SU453844A3 - - Google Patents

Description

(54) METHOD FOR OBTAINING DERIVATIVES OF BENZO- R-THIOPHENE

o (: iH- (CH2) irBi

Xi KI

is reacted with an amine selected from the following group: dimethylamine, diethylamine, di - “- propylamine, di-n-butylamine, pyrrolidine, piperidine or perhydroazepine.

Example 1. 2-ethyl-3- (3,5-dibromo-4-7-di-n-propyl-aminopropoxybenzoyl) beisor-thiophehydrochloride.

but. Preparation of 2-ethyl-3-anisoylbenzor-thiophene.

In a one liter flask equipped with a mechanical stirrer and an addition funnel, 53.6 g (0.33 mol) of 2-ethyl benzene thiophene and 59 g (0.346 mol) of anisoplchloride are dissolved in 200 ml of dichloroethane. After cooling the solution to 5 ° C using an ice bath, 86 g (0.33 mol) of chlorine tin is introduced into it with stirring from an addition funnel, and the temperature of the reaction mixture is maintained at 5-10 ° C. Then the cooling bath is removed and the reaction mixture is stirred at room temperature for 4 hours. The resulting complex is decomposed with 250 ml 5 and. hydrochloric acid. The organic layer is separated, washed with an aqueous solution of caustic soda and then with water until neutral. Next, the organic fraction is dried and the solvent is evaporated in vacuo. The result is 80 g of 2-ethyl 3-anisoyl-benzene-thiophene with T. Il. 71 ° C after recrystallization from petroleum ether at 100-120 ° C. The yield of 81%.

By the same method, the following products are obtained from the corresponding starting materials:

ConnectionT. pl., ° C

3-anisoyl - benzo-p-thio- 122

2-methyl-3-anisoylbenzo-73 hair dryer

p-thiophene 2-n-propyl-3-anisoylbee 225 - 230 / 0.2 mm

zor-thiofenrt. Art.

2-isopropyl - 3 - anisoyl- 89

benzo-§-thiophene 2-n-butyl-3-anisoylbenzo-fusible p-thiophenelo, recrystallization is not possible.

b. Preparation of 2-ethyl-3- (4-hydroxybenzoyl) benzor-thiophene.

In a one-liter flask equipped with a reflux condenser, mechanical broom and a thermometer, 80 g (0.27 mol) of 2-ethyl-3-anisoyl benzor-thiophene and 400 g of pyridine hydrochloride are charged. The resulting mixture is heated to melt and the melt is heated to 220 ° C for 1 hour and then FALLED on slightly acidified ice. The organic fraction is extracted with diethyl ether, the ether solution is washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness in vacuo. In the residue after evaporation, 71.7 g of 2-ethyl-3- (4-oxybenzoyl) -benzo-thiophene are obtained in the form of a viscous oil, which slowly crystallizes 10 on standing. T. pl. crystalline product 110 ° C. Yield 94%.

By the described procedure, using the appropriate starting materials Beuj, ec7B, the following compounds were prepared.

ConnectionT. pl., ° C

3- (4 - hydroxybenzoyl) -benzo-1 (95

p-thiophene

2-methyl- (4-hydroxybenzoyl) - 166 0 benzo-p-thiophene

2-n-propyl-3- (4-hydroxy- (oil, not crisoyl) - benzo-r) -thiotalized) hair dryer

2-n-butyl-3- (4-hydroxybenzo-81 5 yl) -benzo-{3-thiophene

at. Preparation of 2-ethyl-3- (3,5-dibromo-4-hydroxybenzoyl) benzo-thiophene. 71.7 g (0.254 mol) of 2-ethyl-3- (4-hydroxybenzoyl) 0 benzo-thiophene to 72 g of trihydrated sodium acetate was added to 200 ml of methanol and the mixture was heated until complete dissolution. The resulting solution is cooled to room temperature and a solution of 84 g (0.525 mol) of bromine in 34 ml of acetic acid is added dropwise to it when it is transferred. Stirring of the reaction mixture is continued for 90 minutes, after which 150 ml of water is added to it. Precipitated

0 The brominated derivative is filtered, washed with diethyl ether until completely dissolved, and the resulting solution is washed in a separatory funnel with water. After evaporation of the solvent, 88.4 g of 2-ethyl 5 of 3- (3,5-dibromo-4-hydroxybenzoyl) benzor -tpophene are obtained, which after recrystallization from isopropanol has a melting point of mp. 142 ° C. The yield of 78.8%. By the described method when using

the corresponding starting materials, the following compounds were obtained.

M.p.

Compound

3- (3,5-dibromo-4-hydroxybenzoyl) -bep30-p-thiophene210

2-methyl-3 - (3,5 - dibromo-4-hydroxybenzoyl) -benzor-thiophene 181

2-n-propyl-3 - (3,5-dibromo-4-hydroxybenzoyl) -benzor-thiophene

2-isopropyl-3- (3,5-dibromo-4-hydroxybenzoyl) benzo-p-thiophene171

2-n-butyl-3- (3,5-dibromo-4-hydroxybenzoyl) -benzo: p-thiophene113

2-ethyl-3- (3,5-diiodo-4-hydroxybenzoyl) -benzo-thiophene132 2-methyl-3- (3,5 - diiodo - 4 - oxybenzoyl) -benzo-r-thiophene 186 2-n- propyl-3- (3,5-diiodo-4-oxybenzoyl) -benzor-thiophene105 2-n-butyl-3- (3,5-diiodo-4-oxybenzoyl) -benzor-thiophene112 2-isopropyl - 3- (3,5-diiodo-4-hydroxybenzoyl) -benzor-thiophene148 2-ethyl-3- (3,5-dichloro-4-hydroxybenzoyl) -benzo-thiophene130 g. Preparation of 2-ethyl-3 - {3,5-dibromo-4-- -DI-npropyl-amiopropoxybenzoyl) benzo-thiophene gndrochloride. In a flask with a capacity of 0.5 g, equipped with a reflux condenser and a mechanical stirrer, 8.8 g (0.02 mol) of 2-ethyl-3- (3.5 dibromo-4-hydroxybenzoyl) benzo-p1 -thiophene and 4 are charged, 2 g (0.03 mol) of anhydrous potassium carbonate, after which 50 ml of dimethylformamide are added. After the mixture was heated for 1 hour, 101 g (0.5 mol) of 1,3-dibromopronan was added to the mixture in a water bath. The reaction mixture is heated for 90 minutes in a tub and evaporated to dryness in vacuo. The residue after evaporation is dissolved in diethyl ether, the ethereal solution is washed in a separatory funnel with water, then dried over anhydrous potassium carbonate and evaporated to dryness in vacuo. After removal of the solvent, 11.2 g of 2-ethyl-3-3.5 dibromo-4- (3-bromopronoxy) benzoyl benzo p-thiophene are obtained in the form of a very viscous oil. This oil is dissolved in 50 ml of benzene, and 5.06 g (0.05 mol) of di---propylampa and 5 ml of dimethylformaine are added to the resulting solution. The mixture thus obtained is heated to boiling and heated under reflux for 2 hours, then cooled to room temperature, washed with water, dried and evaporated to dryness in vacuo. In the residue after the removal of the solvents, a solution is obtained, which is dissolved in sulfur efpr, and a solution of dry hydrogen chloride in lyl tyl ether is added to the solution obtained with ether. This gives a hydrochloride precipitate, which is filtered off, washed with ether, and after drying to constant weight, 3.9 g of 2-ethyl-3- (3,5-dibromo-4-.7-di-n-pronylaminopropoxybenzoyl) -benzo- - p-thiophene hydrochloride in the form of a crystalline vein with so-tnnl. 152 ° C. The yield of 39%. Using the corresponding starting materials but the described procedure, the following compounds were synthesized. ConnectionT. nl, ° C 3- (3,5-dibromo-4-y-di-n-nropylaminopropoxybenzoyl) -benzo-p-thiophene hydrochloride 149 2-methyl-3- (3,5-dibromo-4-7-dimethylaminopropoxybenzoyl) -benzor thiophene hydrochloride - .. 177 2-methyl-3- (3,5-dibromo-4-7-piperidopropioxybenzoyl) -benzo-r-thiophene hydrochloride 173 2-methyl-3- (3,5-dibrom-4 -7-di-n-propylaminopropioxybenzoyl) benzo-p-thiophene hydrochloride149 2-ethyl-3- (3,5-dibromo-4-f-diethylaminopyroxybenzoyl) benzo-p thiophene hydrochloride 132 2 -ethyl-3- (3.5 - dibromo-4-7-pyrrolidinonepropoxybepzoyl) - benzo - p thiophene oxalate 163 2-ethyl-3- (3,5-dibromo - 4-y-pyeridinonropoxyb Enzoyl) - benzo - p thiophene hydrochloride 152 2-ethyl-3- (3,5 - dibromo - 4 - y - perhydroazepinopropoxybenzon) - benzo r-thiophene hydrochloride 123 2nn-nropyl - 3 - (-3,5 - dibromo- 4-7 diethylaminopropoxybenzoyl) -benzo-p-thiophene oxalate152 2-n-nropyl-3- (3,5-dibromo-4-y-Ditt-proia l amyiopropoxybenzoyl) -benzo-r-thiophene oxalate 120 2-ethyl-3- ( 3,5-dibromo-4-7-di-n-butylamino-iioxnbenzoyl) -benzo P1-thiophene gndrochloride149 2-n-butyl-3- (3,5-dibromo-4-v-Diethylaminopropoxybenzoyl) -benzo P1-thiophene oxalate171 2 -ethyl-3- (3,5 - dibromo - 4-p-di-niropylaminoethoxybenzoyl) - benzo p1-thiophene gpdr ohlorid165 2-ethyl-3- (3,5-dibromo-4-p-diethylaminoethoxybenzoyl) -benzo-r-thiophene oxalate 158 2-n-propyl-3- (3,5-dibromo-4-p-diethylaminoethoxybenzoyl) -benzo - p thiophene oxalate 120 2-ethyl-3 - (3,5 - dibromo - 4 - p-dnmethylaminoethoxybenzoyl) - benzene p thiophene oxalate 185 2-n-butyl-3 - (3,5-dnbrom-4-p-di- niropilaminoetoksibenzoil) - benzo-p1 tnofei oksalat167 2-nzoproiil - 3 - (3,5-dibromo - 4-rdietilaminoetoksnbenzonl) - p bepzo -thiophene oksalat148 2-ethyl - 3 - (3,5-dibromo - 4-p-di- npropplaminomethylenesibibosoyl) benzop-thiophene oxalate, 166 2-ethyl-3- (3,5-dibromo-4-y-Dimethylaminopropoxyben opl) -benzo p1-thiophene hydrochloride129 2-n-yropyl-3- (3,5-dibromo-4-y-dimethylginophenoxybenzoyl) benzo p -nofen oxalate 132 2-to-butyl-3- (3,5-dibromo - 4-y-Dimet. Chaminonronoxybenzoyl) - benzo p1-thiophene oxalate179 2-iso-yropyl - 3 - (3,5-dibromo-4-y-dimethylaminopropioxnbenzoyl) - benzo p-thiofy oxalate sulphate 172 2-n-butyl-3 - , 5-dibromo-4-7-di-n-propylamino-iropoxybenzoyl) -ben.: Or- thiofep-gpdrochloride 133 2-isopropyl-3- (3,5-dibrom-4-7-diethylaminopropoxybenzoyl) -benzo-p-thiophene oxalate 147 2- isopropyl-3- (3,5-dibrom-4-y-DI-n-propylaminopropoxy benzoyl) -benzo-r-thiophene salad122 2-methyl-3- (3,5-diiodo-4-7-di-7-propylaminopropoxybenzoyl) -benzo | 3-thiophene hydrochloride 180 2-ethyl-3 - (3,5-diiodo - 4-7-di n-propylaminopropoxybenzoyl) benzo-p-thiophene hydrochloride 198 2-ethyl-3- (3,5-diiodo-4-7-diethylaminopropoxybenzoyl) -beizor-thiophene hydrochloride 178 2-ethyl-3- (3,5-diiodo-4 -y-piperidinopropoxybenzoyl) -beizo-thiophene hydrochloride181 2-n-propyl-3- (3,5-diiodo-4-7-diethylaminopropioxybenzoyl) -beizo-p-thiophene oxalate 155 2 - "- propyl-3- (3, 5 - diiodo-4-l.-di-npropylamino-iropoxybepzoyl) - beiso-H | 31-thiophene oxalate93 2-iso-yropyl-3- (3,5-diiodo-4 - y - diet ilaminopropoxybeisoyl) -beiso p-thiophene oxalate130 2-n-butyl-3 - (3,5-DIODO-4-7-Diethylaminopiroxybenzoyl) - benzo p1-thiophene oxalate 164 2-n-butyl-3 - (3,5 - diiodo - 4-y-di-npropylaminopropoxybenzoyl) -benzo-Gr-thiophene oxalate76 2-isopropyl-3- (3,5-diiodo - 4-7-DI "- proylaminopropoxybenzoyl) beisor-thiophene hydrochloride 95 2-ethyl-3- (3,5-diiodo-4-y-dimethylaminopropoxybenzoyl) - benzo-thiophene hydrochloride 184 2-n-propyl-3- (3,5-diiodo-4-7-dimethylamino-proioxybenzoyl) -benzo p1-thiophene oxalate 170 2-isopropyl - 3 - (3,5-diiodo-4-y-dimethylaminopropoxybenzoyl) - benzo p -thiophene oxalate165 2-ethyl-3- (3.5-diiodo-4-p-diethylaminoethoxybeisoyl) -benzo-p thiophene oxalate180 2-n-propyl-3- (3,5-diiodo-4-p-diethylaminoethoxybeisoyl) -beiso- p thiophene oxalate121 2-n-butyl-3- (3,5-diiodo-4-p-diethylaminoethoxybenzoyl) - benzo - p thiophene hydrochloride 149 2-isopropyl - 3- (3,5-diiodo-4- | p-diethylaminoethoxybenzoyl) -benzor thiophene oxalate175 2-ethyl-3- (3,5-dichloro-4-y-DI-n-iropylaminopropoxybenzoyl) -benzo p-thiophene hydrochloride 39 2-ethyl-3- (3,5-dichloro-4 -7-diethylaminopropoxybenzoyl) -benzo-thiophene hydrochloride131 2-ethyl-3- (3,5-dichloro-4-y-pyride iopyropoxybenzoyl) -bensor-thiophene hydrochloride143 2-n-butyl-3- (3,5-dichloro-4-y-di-n-propylamino-irooxybeisoyl) -beio-thiopheno oxalate 112 2-n-butyl-3- (3,5- dibromo-4-y-di-n-propylamino-iropoxy-isoisoyl) -beno-thiophene hydrochloride 133 2-isopropyl-3- (3,5-dibromo-4-Y-Dithylaminoproioxiboisoyl) - bsnzo BT-thiopa oxalate 147 2-isopropyls , 5-dibromo-4-7-din-proiylampiopropoxpbezoyl) bsizor-thiofei oxalate122 PRI mme p 2. Synthesis of 2-ml-3-g- (3,5-dibrom4-b-iiieridinobutoxy-133oyl) -benzoror- thiofep hydrochloride. 6.39 g (0.0155 mol) 2-methyl-3- (3,5-dibromo-4-hydroxy-isoyl) -beisor) 1-thiophene is dissolved and -10 ml of dimethyl amide, amide, 3.1 g (0, 0225 anhydrous potassium carbonate. To receive the mixture during peremegaiviii iribribvlyu 16.2 g (0.075 mo.-) 1.4-1ibrombutap and reheptoynuyu mixture ng gropayat bachney water for 1 h. After cooling the salt is filtered, after p.stuvtopite.ti The residue after evaporation is dissolved in diethyl ether, the ether solution is washed in a separatory funnel with water and then dried over anhydrous sodium sulfate. Next, the ether is evaporated and The excess .4-dibromobutane is removed by distillation in vacuo. The residue yields 3.8 g of 2-methyl-3- (3,5-dibromo-4-b-bromobutoxybenzoyl) -benzo-p-thiophene (after recrystallization from petroleum ether ) with so on. 100-120 ° C. A solution containing 1 g (0.0018; ol) 2-methyl-3- (3,5-dibromo-4-b-bromobutoxybenzoyl) -beiso-Gr-thiophene and 0.51 g (0.0053 mol) of piperidine in 15 ml of benzene left to stand for 72 hours at room temperature. The resulting reacini salts are filtered and the benzene solution is evaporated in vacuo at room temperature. The residue after evaporation is treated with diethyl ether; the insoluble fractions are filtered off and the resulting base is treated with its ethereal salt solution with an ethereal solution of hydrogen chloride. 5 ml of 2-methyl-3- (3,5-dibromo-4-b-piperidinobutoxybenzoyl) -benzothiophenol hydrochloride is obtained, which, after recrystallization from petone, has a melting point of 180 ° C. Example 3. Preparation of 2-ethyl - 3- (3,5-dibromo-4- (o-diethylaminoentoxy-isoyl) benzo p-thiophene oxalate. 8.8 g (0.02 mol) 2-ethyl-3- (3, 5-dibromo-4-hydroxybenzoyl) benzo-p-thiophene is dissolved in 100 ml of dimethylformamide containing -114 g (0.03 mol) of anhydrous potassium carbonate. 92 g (0.4 mol) 1 is added to this mixture, The 5-dibromientane and the reaction mixture are heated in a water bath for 1 hour. After cooling, the salts formed by the reaction are filtered off and the solvent is evaporated in vacuo. The residue after evaporation is treated with diethyl ether, the ether solution is washed in a separatory funnel with water and then dried over anhydrous sodium sulfate. The ether is then evaporated and the excess 1,5-dibromopentane is distilled off in vacuo. After distillation and washing with methanol, 8.1 g of 2-ethyl-3- ( 3.5 dibromo-4-co-bromopentoxybenzoyl) -benzo p-thiophene in the form of a viscous oil. A solution containing 4.5 g (0.0075 mol) of 2-ethyl-3- (3.5-dibromo-4-th -brompeitoxybenzoyl) -benzor-thiophene and 2.36 ml (0.0225 mol) of diethylamine in 35 ml of dimethylformamide are stirred for 48 hours at room temperature. The resulting crude product is poured into water and extracted with diethyl ether. The ether extract is evaporated to dryness and the free base thus obtained is converted to its alkali acid salt by treatment in diethyl ether with an alcohol solution of oxalic acid. Obtain 0.8 g of the target 2-ethyl-Z- (3,5-dibromo-4-co-diethylaminopentoxybenzoyl) benzor-thiophene oxalate, t. Pl. which after recrystallization from acetone 125 ° C. The yield of 16%. According to this procedure, 2-ethyl-3 - (3,5-dibromo-4-a) -dimethylaminopentoxybenzonyl) -benzo-thiophene oxalate with m.p. 154 ° C. Example 4. Preparation of 2-ethyl-3- (3,5-dibromo-4th) -dimethylaminohexoxybenzoyl) benzo-G0-thiophene oxalate. 2.2 g (0.005 mol) of 2-ethyl-3- (3,5-dibromo-4-hydroxybenzoyl) -benzor-1-thiophene are dissolved in 25 ml of dimethylformand containing 1.05 g (0.0076 mol) of anhydrous potassium carbonate . While stirring, 24.4 g (0.1 mol) of 1,6-dibromhexane was added to the reaction mixture, after which the reaction mixture was heated on a water bath for 1 hour. After cooling, the precipitated salts were filtered, and the filtrate was evaporated in vacuum to remove the solvent. The residue obtained after evaporation is treated with diethyl ether, the ethereal solution is washed in a separatory funnel with water, then it is washed over anhydrous sodium sulphate and evaporated to remove the solvent and an excess of 1.6-dibromhexane (the latter is distilled off in vacuo). The residue gives 2.1 g of 2-ethyl-3-C3.5-dibromo-4-co-bromohexoxybenzoyl-benzo-thiophene as a viscous oil which does not crystallize. A solution containing 2.1 g (0.0035 mol) of 2-ethyl-3- (3,5-dibromo-4-m-bromohexoxybenzoyl) -benzo-G (3-thiophene and 3 ml (0.046 mol) of dimethylamine in 20 ml of dimethylformamide and 100 ml of diethyl esyr are placed in a refrigerator and kept there for 8 days. The crude product is poured into water and extracted with diethyl ether. The organic layer is washed with water and dried over anhydrous potassium carbonate. Then, dissolve: -u} -steam under vacuum and the residue is treated with anhydrous diethyl ether. Pr1 by adding a solution of an alkaline acid solution to the firioma is obtained oxalate 2-ethyl-3, 5-dibromo-4-a) - dimethylaminohexoksbenzene) -benzor-thiophene, so pl. which after recrystallization from a mixture of acetone and metaol. The yield of 40%. The subject matter of the invention is 1. A method for producing benzo- (5 iophene derivatives of general formula I ° / (CH2) xGAH X, where R is hydrogen or straight or branched chain alkyl containing 1-4 carbon atoms; RI is hydrogen or methyl; X , Xi - chlorine, bromine or iodine; Ash - dimethylamine, diethylamino, di-nropylamino, di-n-butylaminogram, pyrIDIDO-, piperidino or perhydroazepinogroup and p-integer 1-5, or their salts, similar to , that the benor-thiophep derivative of the general formula P where R, X, XI have the indicated meanings dibromoalkane of general formula III (CH2VBr RI where Ri and p have the indicated values, and the resulting bromoalkoxybenzoylbenzo - p - thiophene formed by the general formula IV, thus formed, rCo-fyo- (H- (ciH2) n-JBr, is reacted with an amine corresponding to AGL above 1112

followed by isolation of the target product — that the reaction between the bromoalkoxybenzoyl-mouth in a free form or in the form of a salt by a known thiophene of the general formula IV and the amine in a conductive way. in an inert solvent, for example

2. The method according to claim 1, wherein, in dimethylformamide.

453844