SU403174A1 - - Google Patents

Description

METHOD OF OBTAINING

CONDENSED DERIVATIVES OF TIAZO, PA OR OXAZOLE

close to 30 ° C. At the same time, a part of the compounds of structural formula III used goes to salt formation with chlorine or hydrogen bromide formed during the reaction, therefore, to obtain good yields, it is necessary either to add compounds of structural formula 111 in excess, or additionally add acid-binding agents to the reaction mixture. The compounds of structural formula I obtained according to the invention can be separated from the reaction mixture by a well-known method, for example, by extracting the axial reaction solution with an aqueous acid solution and then freeing the base from its salt, and, if appropriate, then by recrystallization, to clear it.

The compounds of structural formula 1 have an asymmetric carbon atom in position 4 and may therefore be in the form of racemates or an optically active form. Otic-active compounds of structural formula I can be obtained if the racemic compounds of formula I are reacted with ontic-active acids, the resulting mixture is separated, the bases and the optically active compounds of structural formula I thus obtained are obtained.

Compounds of structural formula I can be isolated in the form of pharmaceutically acceptable acid addition salts. These salts have the same effect with free bases and can be obtained by introducing the free bases of structural formula I into reaction with the corresponding acids. For this salt formation, the following acids proved to be unsuitable; hydrochloride, hydrogen bromide, chamois, phosphorus, acetic acid, citric, tartan and l-toluenesulfonic.

Example 1. 2-Methyl-4- (4-methyl-l-piperazinyl) -9,10-dihydro-4H-benzo - (5,6) - cyclohepta 1,2-d oxazole.

A. 4-Oxy-2-methyl-9,10-dihydro-4I-benzo (5,6) -cyclohepta 1,2-d oxazole.

In a solution of 120 g of 2-methyl-9,10-dihydro-4Nbeiso (5,6) -cyclohepta 1,2-oxazol-4-one in 800 ml of methylene chloride and 1200 ml of absolute ethanol, stirred at 0 ° C, 40 g sodium borohydride are added. Then enj.e is stirred for 3 hours and then 3000 ml of ice water is added. The methylene chloride layer is separated, dried over sodium sulfate and evaporated in vacuo. As a residue, crude 4oxy-2-methyl-9, 10-dihydro-4H-benzo- (5.6) -cyclohexyl l, 2-d hydroxazole with m.p. 126-130 ° C. After recrystallization from ethyl acetate so nl. But it rises to 132-135 ° C.

B. 4-Chloro-2-methyl-9,10-dihydro-4P-benzo (5,6) -cyclohepta 1,2-d-oxazole.

To a solution of 120 g of 4-hydroxy-2-methyl-9,10-dihydro-4H-bepzo- (5,6) -cycloheptane I, 2-d hydroxyl in 1200 ml of toluene at 0 ° C is added dropwise 66, 5 g of thionyl chloride. It is then allowed to stand for 16 hours at, and 2-methyl-4-chloro-9,10-dihydro-4Pbenzo (5,6) -cyclohepta 1,2-d oxazole crystallizes out. It is filtered and washed with cold TOJiyol. The compound melts at 68-70 ° C (decomposed).

B. 2-Methyl-4- (4-methyl-G-pinerasicyl) -9,10 dihydro-4H-benzo- (5,6) -cyclohepta 1,2-d oxazole.

In a suspension of 130 g of 4-chloro-2-methyl-9,10-dihydro4P - benzo - (5.6 - cyclogenate 1, 2d oxazolol in 1300 ml of toluene at 0 ° C and stirring is added dropwise approximately 2 hours

320 g of N-methylpinerazine. The mixture is then allowed to stand at room temperature for 16 hours. 600 ml of 1 and are added to the mixture. aqueous solution of Yatri hydroxide, the resulting biphasic mixture is extracted in vacuo to obtain a residue. This residue is dissolved in 600 ml of benzene, and the resulting solution is extracted with 1000 ml of ZM aqueous acetic acid. The acetic acid solution is poured into 1000 ml of 5N. an aqueous solution of sodium hydroxide. This mixture is extracted three times with 300 ml of benzene, then the benzene solution is evaporated. The resulting crude residue is purified by molecular distillation (bath temperature 130 ° C, pressure 0.01 mm

Hg Art.). The distillation product is mixed with ether and a crystalline 2-methyl-4- (4-methyl-1-piperazinyl) -9,10-dihydro-4H-bepzo- (5,6) -cyclohepta 1,2-d oxazole is obtained, with t. pl. 114-PGS.

Bisfumarate

A mixture of 169 g of 2-methyl-4- (4-methyl-1-piperazinyl) -9,10-dihydro-4H-benzo - (5,6) - cyclohepta 1,2-d oxazole as a free base, 132 g of fumaric acids and 850 ml of isopropyl alcohol are heated slightly. Then cooled and get a crystalline salt of bisfumaric acid 2-methyl-4- (4-methyl-Gpiperazinil) -9,10-dihydro-4H - benzo- (5,6) cyclohepta 1, 2-d okazolova with so pl. 175-178 ° C.

Example 2. 2-Methyl-4- (4-methyl-G-piperazipyl) -9,10-dihydro-4H-benzo - (5,6) - cyclohepta 1,2-d thiazole.

A. 4-Oxy-2-methyl-9,10-dihydro-4H-benzo (5,6) -cyclohepta 1,2-d thiazol.

When using the procedure described in Example 1A, A is obtained and replacing 2-methyl-9,10 dihydro-4H-benzo- (5.6) -cyclohepta l, 2-d oxazole-4-opa with an equivalent amount of 2-methyl-9, 10 -dihydro - 4H - bepzo - (5,6) - cyclohepta l, 2-d thiazol-4-ona get 4-hydroxy-2-methyl-9, 10-dihydro - 4H - benzo - (5,6) - cyclohepta l, 2-d thiazole with m. Pl. 147-149 ° C.

B. 4-Chloro-2-methyl-9,10-dihydro-4H-benzo (5,6) -cyclohepta (1,2-d) thiazole.

Using the method described in example 1, B and the 4-hydroxy-2-methyl-9, 10-dihydro-4P - benzo - (5,6) - cyclohepta 1,2-d oxazole used in it, an equivalent amount of 4-hydroxy 2-methyl-9,10-dihydro-4H - benzo - (5,6) cyclogenate l, 2-d thiazole get 4-chloro-2