CS241852B1 - Preparation method of 5-dimethyleaminomethyl-2-(2-aminoethyl)thiomethyl)-furane - Google Patents

Abstract

The invention relates to a method of preparation 5-dimethylaminomethyl-2- (2-aminoethyl) thiomethyl [furan of formula I as a key intermediate in the manufacture of some synthetic drugs (ch3) 2nch2 ——ch2sch2ch2nh2 (I). This material was prepared by 5-dimethylaminomethyl-2-furanmethanol first by reaction with thiourea in the presence hydrogen chloride in aqueous alcoholic or an aqueous-alcoholic medium to 5-dimethylaminomethyl-2-furylmethylisothiuronium chloride, which is without isolation hydrolyses alkali hydroxide solutions to 5-dimethylaminomethyl-2-furanmethanethiol and this is then further condensed in lower alcohol environments for the presence of alkaline hydroxides with 2- halomethylamines, wherein halogen denotes chlorine or bromine, thereby yielding as described treating the reaction mixture continuously in sequence 3, the desired amine of the formula is obtained I in yields exceeding 90% on one reaction step.

Description

The invention relates to a process for preparing 5-dimethylaminomethyt2 [(2-aminoethyl) thiomethyl -furan of the formula I _{(CH3) 2} NCH ₂ CH ₂ yy SCH ₂ CH ₂ NH ₂ fi

The compound of formula (I) according to the invention is a key intermediate in the synthesis of N- [2- (4-dimethylaminomethyl) -2-furanylmethylthio) ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine. This substance is known under the international name ranitidine and was first described in 1978 (BJ Príce et al., DOG 2,734,070). It belongs to the group of selective H ₂ -antagonists of histamine and thus inhibits gastric avae secretion caused by the irritation of histamine H 2 -receptors.

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

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According to the original patent (DOS 2 734.070), the compound of formula I is obtained by condensing 5-dimethylaminomethyl-2-furanmethanol II with cysteamine hydrochloride in yields of 36 to 54% 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 oxidability by air oxygen, is not very stable. Its preparation, consisting mostly of reaction of hydrogen sulphide with ethyleneimine (for example WOFoy et al .: J.Pharm. Sci. 51, 168, 1962), is technologically and time-consuming, yields are low and very fluctuating and, above all, based on 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 aynthesis, thereby both positively affecting economic indicators and eliminating labor. with ethyleneimine, the disadvantages of which have been identified above.

These disadvantages are overcome by the method according to the invention, the principle of which is represented by the following scheme:

3 -3 'C ^ QII _{(CH3) 2} NCH ₂ CH ₂ 0H + ¹

H ₂ NCSNH ₂ + 2 HCl NH

CH _O SC5. 2 HC1 0 _'in ^ά ^ NH

241,852 ->

NaOH or

KOH _{(CH3) 2} NCH ₂ CH SH ⁰ III XCHpCHgNHg.HX + (IV) + KOH NaOHči

-> (CH _{3) 2} NCH ₂

CH ₂ SCH ₂ CH ₂ NH ₂

According to the present invention, 5-dimethylaminomethyl-2-furanmethanol II is heated in an aqueous, aqueous-alcoholic or alcoholic medium with thiourea in the presence of hydrogen chloride to give the crude isothiuronium salt of formula V after evaporation of the solvents. a lower alcohol having 1 to 3 carbon atoms with an alcoholic or aqueous solution of excess alkali hydroxide to form the corresponding alkali salt of thiol III. A solid salt of 2-halenethylamine IV (X = Cl or Br) or an alcoholic solution thereof is then added to the reaction mixture and reacted first at 0 to 30 ° C and then at a temperature increased to 40 to 65 ° C. After cooling to 0 to 20 ° C, the precipitated salts are filtered off and the solvents are evaporated under vacuum. The residue was either triturated between an organic solvent, preferably aromatic hydrocarbons, benzene or toluene _to or further ether or tetrahydrofuran and the concentrated aqueous alkali metal carbonate or hydroxide, or the residue was triturated with only the organic solvent obtained suspenae was filtered, the organic layer was separated the solvents are distilled off and the residue is subjected to vacuum distillation to give the desired amine of formula I in a yield of 70-75%, corresponding to an average wheel yield of 90% per reaction step.

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

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

(b) the bases of substances III and IV, whose isolation from their salts is always associated with considerable losses due to the high solubility of both the salts and the bases of these compounds, are not to be used. In addition, the free thiol III is easily oxidized by air oxygen to a disulfide which is worthless for the reaction. Base 2-halogenethylamines IV (X = Cl or Br) are thermolabile and highly unstable, as they have been subjected to autocondensation and polymerization in a very short time (eg GD Jones et al., J. Org. Chem. £, 125 »1944) . Furthermore, the 2-halogenethylamines are harmful to health because they are structurally similar to nitrogen mustard.

The fact that said drawbacks are practically eliminated according to the invention allows a high yield of the compound of formula (I), greatly increases safety at work by eliminating the need for handling hazardous substances and at the same time substantially reduces the energy consumption of the process.

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- 5 241 852

The starting 5-dimethylaminomethyl-2-furanmethanol II is readily obtained, e.g., by the Mannich reaction of 2-furanmethanol with dimethylamine hydrochloride and formaldehyde or para formaldehyde with wheel yields of 90 # (R.F.Holdren and R.M.Hixon:

J.Am.Chem.Soc. 68, 1198 (1946); R.F.Holdren: J.Am.Chem.Soc. 6j, 464 (1947); B.W.Gill and H.R.Ing: J.Chem.Soc. 1958,

4728; R.Toso et al .: Acta Pharm.Jugoslav. 31, 117, 1981, et al.). The second reaction components are preferably 2-chloroethylamine hydrochloride (TV, X = Cl), obtained in the yield of round 95 # from ethanolamine after conversion to the hydrochloride followed by reaction with thionyl chloride (K. Ward, Jr. .: J. Am.Chem.Soc., 915, 1935, GWRaizis et al

L.W.Clemence: J.Am.Chem.Soc. 63, 3126 (1941); P.B.Jones et al., J. Org. £ 125, 1944; G.I.Braz: Journalism.chim.

763, 1955, and the like), or 2-bromoethylamine hydrobromide (IV, X = Br), which may be prepared, inter alia, is used. directly by boiling ethanolamine with 48% hydrobromic acid in yields also above 90 # (F. Cortese et al., Org. Synth., Coll. Vol. 2, 91, 1946).

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 stirred suspension of 54.6 g of 5-dimethylaminomethyl-2-furanmethanol, 110 ml of ethanol and 26.6 g of thiourea was added 88 ml of aqueous hydrochloric acid and the mixture was heated.

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- 6 7.5 hours at reflux. The water and ethanol are evaporated in vacuo, the amorphous residue of isothiuronium salt V is stirred in 600 ml of 2-propanol, a solution of 70 g of 95% sodium hydroxide in 70 ml of water is added dropwise under nitrogen. to boil. After cooling to 0 ° C, the resulting suspension, containing, inter alia, a. sodium thiol III, added 41 g of 2-chloroethylamine hydrochloride and stirred first at 15-30 ° C for 45 min and then at 40-65 ° C for 1 h, blowing nitrogen off and allowing the mixture to stand overnight. The inorganic salts are filtered off with suction, washed with 2-propanol and the filtrates are evaporated in vacuo. The residue is stirred with 3 times of benzene, the insoluble matter is filtered off, the toluene is evaporated and the remaining liquid is distilled.

A fraction of b.p. 130-135 ° C / 130-140 Pa. Thus, 56.5 g of a colorless liquid are obtained, n = 1.5301, which corresponds to a yield of 75.3% and thus an average yield of 91% per reaction step. According to gas chromatography (GLC) the content of amine I is 99% ·

Example 2

To a stirred suspension of 228 g of thiourea in 1800 ml of a solution containing 438 g of hydrogen chloride in 2-propanol was added within 20 min. 465 g of 5-diethylaminomethyl-2-furanmethanol are added dropwise and the mixture is refluxed for 9 hours. The 2-propanol is distilled off in vacuo, the crude residue of isothiuronium salt V is stirred in 5000 ml of 2-propanol, a solution of 600 g of sodium hydroxide in 600 ml of water is allowed to stir with stirring and the mixture is refluxed for 6 hours. Then

7 241 852 the resulting suspension is cooled to 25 to 28 ° C, 351 g of 2-chloroethylamine hydrochloride is added, stirred first at room temperature for 1 hour and then at 45 to 55 ° C for 1 hour and allowed to stand overnight. The precipitated salts are filtered off with suction, washed with 2-propanol and evaporated from the combined filtrates in vacuo. The residue is stirred with 1500 ml of toluene, the suspension is filtered off with suction, the filter salts are washed with toluene and the solvent is distilled off from the combined filtrates. The residual liquid is subjected to vacuum distillation. There were obtained 488 g fractions of the TV 128 to 133 ° C / Pa 110 to 135, n ^ ⁴ = 1.5300. This corresponds to a yield of 76.0% and thus an average yield of 91.4% per reaction step.

Example 3

The procedure is as described in Example 1 except that, instead of 41 g of 2-chloroethylamine hydrochloride (IV, X = Cl), 73.2 g of 2-bromoethylamine hydrobromide (IV, X = Br) is added to the reaction mixture. After the same treatment of the reaction mixture, 54.8 g of the desired amine I are finally obtained, corresponding to a total yield of 73.0%.

Example 4, _{241 8S2}

To a solution of 360 g of 5-dimethylamino-allyl-2-furanmethanol in 720 ml of ethanol was added 177 g of thiourea and 578 ml of concentrated aqueous hydrochloric acid was added to the mixture and the resulting reaction mixture was heated at reflux for 6 hours. A solution of 564 g of sodium hydroxide in 560 ml of water is then added and the mixture is heated at reflux for 3.5 hours. Before boiling, the reaction vessel is filled with nitrogen, cooled to 20-25 ° C, treated with a solution of 255 g of 2-chloroethylamine hydrochloride in 260 ml of water, and stirred first at room temperature for 90 min and then at 42-60 min. High: 32 ° C. The nitrogen inlet is discontinued, the ethanol is distilled off and the remaining suspension is extracted repeatedly with toluene. From the combined toluene extracts, the solvent was distilled off and the remaining amine was distilled in vacuo. A fraction passing at 135-142 ° C and 260-340 Pa was collected as the main fraction. n ^ ⁴ = 1.5200.

This gives 373 g of amine I corresponding to a yield of 75% and thus an average yield of 91% per reaction step.

Claims (2)

SUBJECT MATTER> E 2 U 241 852 A process for preparing 5-d imethylaminometJ-yl-2-f2 £ aminoeth.yl ⁱ⁾ thiomethyl-furan of the formula I _{(CH3) 2} NCH ₂ CH ₂ SCH ₂ CH ₂ NH _2, characterized in that 5-dimethylaminomethyl-2-furanmethanol is reacted continuously with thiourea in an aqueous, aqueous-alcoholic or alcoholic hydrogen chloride solution, then the mixture is heated under a nitrogen atmosphere to heat the mixture. The sodium or potassium hydroxide solution, preferably sodium or potassium, and the resulting 5-dimethylaminomethyl-2-furanmethanethiol are reacted with solid salts at temperatures of 25 to 65 ° C. 2-haloethyl amines, where halogen is chlorine or bromine, or with their alcoholic or aqueous solutions, most of the solvents are evaporated from the reaction mixture and the amine is extracted into the water-immiscible organic solvent, preferably an aromatic hydrocarbon or ether, and separated the solvent is distilled off and the remaining amine I 3e is purified by distillation under vacuum ·