CA1064940A - Reduction process for the preparation of 4-(hydroxymethyl) imidazole compounds - Google Patents

Reduction process for the preparation of 4-(hydroxymethyl) imidazole compounds

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Publication number
CA1064940A
CA1064940A CA256,981A CA256981A CA1064940A CA 1064940 A CA1064940 A CA 1064940A CA 256981 A CA256981 A CA 256981A CA 1064940 A CA1064940 A CA 1064940A
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added
hydroxymethyl
methyl
ammonia
ester
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French (fr)
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Wilford L. Mendelson
Elvin L. Anderson
George R. Wellman
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GlaxoSmithKline Inc
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Smith Kline and French Canada Ltd
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Priority claimed from US05/690,476 external-priority patent/US4063023A/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Steroid Compounds (AREA)

Abstract

ABSTRACT

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

41[~

This invention relates to an improYed process for the preparation o~ 4-(hydroxymethyl~imidazole compounds by reducing 4-imidazolecarboxylic acid est-exs using an alkali metal or calcium in liquid ammonia with an additional proton source provided during the reaction or upon workup~
4-(Hydroxymethyl)imidazole compounds may be prepaxed by reducing 4-imidazolecarboxylic acid esters using lithium aluminum hydride. This process is expensive, particularly for large scale preparation of 4-(,hydroxymethyl)imidazoles.
Tamamushi~ J. Pharm~ Soc. ~apan 53; 664-8 (1933~, C.A. 28:20049 (1934), reported that attempts to reduce
2-methylimidazole-4,5-dicarboxylic acid and ester thereo~
by various methods were unsuccessful. ~ith th.e 5-monochloride, reduction with Sn and HCl gave 2-methyl-5-h.ydroxymethylimid-azole-4-carboxylic acid.
It is known to the art that heterocyclic ring systems may be reduced by metals in liquid ammonia via a Birch type reaction. For example, Remers et al., J. Amex, Chem. Soc.
89:5513-4 (,1967) report that indole and quinoline rings are reduced using lithium and methanol in liquid ammonia~ ~lso, O'Brien et al., J. Chem. Soc. 4609-4611 (1960) report that indole and carbazole, but not pyrrole, rings can be reduced by metals in liquid ammonia in the presence o alcohol.
~ccording to the process o~ this invention, the carboxylic acid ester group o a 4-imidazolecarboxylic acid ester is selectively reduced to hydroxymethyl without reducing the imidazole ring by using an alkali metal or calcium in liquid ammonia and an additional proton source~

1 ~0~ 4~
rne process or this invention is advantageous, partlcularly ~ th the preferred alkali meta~s, i.e.
sodium, poLassium and lithium, because the ma~erials used in the red~ction of ~he imidazolecarbo~lic acid esters are inexpensive and high yields o the hydroxy-methylimidazoles are obtained in a high degree of purity, i.e. at leas~ 90% pure.
The process of this invention may be represented as follows:
R COOR' R C'H20X
~< ~
HN ~ N ) HN~N

Formula I Formula II

in which R is hydro~en or lower alkyl of l to 4 carbon atoms, preferabLy methyl, and R' i9 lower alkyl o~ l to 4 carbon atoms, preerably methyl or ethyl.
According to the above process, a lower allxyl eqter o~ a 4-imidazolecarbo~lic acid i9 reduced using an alkali metal or calcium in liquid ammonia with an additional proton source to give a 4-(hydroxymethyl)-imidazole. Preerably, an alkali metal is used, most preferably sodium or lithium. Four equivalents of the alkali metal or ~wo equivalen~s o calcium are required for each equivalent o the ester. Preferably, a slight e.~cess o~ four equivalents of the allcali metal or a slight excess o~ two equivalen~s o calcium is present.
The partlcular ester of the 4-imidazole-carbox~Jlic acid used is not critical to applicants' process. The lower alkyl esters are advantageous because ~)64~4L3 the alcohols from which they are derived are inexpensive. How-ever, other esters, for examplé substituted alkyl or aryl esters, such as a benzyl 4-imidazolecarboxylate, may be used alternatively but with little advantage.
A proton source, as required in the process of this invention, is a substance which yields a hydrogen ion. A
total of three equivalents of protons per equivalent of ester needs to be provided in order to isolate the free hydroxy-methylimidazole compound. They may be provided during the reaction, during the workup or a combination o~ both. The additional proton sources used in the process of this invent-ion are, most conveniently, commercially available substances.
An alcohol such as, preferably, a lower alkanol containing 1-6, most preferably 2-4, carbon atoms or a cycloalkanol containing, preferably, 5-6 carbon atoms is most conveniently used to provide two of the necessary three equivalents o~ protons. It may be present in the reaction mixture in any amount up to about two e~uivalents of alcohol per equivalent of ester. Greater amounts can be used but cause faster loss of the alkali or alkali earth metal due to foxmation of hydrogen gas. Alternatively, two equivalents or more of the alcohol may be added during the workup. In place of these alcohols, compounds with a pKa in the range of 16-35, preferably 16-18, which are not reduced in the process may be used to supply the initial two protons. For example, the solvent ammonia initially supplies protons when an additional proton source such as an alcohol is not added until the work-up phase.
In the workup and ater the alcohol addition, four equivalents of protons per equivalent of ester are added from a proton source more acidic than hydroxymethylimidazole such .~' , L9~(~

as water, ammonium sulfate, acetic acid or preferably ammonium chloride. Three of these equivalents serve to neutralize the kwo previously formed equivalents of alkoxide (or other base) plus the one equivalent of alkoxide formed from the imidazole ester during the reduction. The fourth equivalent supplies the last equivalent of protons to the hydroxymethylimidazole anion present at that point. If it is desired to isolate the imidazole alcohol as the acid addition salt, a fifth equivalent of protons must be provided from a sui~ably strong acid such as hydrogen chloride.
Metals used in this process are, for example, alkali metals, such as sodium, potassium or lithium, or an alkali earth metal, such as calcium. However, from the standpoint of economy for large scale work and ease of handling the process, sodium or lithium is preferable.
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 about -25C. to -70C., prefer-ably about -35C. to -50C. Alternatively, the reaction may 2 a be carried out at a higher temperature under pressure at which the ammonia is liquid.
It is preferable in the process of this invention - to dissolve the metal in li~uid ammonia and to add to that solution the imidazolecarboxylic acid ester and an alcohol.
Preferably,the ester and the alcohol are added simultaneously either separately or previously mixed; or most conveniently, the alcohol is added, followed immediately by the ester.
The last method is particularly convenient for large scale work. When the alcohol is added first followed by the ester, it is preferable to use a less acidic alcohol, such as t-butanol, n-butanol or isopropanol, rather than a lower alkanol such as methanol.
Preferably, the alkaline reaction mixture is worked up by quenching the reaction, for example by adding an alcohol, then adding the more acidic proton source such as ammonium chloride, ~hen evaporating the ammonia. Filtration and concentration give a residue which contains the 4-(hydroxy-methyl)imidazole compound of Formula II.
Alter~atively, the reaction may be quenched by adding water. Then the 4-~hydxoxymethyl) imidazole of Formula II is extracted with an alcohol having 3 to 6 carbon atoms such as n-butanol, n-pentanol or preferably t-butanol.
Evaporation of the alcohol from the extracts gives a residue which contains the 4-(hydroxymethyl)-imidazole.
The 4-(hydroxymethyl)imidazole compound is preferably isolated as an acid addition salt, preferably the hydrochloride salt, by treating with an acid during the workup, for example by treating with hydrogen chloride, and crystallizing from a suitable solvent~such as isopropanal or preferably ~rom a solvent mixture such as isopropanol/acetone/ethyl ether.
The 4-~hydroxymethyl)imidazoles are useful as inter-mediates for the production of pharmacologically active compounds, in particular histamine H2-antagonists r for example N-methyl-N'-[2-~5 R-4-~mid~zolyl)methylthio)-ethyl] thiourea and N-cyano-N'-methyl-N"-[2-((5-R-4-imidazolyl)methylthio)ethyl]
guanidine compounds. Histamine H2-antagonists act at hista-mine H2-receptors which as described by Black et al. (Nature, 1972,236, 385) may.be defined as those histamine receptors 34~

which are not blocked by "antihistamines" such as mepyramine but are blocked by burimamide. Blockade of histamine H2-receptors is o~ utility in inhibiting the biological actions of histamine which are not inhibited by "antihistamines"O
Histamine H2-antagonists are useful, for example, as inhibitors of gastric acid secretion.
N-Methyl-N'-~2-((5-R-4-imidazolyl)methylthio~-ethyl]
thioureas are prepared from the 5-R-4-(hydroxymethyl)-imidazoles of Formula II by reacting the hydroxymethyl com-pound with cysteamine and then reacting the resulting 5-R-4-~(2-aminoethyl)thiomethyl]imidazole with methyl isothiocyanate.
N-Cyano-N'-methyl-N"-[2-((5-R-4-imidazolyl)-methylthio) ethyl]guanidines are prepared from the 5-R-4-~hydroxymethyl) imidazoles of Formula II by reacting the hydroxymethyl compound with cysteamine and then reacting the resulting 5-R-4-[(2-aminoethyl)thiomethyl]imidazole with N-cyano-N', S-dimethylisothiourea or by reacting the 5-R-4-[(2-aminoethyl) thiomethyl]imidazole compound with dimethyl-N-cyanoimidodi-thiocarbonate and reacting the resulting N-cyano-N'-[2-((5-R-4-imidazolyllmethylthio)-ethyll-S-methylisothiourea with methylamine.
These thiourea and cyano~uanidine products prepared ~rom the 4-(hydroxymethyl)imidazoles of Formula II are described in British Patent 1,338,169 and U.S. Patents
3,950,333 and 3,950,353~
I'he 4-(hydroxymethyl)imidazoles are used preferably in the form o~ acid addition salts such as hydrochloride salts in the above procedures to prepare the thiourea and cyanoguanidine compounds.

1~6~ 0 The followiny examples are not limiting but are illustrative of the process of this invention.
In the following examples the yields reported are of the crude isolated products. In each case, except as noted, the product is at least 90~ pure. The major impurity present from this procedure is ammonium chloride which is usually present to the extent of about 1 to 7%
by weight. 5-R-imidazole-4-carboxylic acid is present to the extent of about 1% or less providing the preferred procedures are followed but can reach 25-50~ if the order of addition of ester to alkali metal/calcium-ammonia is reversed tExample 4). In no case were products resulting from reduction of the imidazole ring found.
When it is desired to obtain a product of the highest purity, especially when large amounts of 5-R-imidazole-
4-carboxylic acid are present, the workup procedure outlined in Examples 2 and 4 is preferable.
EX~MPLE 1 A 2 liter flask was fitted with an overhead stirrer and a nitrogen inlet and charged with 600 ml. of anhydrous ammmonla. A dry-ice acetone cooling bath was provided to aid the collection of ammonia and to cool the reaction~ ~fter the ammonia was colleated, sodium (33 g., 1.435 m.) was added in portions and dissolved giving a deep blue color. k-Butanol (25 ml., 0.266 m.) was added to this solution. 5-Methyl-4-imidazole-carboxylic acid ethyl ester (50 g., 0.32 m.) was added portionwise.
After addition of the ester, the blue solution was stirred for five minutes and methanol (100 ml.) was added dropwise causing the blue color to be discharged after a few ml.
had been added. Ammonium chloride (78 g., 1.458 m.) was , . , .

-added in portions. The ammonia was evaporated and isoprop-anol (700 ml.) was added to the residue and the mixture was refluxed for 30 minutes with vigorous stirring. The mixture was cooled at 40C. and acidified (pH about 1) with hydrogen chloride gas. Water (10 ml.) was added and the mixture stirred at 50C. for 30 minutes. The mixture was filtered and the filter cake washed with 200 ml. of warm (40-50C.) isopropanol. The solution was concentrated 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.

Alternatively, in the procedure of E~ample 1, the 4-(hydroxymethyl)-5-methylimidazole may be isolated as the base by the following method:
After the ammonia is removed by evaporakion in the procedure of Example 1, isopropanol (700 ml.) is added to the residue and re1uxed for 30 minutes with vigorous stirring, the resulting mixture is filtered and the isopropanol removed by evaporating in vacuo to give 4-(hydroxymethyl)-5-methylimidazole as the residue.

A 12 liter flask was ikted with an overhead stirrer and nitrogen inlek and charged with 6 liters of ammonia. A dry-ice acetone cooling bath was provided to aid in the collection of ammonia and to provide cooling during the reaction. After the ammonia was collected, sodium (335 g., 15.23 m.) was added in portions and dissolved in the ammonia giving a deep blue solution.
The addition of sodium required about 15 minutes.

_ g _
5~ e~hyl-4-imidazolecarbo.~ylic acid ethyl ester (500 g., 3.25 m.) was added to 400 ml. of dry ethanol giving a wet po~der. ~his wet po~der was added portior.~ise with caution to the sodium-am~onia solution over a period of about 30 minutes. After the addition was completed, one liter of methanol was added carefully. Ammonium chloride (810 g., 15.28 m.~ was added very cautiously until the blue color was discharged whereupon the remaining ammoniwm chloride could be added more rapidly.
After the addition of the ammonium c'nloride, the ammonia was evaporated using a cold water heating bath. As ~he volume of the mixture decreased, the heating bath was made warmer. When nearly all the ammonia was gone, the mi~ture was heated with steam under a vacuum to remove the last traces o~ ammonia. The removal o~ ammonia requires 7-15 hours. Isopropanol t6 liters) was added to the residue and reflu~ed for one hour with vigorous stirring, Water (100 ml.) was then added and the stirring continued for 10 minutes. The mixture was then cooled to about 40C~.
and acidified with 'nydrogen chloride gas and ~iltered. The filter cake was washed with hot isopropanol and the combined ~iltrate concentra~ed to about one liter and diluted with 4 liters of acetone and 2 liters of e~hyl ether, The product was collected and dried at 60C. under vacuum to g~ve 4-(hydroxymethyl)-5-~ethylimidazole hydrochloride, yield 97%.
E~A~LE 4 A suspension of 5-methyl-4-imidazolecarbo~ylic acid ethyl ester (3.0 g., 0.02 m.) and absolute ethanol (10 ml.) was stirred at dry-ice te~perature in a dry 200 ml. flask equipped with a dry-ice condenser as -~0-80 m1. OL ammonia was added. (Alternatively 10 ml.
or t-butanol m2y be used in place of ethanol.) Sm~ll pieces o sodium (rrom .sylene) ~7ere added over 15-20 minutes. The solutlon became clear during the addition, then a blue color persisted ~or one minute and ~he solution became clouded. This required 2.2-2.7 g, o~
sodium. The reaction required 20-30 minutes.
The ammonia was allowed to evaporate and water (50 ml,) and solid sodium chloride were added. rne aqueous solution was e~stracted with several 40 ml~ portions of t-bu~anol, Sodium chloride was added durin~ the course OL
the extraction.
The alcohol layer was evaporated. The 4-(hydroxy-methyl)-5-methylimidazole which was present ln ~he residue was converted to the hydrochloride salt by ~reating with ether and isopropanol and passing hydrogen chloride gas into the chilled solution. The 4-(hydro~ymethyl)-5-methylimidazole hydrochloride (1.6 g., 55%) was isolated by filtration.

By the procedure o E:cample 1, using in place o~
5-methyl-4-imidazolecarboxylic acid ethyl ester, the ethyl ester o~ 4-imidazolecarboxylic acid~ the product is 4-(hydro:~ymethyl)imidazole.
Also~ reducing 5-ethyl-4-im~dazolecarbo}sylic acid ethyl ester by .he procedure o~ ~xample 1 gives 5~ethyl-4-(hydroJsymethyl)imidazole and reducing 5-isopropyl-4-imidazolecarboxylic ac~d eLhyl ester by .he same procedure gives 4-(hydro~Jmethyl)-5-lsopropyl-3~
imidazole.

A liter flask, ~itted with an ovexhe~d stirxer and a nitrogen inlet, was charged with 300 ml~ of anh~drous ammonia. Potassium (26.0 g., 0.66 m.) was~ added. t-Butanol (12.5 ml., 122 m.) was added, then 5-meth~1-4 imidazole-carboxylic acid ethyl ester ~25.0 g., 0.16 m.) was added portionwise over 20 minutes. The reaction mixture was stirred for fi~e minutes then quenched ~ith 50 ml. of methanol. Ammonium chloride (40.0 ~., 0.74 m.~ and isopropanol (400 ml.) were added and ammonia removed b~
distillation. Hydrogen chloride gas was added to about pH 1 and the solids filtered off. The filtxate was concentrated 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)-5-1nethylimidazole hydrochloride.

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 m.~ was added carefully in portions. t-Butanol (25 ml., 0.266 m.~ was added in one portion and 5-methyl-4-imidazolec~rboxylic acid ethyl es~er (50 g., 0.32 m.) was added in portions over 30 minutes. The blue solution was stirred ~or 40 minutes and methanol (120 ml.) added dropwise. Ammonium chloride ~80.0 g., 1.48 m.) and isopropanol (800 ml.) were added and the ammonia removed. Hydrogen chloxide gas was added (pH about 1) and the solids filtered off.
The filtrate was concentrated to 100 ml. and acetone (500 ml.) was added. The product was collected and dried to give 4-hydroxymethyl-5-methylimidazole hydro-chloride (23.0 g. of 65% pure material; yield 30%).

l ~6 ~
EXA~PLE 8 A 2 liter flas7~ was ~ltted with a ni~rogen inlet and an o~Jerhead stirrer. IJi~h the cooling o~ a dry ice-acetone bath, appro2i~tely 50~ ml. of liquid a~onia was collected in the flasLc. Lithium metal (6.3 g., 0.895 m., about 25% excess) was dissolved in liquid a~monia to form a blue solution. With continuous cooling and stirring, 5-methyl-4-imidazolecarbo~ylic acid ethyl ester (27.58 g., 0.179 mole) ~as added in very small portions~ After the ester was added, the reaction solution remaIned blue and was stirred ~cr five minutes. The blue solution was quenched by addi~g dropwise 60 ml. o~ methanol. ~nen, oxalic acid powder (41 g., 0.45 mole) was added with caution. Ammonia was evaporated on a hot water bath to obtain a th~ck slurry which was taken up in 500 ml. o isopropanol. rne mi~ture was heated for 1/2 hour at ~0-75C. and cooled before filtering. The filtrate was acid~ied to pH 1 w~th hydrogen chloride ga3 and ~iltered again. This second iltrate was concentrated to a thick slurry and diluted with acetone. The product was collected and dried to ~ive 20.7 g. (78%) of 4-(hydro~ymethyl)~5-methylimidazole hydrochloride.
E~AME LE 9~

A S liter 1ask was ~itted with an overhead stirrer and flushed ~ith nitro~en. T'ne vessel was charged with 2.7 liters o$ anhydrous liquid ammonia without e~ternal cooling. After ammonia was collected, sodium (112 g., 4.87 moles) was added in small por~ions. A ter the sodium had dissolved, slaw stirring ~as started and 5-methyl-4-imidazolecarboxylic acid ethyl ester (150 g., 0.974 m., ~ormulated as 0.5 g. tablets) was added in l ~O~ 4~ 4~
2 g~ portions at 25-30 second intervals. rl~e temperature sta~Jed around -28C. during this addition.
~ft2r the addition of tne ester, t'ne solution remained blue in color. ~ethanol, 300 ml., was cautiously added dropwise to quench the blue color (if the olue color does not discharge after the methanol addition, the stirring should be continued until ~t does)O Following the methanol addition, ammonium chloride (265 g., 4.97 m.
about 2% excess of molar sodium) was added portionwise with caution. Following the addition of ammonium chloride, ammonia was evaporated to give a thic~ slurry. The temperature of the walls of the vessel should not exceed 50C. Isopropanol (2.1 liters) was added and the mixture was vigorously agitated while warming the mixture to 75C.
The mixture was then acidified with hydrogen chloride gas (to pH about 1) and 30 ml. of water was added. The mi~ture was stirred ~or lS minutes and cooled to 40-50C. and iltered. The residue was washed with warm isopropanol (2 x 300 ml.). The filtrate and washing was concentrated ~0 to near dryness (thick slurry) and diluted with acetone ~about 1.5 liters). The product was collected and dried to give 125.8 g. (87%) o 4-{hydroxymetnyl)-S-methylimldazole hydrochloride.
E~ ~LE 10 A 5 liter flask was itted with an overhead stirrer and flushed with nitrogen. The vessel was charged wlth 2.3 L. of anhydrous liquid ammonia wlthout e~ternal cooling. Aftar the ammonia was collected, sodium ~97 g., 4.22 m., 25% molar e}~cess) ~as added in portlons. r,~hen th~ sodium was dissolved, stirring was started and o 5-methyl-4-imidazolecarboxylic acid ethyl ester (130 g., 0.844 m. and formulated as 0.5 g. tablets) was added in 2 g. portions at about 30 sec. intervals.
Following the addition o~ the ester, the blue solution was stirred for five minutes. n-Propanol (260 ml.) was cautiously added dropwise to discharge the blue color (if the blue color does not discharge during the n-propanol addition, the stirring should be continued until it does), Ammonium chloride (232 g., 4.34 m., a 2% excess of molar ~odium) was added portionwise over 20-30 minutes with caution. The resulting am~onia mixture was evaporated to a thick slurry. The walls o~ the vessel should not exc2ed 50C. n-Propanol (2.0 L.) was then added and the mixture heated to re1ux ~or about 10 minutes to drive off most of the remaining ammonia. rne miæture was acidified to pH about L wi~h concentrated hydrochloric acid and stirred for 15 minutes while being cooled to about 40C. The mixture was filtered and the cake washed with 2 x 300 ml. warm (about 4QC.) n-propanol.
The filtrate was concentrated under reduced pressure to 300 ml, and the mixture allowed to stand at about 20C.
for 12 hours. ~he product was collected and dried to give 90,0 g, (72%) o~ 4-~hydroxyme~hyl)-5-methylimidazole hydrochloride.
EXA~LE 11 Liquid ammonia, 600 ml., was collected in a 1 liter 3-nec~ lask equipped ~ith nitrogen inlet and overhead stirrer. Under ni~rogen, 13 g. o~ sodium metal was dissolved in the liquid ammonia and 30.2 g. or 5-methyl-4-imidazolecarboxylie acid ethyl es~er was added -lS-in s~ll ?ortions over 25 minutesO The reaction mixture remair.ed light blue. Ammoni~m chloride, 43.4 g., was added in small portions carefully until the blue color disap~eared.
The rate of addition was increased so that the ammonia was re~lusing. At the end OL the addition, 400 ml. or isopropanol was added and the mixture was refluxed for 1.5 hours. The suspension was cooled and acidifed with hydrogen chloride gas and filtered. The filtrate was concentrated to a slurry and diluted with acetone. rQe product was dried in a vacuum oven to give 23.2 g.-of 4-(hydroxymethyl)-5-methylimidazole hydrochloride.
E~MPLE 12 A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochLoride (23.~ g.) in acetic acid (200 ml.) was heated under reflu;c ~or 10 hours. FoLlowing cooling to 15~20C., the solid which crystallized was collected and washed with isopropyl alco'nol to give 4-methyl-5-~(2-aminoethyl)thiomethyl]-imidazole dihydrochloride, m.p. 189-lg2C.
Potassium carbonate (7.75 g.) was added to a solution of 4-methyl-5-~(2-aminoeth~l)thiometllyl]imidazoLe dihydrochloride (14.6 g.) in water (120 ml.). ~he solution wa~ stored at room temperature or lS minutes and methyl isothiocyanate (5.15 g.) was added. After heating under reflux for 30 minutes, the solution was slowly cooled to 5C. The product was collected and recrystallized from water to give N-methyl-N'-~2-((5-methyl-4-imidazolyl)-methylthio)ethyl]Lhiourea, m.p. 1;0-152C.

- - -EXAMPL~ 13 (a) A solution of 4-methyl-5-[(2-aminoethyl)-thio-methyl]imidazole (17.0 g.) and N-cyano-N', S-dimethyl-isothiourea (11.2 g.) in acetonitrile (500 ml.) was heated under reflux for 24 hours. Following concentration, the residue was chromatographed on a column of silica gel with acetonitrile as eluant and the product obtained was finally recrystallized from acetonitrile-ether to yield N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl~-guanidine, m.p. 141-142C.
(b) A solution of 4-methyl-5-[(2-aminoethyl)-thiomethyl]imidazole (23.4 g.) in ethanol was added slowly to a solution of dimethyl-N-cyanoimidodithiocarbonate (20.0 g.) in ethanol, with stirrin~ at room temperature.
The mixture was set aside overnight at room temperature.
Filtration af~orded N-cyano-N'-~2-((5-methyl-4-imidazolyl)-methylthio)ethyl]-S-methylisothiourea, m.p. 148-150C.
The filtrate was concentrated under reduced pressure and the mixture was triturated with cold water and the solid 20~ obtained, filtered off and recrystallized twice from isopropyl alcohol/ether to yield further product, m.p.
148-150C~
A solution of methylamine in ethanol (33~, 75 ml.) was added to a solution of N-cyano-N'-~2-((5-methyl-4-imidazolyl)methylthio)ethyl]-S-methylisothiourea (10.1 g.) in ethanol (30 ml.). The reaction mixture was set aside at room temperature for 2.5 hours. Following concentration under reduced pressure, the residue was recrystallized twice ~rom isopropyl alcohol/petroleum ether, affordin~

N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)-ethyl]guanidine, m.p. 141-143C.

Claims (11)

What is claimed is:
1. A process for the preparation of a 4-(hydroxymethyl)imidazole compound of the formula:

in which R is hydrogen or lower alkyl, which comprises reducing a 4-imidazolecarboxylic acid ester of the formula:
in which R is as defined above and R' is lower alkyl, using an alkali metal or calcium in liquid ammonia with an additional proton source.
2. A process of claim 1 in which the additional proton source is present during the reaction of the ester with the alkali metal or calcium and liquid ammonia.
3. A process of claim 1 in which the 4-(hydroxymethyl)imidazole is isolated as an acid addition salt.
4. A process of claim 1 in which sodium in liquid ammonia is used and the additional proton source is a lower alkanol or cycloalkanol.
5. A process of claim 4 in which 5-methyl-4-imidazolecarboxylic acid lower alkyl ester and a lower alkanol are added to sodium in liquid ammonia.
6. A process of claim 1 in which at least four equivalents of the alkali metal or two equivalents of calcium are present for each equivalent of the 4-imidazolecarboxylic acid ester.
7. A process of claim 1 in which an alkali metal is used.
8. A process of claim 7 in which the alkali metal is sodium.
9. A process of claim 1 in which R is methyl.
10. A process of claim 9 in which R' is methyl or ethyl.
11. A process of claim 10 in which sodium in liquid ammonia is used and the additional proton source is a lower alkanol or cycloalkanol.
CA256,981A 1975-08-20 1976-07-14 Reduction process for the preparation of 4-(hydroxymethyl) imidazole compounds Expired CA1064940A (en)

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NZ184893A (en) * 1976-09-21 1980-11-28 Smith Kline French Lab Pure crystalline form of cimetidine a(n-methyl-n-cyano-n-(-2-(5-methyl-4imidazolyl) methylthio) ethyl)-guanidine andpharmaceutical compositions containing it
DE2800148A1 (en) 1978-01-03 1979-07-12 Basf Ag PROCESS FOR THE PRODUCTION OF 4-METHYL-5-CHLOROMETHYL-IMIDAZOLE
DE2825547A1 (en) * 1978-06-10 1979-12-20 Basf Ag 1-HYDROXYMETHYLIMIDAZOLE AND ITS USE AS CHEMICAL INTERMEDIATES
JPS5914460B2 (en) * 1978-12-27 1984-04-04 相互薬工株式会社 Production method of cimetidine, an anti-H↓2 receptor
JPS63117318U (en) * 1987-01-24 1988-07-29
JPH0619559U (en) * 1992-03-16 1994-03-15 加藤 利夫 toothbrush

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NL183581C (en) 1988-12-01
PT65369A (en) 1976-08-01
DD126871A5 (en) 1977-08-17
DK143749B (en) 1981-10-05
NO145072C (en) 1982-01-06
GB1562811A (en) 1980-03-19
GR61130B (en) 1978-09-15
FI64356B (en) 1983-07-29
IL50147A (en) 1980-11-30
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AU1703976A (en) 1978-02-23
DE2637670A1 (en) 1977-03-03
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ATA606376A (en) 1980-02-15
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FR2321490B1 (en) 1978-05-05
SE415097B (en) 1980-09-08
JPS5225770A (en) 1977-02-25
IL50147A0 (en) 1976-09-30
IE44020L (en) 1977-02-20
RO72826A (en) 1982-09-09
PH13166A (en) 1980-01-08
PT65369B (en) 1978-01-10
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AT358574B (en) 1980-09-25
YU191376A (en) 1982-08-31
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FI64356C (en) 1983-11-10
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