KR870000165B1 - Process for preparing n- (2- ((( 5-(dimethylamino)-methyl-2-furanyl)methyl)thio) ethyl-n-2-nitro-1,1-ethenediamine - Google Patents

Abstract

Compd. of the formula (I) and their acid-addn. salts were prepd. Thus, a soln. of 198mg CuCl in 25ml acetonitrile was reacted with a soln. of 428mg 2-[[[5-(dimethylamino)methyl- 2 furanyl methyl thio ethaneamine, 296mg 1-methylthio-1-methylamino2- nitroethane, and 200mg TEA in 10ml acetonitrile. The resulting ppt. was filtered and removed. The filtrate was mixed with 30ml chloroform and extd. with 20ml ammonia water 3 times. The organic phase was dried on Na2SO4, filtered, and vaporized to give (I)(yield, 94%). Compd. I inhibits the secretion of gastric acid stimulated by histamine-H2-acceptor.

Description

Method for preparing N- [2-[[[5-dimethylamino) -methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine

The present invention provides N- [2-[[[5-dimethylamino) -methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine of the following general formula: And a process for preparing pharmaceutically toxic acid addition salts thereof such as hydrochloride, hydrobromide:

This compound is known under the generic name ranitidine. Ranitidine was first described in German Patent Publication No. 2734070 as a compound that inhibits the secretion of gastric acid stimulated by selective H ₂ -antagonists, ie histamine-H ₂ -receptors. Ranitidine is preferably in the form of its hydrochloride, an important medicament for the treatment of ulcers.

The aforementioned German patent publication also describes several methods of synthesizing ranitidine. In the most advantageous method of synthesis, Gill and Ing., J. Chem, Soc. 4728 ~ 4731 (1985)] 5- (N, N-dimethylamino) of the following formula which can be obtained in a good yield (70%) from 2-furan-methanol (furfuryl alcohol) by the Mannich reaction. Methyl-2-hydroxy-methylfuran is used as starting compound:

5- (N, N-dimethylamino) methyl-2-hydroxy-methylfuran is then reacted with cysteamine hydrochloride to give 2-[[[5-dimethyl] Amino) methyl-2-furanyl] methyl] thio] ethanamine (Example A of German publication, yield 54%) is obtained.

This intermediate can then be reacted with 1-methyl-thio-1-methylamino-2-nitroethene of the formula to produce ranitidine (Example 15 of German publication mentioned):

On the other hand, the intermediate is also reacted with 1,1-bis (methylthio) -2-nitroethene of the formula: N- [2-[[[5-dimethylamino) methyl-2-furanyl] methyl] thio Ethyl] -N'-methyl-thiourea is produced and reacted with dimethylamine to give the desired compound:

(CH ₃ S) ₂ C = CHNO ₂

A drawback of the prior art processes is that not only expensive chemicals (cysteamine hydrochloride) have to be used in the preparation of the intermediate, but also the yield is low at this stage. At the end of the reaction of the intermediate compound to obtain ranitidine, methyl mercaptans are produced that are toxic, malodorous and contaminating. Moreover, the reaction takes a very long time.

A recent German publication 3100364 describes the use of inexpensive 2-chloroethylamine instead of expensive cysteamine as an important compound in the synthesis of ranitidine. In this reaction, however, the starting compound 5- (N, N-dimethylamino) methyl-2-hydroxymethylfuran first reacts with the corresponding thiol, one of the important intermediates, resulting in two additional steps. .

Main reactions, namely two intermediate compounds, oxalic acid and 5- (N, N-dimethylamino) methyl-2-thiomethylfuran and 1- (2-chloroethyl) amino-1-methylamino-2-nitro in salt form The ethengan reaction is very long.

It is an object of the present invention to provide a process for producing ranitidine in good yields in a short time, which saves energy and is inexpensive and easy to use instead of expensive cysteamine hydrochloride, much more than 2-chloroethylamine hydrochloride. Inexpensive 2-mercapto-ethanol can be used, the main reaction is carried out at room temperature and the production of toxic methyl mercaptan can be avoided.

This object is achieved by 2-[[[5-dimethylamino) methyl-2-furanyl] methyl] thio prepared according to the method described in the pending patent application (Yugoslavia application P 2607/82 dated November 22, 1982). Ethanamine is a novel compound not yet described in the literature

It can be achieved by the process of the invention characterized by reaction with extremely reactive 1-nitro-3-methyl-ketenamine (N-methyl-nitroketenimine) with

It is known in the literature to obtain a guanidine derivative by removing methylmercaptan from an N-substituted N'-cyano-S-methyl-isothiourea. [A.P. Ferris and B.A. Schultz, J. Org. Chem. 26 (1963), 71-74; C.G. Mc Carty et al, J. Org. Chem. 35 (1970), 2067-2069]. This reaction proceeds via N-cyanocarbodiimide, the extremely reactive intermediate produced. However, such compounds are not stable and therefore cannot be separated and are difficult to characterize.

Formula formed from a novel 1-nitro-3-methyl-ketenamine (N-methylnitroketeniimine) of the highly reactive formula CH ₃ N = C = CHNO _{2 as} an intermediate in the literature.

A reaction similar to the removal of methyl mercaptan from 1-methylthio-1-methylamino-2-nitroethene is known in the synthesis of keteneamines. However, such a reaction process has surprisingly been found in the method of the present invention.

A key step in the novel inventive process for synthesizing ranitidine is the 2-[[[5-dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine and the resulting 1-nitro-3-methyl-keteneimine Is a reaction. The latter compound is formed in the same place and in solution of heavy metal salts such as AgNO ₃ , CuCl ₂ , CuCl, HgCl ₂ , ZnCl _2, etc. as a catalyst in an organic solvent such as methanol or acetonitrile, 1-methylthio-1 in the same solvent at room temperature -A solution of methylamino-2-nitroethene and triethylamine is added. Triethylamine is used as proton acceptor. A metal mercaptide is isolated which is immediately quantitatively separated. In this way, contamination with toxic methyl mercaptan is avoided.

The reaction proceeds extremely fast in minutes at room temperature to produce ranitidine. Good yield of the synthesis and continuous rapid addition of reactants as shown in the examples is very important.

The resulting 1-nitro-3-methyl-ketenimine is detected by the IR spectrum of the mixture showing absorption at 2170 cm ^-1 IR, which is characteristic of the keteneimine (C = C = N-) absorption range (2200-2050 cm ^-1 ) Can be.

The production of 1-nitro-3-methyl-ketenimine can be detected indirectly by separation with a lower alcohol such as methanol.

This produces new crystalline 1-methoxy-1-methylamino-2-nitroethene.

It is known that ketenimines can react rapidly with alcohol to produce well crystallized products.

The invention is illustrated by the following non-limiting examples.

Example 1

N- [2-[[[5-dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine (ranitidine)

CuCl (198 mg, 2 mmol) is dissolved in acetonitrile (25 mL). To this solution, 2-[[[5-dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine (428 mg, 2 mmol) and 1-methylthio-1-methylamino-2-nitroethene (296 mg , 2 mmol) and triethylamine (200 mg) in acetonitrile (10 mL) were added dropwise within 5 minutes under stirring. The resulting precipitate is aspirated off and the filtrate is evaporated to half the original volume. Chloroform (30 ml) was added thereto, followed by extraction with ammonia water (3 x 20 ml). Incline the ammonia extract. The organic phase is dried (Na ₂ SO ₄ ), filtered and evaporated.

In this way, pure ranitidine is obtained, which has the same melting point, IR, NMR and MS as the product obtained in Example 15 of German Patent 2734070.

Example 2

N- [2-[[[5-dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine (ranitidine)

AgNO ₃ (340 mg, 2 mmol) is dissolved in methanol (12 mL). To this solution, 2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine (214 mg, 1 mmol), 1-methylthio-1-methylamino-2-nitroethene ( 163 mg, 1.1 mmol) and triethylamine (100 mg) were added dropwise within 5 minutes with slow stirring. The resulting precipitate is filtered off and added to the filtrate of chloroform (20 mL) and extracted with HCl (1: 1, 15 mL). The aqueous phase is neutralized with NaHCO ₃ and extracted twice with chloroform (30 ml each time). The combined extracts are dried (Na ₂ SO ₄ ) and evaporated. Obtain pure ranitidine. Its melting point, IR, NMR and MS are the same as those obtained in Example 15 of German Patent No. 2734070.

Example 3

Detection of 1-nitro-3-methyl-ketenimine in the reaction mixture

Production of 1-methoxy-1-methylamino-2-nitroethene

AgNO ₃ (170 mg, 1 mmol) is dissolved in methanol (6 mL). To this solution was added 1-methylthio-1-methylamino-2-nitroethene (30 mg, 0.2 mmol) and triethylamine (100 mg). Remove silver mercaptide immediately. The precipitate is filtered off and the filtrate is evaporated to add i-propanol (2 mL) to crystallize the product. In this manner, 1-methoxy-1-methylamino-2-nitroethene having a melting point of 98 to 103 ° C is formed in a good yield (90%). Melting point after recrystallization with anhydrous ethanol: 112 ~ 114 ℃.

Elemental Analysis for C ₄ H ₈ N ₂ O ₃

Theoretic: C 36.36% H 6.10% N 21.20%

Found: C 36.13% H 64.24% N 21.30%

M = 132

NMR (CDCl ₃ ): 7.0 and 7.1 (2s, NHMe); 6.16 (s, OMe); 3.36 (s, CH), 1.4 (brood, NH-).

Claims (5)

Reacting 2-[[[5-dimethylamino) methyl-2-furanyl] methyl] thio] ethanamine of formula (II) with 1-nitro-3-methyl-ketenimine of formula (III) N- [2-[[[5- (dimethylamino) methyl-2-furanyl] methyl] thio] ethyl] -N'-methyl-2-nitro-1,1- of formula (I) Method for producing ethenediamine.

CH ₃ N = C = CHNO ₂ (III) (Correction) The formula according to claim 1 dissolved in a polar organic solvent.

Wherein 1-methyl-thio-1-methylamino-2-nitroethene is reacted with a heavy metal salt dissolved in the same solvent in the presence of a proton acceptor at room temperature to produce 1-nitro-3-methyl ketenimine . The process according to claim 2, wherein methanol or acetonitrile is used as the polar organic solvent. The process according to claim 2, wherein AgNO ₃ , CuCl ₂ , CuCl, HgCl ₂ or ZnCl ₂ is used as the salt of the heavy metal. 3. The method of claim 2, wherein triethylamine is used as proton acceptor.