CS234470B1 - Method of preparation of 5-dimethylaminomethyl-2-(l)l2-aminoethyl(pthiomethyl) p-furane - Google Patents

Abstract

The invention relates to a method of preparation 5-dimethylaminomethyl-2- (2-aminoethyl) thiomethyl] -furan of formula I as important intermediate in the manufacture of some synthetic drugs (CH 3) 2 NCH 2 -? CH 3 CH 2 CH 3 NHg (I). This material was prepared from 5-dimethylaminomethyl-2-furanylmethylisothiuronium chloride, which is first hydrolysed low alcohols, al- "Potassium hydroxides, preferably sodium or potassium salt and the resulting alkaline salt 5-dimethylaminomethyl-2-furanmethanethiol is condensed with 2-halomethylamines, wherein halogen is chloro or bromo, wherein thus in a continuous sequence of two the reaction yields the desired amine of formula I in yields according to the method carried out 86 to 95% on average per one reaction stage.

Description

The invention relates to a process for the preparation of 5-dimethylamino-

ethendiamine. This substance is known under the international name ranitidine and was first described in 1978 (BJ Price et al .: DOS 2,734,070). It belongs <30 group of selective H ₂ -antagonists and causes the inhibition of gastric acid secretion induced by irritation of histamine H ₂ -receptor.

As a result, ranitidine is used, mainly in the form of salts, especially hydrochloride, with success in the treatment of stomach ulcers as well as duodenal ulcers, pathological hypersecretory conditions and the like.

234 470

According to the original patent (DOS 2,734 * 070), the compound of formula I is obtained by condensation of 5-dimethylaminomethyl-2-

furanmethanol (ΪΙ with cysteamine hydrochloride in 36-54% yields according to the embodiment).

The disadvantage of this process is the necessity to use cysteamine hydrochloride, which is very expensive and, due to its easy oxidation by air oxygen, little stable. Its preparation, consisting mostly of reaction of hydrogen sulphide with ethyleneimine (for example WO Poy et al .: J.Pharm. Sci .SI, 168, 1962), is technologically and time consuming, yields are low and very fluctuating and above all based on a very expensive, very toxic and explosive ethylenimine *

The object of the present invention was therefore to find a novel process for the preparation of a compound of formula I which does not require the use of cysteamine or any other compound which requires ethyleneimine at some stage of the synthesis, thereby both positively affecting economic performance and eliminating labor. with ethyleneimine, the disadvantages of which have been identified above.

The principle of the solution now proposed is illustrated by the following scheme:

- 3 234 47 (CH ₃ ) ₂ NCH ₂

o / NH ₀ - CH ₅ SC ^{t d} .2 HCl (II) + NaOH or KOH (CH ₃ ) ₂ NCH,

+ NaOH or KOH

CH _O SH> _{(CH3) 2} NCH

5- CH ₂ SCH ₂ CH ₂ NH ₂

WHAT

According to the present invention, 5-dimethylaminomethyl-2 furanylmethylisothiuronium chloride of the formula II (e.g. R. Toso et al., Acta Pharm. Jugoslav. 31, 117, 1981) is alkaline hydrolyzed to 5-dimethylaminomethyl-2-furanylmethananthiol of the formula III. se

The alkali is converted to an alkali thiolate and the teij is directly condensed with salts of 2-haloethylamine <IV (X = Cl or Br) in the presence of an alkali hydroxide to the desired amine I, which is thus obtained in a single operation

The process according to the invention consists in hydrolyzing the isothiuro niobium salt of the formula II in a lower alcohol having 1 to 3 carbon atoms under a nitrogen atmosphere by boiling with an alcoholic or aqueous solution of excess alkali hydroxide to form the alkali salt of thiol III. A solid salt of 2-halo-ethylamine IV, preferably 2-chloroethylamine hydrochloride (IV, X = Cl) or 2-bromoethylamine hydrobromide (IV, X = Br) is then added to the reaction mixture cooled to 0 to 30 ° C. , or an alcoholic solution thereof, and the resulting suspension is stirred first at said temperature and then at a temperature

234 470 ° to 60 ° C and after cooling, the precipitated inorganic salts are filtered off. The filtrate is freed from the solvents by evaporation and the residue is either stirred between an organic solvent, preferably benzene or toluene, and a concentrated aqueous solution of an alkali carbonate or hydroxide, preferably sodium or potassium, or the residue is only mixed with an organic solvent. After separation, the solvent was filtered, the solvent was evaporated and the residual oil was subjected to vacuum distillation to give the desired amine I in 74-91% yield.

The required 2-chloroethylamine hydrochloride is obtained in a yield of up to 95% from ethanolamine after conversion to the hydrochloride by treatment with thionyl chloride (K. Ward, Jr .: J. Am. Chem. Soc.

915 »1935; G.W.Raizis and L.W.Clemence: J.Am.Chem.Soc. 63.

3126, 1941; P. D. Jones et al., J. Org. 2, 125, 1944 et al.), 2-bromoethylamine hydrobromide can be prepared directly from ethanolamine by boiling with 48% hydrobromic acid in yields above 90% (F. Cortese et al., Org. Synth., Coll. Vol. 2) » 91 »

1946, et al.).

The advantages of the process according to the invention can be summarized in particular as follows:

(a) Work with toxic and explosive ethyleneimine as well as hydrogen sulphide is eliminated;

(b) it is not necessary to work with the bases of thiol III and halenethylamines, the isolation of which, due to the high solubility of both salts and bases in water, entails considerable losses.

- 5,234,470

In addition, the free thiol III is oxidized readily by air oxygen to a disulfide which is worthless for the reaction and presents additional losses. The 2-halogenethylamines IV (X = Cl or Br) bases are thermolabile and very unstable as they undergo autocondensation and polymerization in a short time (e.g., GDJones et al., J. Org. Chem., 125, 1944). In addition, these bases are harmful to health because they are substances close to nitrogen mustard.

The fact that said drawbacks are practically eliminated according to the present invention allows a high yield of the amine of formula (I), greatly increases safety at work, eliminates the need for handling health hazards and reduces the energy consumption of the described process.

The following examples illustrate only some embodiments of the preparation of the compound of formula I and do not limit the invention in any way.

Example 1

To a mixture of 40 g of isothiuronium salt II and 280 ml of methanol is added dropwise a solution of 40.3 g of 85% potassium hydroxide in 160 ml of methanol under nitrogen, heated to reflux for 5 hours, cooled to 20 ° C. and added 16.2 g of 2-chloroethylamine hydrochloride. Stir first 45 min. at room temperature and then for 1 hour at 45 to 55 ° C, then cooled, the precipitated salts are filtered off and the filtrates are evaporated in vacuo. The residue is partitioned between saturated potassium carbonate solution and 200 ml of ether, the organic portion is separated and the extraction is repeated two more times. The combined extracts were dried over anhydrous sodium sulfate, the ether was evaporated and the remaining liquid was distilled. 22.1 g are obtained

- 6,234,470 fractions of b.p. 127-130 ° C / 100 Pa, corresponding to a yield of 74% of the desired amine I, with an average yield of 86% per reaction step.

Example 2.

g of isothiuronium salt II is stirred in 125 ml of methanol, a solution of 16 g of 85% potassium hydroxide in 75 ml of methanol is added dropwise under a nitrogen atmosphere, and the mixture is refluxed for 5.5 hours. After cooling, a solution of 4.5 g of potassium hydroxide in 20 ml of methanol is added, while stirring, a solution of 14.3 g of 2-bromoethylamine hydrobromide in 35 ml of methanol is added dropwise, and it is stirred for 30 minutes. at room temperature and then for 40 min at 45-50 ° C, the suspension is cooled, potassium bromide is filtered off and methanol is evaporated from the filtrates. The residue is stirred with benzene, the suspension is filtered, the filtrates are evaporated and the remaining liquid is distilled. 12.1 g of the fraction of the TV 133 to 137 ° C / 140-150 Pa, n = ² ^

1.5300, corresponding to a yield of 80.9% and thus an average yield of 90% per reaction stage.

Example 3

567 g of isothiuronium salt II is suspended in 3400 ml of 2-propanol, a solution of 397 g of sodium hydroxide in 400 ml of water is added dropwise under stirring under nitrogen, the mixture is heated at reflux for 5.5 hours, cooled to 24-27. ° C, 232 g of 2-chloroethylamine hydrochloride is added, stirred for 50 min. at room temperature and then for an additional 60 min at 50-55 ° C and allowed to stand overnight. Excluded salts

7 234 470 are sucked off, washed with 2-propanol, the filtrates are evaporated, the residue is stirred with 1200 ml of toluene and the residue of undissolved salts is filtered off. After evaporation of the solvent, the remaining liquid is distilled. 386 g of a fraction of b.p.

138-142 ° C / 133-200 Pa, n = ⁴ = 1.5301-, which corresponds to a yield of 91.0% and thus an average yield of 95.4% per reaction step.

Claims (1)

A process for the preparation of 5-dimethylaminomethyl-2-β-aminoethyl) thiomethyl] furan of the formula I (ch ₃ ) ₂ nch ₂ - (y ch ₂ sch ₂ ch ₂ nh ₂ fl), characterized in that 5-dimethylaminomethyl-2-furanylmethylisothiuronium chloride is heated to reflux with an aqueous or alcoholic solution of an alkali hydroxide, preferably sodium or potassium, under a nitrogen atmosphere and a lower alcohol medium with 1 to 3 Luhliks, whereby the resulting 5-dimethylaminomethyl-2-furanmethanthide is converted by excess alkali to its alkali salt, reacted directly in suspension at a temperature of up to 60 ° C with solid salts of 2-halenethylamines where halogen is chlorine or bromine, or with their alcoholic solutions, whereby the desired amine is isolated by shaking to remove the inorganic salts. organic solvent, preferably benzene, toluene or ether, its solution is evaporated after filtration and the amine is purified by distillation in vacuo. «> ·