SU548210A3 - Method for preparing 4n-benzo (4,5) -cyclohepta (1,2-b) -thiophene derivatives or their salts - Google Patents

Description

However, there is no information in the literature about the method of preparing compounds of formula 1. The obtained compounds possess interesting pharmacodynamic properties and can be used in the pharmaceutical industry. The proposed method for preparing the compound of formula 1 is that the compound of the general formula 2 L is S. where h, V., h and A have the indicated values, are reacted with a compound of the general formula 3 xso (fn,) where (1 - has the indicated values; X is chlorine or bromine; Y is lower alkyl or X and Together form a bond; with the subsequent isolation of the target product in free form or in the form of salt. In the formula, the formula ITij predominantly means hydrogen or chlorine and most often is in position 6 or 7 with respect to the cyclic group. lower alkyl, it preferably contains 1-4 carbon atoms, in particular it is. R. notice the advantage is hydrogen. Kepi RJ is lower alkyl, it contains, for example, 1-4 carbon atoms, in particular, is methyl and / w ethyl. Prefer Cd together are acidic K and body, most often equal to 2 The reaction of compounds of Formula 2 with compounds of Formula 3 is carried out in the presence of an acidic condensing agent. The process is carried out, for example, in npauyTCTw of the Institute of Lewis Acids in an organic solvent inert under these reaction conditions, for example, in a chlorinated hydrocarbon medium, such as methylene chloride or tetra Chloroethane, or in the environment of sulfur-Laurode, and the reaction conditions correspond to the conditions of the Friedel-Crafts reaction. As Lewis acids, for example, aluminum trichloride or tin tetrachloride are applicable. . The reaction of compounds of formula 2 with compounds of formula 3 can also be carried out in the presence of strong mineral salts, for example, polypropylene or phosphoric acids, and also with the addition of an organic solvent inert in these internal reaction reactions, for example, a hydrocarbon such as benzene, toluene, xylene or tetralin. If the e-gu reaction is carried out in the presence of a Lybis acid, then the reaction temperature is preferable from room temperature to the temperature of the reaction mixture, and the reaction time is 5 minutes to 24 ac. The reaction in the presence of a strong mine acid is preferably carried out at 50-150 ° C for 30 minutes to 24 hours. When interacting in the presence of a strong mineral acid, all the ether groups -COORj in the compounds of formula 1 are hydrolyzed simultaneously, and thus the acids of formula 1 are obtained. The compounds of formula 1 are separated out from the reaction mixture by known methods and purified. The free acids of formula 1, if necessary, are converted into chq salts, or vice versa, from salts to extract acid. Source compounds f. Mules 4, where A has the indicated, 1-Cacheain can, for example, be obtained by reducing compounds of the formula 5 where A has the indicated values. The reduction can be carried out, for example, according to the Klemensen method by the action of amalv gama of zinc in hydrochloric acid or, if A is an ethylene group, by treatment with metallic sodium in alcohol. The compounds of formula 1 are not described in the literature. They have interesting pharmacodynamic properties, they can therefore be used in medicine. Example 1 4- (9DO-Dihydro-4H-benzo 4,53 cyclohepta l, 2-thiofre1.2-yl) -4-oxo-butl acid. 11.0 g of tartaric anhydride are diluted with heating in 22O ml of anhydrous methylene chloride, the resulting solution is cooled to 2 ° C and in parts added 30 g of aluminum chloride to it. After 15 min of stirring at room temperature, 220 g of 9,10-dihydro-4H-benzo {4.53 cyclopenta 1, 2- || tofen in 100 ml of anhydrous methylene chloride are added dropwise to this solution for JU min for 2 min. The mixture is stirred at room temperature

More than 45 mvv and then poured into a mixture of 200 ml of concentrated hydrochloric acid (you and 200 g of ice. Add 300 ml of m. of thylene chloride, heat for 15 min in a water bath, cool, remove methyl methylene chloride, and recover the aqueous phase with methylene chloride. From the combined methylene chloride extracts, the Bidel: g acidic part is extracted with 0.5N sodium hydroxide solution, the basic extract is neutralized with 5N hydrochloric acid and shaken with chloroform. The chloroform solution is washed with water, dried over magnesium sulfate, filtered through activated carbon and evaporation The target product, which remains in the pide of the solid residue, is recrystallized from a mixture of dimethyl forms / acetone, mp 202. -2 O3 ° C.

The starting material can be obtained as follows. To a solution of 25.0 g of 9.1O-digdro-4H-benzo 4,5 of cyclopenta 1,2 | .-aiophen-4. 25.0 g of sodium are added in 20.0 ml of anhydrous ethyl alcohol in portions. After it is completely dissolved, the reaction mixture is heated for 2.5 hours until submergence 0 is distilled off the solvent under reduced pressure. To the residue was slowly added 5OO ml of ice water and 20O ml of methylene chloride, the organic layer was separated, and the solution was again extracted with methylene chloride. The combined organic extracts are washed with water until neutral. dried over a sulf & n atom; the solvent is distilled off. The residue is cryo-talized from ethanol, 9.1 O-dihydro-4Nbenzo 4.531shlohepta l, 2 -thiophene melts at 117-119 ° C.

Example 2. 4- (9DO-DihydpCN-4-oco-4H-benzo 4,5-cyclohepta 1, 2-1-Fiophen-2-yl) -4-oxo-butyric acid.

According to the method written off in example 1, from 12.2 g of anhydride of 51tartaric acid, 30 g of aluminum chloride and 15.0 g of 9.1O-dihydro-4H-benzo 4,5 of cyclohepta 1,2- -thiophen-4-one 320 ml of anhydrous mylene chloride receive the desired product, so pl. 167-168 43 (recrystallized from ethanol / ether.

Example 3. 5- (4-Oxy (, 5 cyclohepta 1,2- |) - | Thiophene-2-41l) -5- "Xovalernic acid.

According to the method described in example 1, get the target product, so pl. 149-151 C (recrystallized twice from acetone), from 13.0 g of glutaric anhydride, 30 g of aluminum chloride and 15.0 g of 4H-ben30 4.5 cyclohepta 1,2-b) -tope No. 4-one in 35O ml of anhydrous methylene chloride

Analogously to example 1, is obtained by interaction of the corresponding 4I-benzo | 4 .51 cnclohepta 1,2-1 (thiophene derivatives with the corresponding carboxylic anhydrides of the worm acid 4Y-benzo 4, 5 cyclohepta 1,2-b acids listed in the table.

4- (4-Oxo-4H-benzo 4,5-cyclohepta l, 2-b) -Fiofen-2-4l) -4-hydroxyl acid

4- (b-Chloro-9DO-dipchro-4-scso-4H-benzo 4,5j cyclohepta 1,2-b) - iofen-2-yl) 4.oxoMa per knot

4- (9,1O-Dihydro-6-methy-N-4-oxo-4H-benzo 4,5-cyclohepta and l, 2-b-iofen-2- "p) -4-oxo-buty acid

6- (9,10-Dihydro-4-oxo-4H-benzo 4,5 cyclohepta l, 2-o) -ifen-2.-yl) -6-oxocaproic acid

5- (9,10-Dihydro-4-oxo-4H-benzo 4,5-cyclohepta 1,2-b} - iofen-2. H1l) -5-oxo-valeric acid

233-234 (from acetone)

198-200

177-179

117-120

Claims (1)

124-126 PREMIRE 4. Methyl 4- (9DS -dig11Pro-4-oxo-411-beiso 4,5J cyclohepta-Gl, 2-b-yufen-2 l) -4-oxy-acid noyclotl .I. To a suspension of 10.0 g of 9,10-dihydro-4H-benzo 4,5 of cyclohepta-Cl, 2-L1-tnofei-4-one and 30, 0 g of anhydrous aluminum chloride D 200 ml of anhydrous carbon disulfide at O C dropwise added a solution of 6.3 ml of nitric acid myadyl hydride dimethyl acid D 100 ml of anhydrous carbon disulfide, the reaction mixture was stirred for 6 hours at room temperature, 23.3 g of olop tetrachloride was added dropwise at 200 ° C and then stirred 15 h at home. The reaction mixture was then heated 1) for 2 hours to 50 ° C, cooled, poured out into 5OO ml of 5 parts of hydrochloric acid and chloroform. Organic wipes iipOMi.iBQjoT 5 n. hydrochloric acid with water, libicyiiJiinaioT and magnesium sulfate and the solvent is distilled off. The residue is dissolved in ZOO ml of methylene chloride, filtered through kieselguhr and evaporated to dryness. The target product is crystallized from benzene / pet roller ether and recrystallized once from ether, m. 97-98 C. And the formula 5. Methyl Ephar 4- (4-oxo-4 1 x 11c. (4,5 1P1 tohepta i, 2-bj-iiofen-2-unj-l-oxo-buty acid. (According to Example 1, the target product is noluch / jior of 1O, O g 4 1-6enzo cpklopintari, 2-bj-Tiioij) .- o "u, 30.0 g of anhydrous aluminum chloride, 23.3 g of tin tetrachloride and 6.3 ml of chloranpypyrida of maiomethyl e4Ir of succinic acid in 300 ml of anhydrous carbon disulfide. The product recrystallized from ether has a melting point of 144-145 pp. Example 6. 5- (4-Oxo-4P-benzo-C4 .5 ts 11hlohepta 1,2- B - nofen-2-nl) -5-okovalerioopov.ch acid A mixture of 10.0 g of 4P-benzo 4, I} cyclohepta 1, 2-b} -thiophen-4-dapa, 6.3 ml chlorine Ngidr of mstllopy ester "ntah {) 1st acid and 8O g full of | 01A and oa acid mix) t 1 hour in 80 ° C, then 3 hours at 120-130 ° C, plaugugd to 9O ° C, dilute 10O ml of 1zoda and again mix ewe 1 ie at this temperature. After settling to room temperature, the reaction mixture is poured with 4OO ml of “cnvtiioii floor. Iavelecch mvtp chloride, the organics were washed with water, dried over sodium sulfate and evaporated. The green product remaining in the precipitate is recrystallized at 3 pm, recrystallized again, and so on. 14951 C. Claim Formula c- (CH2) n.HOOK2 R RS hydrogen, fluorine, bromine, chlorine, or where most alkyl; Rj is hydrogen or il mya a / psvl; each of CdI R-hydrogen or both omeo-oxygen; N 2, 3 or 4; A - ethyl or vinstrna rpyirna, or their salts, say, that the compound of the general formula 2 R4 «3 where, hj, 4 and A have the indicated and A have ichen, HoaiippraioT interaction with the coordination of the general formula1 1 3 XCO (CH2) COOY where and eiit are the indicated values; X is chlorine or bromine; Y is lower alkyl or X and Y together forms a bond, & in the presence of an acidic co-suspension, followed by the release of unpleasant npouj-KTa in free form or p. Sources of information taken into consideration in the examination: 1. Swiss Patent Nb 47,604, M. class. 07d 63/18, 15.09.69.