SU1419519A3 - Method of producing 1-@2-[5-(dimethylaminomethyl)-2-(furylmethylthio)-ethyl]@-amino-1-methylamino-2-nitroethylene or hydrochloride thereof - Google Patents

Abstract

1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-methyl amino-2 - nitroethylene of the formula (I> <IMAGE> and its hydrochloride, are prepared by reacting an 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-(subst ituted thio)-2- nitroethylene of the formula (VI), <IMAGE> wherein R represents an optionally substituted C1-4 alkyl group or an oxoalkyl, aryl, aralkyl, or oxoaralkyl group, with an agent capable of splitting off a mercapten, in an organic solvent, optionally in the presence of an acid-binding agent, then reacting the in situ prepared 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-3-nitroketenei mine of the formula (VII> <IMAGE> with methylamine and finally, if desired, separating the obtained base of formula (I), purifying it and/or, if desired, transforming it to its hydrochloric salt.

Description

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This invention relates to an improved process for the preparation of 5- (dt1-methylaminomethyl) -2- (furylmethyl-thio) -ethyl | -amino-1-methylamino-2-nitrosostelen (ranitidine) or its hydrochloride, which, due to the inhibition of the selective action exerted on H-2 histamine receptors, is used in the treatment of gastric or duodenal ulcers.

The purpose of the invention is to increase the yield of the target product by using as the starting compound 1 -2- 5-dimethylaminomethyl -2- (furylmethylthio) -ethyl-amino-1-alkyl-substituted thio-2-nitroethylene and silver nitrate.

Example 1. (Dimethyl-aminomethyl) -2- (furylmethylthio) -ethyl | - amino-1-methylamino-2-nitroethylene.

To a solution of 99.5 g (0.30 mol) (dimethylaminomethyl) -2- (furylmethylthio) -ethyl-amino-methylthio-2-nitroethylene in 2500 ml of absolute ethanol was added a solution of 51.0 g (0.30 mol) of nitrate silver in 4000 ml of absolute ethanol for 1 min at 10 ° C. Immediately precipitate methyl mercaptide silver. Then 557 ml of a 29.2% solution of methylamine are added and the mixture is stirred for 2 hours at room temperature. The precipitate (which by mass and composition corresponds to 98.1% silver mercaptide) is filtered off and the filtrate is evaporated to dryness at room temperature. The residue is taken up in 600 ml of water and extracted eight times with 1200 ml of ethyl acetate. The pH is adjusted to 10. The organic phases are combined, dried and evaporated in vacuo. Pure ranitidine is obtained as a distillation residue with a yield of 79 g (84%).

To obtain the hydrochloride, the crude base is dissolved in 380 ml of absolute ethanol and the pH is adjusted to 5.5 at 0-5 ° C by addition of concentrated hydrochloric acid, stirred for 40 minutes at 0 ° C, then the mixture is left overnight at 0-5 ° C. the precipitate is filtered off, washed with ethanol and dried. Hydrochloride is obtained with the yield of 57.45 g (54.6%), m.p. 143 ° C. From the mother liquor, another 23.15 g (22.0%) of hydrochloride can be obtained from the second extraction.

As the starting compound, 3- (dimethylaminomethyl) -2- (furylmethylthio) -ethyl-amino-1-methylthio-2-nitroethylene (Example 6) is used.

PRI mme R 2. (dmmethyl-aminomethyl) -2- (furylmethylthio) -ethyl-amino-1-methylamino-2-nitroethylene and its hydrochloride.

To a solution of 5 g (0.015 mol) of 1-p-5- (dimethylaminomethyl) -2- (furylmethylthio) ethyl 3 | -amino-1-methylthio-2-nitro ethylene in 125 ml of absolute ethanol was added a solution of 2.55 g (0.015 mol) of silver nitrate D with 200 ml of absolute ethanol for 1 min at 6 ° C, silver methyl mercaptide was immediately precipitated. The mixture is stirred for 3 minutes at 5 ° C, then 30 ml of a 27% ethanolic solution of methylamine are added. The solution is continued to stir for another 2 hours at room temperature and then filtered. The filtrate is left to stand at 5 ° C for a day, filtered again and the filtrate is evaporated in vacuo at room temperature. 50 ml of water are added to the residue and the pH is adjusted to 5.5 by adding 1N. hydrochloric acid. The mixture is extracted twice with 70 ml portions of dichloromethane, then the pH of the aqueous phase is adjusted to 10 by adding 1N sodium hydroxide and extracted four times with 70 ml portions of dichloromethane. The organic phases obtained from the last extracts are combined, dried and evaporated. A fourfold volume of ethyl acetate is added to the residue, the evaporated crystals are filtered and dried. Obtain 3.02 g (64%) of the desired product, so pl. 68-70 ° C. Upon repeated evaporation and crystallization of the mother liquor, an additional 0.55 g (11.2%) of the desired base is obtained.

The resulting base can be converted to the hydrochloride as follows.

3.5 g of crude ranitidine is dissolved in 17.5 ml of absolute ethanol and the pH value of the solution is adjusted to 5.0-5.5 by adding concentrated hydrochloric acid at a constant overburning at 0 ° C. The solution is continued to be stirred for 40 minutes at 0 ° C, then left to stand overnight at 0-5 ° C. The crystalline precipitate is filtered off, washed with ethanol and dried. Get ranitidine hydrochloride with the release of 3.72 g (84.4%), so pl. 143 ° C.

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P p and m e p 3. 5 - (Limetil-amiimetnl) -2- (furylmethylthio) -ethyl 1 - amino-1-methyamio-2-and nitroethylene,

To a suspension of 1.66 g (0.005 mol) (dimethylaminomethyl) -2- (furyl methylthio) -ethyl | -amino-1-methylthio-2-cytoethyl in 10 ml of absolute ethanol was added a solution of 0.85 g (0.005 mol) of silver nitrate in 10 ml of an ethanolic solution of methylamine with constant stirring at room temperature. The mixture was further stirred at room temperature for another 30 minutes, after which it was filtered and the filtrate was evaporated. The residue is treated in the same manner as described above. Thus, 1.21 g (77.1%) of the desired base is obtained, mp. 68-70 ° C.

Example A, 1- | 2- 5- (Dimethyl-aminomethyl) -2- (furylmethylthio) -ethyl | - amino-1-methylamino-2-nitroethylene.

To a solution of 1.66 g (0.005 mol) (dimethylaminomethyl) -2- (furylmethylthio) -ethyl-amino-1-methylthio-2-nitroethylene in 20 ml of allyl alcohol is added a solution of 0.85 g (0.005 mol) of nitrate silver in 60 ml of allyl alcohol for 2-3 minutes with constant stirring at 8-10 ° C. 8 ml of methylamine ethanolic solution are added dropwise for 1-2 minutes and the solution is stirred at room temperature for 2 hours at the same temperature. Treat the solution in the same manner as described above. Obtain 0.95 g (60.5%) of the desired base, m.p. 70-72 C,

PRI me R 5 (control). Control experiments were carried out to confirm that 1-fz-5- (dimethylaminomethyl) -2- (furylmethylthio) -ethyl-amino-1-methylthio-2-nitroethylene first reacts with silver nitrate and formed during the precipitation of methyl mercaptide Silver (dimethylaminomethyl) -2- (furylmethylthio) -ethyl-3-nitroketenimine reacts with methylamine.

The method of operation described in example 1 is carried out as follows.

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After the addition of silver nitrate, the precipitate formed in the solution is filtered off and analyzed after washing and drying. The sediment weight is 2.28 g (98.1%).

Found: C, 7.96 H, 1.36, Ag, 69.1.

 (154.98)

Calculated 7.: C, 7.75; H 1.95; Ag 69.6.

PRI me R 6. Preparation of (dimethylaminomethyl) -2- (furylmethyltone) ethyl 3 -amino-1-methylthio-2-nitroethyl

Lena.

To liacTBopy 52.80 g (0.32 mol) of 1,1-bis (methylthio) -2-nitroethylene, prepared at 80 ° C with 238 ml of toluene, was added 17.12 g (0.08 mol)

2- (2-aminoethyl) -thiomethyl-5- (dimethyl-aminomethyl) -furan and the resulting reaction mixture is stirred at this temperature for 70 minutes, after “lero” cooled to 3-4 ° C. Distinguished

the (excess) dithioester is removed by filtration. Weight 23.9 g, melting point (Fp): 121-12A ° C. The toluene filtrate is extracted with 120 ml of hydrochloric acid and then 80 ml of water. The combined aqueous phases are washed with toluene. (By evaporation of the toluene phase, another 7.05 g of dithioether is obtained). The pH is adjusted to 8 and extraction is carried out three times with 120 ml of ethyl acetate. United Organic

The phases are dried with sodium sulfate. After filtration and evaporation, 22.87 g (86.3%) are obtained. product. Melting point 68-69 C.

This method allows to increase the overall yield of the target product in the case of ranitidine - base by 26% and in the case of ranitidine - hydrochloride by 24%.

Claims (2)

1. The method of obtaining (dimethylaminomethyl) -2- (phyrylmethylthio) -ethyl-amino-1-methylamino-2-nitroethylene of formula SN-H2C-O-CH2-S- (CH2) 2-NH-C-NHCH3 H-tC II  CH-N02 or its hydrochloride using a derivative of 5- (dimethylaminomethyl. methyl) -2- (furylmethylthio) ethane, a polar organic solvent and a solution of silver nitrate in the same solvent, which differs 514195196 by the fact that, in order to increase the yield of 5- (dimethylaminomethyl) -2- (furylmethyl-targeted product, as a pro- duction) ethyl 2 -amino-1-alkyl-substituted aqueous 5- (dimethylaminomethyl) -2- (fucto- 2-nitroethylene of the general formula rylmethylthio) -ethane uses 1- {2) N-H2C-JV CH2-S- (CH2) 2-NH-CSP, NZS CH-N02 where R, - C, -C2-alknl, re from 5 C to room temperature which in the environment of polar organic and obtained in situ (the solvent is subjected to inter-thylaminomethyl) -2- (furylmethylthio) - action with a solution of silver nitrate of ethyl 3-nitroketenimine of the formula in the same solvent at a temperature of 3C N H2C-O-CH2-S- (CH2) 2-N C CH-N02 NzSpoljutat interaction with methylamine 2. The method according to claim 1, which is distinctive and isolates the target product in its own way and with the fact that lower aliphatic alcohol is used as a free-form or as a hydro-organic organic solvent chloride. CH-N02