CS241852B1 - Process for preparing 5-dimethylaminomethyl-2- [2-aminoethyl) thiomethyl-3-furan - Google Patents

Abstract

The invention relates to a process for the preparation of 5-dimethylaminomethyl-2-](2-aminoethyl)thiomethyl[- furan of formula I as a key intermediate in the production of some synthetic drugs (ch3)2nch2——ch2sch2ch2nh2 (I). This substance is prepared by first reacting 5-dimethylaminomethyl-2-furanmethanol with thiourea in the presence of hydrogen chloride in an aqueous, alcoholic or aqueous-alcoholic environment to 5-dimethylaminomethyl-2-furylmethylisothiuronium chloride, which is hydrolyzed without isolation with alkali hydroxide solutions to 5-dimethylaminomethyl-2-furanmethanethiol, which is then further condensed in a lower alcohol environment in the presence of alkali hydroxides with 2-haloethylamines, where halogen denotes chlorine or bromine, whereby, after the described treatment of the reaction mixture in a continuous sequence of 3 reactions, the desired amine of formula I is obtained in yields exceeding 90% per reaction stage.

Description

The invention relates to a process for the preparation of 5-dimethylaminomethyl2 [( 2-aminoethyl)thiomethyl] -furan of formula I (CH ₃ ) ₂ NCH ₂ yy ch ₂ sch ₂ ch ₂ nh ₂ fi

The substance of formula I according to the invention is a key intermediate in the synthesis of N-^2-^[(5-dimethylaminomethyl)2-furan-methylthio)ethyl-N'-methyl-2-nitro-1,1-ethendiamine. 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 causes inhibition of gastric acid secretion, induced by irritation of histamine H2-receptors.

As a result, ranitidine is used, mainly in the form of salts, especially hydrochloride, with success for the treatment of gastric ulcer diseases as well as duodenal ulcers, as well as pathological hypersecretory conditions, etc.

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According to the original patent (DOS 2^734.070), the substance of formula I is obtained by condensation of 5-dimethylaminomethyl-2-furanmethanol II with cysteamine hydrochloride with yields of 36 to 54% depending on the method of execution.

The disadvantage of this method is the necessity of using cysteamine hydrochloride, which is very expensive and not very stable due to its easy oxidation by atmospheric oxygen. Its preparation, which mostly consists of the reaction of hydrogen sulfide with ethyleneimine (e.g. W.O.Foye et al.: J.Pharm.Sci. 51. 168, 1962), is technologically and time-consuming, yields are low and highly variable, and above all it is based on the very expensive, highly toxic and explosive ethyleneimine.

The purpose of this invention was therefore to find a new method for preparing the substance of formula I, which would not require the use of cysteamine or any other compound for the preparation of which it would be necessary to use ethyleneimine at some stage of the synthesis, thereby achieving both a positive influence on economic indicators and at the same time eliminating the work with ethyleneimine, the disadvantages of which were indicated above.

The above disadvantages are eliminated by the method according to the invention, the principle of which is expressed by the following scheme:

-3 3'* C ^QII (CH ₃ ) ₂ NCH ₂ CH ₂ 0H + ¹

H ₂ NCSNH ₂ + 2 HC1 ,NH,

CH _O SC5 . 2 HC1 0' _v ^ά ^NH

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NaOH or

KOH (CH ₃ ) ₂ NCH CH ₂ SH ⁰ III + XCHpCHgNHg.HX (IV) + NaOH or KOH

-> (ch ₃ ) ₂ nch ₂

_{CH2SCH2CH2NH2 ​ ​ ​}

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, whereby, after evaporation of the solvents, the crude isothiuronium salt of formula V is obtained from the reaction mixture. This is hydrolyzed in a nitrogen atmosphere and in a lower alcohol with 1 to 3 carbon atoms with an alcoholic or aqueous solution of excess alkali hydroxide to form the corresponding alkali salt of the thiol III. The solid salt of 2-halogenethylamine IV (X = Cl or Br) or its alcoholic solution is then added to the reaction mixture and allowed to react first at a temperature of 0 to 30 °C and then at a temperature increased to 40 to 65 °C. After cooling to a temperature of 0 to 20 °C, the precipitated salts are filtered off and the solvents are evaporated from the filtrate in vacuo. The residue is then mixed between an organic solvent, preferably aromatic hydrocarbons such as benzene or toluene _, or further ether or tetrahydrofuran, and a concentrated aqueous solution of an alkali carbonate or hydroxide, or the residue is mixed only with the said organic solvent, the resulting suspension is filtered, the organic portion is separated, the solvents are distilled off and the residue is subjected to vacuum distillation, whereby the desired amine of formula I is obtained in a yield of 70-75%, which corresponds to an average yield of about 90% per reaction stage.

The advantages of the process according to the present invention can be summarized mainly in the following points:

a) Work with toxic and explosive ethyleneimine and hydrogen sulfide is no longer required;

b) do not work with bases of substances III and IV, whose isolation from their salts is always associated with significant losses due to the high solubility of both salts and bases of these compounds. Free thiol III is also easily oxidized by atmospheric oxygen to disulfide, which is worthless for the reaction. Bases of 2-haloethylamines IV (X = Cl or Br) are thermolabile and very unstable, because they undergo autocondensation and polymerization in a very short time (e.g. G.D. Jones et al.: J.Org.Chem. £, 125» 1944). Bases of 2-haloethylamines are also harmful to health, because they are substances structurally close to nitrogen mustard.

The fact that the above-mentioned shortcomings are practically eliminated according to the present invention enables a high yield of the substance of formula I, significantly increases safety at work, as it eliminates the need to handle substances hazardous to health and at the same time significantly reduces the energy requirements of the process.

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- 5,241,852

The starting 5-dimethylaminomethyl-2-furanmethanol II is easily obtained, for example, by the Mannich reaction of 2-furanmethanol with dimethylamine hydrochloride and formaldehyde or para formaldehyde with yields of about 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, and j.). As the second reaction component, 2-chloroethylamine hydrochloride (TV, X = Cl) is preferably used, obtained in a yield of about 95% from ethanolamine after conversion to the hydrochloride and its subsequent reaction with thionyl chloride (K. Ward, Jr.: J. Am. Chem. Soc. 915, 1935; G. W. Raizis et al.

L.W.Clemence: J.Am.Chem.Soc. 63, 3126, 1941; P.B.Jones et al.: J.Org.Chem. £125, 1944; G.I. Braz: Journal of General Chemistry.

763, 1955, et al.), or 2-bromoethylamine hydrobromide (IV, X = Br) is used, which can be prepared, among other things, 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 describe only some possible methods of preparing 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 is added 88 ml of aqueous 36% hydrochloric acid and the mixture is heated

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- 6 7.5 hrs. to reflux. Then water and ethanol are evaporated in vacuum, 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 in a nitrogen atmosphere and the reaction mixture is heated to boiling for 6 hrs. with stirring. After cooling to °C, 41 g of 2-chloroethylamine hydrochloride is added to the resulting suspension, containing, among others, the sodium salt of thiol III, and stirred first for 45 min at a temperature of 15 to 30 °C and then for 1 h at a temperature of 40 to 65 °C, the nitrogen injection is stopped and the mixture is left to stand overnight. The inorganic salts are filtered off with suction, washed with 2-propanol and the filtrates are evaporated in vacuum. The residue is mixed with three times the volume of benzene, the undissolved portion is filtered off, the toluene is evaporated and the remaining liquid is distilled.

A fraction with a b.p. of 130 to 135 °C/130 to 140 Pa is collected. 56.5 g of a colorless liquid are thus obtained, n^ = 1.5301, which corresponds to a yield of 75.3% and thus an average yield of 91% per reaction stage. According to gas chromatography (hereinafter 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, 465 g of 5-diniethylaminomethyl-2-furanmethsnol are added dropwise over 20 min and the mixture is heated to reflux for 9 h. 2-propanol is then 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 added under a nitrogen atmosphere with stirring and the mixture is heated to reflux for 6 h.

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

Example 3

The procedure is the same 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) are added to the reaction mixture. After the same treatment of the reaction mixture, 54.8 g of the desired amine I are finally obtained, which corresponds to a total yield of 73.0%.

Example 4, _{241 8S2}

To a solution of 360 g of 5-dimethylaminoethylamine in 720 ml of ethanol, 177 g of thiourea are added, and 578 ml of concentrated aqueous hydrochloric acid are added in portions, and the resulting reaction mixture is heated to boiling for 6 hours. Then, a solution of 564 g of sodium hydroxide in 560 ml of water is added, and the mixture is heated to boiling for 3.5 hours. Before the boiling is complete, the reaction vessel is filled with nitrogen, the mixture is cooled to a temperature of 20 to 25 °C, a solution of 255 g of 2-chloroethylamine hydrochloride in 260 ml of water is added, and the mixture is stirred first for 90 min at room temperature and then for 60 min at a temperature of 42 to 48 °C. The nitrogen supply is interrupted, the ethanol is distilled off, and the remaining suspension is extracted repeatedly with toluene. The solvent is distilled off from the combined toluene extracts and the remaining amine is distilled in vacuo. The portion passing at a temperature of 135 to 142°C and a pressure of 260 to 340 Pa is collected as the main fraction. n^ ⁴ = 1.5300.

373 g of amine I are thus obtained, which corresponds to a yield of 75% and thus an average yield of 91% per reaction stage.

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 ·