HU177508B - Process for preparing 4-/hydroxymethyl/-imidazoles - Google Patents

Abstract

ANDERSON-MENDELSON-WELLMAN CASE 1-2 An improved process for the preparation of 4-(hydroxymethyl)imidazoles by reducing 4-imidazolecarboxylic acid esters using an alkali metal or calcium in liquid ammonia with an additional proton source provided during the reaction or upon workup.

Description

Anderson Elvin Lowell Chemist, Moorestown, New Jersey, Mendelson Wilford Lee Chemist, Philadelphia, Pennsylvania, Wellman George Roberts Chemist, Warminster, Pennsylvania, USA

patentee:

Smithkline Corporation, Philadelphia, Pennsylvania, USA

Process for the preparation of 4- (hydroxymethyl) imidazoles

The present invention relates to an improved process for the preparation of 4- (hydroxymethyl) imidazole derivatives by reduction of a 4-imidazolecarboxylic acid ester in liquid ammonia with an alkali metal or calcium in the presence of an additional source of proton added during the reaction or processing.

The 4- (hydroxymethyl) -imidazole derivatives are known to be prepared by reducing a 4-imidazole carboxylic acid ester with lithium aluminum hydride. However, this process is extremely expensive, especially for industrial scale production.

Tamamushi by J. Pharm. Soc. Japan 53, 664-668 (1933) [C. A. 28,20049 (1934)] reports that the reduction of 2-methylimidazole-4,5-dicarboxylic acid and its esters in various ways remains unsuccessful. Reduction of 5-monochloride with tin and hydrochloric acid gave 2-methyl-5-hydroxymethylimidazole-4-carboxylic acid.

It is known in the art that systems containing a heterocyclic ring can be reduced with metal by Birch reaction in liquid ammonia. Accordingly, Remers et al., J. Amer. Chem. Soc. 89, 5513-4 (1967) report that indole quinoline rings can be reduced in liquid ammonia using lithium and methanol. O'Brien et al., J. Chem. Soc. 4609-4612 (1960) disclose that indole and carbazole can be reduced with metals other than red in the presence of alcohol in the presence of alcohol. In the process of the present invention, the carboxylic acid group of 4-imidazole carboxylic esters can be selectively reduced to the hydroxymethyl group without reduction of the imidazole ring when the reduction is carried out in liquid ammonia in the presence of an alkali metal and an additional proton source.

The proposed process is particularly advantageous when using alkali metals of metal sodium, potassium metal or lithium, since these materials are not expensive to reduce the imidazole carboxylic acid esters and the hydroxymethylimidazoles can be prepared in high yield, high purity, i.e. at least 90% purity.

The process of the present invention is illustrated in the following Scheme A, wherein each substituent has the following meaning:

R is hydrogen or C 1-4 alkyl, preferably 15,

R 'is C 1-4 alkyl, preferably ethyl or methyl.

According to the process, a lower alkyl ester of 4-imidazolecarboxylic acid is reduced in liquid ammonia to 4-hydroxymethylimidazole in the presence of al 2 O potassium or calcium and an additional proton source. The preferred alkali metal is sodium or lithium. One equivalent of ester requires four equivalents of alkali metal or two equivalents of calcium. It is expedient to use a small excess relative to this.

The choice of the 4-imidazole carboxylic acid ester is not critical to carrying out the process. Lower alkyl esters are preferred because of their low cost. Other esters such as substituted alkyl or aryl esters may also be used, such as 4-imidazolecarboxylic acid benzyl ester, but this is not preferred.

The proposed proton source is a compound capable of releasing hydrogen ion. One equivalent of the ester requires a total of three equivalents of protons to separate the free hydroxymethylimidazole derivative. The proton-releasing compound is used either during processing or by a combination of the two methods. The additional proton source is suitably a commercially available compound. Of the three equivalents of protons, two equivalents of an alcohol are predominantly C 1 -C 6, more preferably C 2 -C 4 lower alcohol or

This can be ensured by the addition of C 5 -C 6 cycloalkanol. These substances may be present in the reaction mixture in the form of up to two equivalents of alcohol to one equivalent of ester. Larger amounts can be used, but disadvantageous because of the loss of alkali metal or alkaline earth metal due to the evolution of hydrogen gas. Alternatively, two equivalents or more of alcohol are added during processing. Instead of alcohols, 16 to 35 pKa are preferred

Compounds in the range of 16-18 pKa that are not reduced during the process can also be used to supplement the initial two equivalents of protons. Thus, for example, the ammonia solvent initially releases a proton even if no additional proton source is added initially until the start of the processing step.

During work-up and after the addition of alcohol, four equivalents of proton are added to one equivalent of ester using a more proton source than hydroxymethylimidazole. These include ammonium sulfate, acetic acid or, preferably, ammonium chloride. Three to four equivalents are required to neutralize the previously formed equivalents of the two alkoxides or other bases as well as the equivalent amount of alkoxide formed from the thymidazole during the reduction. The fourth equivalent is considered to be the last equivalent amount of proton present at this stage of processing to neutralize the hydroxymethylimidazole anion. If it is necessary to isolate the imidazole alcohol in the form of an acid addition salt, the fifth equivalent amount of proton source is provided by the addition of a suitable strong acid such as hydrochloric acid.

The metal used in the process may be, for example, an alkali metal such as sodium, potassium or lithium or an alkaline earth metal such as calcium. Sodium or lithium are preferred for the economy of industrial scale work and for ease of treatment.

The reaction is carried out at or below the boiling point of the liquid ammonia solution or mixture, preferably at a temperature of from -25 to -70 ° C, more preferably from 35 to -50 ° C. Alternatively, the reaction may be carried out at elevated temperature under pressure, where the ammonia is in a liquid state.

In the process according to the invention, it is preferable to dissolve the metal in liquid ammonia and add the imidazole carboxylic acid ester and the alcohol. The ester and alcohol are preferably added separately or in a premixed state. More preferably, the alcohol is added directly to the reaction mixture first, followed by the ester. The latter order of operations can be recommended at industrial scale. If alcohol is the first addition, then the ester is then introduced into the reaction mixture by adding t-butyl alcohol, n-butanol or isopropanol to the lower alcohol. so instead of methanol.

Preferably, the alkaline reaction mixture is worked up by quenching it, for example by adding alcohol, then adding a more acidic proton source, such as ammonium chloride, and then evaporating the ammonia. After filtration and concentration of the reaction mixture, 4- (hydroxymethyl) -indudazole (11) is obtained as a residue.

Alternatively, however, the reaction mixture may be quenched by addition of water. The 4- (hydroxymethyl) imidazole is then extracted with a C 3 -C 6 alcohol such as n-butanol, n-pentanol, preferably t-butanol. Evaporation of the alcohol from the extract yields a residue containing 4- (hydroxymethylbimidazole).

The 4- (hydroxymethyl) imidazole, preferably an acid addition salt, such as used as such salt form in that during the processing of an acid such as hydrochloric acid ^- was added and the salt was recrystallized from a suitable solvent, such as propanol or more preferably isopropanol, acetone and ethyl ether mixture.

The 4- (hydroxymethylimidazole derivatives) are useful intermediates, and are pharmaceutically active compounds, especially histamine H ₂ antagonists, such as N-methyl-N '- [2 - {(5-R-4-imidazolyl) methylthio} ethyl] -. thiourea and N-cyano-N'-methyl-N- [2 - {(5-R-4-imidazolyl) methylthio} ethyl] -guanidine Histamine antagonists act as histamine H 1 receptor These histamine receptors are not blocked by so-called "antihistamines" such as Mepyramine, but they are blocked by burimamide. Blockade of the histamine H ₂ receptor is inhibition of its biological effect, which is not inhibited by the so-called "antihistamines."

N-Methyl-N '- [2 - {(5-R-4-imidazolyl) methylthio} ethyl] thiourea is prepared from 5-R-4- (hydroxymethyl) imidazole of formula II by reacting hydroxymethyl functional group with cysteaminrial, and then cave

5-R-4 - [(2-aminoethyl) thiomethyl] imidazole is reacted with methyl isothiocyanate.

The N-cyano-N'-methyl-N- [2- (5-R-4-imidazolyl) methylthio] ethyl] guanidines can be prepared by reacting a 5-R-4- (hydroxymethyl) ) hydroxymethyl functional group of imidazolyl is reacted with cysteamine and the resulting 5-R-4 - [(2-aminoethyl) thiomethyl] imidazole is reacted with N-cyano-N ', S-dimethylisothiourea or 5-R-4 - [( 2-aminoethyl) thiomethyl] imidazole was first treated with dimethyl N-cyanoimidodithiocarbonate to give N-cyano-N '- [2 - {(5-R-4-imidazolyl) methylthio} ethyl] -S- and methylisothiourea is reacted with methylamine.

The following thiourea and cyanoguanidine derivatives are prepared from 4-hydroxymethylimidazoles of formula II according to British Patent Nos. 1338169 and 3,950,333 and 3,950,353.

The 4- (hydroxymethyl) imidazoles, preferably in the form of their acid addition salts, such as their hydrochloride salts, are useful in the preparation of thiourea and cyanoguanidine derivatives.

The following examples are not intended to limit the embodiments, but merely serve to illustrate the process of the present invention.

The yield agents described in the examples relate to isolated products. In all cases, unless otherwise specified, these shall be at least 90% pure. The largest impurity from the process is ammonium chloride, which is usually present in an amount of 1-7% by weight. The final product will contain about 1% or less of 5-R-imidazole-4-carboxylic acid, provided that preferred ratios may increase to 25-50% if the ester has an alkali metal / calcium ammonia the order of addition to the mixture was reversed (cf. Example 4). In no case were any derivatives formed by reduction of the imidazole ring. For the preparation of highly pure products, especially when the 5-R-imidazole-4-carboxylic acid is present in larger amounts, the processing procedures described in Examples 2 and 4 are preferred.

Example 1

Add 600 ml of anhydrous ammonia to a 2 liter flask fitted with a stirring stirrer and a nitrogen inlet tube. The ammonia was liquefied using a dry ice-acetone cooling bath and the reaction mixture was cooled. After the ammonia was liquefied, 33 g (1.435 moles) of sodium metal were added in small portions, which were soluble in deep blue. To the solution was added t-butanol (25 mL, 0.266 mol). Subsequently, 50 g of ethyl 5-methyl-4-imidazole carboxylic acid (0.32 mol) were added in small portions to the reaction mixture. After the addition of the ester, the blue solution was stirred for 5 minutes and 100 ml of methanol was added dropwise. a few ml of which causes the blue color to disappear. Ammonium chloride (78 g, 1.458 mol) was added portionwise. The ammonia was evaporated and 700 ml of isopropanol was added to the residue and the mixture was heated under reflux for 30 minutes with vigorous stirring. The reaction mixture was then cooled to 40 ° C and acidified to pH 1 with hydrochloric acid gas. Water (10 mL) was added to the reaction mixture and stirred at 50 ° C for 30 min. The reaction mixture is filtered and the filter cake is washed with 200 ml of isopropanol at 40-50 ° C. After washing, the solution is concentrated to 100 ml and then diluted with 400 ml of acetone and 100 ml of ether. The product obtained is isolated and dried. 46.0 g (96%) of 4- (hydroxymethyl) -5-methylimidazole hydrochloride are obtained (m.p. 240 ° C, dec.)

Example 2

Using the procedure of Example I, the 4- (hydroxymethyl) -5-methylimidazole final product can be isolated in its base form by the following procedure:

After the ammonia was removed by evaporation as in Example 1, 700 ml of isopropanol was added to the residue and refluxed under vigorous stirring for 30 minutes, the resulting mixture was filtered and the residue was evaporated in vacuo to give 4- (hydroxymethyl) -5-methylimidazole. (op.

137-145 ° C dec.)

Example 3

Add 6 liters of ammonia to a 12 liter flask with a stirring stirrer and a nitrogen inlet tube. The ammonia was liquefied in a dry ice-acetone cooling bath and the cooling bath was also used to cool the reaction mixture. After liquefaction of ammonia, metal sodium (335 g, 15.23 mol) was added in small portions and dissolved in liquid ammonia with a deep blue coloration.

The metal sodium is added over a period of about 15 minutes.

Ethyl 5-methyl-4-imidazole carboxylic acid ethyl ester (500 g, 3.25 mol) was added as a powder wetted with 400 ml of anhydrous ethanol. This moistened powder is carefully added in small portions over about 30 minutes to a solution of ammonium containing sodium metal. After completion of the addition, 1 liter of methanol was carefully added. After the addition of methanol, 810 g (15.28 mol) of ammonium chloride were added until the blue color disappeared, and then the remaining ammonium chloride was added more rapidly with salts. After the addition of ammonium chloride, the ammonia was evaporated using a cold water bath. When the reaction volume begins to decrease, the bath is heated. After almost complete evaporation of the ammonia, the reaction mixture was heated under vacuum under vacuum. Thus, the last traces of ammonia are also removed. It takes 7-15 hours to remove the ammonia. To the residue is added 6 L of isopropanol and the reaction mixture is refluxed for 1 hour. Water (100 mL) was added and stirring continued for 10 minutes. The reaction mixture was then cooled to about 40 ° C, acidified with hydrochloric acid and filtered. The filter cake was washed with hot isopropanol and the combined filtrates were concentrated to a total volume of about 1 liter, diluted with 4 liters of acetone and 2 liters of ethyl ether. The resulting product was collected and dried in vacuo at 60 ° C. 97% yield of 4- (hydroxymethyl) -5-methylimidazole hydrochloride, m.p. 240 ° C, dec.

Example 4

3.0 g (0.02 mol) of ethyl 5-methyl-4-imidazole carboxylate are suspended in 100 ml of anhydrous ethanol and 60 ml to 80 ml of ammonia are added to a 200 ml flask equipped with a dry ice-cooled condenser. (10 ml of t-butanol may be added instead of ethanol.)

Small pieces of metal sodium (from xylene) are added over a period of 15 to 20 minutes. The solution clears during addition, the blue color remains for 1 minute, and the solution becomes cloudy. This requires 2.2-2.7 g of sodium metal. The reaction takes about 20-30 minutes.

The ammonia was allowed to evaporate and 50 mL of water and solid sodium chloride were added. The aqueous solution was extracted with several portions of 40 ml of t-butanol. Sodium chloride was added during extraction. The alcoholic phase is evaporated. The 4- (hydroxymethyl) -5-diethylimidazole present in the residue is converted to the hydrochloride salt by passing hydrochloric acid gas through a solution of ether and isopropanol. The resulting 1.6 g (55%) of 4- (hydroxymethyl) -5-methylimidazole hydrochloride was isolated by filtration (m.p. 240 C, dec.)

Example 5

Example 1 except that ethyl 4-imidazolecarboxylic acid was used instead of ethyl 5-methyl-4-imidazole carboxylic acid to give 4- (hydroxymethyl) imidazole.

Similarly, when 5-ethyl-4-imidazole carboxylic acid ethyl ester is reduced as in Example 1, 5-ethyl-4- (hydroxymethyl) imidazole and 5-isopropyl-4-imidazole carboxylic acid ethyl ester are obtained by the same method. reduced

4- (hydroxymethyl) -isopropyl-iraidazole is obtained.

Example 6

Add 300 ml of anhydrous ammonia to a 1 liter flask with a stirring stirrer and a nitrogen inlet tube. Potassium (26.0 g, 0.66 mol) was added to the ammonia. After potassium addition, 12.5 ml (0.133 mol) of t-butanol and then 25.0 g (0.16 mol) of ethyl 5-methyl-4-imidazole carboxylic acid were added in small portions over 20 minutes. The reaction mixture was stirred for 5 minutes and then quenched with methanol (50 mL). Ammonium chloride (40.0 g, 0.74 mol) and isopropanol (400 ml) were added and the ammonia was removed by distillation. After distillation, HCl gas was added to pH 1 and the resulting solid was filtered off. The filtrate was concentrated to 60 ml and acetone (300 ml) was added. The resulting product was collected by filtration and dried. 24 g (98%) of 4- (hydroxyethyl) -5-methylimidazole hydrochloride (m.p. 240 ° C, dec.)

Example 7

Add 700 ml of anhydrous ammonia to a 2 liter flask fitted with a stirrer and a nitrogen inlet tube. To this is carefully added, in small portions, 29.0 g (0.723 mol) of calcium. After the addition of calcium, 25 ml (0.266 mol) of t-butanol were added in one portion, followed by the addition of 50 g of ethyl 5-methyl-4-imidazole carboxylic acid in smaller portions over 30 minutes. The blue solution was stirred for 40 minutes and 120 ml of methanol was added dropwise. Ammonium chloride (80.0 g, 1.48 mol) and isopropanol (800 ml) were added and the ammonia was removed. Hydrogen chloride gas is added to the reaction mixture to a pH of about 1 and the precipitated solid products are filtered off. The filtrate was concentrated to 100 mL and 500 mL of acetone was added. The precipitated product was collected and dried to give 23.0 g (65%) of 4-hydroxymethyl-5-methylimidazole hydrochloride (30%). (mp 240 ° C, dec.)

Example 8

The 2 liter flask equipped with a nitrogen inlet tube and a suspended stirrer was cooled with a dry ice-acetone bath and approximately 500 ml of liquid ammonia was prepared in the flask. 6.3 g (0.895 mol) of lithium metal (about 25% excess) were dissolved in liquid ammonia to give a blue solution. While cooling and stirring, very small amounts of 5-methyl-4-imidazole carboxylic acid ethyl ester (27.58 g, 0.179 mol) were added. After the addition of the ester, the reaction mixture remained blue and stirred for a further 5 minutes. The blue solution was cooled by dropwise addition of methanol (60 mL). Then, 41 g (0.45 mol) of powdered oxalic acid is carefully added. The ammonia was evaporated in a hot water bath to give a thick slurry which was taken up in 500 mL of isopropanol. The reaction mixture was heated at 60-75 ° C for 30 minutes and cooled before filtration. The filtrates were acidified to pH 1 with hydrochloric acid gas, and the second filtrate was again concentrated to a dense smoky consistency and then diluted with aoetone. The precipitated product is collected and dried. 20.7 g (78%)

4- (hydroxymethyl) -5-methylimidazole hydrochloride is obtained (m.p. 240 ° C, dec.)

Example 9

A 5 liter flask with a stirred stirrer was purged with nitrogen. 2.7 L of anhydrous ammonia was prepared in the flask without external cooling. After the ammonia was prepared, 112 g (4.87 moles) of sodium metal were added in small portions. After dissolution of the sodium metal, slow stirring was started and 150 g (0.974 mol) of 0.5 g of 5-methyl-imidazole carboxylic acid ethyl ester in tablet form were added in 2 g portions over a period of 25-30 seconds. The temperature remains at -28 ° C during the addition. Even after the addition of the ester, the solution remains blue. 300 ml of methanol is carefully added to discoloration, but if the blue color does not disappear after addition of methanol, stirring is continued until colorless. After the addition of methanol, 265 g (4.97 moles) of ammonium chloride (about 2% excess based on metal sodium) was added cautiously. After the addition of ammonium chloride, the ammonia is evaporated to give a thick slurry. The maximum temperature of the walls of the flask is not more than 50 ° C. Isopropanol (2.1 L) was added and the reaction mixture was stirred vigorously while heating to 75 ° C. The reaction mixture was then acidified to pH 1 with hydrochloric acid gas and water (30 mL) was added. The reaction mixture was stirred for 15 minutes, cooled to 40-50 ° C and filtered. The residue was washed with hot isopropanol (2 x 300 mL). The filtrate and washings were evaporated to near dryness (consistency of dense suspension) and diluted with about 1.5 L of acetone. The product obtained is collected and dried. 125.8 g (87%) of 4- (hydroxymethyl) -5-methylimidazole hydrochloride are obtained, m.p. 240 DEG C., dec.

Example 10

A 5 liter flask equipped with a suspended stirrer was purged with nitrogen and 2.3 L of anhydrous liquid ammonia was poured into the flask without external cooling. To the ammonia was added portionwise 97 g (4.22 mol, 25% molar excess) of sodium metal, and after stirring, stirring was started and ethyl 5-methyl-4-imidazole carboxylic acid ethyl ester (130 g, 0.844 mol) was added in 0.5 g. In the form of tablets, the solution is added at intervals of 2 to 2 g at 30 second intervals. After the addition of the ester, the blue solution was stirred for 5 minutes. After stirring, 260 ml of n-propanol are added dropwise to remove the blue color. If the blue color does not disappear with the addition of n-propanol, stirring is continued until colorless. Ammonium chloride (232 g, 4.34 mol; 2% excess over metal sodium) was then added in small portions over 20-30 minutes. The resulting ammonia mixture was evaporated to a dense slurry consistency. During evaporation, the temperature of the flask wall may not exceed 50 ° C. After evaporation, 2.0 L of n-propanol are added and the mixture is heated at reflux for 10 minutes to evaporate most of the residual ammonia. The reaction mixture is then acidified with concentrated hydrochloric acid to a pH of about 1 and stirred for a further 15 minutes with cooling to about 40 ° C. The reaction mixture is then filtered and the filter cake is washed with 2 x 300 mL of warm (about 40 ° C) n-propanol.

The filtrate was concentrated under reduced pressure to 300 ml and the reaction was allowed to stand for 12 hours at about 20 ° C. The product obtained is collected and dried. 90.0 g (72%) of 4- (hydroxymethyl) -5-methylimidazole hydrochloride (m.p. 240 ° C, dec.)

EXAMPLE 11 In a three-liter three-necked flask with nitrogen inlet and hanging stirrer, 600 ml of liquid ammonia was prepared, dissolved in 18 g of sodium metal under nitrogen and added in small portions to 5-methyl-4-imidazolecarboxylic acid ethyl ester in 30.2 g. . The reaction mixture remains blue. 43.4 g of ammonium chloride were added in small portions until the blue color disappeared. The addition rate is increased so that the ammonia comes to a boil. At the end of the addition, isopropanol (400 mL) was added to the reaction mixture and refluxed for 1.5 hours. The suspension is then cooled, acidified with hydrogen chloride gas and filtered. The filtrate was concentrated to a dense slurry consistency and diluted with acetone. The product was dried in vacuo to give 23.2 g of 4- (hydroxymethyl) -5-methylimidazole hydrochloride, m.p. 240 ° C, dec.

Example 12

A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g) and cysteamine hydrochloride (23.0 g) in acetic acid (200 ml) was heated under reflux for 10 hours. After heating, it is cooled to 15-20 C, and the crystallized solid product is collected and washed with isopropyl alcohol. This gives 4-methyl-5 - [(2-aminoethyl) thiomethyl] imidazole dihydrochloride, m.p. 189-192 ° C.

To a solution of 14.6 g of 4-methyl-5 - [(2-aminoethyl) thiomethyl] imidazole dihydrochloride in 120 ml of water was added 7.75 g of potassium carbonate. After 15 minutes at room temperature, 5.15 g of methyl isothiocyanate are added. After refluxing for 30 minutes, the solution is slowly cooled to 5 ° C. The product formed is collected and recrystallized from water. N-methyl-N '- [2 - {(5-methyl-4-imidazolyl) methylthio} ethyl] thiourea, m.p. 150-152 ° C.

Example 13

a) 17.0 g of 4-methyl-5 - [(2-aminoethyl) thiomethyl] imidazole; and

11.2 g of N-cyano-N ^, ', 5'-dimethylisothiourea are dissolved in 500 ml of acetonitrile and heated under reflux for 24 hours. After evaporation, the residue is chromatographed on a silica gel column, eluting with acetonitrile. The product was finally recrystallized from acetonitrile ether to give N-cyano-N'-methyl-N- [2 - {(5-methyl-5-imidazolyl) methylthio} ethyl] guanidine, m.p. 141-142 ^° C. mp 141-142 ° C.

b) 23.4 g of 4-methyl-5 - [(2-aminoethyl) thiomethyl] imidazole are dissolved in ethanol and the ethanolic solution is slowly added to a solution of 20.0 g of dimethyl N-cyanoimidodithiocarbonate in ethanol with stirring at room temperature. The reaction mixture was stored at room temperature overnight. Filtration gives N-cyano-N '- [2 - {(5-methyl-4-imidazolyl) methylthio) ethyl] -S-methylisothiourea, m.p. 148-150 ° C. The filtrate is concentrated under reduced pressure and the mixture is cooled under reduced pressure. triturate with water to give a solid which is filtered off. The filtered product was recrystallized twice from isopropyl ether mixture to give another product. 148-150 ° C.

A solution of 33% methylamine in ethanol (33 ml) was added to a solution of 10.1 g of N-cyano-N '- [2 - {(5-methyl-4-imidazolyl) methylthio} ethyl] -S-methylisothiourea in 30 ml of ethanol. The reaction mixture was kept at room temperature for 2.5 hours. It is then concentrated under reduced pressure, and the residue is recrystallized twice from isopropyl alcohol / petroleum ether. This gives N-cyano-N ² -methyl-N- [2 - {(5-methyl-4-imidazolyl) methylthio} ethyl] guanidine, m.p. 141-143 ° C.

Claims (5)

Patent claims 1. A process for the preparation of 4- (hydroxymethyl) imidazoles of the formula II and their acid addition salts, wherein R is hydrogen or lower alkyl, characterized in that a 4-imidazole carboxylic acid ester of formula 1, wherein R is as defined above and R ^{z is a} lower alkyl moiety, is reduced in a liquid ammonia in the presence of an additional alkali metal or calcium source. The resulting 4- (hydroxymethyl) imidazole of formula II is optionally converted into an acid addition salt. (Priority: 27 June 1976) 35 2. A process according to claim 1, wherein the reducing agent in liquid ammonia is metallic sodium and an additional proton source is a lower alcohol or cycloalkanol. (Priority: June 20, 1975.) 40 3. The process according to claim 1, wherein the lower alkyl ester is 5-methyl-4-imidazole carboxylic acid ester of the formula I and a lower carbon alkanol is added as an additional proton source to the metal sodium in the liquid ammonia medium. (Priority: March 20, 1975) 4. The process of claim 1, wherein at least four equivalents of an equivalent amount of 4-imidazole carboxylic acid ester are used. 50 g of alkali metal are used. (Priority: March 20, 1975) 5. A process according to claim 1, wherein the imidazole carboxylic acid ester of formula I is methyl or ethyl ester. (Priority: March 20, 1975) 6. The process of claim 1, wherein the reducing agent used in the liquid ammonia medium is metal sodium and an additional proton source is a lower alkanol or cycloalkanol. (Priority: June 20, 1975.)