SU176903A1 - METHOD OF OBTAINING CITRATE1-METHIL-3- - Google Patents

Description

For the preparation of citrate of 1-methyl-3-piperidylidene-di- (2-thienyl) - methane (bithiodipa), where 1-methyl neipotinic acid ester is treated with ethereal bromothiophene and magnesium, the mixture obtained is treated with water and ammonium chloride. The precipitated 1-methyl-3-piperidyl-di- (2-thienyl) - carbinol is filtered and treated with a mixture of hydrochloric and acetic acids, followed by treatment with citric acid. Citrate 1 -methyl-3-piperidylidene-di- (2-tyepyl) methane is recovered from the obtained reaction mixture by filtration in a yield of less than 35Vo. The proposed method differs from the well-known fact that in the step of preparing the weft product 1-methyl-3-piperidone For 1- (2thienyl) -carbinol, another order of mixing of the reagents is used, namely; 1-methylnipicotinic acid ethyl ester is added to the ethereal solution of bromothiophene and magnesium, and also by the fact that the above intermediate is dehydrated with formic acid. Due to this, the yield of the target product reaches 56-Vo.

Example. In a one-liter three-necked flask equipped with a mercury gate stirrer (glycerin was used instead of mercury), a dropping funnel, a reflux condenser equipped with a calcium chloride tube, 12.72 g (0.53 mol) of magnesium in a chip, 80 ml

abs ether and 2 crystals of iodine. 86.4 g (0.53 mol) of bromothiophene, 90 ml of abs are placed in an addition funnel. the ether. From the dropping funnel pour 5 ml of the specified solution. If the reaction does not start itself (the ether should become cloudy and boil), the flask is immersed in a water bath with warm water, then the ethereal solution of bromothiophene is removed and added dropwise at such a rate that the ether all the time is evenly and not too violently boiling. After all of the bromothiophene has been added, the reaction flask is heated on a water bath for 2.5-3 hours until the magnesium is completely dissolved. The flask is well cooled (with snow and salt) and the solution is added dropwise with cooling, then 43.7 g (0.255 mol) of 1-methyl-necotinic acid ethyl ester in 80 ml of abs. the ether. From the first drops of ether, a white precipitate is formed, which first dissolves and then re-precipitates as a brown viscous mass. After adding the total amount of 1-methylneppecotonic acid ethyl ester, the cooling is stopped, the flask is allowed to warm to room temperature, and then it is heated in a water bath for 2-3 hours (at the end of the mass, the mixture hardens) and allowed to stand overnight. O.cool the flask with a mixture of ice and salt, decompose the reaction mixture by adding 300 g of crushed ice, 200 ml of water and 130 g of ammonium chloride. Selected gray crystals are sucked off on a Buchner funnel, washed with water, alcohol, ether, and dried in air. Get 56.2 g (75,1z / o from theoretical) 1-methyl-3-piperidyl-di- (2-tyechyl) -carbinol Art. square 136-139 ° C.

To 110 ml of 85 / o-fi; formic acid, mixed with: in a 250 ml wurtz flask, 56.2 g of (1-methyl 3-piperidyl) -di- (2-thienyl) -carbinol are very carefully added. in divided doses in small portions (approximately 5 g each). After that, the flask is heated for 10 minutes, then formic acid (90 ml} is distilled off under reduced pressure. The contents of the flask are carefully poured into a saturated solution of soda (80 g in 250 ml of water). The thick dark oil that separates is separated off, the aqueous residue is extracted with ether The oil and ethereal extracts are combined and dried with calcined sodium sulfate. The ether is distilled off, the residue is distilled in a vacuum, collecting the fraction with m.p. 178-180 ° C at 6 mmHg in the amount of 44.15 g 1-methyl-3-piperidylidene - di- (2-thienyl) - methane is obtained in a yield of 83.7% of theoretical.

To a boiling solution of 44.15 g of 1-ltethyl-3-piperidylidene-di- (2-thienyl) methane in 75 ml of alcohol is added a hot solution of 30.72 g of citric acid in 50 ml of alcohol and left at room temperature on

2-3 hours If crystallization does not begin, it is necessary to rub the glass rod against the walls of the glass. The precipitated crystals are filtered on a Buchner funnel, washed

alcohol and ether and dried (not in the light). 67.3 g of citrate of 1-methyl-3-pyridylidene-di- (2-tcenyl) -methane are obtained, which makes up 90Vo from theoretical and 48% calculated. nicotinic acid ethyl ester,

m.p. citrate 135-137 ° C- (with decomposition). The technical product is recrystallized from alcohol. Get 59.2 g with so pl. 137-139 ° С pharmacopoeial product of citrate 1-methyl-3-pineridylidene-di- (2-thienyl) - methane (bitiodin).

Subject invention

Method for producing citrate of 1-methyl-3-piperidylidene-di- (2-thienyl) - methane (bithiodine) from 1-methyl-nepecotinic acid ethyl ester, bromothiophene and magnesium with the subsequent acid dehydration of the obtained 1-methyl-3-piperidyl-di - (2-thienyl) -carbinol, characterized in that, in order to increase the yield of the product, ethyl ester of 1-methyl-nepecotinic acid is added to the ether solution of bromothiophene and magnesium and dehydration

lead formic acid.