -1,4-diazepines corresponding to the general formula 1 The compounds of the formula I and their preparation, starting from the compounds of the formula II, are known from the book Annalen der Chemie 1978, pp. 1257-1265. It describes the conversion of the starting products of the formula II into the end products of the formula I shown in Scheme 1. However, it turned out that this route has some disadvantages: In order to obtain good yields on the compound of formula IIa, it has to be introduce a very large excess of liquid ammonia (I: liquid NH8 = 1: 180). Due to the aggressiveness (irritation of the mucosa) and the toxicity of volatile ammonia (boiling point: -33.4 ° C, MAK value: 35 mg / m.sup.8) all operations must be carried out under gastight conditions. That is, using an autoclave and gas-tight tubing. After the reaction with ammonia, the reaction mixture must be aerated in a specially installed flush for reasons of health and environmental protection. In the case of processing which takes place in a mixing device, one also works with the use of the installed flush. The operations described here are of the above-mentioned or 20 2 * cases, which are very time-consuming and require a lot of effort. The invention therefore had the task of simplifying the method, reducing costs and, due to the increasingly stringent environmental protection conditions, the elimination of elements harmful to the environment. This task was solved by developing a new, better method for the production of the end products of formula I, in which R 1 and R 2 are identical or different and represent hydrogen or halogen atoms, lower alkyl groups with 1-2 carbon atoms or together represent an alkylene chain, 5- or 6-membered ring, Rt represents a hydrogen, chlorine or bromine atom or a branched alkyl group with 1 to 3 carbon atoms, a n-hydroxyalkyl group with 1 to 3 carbon atoms, a n-hydroxy group with 3 to 6 carbon atoms or a 5- or 6-chlorine group containing an oxygen, sulfur or nitrogen atom, a saturated ring, the nitrogen-containing ring optionally being substituted on the nitrogen atom by a lower alkyl group or representing a group of the formula 6 in which R'8 and R'3 are the same or different and represent hydrogen atoms, alkyl groups of 1-4 carbon atoms or hydroxyalkyl groups of 2-3 carbon atoms, or both symbols together form a 4- or 5-membered alkylene chain which may optionally be substituted with a single or twice a methyl group and will make the 6-membered ring optionally contain as a further oxygen heteroatom, and R4 and R5 are the same or different and represent a hydrogen, fluorine, chlorine or bromine atom. The general formula I is prepared by reacting a dihalide of general formula II, in which R 1, R 1, R 3, R 4 and R 5 are as defined above, with hydroxylamine, and the resulting hydroxylamine compound of general formula 3 wherein R 1, R 2, R3, R4 and R "have the meaning given above, Pr is converted into the end product with a water splitting agent, the eventually obtained end compound is then converted to a physiologically acceptable acid addition salt. The process is carried out according to the attached reaction scheme 2. The reactions of the dihalide of the formula II with hydroxylamine are carried out at temperatures between 20 and 150 ° C in organic solvents, for example in lower alcohols such as methanol, ethanol or isopropanol, with the addition of potassium iodide and a hardly alkylating base, such as, for example, N, N-diisopropylethylamine, dicyclohexylethylamine or 4-hydroxy-2,2,6,6-tetraethylpiperidine as hydrogen halide acceptor. In this case, a hydroxylamimine compound of general formula III is obtained which is converted into the end product of general formula 1 by the removal of water. For this purpose, hydroxylamine is dissolved in an organic solvent, for example methylene chloride, in chloroform, ethylene chloride or chlorine. .robenzene and at temperatures between 20 and 15 ° C it is treated with a water splitting agent, e.g. thionyl chloride, methanesulfonic acid chloride, 2-bromo (or 2-chloro) - N-methylpyridinium iodide or dicyclohexylcarbodium imide. Particularly careful separation of the water is achieved with thionyl chloride, since in this case the reaction takes place already at room temperature. The end products of general formula I can be converted into their physiologically acceptable acid addition salts. Acids suitable for the formation of the salt are, for example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, ascorbic acid, maleic acid, formic acid, salicylic acid, methanol or toluenesulfonic acid. The preparation of the compounds of general formula II used as starting products is known, for example, according to Belgian Patent Specification No. 844170 or German Patent Specification No. 2,830,782. It is apparent from the process described there that in the triazole-thieno-oxazepine of the general formula IV, in which R 1, R 1, R 3, R 4 and R 5 are as defined above, the oxazepine ring at the oxygen atom is cleaved and the compound of the general formula 5 obtained, in which R 1, Ra, R 8? R4 and R5 have the meaning given above, the exceptions are. Phosphorus halide or sulfur halide. The operating time required for the new process is only half the operating time required for an already known process due to autoclave operations and the absorption of large amounts of ammonia. Since the investments in the known methods are also much higher, the new method brings manufacturing cost savings of up to about 35%. The end products of formula I and their acid addition salts have excellent anticonvulsant, sedative, anti-drug and aggressiveness-reducing properties. in doses of 0.1-3 mg / kg with very low toxicity. The following examples explain the invention in more detail, without limiting its scope. Example I. 8-Bromo-6-yl-4H-s-triazolo - [3,4-c] -thieno- {2,3-e] -1,4- diaazepine. a) 8-bromo-6- (o-chlorophenyl) - 5-hydroxy-l-methyl-4H, 6H-s-triazolo - [3,4-c] -thien- (2:, 3- e] -1,4-diazepine. 30 g (0.06 mol) 3-methyl-4-i [3- (o-chlorophenyl * bromomethyl) -5-bromo-thienyl (2)] - 5 -chloromethyl-1,2,4-triazole is refluxed * ° with 10.1 g (0.06 mol) of potassium iodide, 116 g (0.89 mol) N, N-diisopropylethylamine and 32.4 g ( 0.47 mol) of hydroxylamine hydrochloride in 1000 ml of methanol, for 2.5 hours. Then it is strained to separate insoluble products, the solvent is distilled off, the residue is dissolved in methylene chloride, washed with water, the methylene chloride phase is dried, evaporated and the residue recrystallizes from ethanol Yield 8- bromo-6- - (o-chlorophenyl) - 5-hydroxy-1-methyl-4H, 6H-s- * -triazole- [3,4-c] -thieno- [2,3-e] -1,4-diazepines: 22.3 g. 90.3% corresponding to 90.3% of theoretical yield, mp: 215-217 ° C. B) Compound title 7.5 g (0.018 mol) 8-bromo-Mo-chloro-rophenyl) -5-15-hydroxy - 1 - methyl-4H, 6H-s-triazolo [3,4-c] -thien- [2,3-e] -1,4-diazepine from 10.2 g (0.086 mol) of thionyl chloride in 240 ml of methylene chloride is stirred at room temperature for 2 hours. Water is then added with cooling, the methylene chloride phase is separated, washed with dilute ammonia, the organic phase is dried, evaporated and the residue recrystallized from ethanol. Yield of 8-bromo-6- (o-chlorophenyl) -1-methyl-4H-s-triazol- [3,4-c] -thien- [2,3-e] -1,4-diazepine: * ¦ 6.55 g = 92.6% of theory, melting point 208-210 ° C. Subsequent batches yielded 89-95% of theory. Example II. 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolq- [3,4-c] -thieno - [2,3-e] -1,4-diazepine. a) 1,8-dibromo-6- (o-chlorophenyl) -5-hydroxy-4H, 6H-s-triazolo - and [3,4-c] -thien- [2,3-e] -1, 4-diasepine. 55 16 g (0.026 mol) 3-bromo-4- [3- (o-chlorophenyl-4) romomethyl (-5-, broino-thienyl) 2)] - 5-bromometh-10 ^ 1,2,4-triazole (mp: 146-148 ° C) 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 it is heated in 530 ml of methanol for 5 hours under reflux. Subsequently, the undissolved substance is strained off, the solvent is distilled off in a vacuum at 40 ° C, the residue is dissolved in methylene chloride, washed with water, and the residue is recrystallized from the ethyl ester, acetic acid. Yield of the title compound: 10% g = 87% of theory, melting point: 188-190 ° C. b) Title link. 5 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-diazepines are mixed 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-orau (DBN) in 370 ml of methylene chloride for 1 hour at room temperature. The organic phase is then washed with an aqueous sodium thiosulphate solution and water, dried, evaporated and the residue recrystallized from methanol. Yield 1,8-di-bromo-6- (o-chlorophenyl) -4H-s- 3-riazolo- i [3,4-c] -thieno- [2,3-e] -1,4-diazepine : 4.3 g = 85.1% of the theoretical yield melting point: 209-210 "C. By analogy to the examples given, this is produced by the intermediates mentioned for the final products: Ri Br 1 C1 1 Br QH5 1 Br Br Br Br Br Br Br Br Br Ri HHHHHHHHHHHHHR, CH8 CH3 CH3 CH8 formula 7 formula 9 H Cl Br formula 10 formula 11 formula 12 R * Cl Cl F Cl Cl a Cl ~ C1 Cl Cl Cl R5 HHHHHHHHHHHHH Intermediate of Formula III Melting Point ° C 215-217 194-196 188-191 158-161 261-263 249-251 224R-226 195-198 186-188 188-190 162-163 208-210 215- 217 end product of the formula I mp. ° C 208-210 204-206 208-210 144-146 | 190-192 257-258 | 212-214 1,216-218 1,161-162 | 209-210 | 166-168 | 143-145 | 224—226 6 PL PL PL PL PL PL PL

Claims (4)

1. Claims 1. A method for the preparation of substituted 6-aryl -4H-s-triazolo - [3,4-c] thieno-l [2,3-e] 1,4-diazepines of general formula 1, wherein R 1 and Rf are the same or different and represent hydro or halogen atoms, lower alkyl groups of 1-2 carbon atoms or together, bound by an alkylene chain, forming a 5- or 6-membered ring, R3 is hydrogen, chlorine or bromine, a straight or branched alkyl group with 1 to 3 carbon atoms, a co-hydroxyalkyl group with 1 to 3 carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms or a 5- or 6-membered group containing an oxygen or sulfur atom or nitrogen is a saturated ring, the nitrogen containing ring optionally being substituted on the nitrogen atom by a lower alkyl group or by a group of formula VI, where R'3 and R "i are the same or different and represent a hydrogen atom, the group A1 A 1 to 4 carbon atom or a 2 to 3 carbon hydroxyalkyl group or both together form a 4- or 5-carbon alkylene chain which is may optionally be substituted once or twice by a methyl group, the 6-membered ring optionally having an oxygen atom as a further heteroatom and R4 and Re are identical or different and represent hydrogen, fluorine, chlorine or bromine atoms, and their physiologically acceptable acid addition salts, characterized in that the dihalide of the general formula (II), in which R 1, R, R, R, R 4 and R 6 have the meaning given above, the reaction with hydroxylamine and the resulting hydroxyl compound are given. the amine compounds of the general formula III, in which R 1, R t, R 3, R 4 and R 5 are as defined above, are converted with a water splitting agent into the final product, which, if appropriate, is converted in a known manner into a physiologically acceptable addition salt with acid. 2. The method according to p. The process of claim 1, characterized in that the reaction of the compound of general formula II with hydroxylamine is carried out with the addition of potassium iodide and a hardly alkylating base. 3. The method according to p. A process as claimed in claim 2, characterized in that N, N-diisopropylethylamine, dicyclohexylethylamine or 4-hydroxy-2,2,6,6-tetramethylpiperidine is used as the difficult alkylating base. 4. The method according to claim A method as claimed in claim 1, characterized in that thionyl chloride, methanesulfonic acid chloride, 2-bromo-N-methylpyridinium iodide, 2-chloro-N-methylpyridinium iodide or dicyclohexylcarbodiimide are used as the water splitting agent. .125 636 RDNMI ^ S ^ N- ^ cHo-HaU R2 R iH "^ ia; ic * M '' NH3 i5trR 'rnetcnoL R- R. 1 N ^ S ^ i- R0 ^ ^ CH-NH - 2 R5nA ^ R4 MODEL 2 N R-. Ii Rc CN R / MODEL SCHEME 1 KMnO, MODEL 2 a RlV! JrN ^ CH2-Hal2 R2 CH-HgIi nh- WZCiR 2 OH R3 — f NN R5Y; kY ^ Rz 'WZCfR 3 y ^ a / odszczepieme v \ / ody N R3 ^ -w R2'J L "¦¦ * C = N Rc FORMULA 1 SCHEME 2125 636 R-3-C * XN S. ^ N-CN Ri., Ro ^ '^ CH -U CH ~ «4 WZCfR 4 R ^ -N / VR MODEL 6 N *! R3 TT oH2 "OH MODEL 7 DESIGN 5 CH, O; n- CH, MODEL 8» VZ0R 9 MODEL 10 C2n5 r. H: n- C2H5 MODEL 12 PL PL PL PL PL PL