DK143749B - PROCEDURE FOR THE PREPARATION OF 4- (HYDROXYMETHYL) IMIDAZOLE COMPOUNDS SOA AND ITS ACID ADDITION SALTS - Google Patents

Description

(19) DENMARK

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^ (ni PUBLICATION MANUAL od 143749 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 3519/76 (§1) IntCI * C 07 D 233/64 (22) Filing date 22 Jul. 1976 (24) Race day 22 Jul. 1976 (41) Aim. available Feb 21 1977 (44) Posted 5 Oct. 1981 (86) International Application No. - (86) International Filing Day - (85) Continuation Day - (62) Master Application No. -

(30) Priority 20 Aug. 1975, 606270, US May 27, 1976, 690476, US

(71) Applicant SMITHKLINE CORPORATION, Philadelphia, US.

(72) Inventor Elvin Lowell Anderson, US: Wilford Lee Mendelson, US: George Robert Wellman, US.

(74) Associate Company Chas. Hude.

(54) Process for the preparation of 4- (hydroxymethyl) imidazole compounds as well as their acid addition salts.

The invention relates to an improved process for the preparation of 4- (hydroxymethyl) imidazole compounds of the formula

Ry_ζ CE ^ OH

HN ^ K

Wherein Q is hydrogen or C 1-4 alkyl and / or acid addition salts thereof, j) wherein a 4-imidazole carboxylic acid alkyl ester of formula

o 7 ^ T

= t HN ^ N

r - wherein R is as defined above and R 'is lower alkyl, which method is characterized by the reduction being made

D

No. 2,23749 with an alkali metal or calcium in liquid ammonia and in the presence of an additional proton-releasing compound which is added during the reaction or during work-up, and if desired, the 4- (hydroxymethyl) imidazole is isolated as an acid addition salt.

4- (hydroxymethyl) imidazole compounds can be prepared by reduction of 4-imidazole carboxylic acid esters using lithium aluminum hydride. This process is expensive, especially for the preparation of 4- (hydroxymethyl) imidazoles on a large scale.

Tamamushi, J. Pharm. Soc. Japan 53: 664-8 (1933), C.A. 28: 20049 (1934), have reported that attempts to reduce 2-methylimidazole-4,5-dicarboxylic acid and their esters by various methods were unsuccessful. With the 5-monochloride, reduction with Sn and HCl results in the formation of 2-methyl-5-hydroxymethylimidazole-4-carboxylic acid.

It is known that heterocyclic ring systems can be reduced by metals in liquid ammonia via a Birch-type reaction. For example, Remers et al., J. Amer. Chem. Soc. 89: 5513-4 (1967) that indole and quinoline rings are reduced by using lithium and methanol in liquid ammonia. Further, O'Brien et al., J. Chem. Soc. 4609-4612, (1960), that indole and carbazole rings, but not pyrrole rings, can be reduced by using liquid ammonia metals in the presence of alcohol. In the process of the invention, the carboxylic acid ester group in a 4-imidazole carboxylic acid ester is selectively reduced to hydroxymethyl without reduction of the imidazole ring using an alkali metal or calcium in liquid ammonia as well as an additional proton-releasing compound.

The process of the present invention is advantageous, especially in connection with the preferred alkali metals, i.e. sodium, potassium and lithium because the materials used for the reduction of the imidazole carboxylic acid esters are not expensive and because high yields of the hydroxymethylimidazoles are obtained in a high degree of purity, ie. at least 90% purity.

The process of the invention can be illustrated as follows: 3 U37A9

Rv_ / COOR 'R χ y CH2 ° H

t = \ r = \

HN N - ^ HN N

Formula I Formula II

wherein R is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl, and R 'is lower alkyl of 1 to 4 carbon atoms, preferably methyl or ethyl.

According to the above process, a lower alkyl ester of a 4-imidazole carboxylic acid is reduced using an alkali metal or calcium in liquid ammonia with an additional proton-releasing compound to give a 4- (hydroxymethyl) imidazole. Preferably, an alkali metal is used, with sodium or lithium being most preferred. Four equivalents of the alkali metal or two equivalents of calcium are required for each equivalent of the ester. Preferably, slightly more than 4 equivalents of the alkali metal or slightly more than 2 equivalents of calcium are present.

The ester in question of the 4-imidazole carboxylic acid used is not critical to the process of the invention. The lower alkyl esters are advantageous because the alcohols from which they are derived are not expensive and the yields of the use of the lower alkyl esters are good.

A proton-releasing compound, as required by the process of the invention, is a compound which gives off a hydrogen ion.

A total of three equivalents of protons per equivalent ester must be provided to isolate the free hydroxyraethylimidazole compound.

They can be added during the reaction, during the work-up or during a combination of both. The additional proton-releasing compounds used in the process of the invention are preferably commercially available materials.

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An alcohol, such as preferably a lower alkanol containing 1-6, but most preferably 2-4, carbon atoms, or a cycloalkanol, preferably containing 5-6 carbon atoms, is most convenient to use to obtain two of the required 3 equivalents of protons. It may be present in the reaction mixture in any amount up to ca. 2 equivalents of alcohol per equivalent ester. Larger amounts can be used, but cause faster loss of the alkali or alkaline earth metal due to hydrogen gas formation. Alternatively, two equivalents or more of the alcohol may be added during working up. Instead of these alcohols, compounds having a pKa value in the range of 16-35, preferably 16-18, which compounds are not reduced during the process can be used to supply the first two protons. For example, dissolving ammonia initially leads to protons when an additional proton source, such as an alcohol, is not added before the reprocessing phase.

At work-up and after the alcohol addition, 4 equivalents of protons are added. equivalent ester from a proton-releasing compound which is more acidic than hydroxymethylimidazole such as water, ammonium sulfate, acetic acid or preferably ammonium chloride. 3 of these equivalents serve to neutralize the 2 previously formed equivalents of alkoxide (or other base) plus the one equivalent of alkoxide formed by the imidazole ester during the reduction. The fourth equivalent adds the last equivalent of protons to the hydroxymethylimidazole anion present at this time. If one wishes to isolate the imidazole alcohol as the acid addition salt, a fifth equivalent of protons must be added from a suitably strong acid such as hydrogen chloride.

Metals used in the process are e.g. alkali metals such as sodium, potassium or lithium, or an alkaline earth metal such as calcium. However, from an economic standpoint, sodium or lithium is preferred for large-scale operation and for ease of execution of the process.

The reaction is carried out at or below the boiling point of the ammonia solution or mixture, conveniently at a temperature in the range of from about. 25 ° C to approx. -70 ° C, preferably from ca. -35 ° C to approx. -50 ° C. Alternatively, the reaction may be carried out at a higher temperature under a pressure at which the ammonia is liquid.

5 143749

It is preferred by the process of the invention to dissolve the metal in liquid ammonia and to add to the solution the imidazole carboxylic acid ester and an alcohol. Preferably, the ester and alcohol are added simultaneously, either separately or mixed beforehand, or also, which is most convenient, the alcohol is followed immediately by the ester. The latter method is particularly suitable for large-scale operation. When the alcohol is first added followed by the ester, it is preferred to use a less acidic alcohol such as t-butanol, n-butanol or isopropanol instead of ethanol or methanol.

The alkaline reaction mixture is preferably worked up by cooling during the reaction, e.g. by adding an alcohol to which the more acidic proton source is added, such as ammonium chloride, and the ammonia is then evaporated. Filtration and evaporation result in a residue containing the 4- (hydroxymethyl) imidazole compound of formula II.

Alternatively, one can cool during the reaction by adding water. Then the 4- (hydroxymethyl) imidazole of formula II is extracted with an alcohol of 3-6 carbon atoms such as n-butanol, n-pentanol or preferably t-butanol. Evaporation of the alcohol from the extracts results in a residue containing the 4- (hydroxymethyl) imidazole.

The 4- (hydroxymethyl) imidazole compound is preferably isolated as an acid addition salt, preferably the hydrochloride salt, by treatment with an acid during work-up, e.g. by treatment with hydrogen chloride, and crystallization from a suitable solvent such as isopropanol, or preferably from a solvent mixture such as isopropanol / acetone / ethyl ether.

The 4- (hydroxymethyl) imidazoles are useful as intermediates for the preparation of pharmacologically active compounds, especially histamine Hg antagonists, e.g. N-methyl-N '- [2 - ((5-H-4-imidazolyl) methylthio) -ethyl] thiourea and N-cyano-N'-methyl-N "- [2 - ((5-R-4- histamine Hg antagonists act as histamine H2 receptors which, as described by Black et al. (Nature 1972, 236, 385), can be defined as those histamine receptors which are not blocked by antihistamines ", such as mepyramine, but are blocked by burimamide. The blocking of histamine H 2 receptors is useful for inhibiting the biological effects of histamine that are not inhibited by" antihistamines ". Histamine H2 antagonists are useful , for example, as inhibitors of gastric acid secretion.

The following examples illustrate the process of the invention.

In the following examples, the yields given refer to the raw, isolated products. In all cases, unless otherwise stated, the products are at least 90S clean. The major impurity present from this procedure is ammonium chloride, which is usually present in an amount of from 1 to approx. 7 weight. 5-R-imidazole-4-carboxylic acid is present in an amount of approx.

1% or less, provided the preferred procedures are followed, but may be 25-50% if the addition order of ester for alkali metal / calcium ammonia is reversed (Example 4). In no case were products resulting from reduction of the imidazole ring. When one wishes to obtain a product of the highest purity, especially when large amounts of 5-R-imidazole-4-carboxylic acid are present, the work-up procedure set forth in Examples 2 and 4. is preferably referred to as hydrogen or alkyl.

Example 1

A 2 liter flask was equipped with an overhead stirrer as well as a nitrogen inlet and filled with 600 ml of anhydrous ammonia. A dry ice-acetone cooling bath was used to facilitate the collection of ammonia as well as for cooling during the reaction. After the ammonia was collected, sodium (33 g, 1.435 mol) was added in portions and dissolved, resulting in a deep blue color, t-butanol (25 ml, 0.266 mol) was added to this solution. 5-methyl-4-imidazole carboxylic acid ethyl ester (50 g, 0.32 mol) was added portionwise. After addition of the ester, the blue solution was stirred for 5 minutes and methanol (100 ml) was added dropwise, causing the blue color to disappear after a few milliliters of bleach were added. Ammonium chloride (78 g, 1.458 mol) was added in portions. The ammonia was evaporated and isopropanol (700 ml) was added to the residue and the mixture was heated under reflux for 30 minutes under vigorous stirring. The mixture was cooled to 40 ° C and acidified (pH about 1) with hydrogen chloride gas. Water (10 ml) was added and the mixture was stirred at 50 ° C for 30 minutes. The mixture was filtered and the filter cake washed with 200 ml of warm (40-50 ° C) isopropanol. The solution was evaporated to 100 ml and diluted with acetone (400 ml) and ether (100 ml). The product was collected and dried to give 46.0 g (96%) of 4- (hydroxymethyl) -5-methylimidazole hydrochloride, mp 240 ° C (decomposition).

Example 2

Alternatively, by the method of Example 1, the 4- (hydroxymethyl) -5-methyl-imidazole can be isolated as the base by the following procedure;

After the ammonia is removed by evaporation during the procedure of Example 1, isopropanol (700 ml) is added to the residue and heated under reflux for 30 minutes with vigorous stirring, then the resulting mixture is filtered and the isopropanol removed by evaporation in vacuo to give 4- (hydroxymethyl) -5-methylimidazole as the residue.

Example 3

A 12-liter flask was fitted with an overhead stirrer and a nitrogen inlet and filled with 6 liters of ammonia. A dry ice-ace tone cooling bath was used to facilitate the collection of ammonia and to produce cooling during the reaction. After the ammonia was collected, sodium (335 g, 15.23 mol) was added in portions and dissolved in the ammonia, resulting in a deep blue solution. The addition of sodium required approx. 15 minutes. 5-methyl-4-imide-azole-carboxylic acid ethyl ester (500 g, 3.25 moles) was added to 400 ml of dry ethanol to give a wet powder. This wet powder was added cautiously to the sodium ammonia solution over a period of approx. 30 minutes. After the addition was complete, 1 liter of methanol was gently added. Ammonium chloride (810 g, 15.28 mol) was added very gently until the blue color disappeared, and the remaining amount of ammonium chloride could be added more quickly. After the addition of the ammonium chloride, the ammonia was evaporated using a cold-water hot bath. As the volume of the mixture decreased, the heating bath became warmer. When almost all the ammonia had disappeared, the mixture was heated with steam under a vacuum to remove the last traces of ammonia. The removal of ammonia requires 7-15 hours. Isopropanol (6 liters) was added to the residue and heated under reflux for 1 hour with vigorous stirring. Water (100 ml) was then added and stirring was continued for 10 minutes. The mixture was then cooled to ca.

40 ° C and acidified with hydrogen chloride gas and filtered. The filter cake was washed with warm isopropanol and the combined filtrate was evaporated to ca. 1 liter and diluted with 4 liters of acetone and 2 liters of ethyl ether. The product was collected and dried at 60 ° C under vacuum to give 4- (hydroxymethyl) -5-methylimidazole hydrochloride in 97% yield.

Example 4

A suspension of 5-methyl-4-imidazole carboxylic acid ethyl ester (3.0 g, 0.02 mole) and absolute ethanol (10 ml) was stirred at drying temperature in a dry 200 ml flask equipped with a drying back cooler when 60-80 ml of ammonia was added. (Alternatively, 10 ml of t-butanol can be used instead of ethanol).

Small pieces of sodium (from xylene) were added over 15-20 minutes. The solution became clear during the addition, after which a blue color remained for one minute and the solution became cloudy. This required 2.2-2.7 g of sodium. The reaction requires 20-30 minutes.

The ammonia was allowed to evaporate and water (50 ml) and solid sodium chloride were added. The aqueous solution was extracted with several 40 ml portions of t-butanol. Sodium chloride was added during the course of the extraction.

The alcohol layer was evaporated. The 4- (hydroxymethyl) -5-methylimidazole present in the residue was converted to the hydrochloride salt by treatment with ether and isopropanol as well as by introducing hydrogen chloride gas into the quenched solution. 4- (hydroxymethyl) -5-methylimidazole, the hydrochloride (1.6 g, 55%) was isolated by filtration.

9 143749

Example 5

A 1 liter flask, equipped with a stirrer and a nitrogen inlet, was charged with 300 ml of anhydrous ammonia. Potassium (26.0 g, 0.66 mole) was added, t-butanol (12.5 mL, 0.133 mole) was added, and 5-methyl-4-imidazole carboxylic acid ethyl ester (25.0 g, 0.16 mole) was added. added portionwise over 20 minutes. The reaction mixture was stirred for 5 minutes and then cooled with 50 ml of methanol. Ammonium chloride (40.0 g, 0.74 mole) and ice-propanol (400 ml) were added and the ammonia was removed by distillation. Hydrogen chloride gas was added to ca. pH 1 and the solids were filtered off. The filtrate was evaporated to 60 ml and acetone (300 ml) was added. The product was collected by filtration and dried to give 24 g (98%) of 4- (hydroxymethyl) -5-methylimidazole hydrochloride.

Example 6

A 2 liter flask fitted with an overhead stirrer and a nitrogen inlet was charged with 700 ml of anhydrous ammonia. Calcium (29.0 g, 0.723 mol) was gently added in portions, t-butanol (25 mL, 0.266 mol) was added in one portion, and 5-methyl-4-imidazole carboxylic acid ethyl ester (50 g, 0.32 mol) ) was added portionwise over 30 minutes. The blue solution was stirred for 40 minutes and methanol (120 ml) 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 was added (pH about 1) and the solids were filtered off. The filtrate was evaporated to 100 ml and acetone (500 ml) was added. The product was collected and dried to give 4-hydroxymethyl-5-methylimidazole hydrochloride (23.0 g of 65% pure material, yield 30%).

Example 7

A 2 liter flask was equipped with a nitrogen inlet and a stirrer located above. By cooling with a dry ice-acetone bath, approx. 500 ml of liquid ammonia collected in the flask. Lithium metal (6.3 g, 0.895 mole, about 25% excess) was dissolved in liquid ammonia to form a blue solution. With continuous cooling and stirring, 5-methyl-4-imidazole carboxylic acid ethyl ester (27.58 g, 0.179 mol) was added in very small portions. After the ester was added, the reaction solution remained blue and it was stirred for 5 minutes. The blue solution was cooled by the dropwise addition of 60 ml of methanol. Then oxalic acid powder (41 g, 0.45 mol) was added carefully. Ammonia was evaporated on a hot water bath to give a viscous liquid which was taken up in 500 ml of isopropanol. The mixture was heated to 60-75 ° C for half an hour and cooled before filtration. The filtrate was acidified to pH 1 with hydrogen chloride gas and filtered again. This second filtrate was evaporated to a viscous liquid and diluted with acetone. The product was collected and dried to give 20.7 g (78%) of 4- (hydroxymethyl) -5-methylimidazole hydrochloride.

Example 8

A 5 liter flask was fitted with an overhead stirrer and rinsed with nitrogen. The vessel was charged with 2.7 liters of anhydrous liquid ammonia without external cooling. After the ammonia was collected, sodium (112 g, 4.87 mol) was added in small portions. After the sodium was dissolved, slow stirring was started and 5-methyl-4-imidazole carboxylic acid ethyl ester (150 g, 0.974 mol, available as 0.5 g tablets) was added in 2 g portions at 25-30 second intervals. The temperature remained around -28 ° C during this addition. After the addition of the ester, the solution remained blue. Methanol, 300 ml, was gently added dropwise to remove the blue color (if the blue color does not disappear after the methanol addition, stirring should be continued until the color disappears). After the methanol addition, ammonium chloride (265 g, 4.97 mole, about 2% excess mole sodium) was added cautiously.

After the addition of ammonium chloride, ammonia was evaporated to give a viscous liquid. The temperature of the container walls should not exceed 50 ° C. Isopropanol (2.1 liters) was added and the mixture was stirred vigorously while heating the mixture to 75 ° C. The mixture was then acidified with hydrogen chloride gas (to pH ca.

1) and 30 ml of water were added. The mixture was stirred for 15 minutes and cooled to 40-50 ° C and filtered. The residue was washed with warm isopropanol (2 x 300 ml). The filtrate and washings were evaporated to near dryness (viscous liquid) and diluted with acetone (1.5 liters). The product was collected and dried to give 125.8 g, 87% of 4- (hydroxymethyl) -5-methylimidazole, hydrochloride.

Example 9

A 5 liter flask was fitted with an overhead stirrer and rinsed with nitrogen. The vessel was charged with 2.3 liters of anhydrous liquid ammonia without external cooling. After the ammonia was collected, sodium (97 g, 4.22 mol, 2596 molar excess) was added in portions.

After the sodium was dissolved, stirring was started and 5-methyl-4-imidazole carboxylic acid ethyl ester (130 g, 0.844 mole, and the present zone of 5 g tablets) was added in 2 g portions with approx. 30 second intervals. After the addition of the ester, the blue solution was stirred for 5 minutes, n-propanol (260 ml) was gently added dropwise to remove the blue color (if the blue color does not disappear during the n-propanol addition, stirring should be continued until the color disappears). . The ammonium chloride (232g, 4.34mL, a 2% excess mole of sodium) was added portionwise over 20-30 minutes with caution. The resulting ammonia mixture was evaporated to a viscous liquid. The container walls should not rise above 50 ° C. n-propanol (2.0 liters) was then added and the mixture was heated under reflux for approx. 10 minutes to expel most of the remaining ammonia. The mixture was acidified to pH ca. 1 with concentrated hydrochloric acid and stirred for 15 minutes while cooling to ca. 40 ° C. The mixture was filtered and the cake was washed with 2 x 300 ml hot (about 40 ° C) n-propanol. The filtrate was evaporated under reduced pressure to 300 ml and the mixture was left to stand at ca. 20 ° C for 12 hours. The product was collected and dried to give 90.0 g (72%) of 4- (hydroxymethyl) -5-methylimidazole, hydrochloride.

Example 10 600 ml of liquid ammonia was collected in a 1 liter 3-neck flask equipped with nitrogen inlet and an overhead stirrer.

Under nitrogen, 18 g of sodium metal was dissolved in the liquid ammonia,