CS237339B2 - Processing of n-/2-///5-/dimethyl-amin/methyl-2-furanyl/methyl/thio/-ethyl/-n-methyl-2-nitro-1,1-ethen-diamine - Google Patents

Description

Preparation of N- (2 - {/ [5- (dimethylamino] methyl-2-furanyl] methyl / thio | ethyl) -N'-methyl-2-nitro- l ^j ethenediamine of the formula I

CH 2 CH 2 CH 2 _from CH ₃ (I) as well as the physiologically acceptable acid addition salts of this compound by reaction of 2 - {[5- (dimethylamino) methyl-2-furanyl] methyl] thiojethanamine and 1-nitro-3- methylketonimine characterized in that the reaction is carried out at room temperature, in a polar organic solvent, with a solution of a heavy metal salt, in the same solvent in the presence of a proton recipient, to form a very reactive 1-nitro-3-methylketenimine in the reaction mixture is reacted with a compound of formula II to give the desired compound of formula I.

The invention relates to a novel production process

N- <2 - ([5- (dimethylamino) methyl-2-furanyl] methyl] thiomethyl) -N‘-methyl-2-nitro-1,1-ethylenediamine of formula I

IC ^ Hi ^NCCI

CHNO ;.

_And GCH CH ₁ CH _{0 i} NHCNHCH

And the acid addition salts of this compound with physiologically acceptable acids such as hydrochloride, hydrobromide and the like. The compound is known under the international name ranitidine and - was first described in DOS 27 34 070 as a selective H 2 -antagonist, which means that it inhibits gastric juice secretion induced by irritation of histamine H 2 -receptors. Preferably, ranitidine is in the form of its hydrochloride a valuable drug for the treatment of ulcer disease.

Various processes for the production of ranitidine are also described in the above publication. The starting material for the most preferred process described is 5- (N, N-dimethylamino) methyl-2-hydroxymethylfuran of formula L

CH 2 OH (II)

which is obtainable in good yield 70% from 2-furanmethanol (furfuryl alcohol) by the Mannich reaction as described by Gill and Ing, J. Chem. Soc. 4728-4731 (1958).

5- (N, N-dimethylamino) methyl-4-hydroxymethylfuran is then reacted with cystamine hydrochloride to give 2 - ([[5- (dimethylamino) methyl-2-furanyl] methyl] thio) ethanamine (54% yield). Example A of the above-mentioned file) of formula LI

ILI), which is a valuable intermediate in the production of ranitidine. This intermediate is then reacted (Example 15) with 1-methylthio-1-methylamino-2-nitroethene of formula IIa.

CHNOII

CH3S-C-NHCH3 to give ranitidine.

Alternatively, the intermediate is first reacted with 1,1-bis (methylthio) -2-nitroethene of formula Lili (CH 3 S) 2 C = CHNC 2 (Lili) to give N- (2 - (/ [5- (dimethylaminomethyl-2-furanyl) methylthioethyl) -N'-methylthiourea and this compound is then reacted with methylamine to give the title compound.

A disadvantage of the known process is that cystamine hydrochloride is used in the preparation of the intermediate product, which is very expensive and, in addition, achieves a low yield. In addition, the final stage of ranitidine production produces a toxic and unpleasant smelling methylmercaptan, which causes air pollution. Moreover, the reaction takes a very long time.

Later DOS 31 00 364 describes the replacement of expensive cystamine with cheaper 2-chloroethylamine hydrochloride or ethyleneimine, which in this case is a key substance in ranitidine synthesis, but in this reaction it is necessary to first convert the starting 5- (1-Ьу <1гоxymethylfuran to - corresponds to the corresponding thiol, which is a key intermediate, so that the production process is extended by 2 steps.

The key reaction, i.e. the reaction of the two intermediates, 5- (Ν, Ν-dimethylamino) methyl-2-thiomethylfuran in the form of the oxalic acid salt and 1- (4-chloroethyl) amino-1-methylamino-2-nitroethene, proceeds very slowly.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for producing ranitidine in good yield with a short reaction time and thus energy savings by using inexpensive and readily available 2-mercaptoethanol which is substantially cheaper than 2-chloroethylamine hydrochloride avoiding expensive cystamine hydrochloride. The key reaction should proceed at room temperature without the formation of toxic methylmercaptan.

Accordingly, the present invention provides a process for the preparation of N- (2 - [[5- (dimethylamino) methyl-2-furanyl] methyl [thiomethyl] -N'-methyl-2-nitro-1H-etriendiamine of formula I (III) ^CH and ^CH = ^CH and ^{N HbNH C} 5 ^H (I) and the addition salts thereof with acids acceptable from the physiological standpoint, reactions 2-4 / 5 - (dirnethyla.mino) .methyl-2-furanyl] methyl / thio [ethanamine of formula II (C ^ _VZ NC.H

CH.SCH.CH.NH,

2 2.

(11) with 1-nitro-S-methylketonimide of formula IV • CH-3-N = C = CHHNO2 (IV) characterized in that the reaction is carried out at room temperature, in a polar organic solvent, e.g. methanol or acetonitrile, with a solution of a heavy metal salt such as AgNO 3 or CuCl in the same solvent in the presence of a proton recipient such as triethylamine to form a highly reactive 1-nitro-3-methylketenimine in the reaction mixture which immediately reacts with the compound of formula II to the desired compound of formula I.

From A, F. Ferris and BA Schultz, J. Org. Chem. 26 (1963) 71-74 and CG McCarty et al., J. Org. Chem. 35- (1,970i, 2067-2069) is a known method for the elimination of methylmercaptan from N-substituted N ⁴ -cyano-S-methylisothioureas to give guanidine derivatives. This reaction proceeds via the highly reactive N-cyanocarbodiimides formed directly in the reaction mixture as but they are not stable, cannot be isolated and are very difficult to characterize.

A similar reaction to eliminate methyl mercaptan from 1-methylthio-1-methylamino-2-nitroethene of formula Lil

CHNOII

CH 3 —S — C — NHCH 3 (LII) which would result in an intermediate, highly reactive novel 1-nitio-3-methylketenimine (N-methylnitroketenimine) of formula (IV) not yet described in the literature, and no such method is known production of ketenimines. However, it was this reaction that was unexpectedly ascertained when carrying out the process according to the invention.

The basic step of the process according to the invention for the production of wounds! dtau is the reaction of 2- (N, {5- (dimethylamino) methyl) huraayl-imethyl / thienoethanamine with 1-methyl-2-methylketenimine, which is formed directly in the reaction mixture by reacting a salt solution in the reaction. heavy metal such as silver nitrate, cuprous chloride, cuprous chloride, mercury (II) chloride, zinc chloride, and like catalyst in an organic solvent such as methanol and acetonitrile with a solution of 1-methylthu-1-methylamin-2-niogoethene and triethylamine in the same solvent at room temperature.

The reaction proceeds rapidly over a few minutes at room temperature to ranitidine. The yield is high with good reaction progress and progressive addition of reagents, as will be seen in the following examples.

Directly in the reaction mixture resulting from 1-nitro-3-methylketinimine can be characterized by a spectrum of the reaction mixture in infrared light, which at 2170 cm ^{-1 has a} characteristic absorption in the range of 2200 to 2050 cm ^-1 , typical for ketenimine Scout C = C = N—.

The formation of 1-methyl-3-methylmethyl is observed indirectly by a separate reaction with a lower alcohol such as methanol. A new crystalline 1-methoxy-2-methylamino-2-nitroethene is formed according to the reaction scheme.

GH 3 OH CH 3 - N = C = CHNO 2 -> CH 3 NH \ T -> C = cCHNO 2 /

CH30

It is known that ketenimines can be converted into well crystalline products by treatment with alcohol.

The invention will be illustrated by the following examples.

CH3 — N = C = CHNO2 (IV)

Example 1

N- (2 - ([[5- (dimethylamino) methyl-1-2-furanyl] methyl] thioethyl) -N‘-methyl-2-nitro-1,1-ethylenediamine (ranitidine)

Dissolve 198 mg (2 mmol) of cuprous chloride in 25 ml of acetonitrile. This solution was added dropwise over 5 minutes to a solution of 428 mg (2 mmol) of 2- ([5- (dimethylamino) methyl-2-furanyl) methyl] thiojethanamine, 296 mg (2 mmol) of 1- methylthio-1-methylamino-2-nitroethene and 200 mg of triethylamine in 10 ml of acetonitrile. The precipitate is filtered off with suction, the filtrate is evaporated to half its original volume, 30 ml of chloroform are added, and the solution is extracted three times with 20 ml of aqueous ammonia. The extracts are discarded. The organic phase was dried over sodium sulfate, filtered and evaporated.

Pure ranitidine is obtained, which is identical to the product of Example 15 of German Patent Specification 27 34 070 with respect to melting point, infrared spectrum, NMR spectrum and mass spectrum.

Example 2

N- (2 - [/ [5- (dimethylamino) methyl-2-furanyl] methyl / thioethyl) -N‘-methyl-2-nitro-1,1-ethylenediamine (ranitidine)

340 mg (2 mmol) of silver nitrate are dissolved in 12 ml of methanol. This solution was treated dropwise with a solution of 214 mg (1 mmol) of 2 - ([[5- (dimethylamino) methyl-2-furanyl] methyl) thioethanamine, 163 mg (1.1 mol) over 5 minutes. 1-methylthio-1-methylamino-2-nitroethene and 100 mg of triethylamine, the precipitate is filtered off, the filtrate is treated with 20 ml of chloroform and shaken with 15 ml of 1: 1 hydrochloric acid, and the aqueous phase is neutralized with sodium bicarbonate and It is extracted twice with 30 ml of chloroform each, the extracts are dried over sodium sulphate and evaporated.

Pure ranitidine is obtained, which is identical to the product of Example 15 of German Patent Specification 27 34 070 with respect to melting point, infrared spectrum, NMR spectrum and mass spectrum.

Example 3

Detection of 1-nitro-3-methylketenimine in the reaction mixture

Formation of 1-methoxy-1-methylamino-2-nitroethene

170 mg (1 mmol) of silver nitrate are dissolved in 6 ml of methanol. To the solution was added 30 mg (0.2 mmol) of 1-methylthio-1-methylamino-2-nitroethene followed by 100 mg of triethylamine. Silver mercaptide is precipitated immediately. The precipitate was filtered off, the filtrate was evaporated and the product crystallized from 2 ml of isopropanol. In a yield of 90%, 1-methoxy-1-methylamino-2-nitroethene is obtained, m.p. 98-103 ° C.

After recrystallization from absolute ethanol, the melting point is 112-114 ° C.

Analysis for C4H3N2O3 calculated:

C: 36.36, H: 6.10, N: 21.20%, found:

C: 36.13, H: 6.24, N: 21.30%.

Molecular Weight: 132

NMR Spectrum [CDCl3]:

7.0 and 7.1 (2 s, NHMe, 6.16 (s, OMe), 1.4 [broad, NH-) where Me is methyl.

Claims (1)

the object of the invention Process for the preparation of N- (2 - {[[5- (dimethylamino) methyl-2-furanyl] methyl] thio} ethyl) -N'-methyl-2-nitro-1,1-ethylenediamine of formula I (CH 2 NCl · ^ CH 2 CH 2 CH 2 NHCNHCH 2 (I) as well as physiologically acceptable acid addition salts of this compound by reaction of 2 - {[[5- (dimethylamino) methyl-2-furanyl] methyl] thio "ethanamine II L-til) and 1-nitro-3-methylketoniraine of formula IV СНз — N = C = CHN02 (IV) characterized in that the reaction is carried out at room temperature in a polar organic solvent such as methanol or cetonitrile with a heavy metal salt solution such as AgNO3 or CuCl as a catalyst in the same solvent in the presence of a proton recipient such as triethylamine to form a highly reactive 1-nitro-3-methylketenimine in the reaction mixture which immediately reacts further with the compound of formula II to the desired compound of formula I.