FI64356C - REFRIGERATION FOR HYDROXIMETYL IMMEDIATE PROTECTION - Google Patents

Description

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1 (44) Date of issue: [date]. -

Patent and ocean registration under the Act of Accession of pubs 29.C7.83 (32) (33) (31) Privilege claimed — Begird prlorltet 20.08.75 27-05-76 USA (US) 606270, 690U76 (71) SmithKline Beckman Corporation, 1500 Spring Garden Street, Philadelphia, Pennsylvania, USA (72) Elvin Lovell Anderson, Moorestovn, Nev Jersey, Wilford Lee Mendelscr., Philadelphia, Pennsylvania, George Robert Wellman, Warminster,

This invention relates to an improved process for the preparation of 4- (hydroxymethyl) imidazole compounds by the preparation of 4- (hydroxymethyl) imidazole compounds. using β-imidazole carboxylic acid alkyl esters using a time transition metal or calcium in liquid ammonia and an additional proton: source either during the reaction or work-up.

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

Tamamushi is in the writings of J. Pharm. Soc. Japan 53 * 664-8 (1933) and C.A. 28: 200119 (193 ^ 0 mentioned that attempts to reduce 2-methyl-imidazole-1'-5-dicarboxylic acid and its esters by various methods failed. Reduction of 5-monochloride with tin and hydrochloric acid gave 2-methyl-h-hydroxy). imidyl imidates of the sol-t-carboxylic acid.

It is known that heterocyclic ring systems can be reduced with metals in liquefied ammonia using a Birch-type reaction. For example, Remers et al. mention in their paper 2 64356 J. Amer. Chem. Soc. 89-551 (1967) that indole and kinclin rings are reduced using lithium and methanol in liquefied ammonia. In addition, O'Brien et al. in their paper J. Chem. Soc. 4609-4611, (I960) that indole and carbazole rings but not pyrrole rings can be reduced by metals in liquid ammonia in the presence of alcohol. In the process of this invention, the carboxylic acid ester group of the 4-imidazolecarboxylic acid ester is selectively reduced to hydroxymethyl without reduction of the imidazole ring using an alkali metal or calcium in liquefied ammonia and an additional proton source.

The process according to the invention is advantageous, especially when using the most suitable alkali metals, i.e. sodium, potassium and lithium, because the materials used for the reduction of imidazole carboxylic acid esters are cheap and because high yields of hydroxymethylimidazoles of at least 90% purity are obtained.

The method according to the invention can be described as follows: R ^ C00R 'p ρμ nμ ^ - \ 2

HN N - ^ HM N

Formula I Formula II

wherein R is hydrogen or lower alkyl of 1 to 4 carbon atoms, most preferably methyl, and Rr is a former alkyl of 1 to 4 carbon atoms, preferably methyl or ethyl.

According to the above method, the lower alkyl ester of 4-imidazolecarboxylic acid is reduced using an alkali metal or calcium in liquefied ammonia and an additional proton source to produce 4- (hydroxymethyl) imidazole. An additional proton source is added during either the reaction or work-up. Alkali metal is most preferably used, with sodium or lithium being most preferred. Four equivalents of alkali metal or two equivalents of calcium are required for each equivalent of ester. Preferably, a little more than 2 · equivalent of alkali metal or a little more than 2 equivalents of calcium is present in the reaction mixture.

The type of β-imidazolecarboxylic acid ester used is not critical to the process of this invention.

The source of proton required in the process of this invention is a hydrogen donor. A total of three equivalents of protons per equivalent of ester is required to isolate the free hydroxymethylimidazole compound. The protons can be delivered either during the reaction, the subsequent post-treatment, or both. The additional proton sources used in the process of the invention are most suitably commercially available substances.

An alcohol such as suitably 1-6, preferably lower alkanol having 2-4 carbon atoms or suitably cycloalkanol containing 5-6 carbon atoms is most suitable to produce two equivalents of protons out of the three proton equivalents required. It may be present in the reaction mixture in an amount up to about 2 equivalents of alcohol per equivalent of ester. Larger amounts can be used, but this results in a faster occurrence of alkali or naa-alkali metal due to hydrogen gas. formation. Alternatively, two equivalents or more of alcohol may be added during the post-treatment. Instead of these alcohols, compounds with a pKa between 16 and 35, preferably between 16 and 18, which are not reduced during the process, can be used to supply the first two protons. For example, the ammonia solvent initially produces protons when an additional proton source, such as alcohol, is not added to the reaction mixture until after the post-treatment step.

In the post-treatment step and after the addition of alcohol, 4 equivalents of protons per equivalent of ester are added from a proton source more acidic than hydroxymethylimidazole, such as water, ammonium sulphate, acetic acid or preferably ammonium chloride. Three of these equivalents neutralize two previously formed * 64 35-6 oct: valent alkoxides (or other bases) and one equivalent of the alkoxide formed from the imidazole ester during the reduction. The fourth equivalent provides the final prone equivalent to the hydroxymethylinidazole anion present at this stage.

If imicat soli alcohol is to be isolated as the acid addition salt, the Fifth equivalent of protons must be supplied from a suitable strong acid, / i j p 1 CO Γ 2 v ^ d V s d 3.

The metals used in the method are, for example, alkali metal or - '' Al, such as n at-lithium, potassium, or lithium, or earth alloys such as • o 'oi,: m. however, taking into account economics of series production 1 '' rise, sodium and lithium are the most suitable metals.

"'" io is carried out in the ammonia solution or mixture at boiling temperature i- • v ···· a lvv. below this temperature, suitably between about -25 ° C and about -7'ä-Ö, s opi 7 Lm.rn.ir. between about -35 ° C “about -50 ° C. Alternatively, the reaction may be carried out at a higher temperature under a pressure of liquid ammonia.

In the process of the invention, it is most preferred to dissolve the metal in cross-linked ammonia and to add imidazolecarbon-epoester and alcohol to the solution. Suitably the ester and alcohol are added simultaneously, either separately or premixed, most preferably the alcohol is added immediately after the addition of the ester. The latter procedure is particularly suitable for use in series production. When alcohol is added before the addition of the ester, it is • It is common to use a less acidic alcohol, such as t-butanol, as the game oil may be substituted with lower alkanes such as methanol.

basic reaction mixture aftertreatment by stopping the reaction, for example by adding alcohol, then adding a more acidic source of proton such as ammonium chloride, and evaporating the ammonia to a trap. Filtration and concentration of the mixture by evaporation support the residue containing the b- (hydroxymethyl) imidazine compound of formula II.

Alternatively, the reaction can be stopped by adding water. The b- (hydroxymethyl) imidazole of formula II is then extracted with an alcohol having 3 to 6 carbon atoms, such as n-butanol, n-pentanol or, more preferably, t-butanol. Evaporation of alcohol from extracts.

5 64356 gives a residue containing (hydroxymethyl H 2 -dazclin.

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

4- (Hydroxymethylimidazoles are preferred intermediates for the preparation of pharmacologically active compounds, especially histamine H2 antibodies, for example N-methyl-N '- [2 - ((5-R-4-imidazolyl) methylthio) ethyl] thiourea and N- cyano-N'-methyl-N "- [1 - ((5-R-4-imidazolyl) methyl) ethyl] guanidinium compounds. Histamine F-2 antibodies act on histamine H2 receptors, which, as described in Black et al. (Nature. 1972, 236, 385) can be defined as histamine receptors whose activity is not inhibited by an "antihistamine" such as mepyramine but which is inhibited by burimamide. prevention of activity is beneficial in inhibiting the biological effects of histamine that are not inhibited by “antihistamines.” Histamine H2 antibodies are useful for use, for example, as an inhibitor of gastric acid secretion.

N-methyl-N '- [2 - ((5-R-4-imidazolyl) methylthio) ethyl] thioureas are prepared from 5-R-11- (hydroxymethyl) imidazoles of formula II by reacting the hydroxymethyl compound with cysteamine and its after reacting the formed 5-R (4- (T2-aminoethyl) thiomethyl) imidazole with methyl isothiocyanate.

N-Cyano-N '-methyl-N "- [2 - ((5-R-4-imidazolyl) methylthio) ethyl] guanidines are prepared from 5-R 1 - (hydroxymethyl) imidazoles of formula II by reacting a hydroxymethyl compound with cysteamine. and then reacting the resulting 5-R (4- (T2-aminoethyl) thiomethyl) imidazole with N-cyano-N ', S-dimethylisothiourea, or by reacting 5-H-4- (T2-aminoethyl) thiomethyl / imidazole compound to react dimethyl N-cyano imidodiocarbonate and give the resulting N-cyano-N '- [2 - ((5-R-4-imidazolyl Li-methyl t lo) et yy 1 / - G-methyl 1: i - i 5 otioc ar amide react with methylamine charisma.

6,648,356 These thiourea and cyanoguanidine products prepared from 4- (hydroxymethyl) imidazoles of formula II are not described in British Patent 1,338,169 and U.S. Patents 3,950,333 and 3,950,353.

4- (Hydroxymethyl) imidazoles are preferably used in the form of acid addition salts such as hydrochloride salts in the above processes for the preparation of thiourea and cyanoguanidine compounds.

The following examples illustrate the method of the invention.

The yields reported in the following examples refer to isolated crude products. In all cases, unless otherwise stated, the purity of the products is at least 90%. The main impurity resulting from this process is ammonium chloride, which is usually present in about 1-7% by weight. 5-R-imidazole-4-carboxylic acid is present in an amount of about 1% or less, provided that the most preferred procedures are followed, but may be up to 25 * 50% if the addition of the ester to the alkali metal / calcium ammonia mixture is performed in reverse order. (Example 4). In no case were products resulting from the reduction of the imidazole ring observed.

If it is desired to obtain a very pure product, especially in the presence of large amounts of 5-R-imidazole-4-carboxylic acid, the post-treatment procedure shown in Examples 2 and 4 is most preferred.

Example 1

The 2-liter flask was equipped with a downward stirrer and a nitrogen line, and 600 ml of anhydrous ammonia was introduced. The flask was placed in a dry ice / acetone cooling bath to facilitate ammonia collection and to cool the mixture during the reaction. After the ammonia was collected, sodium (33 g, 1.435 moles) was added portionwise, which dissolved. formed a strong blue color. To the solution was added t-butanol (25 mL, 0.266 mol) and 5-niothyl-4-indidolecarboxylic acid ethyl ester (50 g, 0.32 mol) portionwise. The blue solution of ester 1 i of the blue solution was stirred for 5 minutes, and honey (100 ml) was added dropwise, causing the blue color to disappear after a few milliliters. Ammonium chloride (78 g, 1.458 mol) was added portionwise. The ammonia was evaporated off, 7 64356 isopropanol (700 ml) was added to the residue and the mixture was heated to reflux. while strongly confusing. The mixture was cooled to 00 ° C and acidified (approximately to pH 1) with hydrogen chloride.

Water (10 ml) was added and the mixture was stirred at 5 ° C for 30 minutes. The mixture was filtered and the filter cake was washed with 200 ml of warm (40-50 ° C) isopropanol. The solution was concentrated by evaporation to a volume of 100 ml and diluted with acetone (400 ml) and ether. (100 ml). The product was collected and dried, yielding 46.0 g (96%) of k- (hydroxymethyl) -5 ** methylimidazole hydrochloride.

Example 2

Alternatively, in the process of Example 1, 4- (hydroxymethyl) -5-methylimidazole can be isolated as a base by the following procedure:

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

Example 3 A 12 liter flask was equipped with a downward stirrer and a nitrogen line and was charged with 6 liters of ammonia. The flask was placed in a dry ice / acetone bath to facilitate ammonia collection and to cool the mixture during the reaction. After the ammonia was collected, sodium (335 g, 15.23 moles) was added portionwise, which, when dissolved in ammonia, gave a strongly blue solution. The addition of sodium took about 15 minutes. 5-Methyl-4-imidazolecarboxylic acid ethyl ester (500 g, 3.5 moles) was added to 400 mL of dry ethanol to form a moist powder. This moist powder was carefully added portionwise to the sodium ammonia solution over about 30 minutes. When this addition was complete, 1 liter of methanol was carefully added. Ammonium chloride (810 g, 15.28 moles) was initially added very gently until the blue color disappeared, after which the rest of the ammonium chloride could be added more rapidly. After the addition of ammonium chloride, the ammonia was evaporated using a cold water bath. As the volume of the mixture decreased, the temperature of the bath was raised. When almost all the ammonia was; 8 64356 removed, the mixture was heated with steam in vacuo to remove the last traces of ammonia. Ammonia removal takes 7-15 hours. Isopropanol (6 liters) was added to the residue, and the mixture was 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 cooled to about 10 ° C, acidified with hydrogen chloride gas and filtered. The filter cake was washed with hot isopropanol, and the combined filtrate was concentrated by evaporation to a volume of about 1 liter and diluted with 4 liters of acetone and 2 liters of ethyl ether. The product was collected and dried at 60 ° C in vacuo to give k- (hydroxymethyl) -5-methylimidazole hydrochloride in 97% yield.

Example 4

A suspension of 5-methyl-N-imidazolecarboxylic acid ethyl ester (3.0 g, 0.02 mol) and absolute ethanol (10 ml) was stirred at ice-cold ice temperature in a 200 ml dry flask equipped with a carbon dioxide deicer while -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 first clarified, then the blue color remained for one minute and finally the solution became cloudy. This required 2.2-2.7 g of sodium. The reaction took 20-30 minutes.

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

The alcohol layer was evaporated. The 4- (hydroxymethyl) -p-methylimidazole contained in the residue was converted to the hydrochloride salt by treatment with ether and isopropanol and passing hydrogen chloride gas into the cooled solution. 4- (Hydroxymethyl) -5-methylimidazole hydrochloride (1.6 g, 55%) was isolated by filtration.

9 6455 6

Example 5 A 1 liter flask equipped with a downward stirrer and a nitrogen line was charged with 300 mL of anhydrous ammonia. Potassium (26.0 g, 0.66 mol), t-butanol (12.5 mL, 0.122 mol) were added followed by 5-methyl-1-imidazolecarboxylic acid ethyl ester (25.0 g, 0.16 mol). in doses over 20 minutes. The reaction mixture was stirred for 5 minutes, after which the reaction was quenched with 50 mL of methanol. Ammonium chloride (4c, 0 g, 0.7h mol) and isopropanol (400 ml) were added and the ammonia was removed by distillation. Hydrogen chloride gas was bubbled into the mixture until the pH was approximately 1, and the solids were separated by filtration. The filtrate was concentrated by evaporation to a volume of 60 ml and acetone (300 ml) was added. The product was collected by filtration and dried to give α4 g (98%) of 4- (hydroxymethyl) -5-methylimidazole hydrochloride.

Example__6 700 ml of anhydrous ammonia were introduced into a 2-liter flask equipped with a downwardly directed seciter and a nitrogen conduit. Calcium (29.0 g, 0.723 mol) was carefully added portionwise, t-butanol (25 ml, 0.266 mol) was added in one portion and 5-methyl-4-imidazolecarboxylic 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 introduced into the mixture (until the pH was about 1) and the solids were filtered off. The filtrate was concentrated by evaporation to a volume of 100 ml and acetone (500 ml) was added. The product was collected and dried to give 4-hydroxymethyl-5-methylimidazole hydrochloride (23.0 g, 65% purity, 30% yield).

Example_7 A 2 liter flask was equipped with a nitrogen line and a downward stirrer. While cooling the flask with a dry ice / acetone bath, about 500 mL of liquefied ammonia was collected in the flask. Lithium metal (6.3 g, 0.895 mol, excess about 25%) was dissolved in liquefied ammonia to give a blue solution. With continuous cooling and stirring, 5-methyl-4-imidazolecarbonic acid ethyl ester (27.58 g, 0.179 mol) was added in very small portions. After addition of the ester, the reactant which remained blue was stirred for 5 minutes. The reaction in the blue solution was quenched by dropwise addition of 60 ml of methanol. Oxalic acid powder (41 g, 0.45 mol) was then carefully added. The ammonia was evaporated on a hot water bath to give a thick slurry which was stirred in 500 ml of isopropanol. The mixture was heated at 60-75 ° C for 1/2 hour and cooled before filtration. The filtrate was acidified to pH 1 with hydrogen chloride gas and refiltered. This second filtrate was concentrated by evaporation to a thick slurry and diluted with acetone. The product was collected and dried to give 20.7 g (78%) of 4- (hydroxymethyl) -R-methylinidazole hydrochloride.

Example 8 A 5 liter flask was equipped with a downward stirrer and purged with nitrogen. 2.7 liters of anhydrous liquefied ammonia were introduced into the flask without external cooling. After the ammonia was collected, sodium (112 g, 4.87 moles) was added in small portions. After the sodium had dissolved, slow stirring was initiated, and 5-methyl-t-imidazolecarboxylic acid ethyl ester (150 g, 0.974 mol, as 0.5 g tablets) was added in 2 g portions at 25-30 second intervals. The temperature remained at approximately -28 ° C during this run. After the addition of the ester, the solution retained its siren color. 300 ml of methanol was carefully added dropwise to the hedgehog to remove its color (unless the blue color disappears after the addition of methanol, stirring must be continued until this occurs). After methanol, ammonium chloride (265 g, 4.97 moles, or about 2% more than the molar amount of sodium) was carefully added portionwise. After the addition of ammonium chloride, the ammonia was evaporated to form a thick slurry. The temperature of the walls of the reaction vessel must 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 a pH of about 1) and 30 ml of water was added. The mixture was stirred for 15 minutes and cooled to 40-50 ° C and filtered. The residue was washed with warm 1-n-propanol (2 x 300 mL). The filter cake was concentrated to near dryness (thick slurry) and diluted with acetone (ca. 1.5 L). The product was collected and dried to give 125.8 g (87%) of (hydroxymethyl) -5-methylimidazole hydrochloride.

Example 9 A 5 liter flask was equipped with a downward stirrer and purged with nitrogen. It was charged with 2.3 liters of anhydrous liquefied ammonia without the use of external cooling. After collection of ammonia, sodium (97 g, 4.22 mol, molar excess 25%) was added portionwise. After the sodium had dissolved, stirring was started and 5-methyl-4-imidazolecarboxylic acid ethyl ester (130 g, 0.844 mol, as 0.5 g tablets) was added in 2 g portions at intervals of about 30 seconds. After addition of the ester, the blue solution was stirred for 5 minutes. n-propanol (260 mL) was carefully added dropwise to remove the blue color (unless the blue color disappears with the addition of n-propanol, stirring must be continued until the color disappears). Ammonium chloride (232 g, 34 moles, or about 2% more than the molar amount of sodium) was carefully added portionwise over 20-30 minutes. The resulting ammonia mixture was evaporated to a thick slurry. The temperature of the walls of the reaction vessel must not exceed 50 ° C. N-Propanol (2.0 liters) was then added and the mixture was heated to reflux for about 10 minutes to drive off most of the remaining ammonia. The mixture was acidified to about pH 1 with concentrated hydrochloric acid and stirred for 15 minutes while cooling to about 40 ° C. The mixture was filtered and the filter cake was washed with 2 x 300 mL of warm (ca. 40 ° C) n-propanol. The filtrate was concentrated by evaporation under reduced pressure to a volume of 300 ml, and the mixture was allowed to stand at about 2 ° 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 liquefied ammonia was collected in a 1 liter 3-necked flask equipped with a nitrogen conduit and a downward stirrer. Under a nitrogen atmosphere, 18 g of sodium metal was dissolved in liquefied ammonia, and 30.2 g of 5-methyl-4-imidazolecarboxylic acid ethyl ester was added in small portions over 25 minutes. The reaction mixture remained light blue in color. 43.4 g of ammonium chloride were carefully added in small portions until the blue color disappeared. The addition rate was increased so that the ammonia was heated to reflux. 400 ml of isopropanol were then added and the mixture was heated to reflux for 1 1/2 hours. The suspension was cooled, acidified with hydrogen chloride gas and filtered. The filtrate was concentrated by evaporation to a thick slurry which was diluted with acetone. The product was dried in a vacuum oven to give 23.2 g of 4- (hydroxymethyl) -5-methylimidazole hydrochloride.

Claims (1)

A process for preparing a 4- (hydroxymethyl) imidazole compound or an acid addition salt thereof having the formula R / CH 0 OH w HN 2 N wherein R is hydrogen or C 1-4 alkyl by reducing a 4-imidazolecarboxylic acid alkyl ester of the formula R COOR 'W HN NX wherein R is the same as above and R' is lower alkyl, characterized in that the reduction is carried out using an alkali metal or calcium in liquid ammonia and in the presence of an additional proton source added during the reaction or work-up, followed by 4- ( hydroxymethyl) imidazole is optionally isolated as the acid addition salt. For the preparation of 4- (hydroxymethyl) imidazole derivatives or cyanide residues, the formation of which is in the form of R CH-OH X HN ^^ N i vilken R is a betkyl or C 1-4 alkyl, the genome being reduced by 4-imidazolecarboxylic acid formula R COOR 'X HN N 1 vilken R betecnar decamma som ovan och R' är en lägre alkyl, kännetecknat av att reductionen utförst använd-Ning av en alkalimetal or calcium or flytande ammoniak similar