GB1582865A

GB1582865A - Process for preparing 4-substituted imidazole compounds

Info

Publication number: GB1582865A
Application number: GB17561/77A
Authority: GB
Original assignee: SmithKline Corp
Current assignee: GlaxoSmithKline LLC
Priority date: 1977-02-22
Filing date: 1977-04-27
Publication date: 1981-01-14
Also published as: IL51898A0; PT66446A; NL7704617A; AT355015B; FR2381031A2; SE442199B; IL51898A; DE2718715A1; CH631168A5; HU174840B; NO152903C; SE452887B; DK168277A; FI771291A; FI73208B; SE7704870L; IE45035L; FI73208C; ATA289577A; PT66446B

Abstract

The imidazole compounds of the general formula II represent valuable intermediates for preparing pharmacologically active compounds. They are obtained by reacting a compound of the formula I in an organic solvent under basic conditions with a compound of formula R<2>-H. The symbols used in the general formulae I and II are defined in Claim 1. <IMAGE>

Description

(54) PROCESS FOR PREPARING 4-SUBSTITUTED IMIDAZOLE COMPOUNDS (711) We, SMIITHKLINE COR- POTATION, of 1500 Spring Garden Street, City of Philadelphia, Commonwealth of Pennsylvania 19101, United States of America, a corporation organized under the laws of the Commonwealth of Pennsylvania, one of the United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a process for preparing substituted imidazole compounds which are useful intermediates in the preparation of compounds having pharmacological activity.

According to the present invention there is provided a process for preparing a compound of the formula:

(where R1 is hydrogen or lower alkyl; R2 is

or NR6R7 '(where Re and R7 are each hydrogen, lower alkyl or together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine or morpholine ring); and R3 is hydrogen, lower alkyl, trifluoromethyl, benzyl, amino or -SR4 (where R4 is lower alkyl, phenyl, benzyl or chlorobenzyl) which comprises reacting a compound of the formula:

(where R1 and R3 are as hereinbefore defined; R5 is lower alkyl or phenyl; and X is halo) with a compound of the formula R2-H (where R2 is as hereinbefore defined) under basic conditions.

When R3 is -SR4, R4 is preferably methyl, R5 is preferably phenyl, and X is preferably chloro or bromo, R2 is preferably

The starting materials of formula II and a process for their preparation are described in British Patent Application No. 44439/76 ('Serial No. 1,570,212). Certain compounds of formula I are described and claimed in British Specification No. 1,397,436.

As used herein, the term "lower alkyl" refers to groups containing from one to four carbon atoms.

Displacement of the trisubstituted phos 19 phonium group [-P(R5)3] of a compound of formula II is effected by reaction of a compound of formula II with R2H under basic conditions, that is with R2H in the form of its anion R. The anion can be formed in situ by reacting a compound of the formula R2H with a strong base. Among the bases which can be used in the process of this invention are those which are capable of removing the proton from a compound of the formula R2H to form the anion Rm9 where R2 is defined as above. Such bases are those having a pKa greater than 12, for example the alkali metal alkoxides, such as sodium methoxide or ethoxide, or the metal hydrides such as sodium hydride which are preferred. When R2H is itself sufficiently basic, for example when R2H is piperidine, no additional base need be used.

In those cases where R2H is extremely volatile, such as when R2 isNRFR7 and one or both of Rss and R7 are hydrogen, it is preferable that R2H be in the form of a metalate, for example a sodium or lithium metalate, such as sodium amide. Preferably, a slight excess of R2H is present.

The reaction will usually be carried out in an organic solvent with solvents such as methanol, ethanol, propanol, butanol, acetone, acetonitrile, dimethylformamide and methyl sulfoxide being preferred. Preferably, the reaction is carried out at a temperature ranging from about ambient temperature to the reflux temperature of the solvent used in the reaction, viz. from 25"C. to 2000 C., 650C.- to 100"C. being advantageous, for from 20 minutes to 24 hours, advantageously from 20 minutes to 3 hours.

Preferably, the reaction mixture is worked up by dilution with water and removal of the trialkyl- or triphenylphosphine by-product by filtration. Extraction of the filtrate when necessary followed by evaporation gives the compounds of formula I. It is often desirable to convert the compounds of formula I into their corresponding salts, preferably hydrochloride salts. Such salts can be prepared by treating a solution of an imidazole of formula I with an acid or acid solution, for example with an ethereal or ethanolic solution of hydrochloric acid, and crystallizing the salt produced from an appropriate solvent.

The 4 - (trisubstituted phosphonium)methylimidazoles of formula H can be prepared by reacting a trisubstituted ss-acylvinyl- phosphonium halide, preferably bromide or chloride, of the formula

where R1, R5 and X are defined as above with an amidine of the formula

where Ra is defined as above and is other than hydrogen, according to the procedure described by Zbiral, Synthesis 11:775 (11974) and Zbiral and Hugl, Phosphorus 2:29 (1972).

When R3 is hydrogen, the corresponding 4 (trisubstituted phosphonium) methylimidazoles of formula II can be prepared by reaction of trichloroacetamidine or formamidine suifinic acid with a triphenyl ss-acylvinylphosphonium halide. In the formamidine sulfinic acid process, a base is used, preferably a non-nucleophilic base such as a tertiary amine.

To prepare the trisubstituted p-acylvinyl- phosphonium halides not known to the art, a halovinyl alkyl ketone such as chlorovinyl methyl ketone can be reacted with a trialkylor triphenylphosphine. When R1 is hydrogen, the trisubstituted ss-formylvinylphosphonium halides can be prepared by oxidation of a haloallyl alcohol such as 8-chloroallyl alcohol and reaction of the product thus formed with a trialkyl- or triphenylphosphine.

The process of this invention provides an inexpensive, efficient and high yield method for preparing certain imidazoles useful as intermediates in the preparation of pharmacologically active compounds. A further advantage of this process for the conversion of compounds of formula II into those of formula I is that the trisubstituted phosphines, P(R6)S, formed during the course of the reaction can be easily removed from the reaction mixture and recycled or otherwise reused.

Histamine H2 - antagonists N - cyano- N'methyl - N" - [2 - (-5 - R1 - imidazolyl methylthio)ethyl] guanidines are prepared by the present invention when R2 is

and R3 is hydrogen. Histamine H2-antagonists, N - cyano - N' - methyl - N" - [2 - (5 - R1- imidazolylmethylthio) ethyl] guanidines are prepared by the present invention when R2 is

and R3 is hydrogen. However, these compounds and other H2-antagonists, for example N - methyl - N' - [2 - (5 - Rt - imidazolyl methylthio)ethyl]thiourea compounds can be prepared from compounds of formula I. Histamine H2-antagonists act as histamine H2receptors which, as described by Black et al.

[Nature 236:385 (1972)], are defined as those histamine receptors which are not blocked by "antihistamines" such as mepyramine zbut are iblocked by burimamide.

Blockade of histamine H2-receptors is of utility in inhibiting the biological actions of histamine which are not inhibited by "antihistamines". Histamine H2-antagonists are useful, for example, as inhibitors of gastric acid secretion.

Conversion of the compounds of formula- I into pharmacologically active guanidine and thiourea products can be accomplished in a variety of ways. When R2 is

and R2 is hydrogen, lower alkyl, trifluoro- methyl, benzyl or amino, guanidines are prepared directly by the process of this invention.

When R2 is

and R2 is -SR4, the compounds of formula I produced can be reduced with a suitable reducing agent to give a guanidine product where R3 is hydrogen.

When R2 is NR6R7 and R3 is -SR4 (where R4 is as defined above), theSR4 group of the compounds of formula I can be removed as described above and the products thus formed can then be treated with cyste amine to give 4 - -(2 - aminoethyl)thio .methylimidazole compounds where R3 is hydrogen. These can then be reacted with methyl isothiocyanate to give the correspond ing N-methyl - N' - [2 - (5 - R1 imidazol - 4 - ylmethylthio)ethyl] thioureas.

Reaction of the same 4i(2-aminoethyl)thio- methylimidazole compounds with N-cyano N',S-dimethylisothiourea gives the corres ponding N - cyano - N' - methyl - N" - [2 (5 - R1 - imidazol - 4 - ylmethylthio)ethyl] guanidines. The guanidine products can also be prepared by reacting the 4-(2-aminoethyl) thiomethylimidazole with dimethyl-N-cyano imidodithiocarbonate, and subsequently react ing the resulting N-cyano-N'-[2z(5-Rl- imidazol - 4 - ylmethylthio)ethyl] - S methylisothiourea with methylamine.

When R2 isNR6R7 and R2 is hydrogen, the compounds of formula I can be reacted with cysteamine to give the 4-l(2-aminoethyl)- thiomethylimidazoles which can then be con verted into guanidine and thiourea products as previously described.

Thioureas and cyanoguanidines prepared from the compounds of formula I are described in U.S. Patent Specifications 3,950,333 and 3,950,353.

The following Examples are given by way of illustration. Temperatures are in degrees Centigrade (do.) unless otherwise indicated.

EXAMPLE 1.

(a) Trichloroacetamidine (;l.iS2 g., 0.1 mole) was dissolved in 20 ml. of dry di methylsulfoxide, and 4.1 g. (0.1 mole) of tri phenyl ss - acetylvinylphosphonium bromide in 40 ml. of dimethylsulfoxide were added in one portion with stirring. The exothermic reaction mixture gradually lightened in color, and the mixture was heated at 1000 for 10 minutes. Evaporation of the solvent gave [S(5- methylimidazolyl) - 4 - methyl] triphenyl phosphonium bromide.

Alternatively, and preferably, the phos phonium bromide is prepared using trichloro acetamidine by the following procedures: Triphenyl ss - acetylvinylphosphonium bromide (8.0 g., 0.019 mole) was dissolved in a minimum amount of dry acetonitrile (about 100 ml.) and trichloroacetamidine (4.0 g., 0.025 mole) was added in one portion. The resulting mixture was stirred at room temperature, and the material which crystallized out was filtered off to give [!(2-trichloro- methyl - 5 - methylimidazolyl) - 4 - methyl] - triphenylphosphonium bromide.

This phosphonium salt (15.0 g., 0.027 mole) was added to 150 ml. of methanol, and the resulting mixture was refluxed for three hours. The mixture was concentrated to about 15 ml., and the solid material was filtered off to give [l(2 - methoxycarbonyl - 5 - methylimidazolyl) - 4 - methyl] triphenylphosphonium bromide.

The above prepared phosphonium salt is heated to its melting point (approximately 1700) and held at this temperature until the evolution of gas is complete. On cooling, the solid product is triturated with chloroform to give [(5 - methylimidazolyl) - 4methyl] triphenylphosphonium bromide.

Triphenyl j3 - acetylvinylphosphonium chloride (36 g., 0.1 mole) and trichloroacetamidine (16.1 g., 0.1 mole) were stirred in 200 ml. of methanol for one hour. The solution was heated to reflux, cooled, and the methanol was evaporated to leave [(2- methoxycarbonyl - 5 - methylimidazolyl) - 4 methyljtriphenylphosphonium chloride. Heating this phosphonium chloride salt at 1700 until evolution of gas is cornplete, and then cooling and triturating with chloroform gives ['(5 - methylimidazolyl) - 4 - methyl]triphenylphosphonium chloride.

(b) Formamidine sulfinic acid (11.0 g., 0.1 mole) was suspended in 250 ml. of dry dimethylsulfoxide and 2.4 g (0.1 mole) of sodium hydride were added. After cessation of hydrogen gas evolution, 36.5 g. (0.1 mole) of triphenyl ss - acetylvinylphosphonium chloride were added. The mixture was stirred for one hour at ambient temperature, and then heated at.1000 for 10 minutes. After cooling, the dimethylsulfoxide was evaporated, and the 'residue was dissolved in 300 ml. of 1:1 chloroform-methanol and the solution was ,filtered.

The filtrate was evaporated to dryness, and the residue was recrystallized from chloroform-acetone to give 20 g. (500/c) of [(5- methylimvldazoIyl)~- 4 - methyl]triphenylphos- phonium chloride, m.p. 223225 .

Alternatively, and preferably, [(5-methylimidazolyl) - 4 - methyl]triphenylphosphonium chloride and bromide are prepared using formamidine sulfinic acid by the following procedures: Triphenyl fi - acetylvinylphosphonium chloride (3.65 g., 0.01 mole) and formamidine sulfinic acid (1.1 g., 0.01 mole) were dissolved in 50 ml. of dimethylsulfoxide. 1,8bis - (Diinethylamino)naphthalene ("proton sponge") (2.14 g., 0.01 mole) was added, and the mixture was warmed to 800. After cooling, evaporating the dimethylsulfoxide, precipitating the inorganic salts with chloroform, filtering, evaporating to dryness, and recrystallizing the residue from chloroformacetone, an essentially quantitative yield of [1(5 - methylimidazolyl) - 4 - methyl]triphenylphosphoniurn chloride was obtained.

Triphenyl ss - acetylvinylphosphonium bromide (20.6 g., 0.05 mole) and formamidine sulfinic acid (6.0 g., slight excess over 0.05 mole) were dissolved in 100 ml. of dimethylsulfoxide. 1,5 - Diazabicyclo [5.4.0] - ur;dec-5-ene (DBU) (7.6 g., 0.05 mole) was added dropwise with stirring. The mixture was maintained at 80" for 20 minutes, and the dimethylsulfoxide was evaporated off. The residue was taken up in chloroform, and inorganic salts were removed by filtration. The filtrate was evaporated to dryness, and the residue was recrystallized from chloroformacetone to give [5(5 - methylimidazolyl)4 - methyl] triphenylphosphonium bromide in 80% yield.

Sodium amide (0.39 g., 0.01 mole) was dissolved in 40 ml. of liquid ammonia and 4.11 g. (0.01 mole) of [( 5-methylimidazolyl) - 4 - methyl] triphenylphosphonium bromide were added. The suspension was stirred at - 400C. for one hour and it was then allowed to warm to room temperature as the ammonia evaporated. The triphenyl phosphine was extracted from the residue with benzene, and the remaining solids were taken up in water and extracted with chloroform. The chloroform extracts were dried and evaporated to give 4 - aminomethyl - 3 - methylimidazole in 70% yield. This amine was refluxed with a molar equivalent of cysteamine in acetic acid and treated with hydrochloric acid to give 4 - (2 - aminoethyl)thiomethyl - 5methylimidazole dihydrochloride.

EXAMPLE 2.

[(5 - Methyl - 2 - methylthioimidazolyl)- 4 - methyl] triphenylphosphonium bromide (4.83 g., 0.01 mole) was stirred in 20 ml.

of piperidine at room temperature for 30 minutes, then refluxes for one hour, cooled and filtered. The filtrate was evaporated under reduced pressure and chromatographed on a silica gel column using chloroform/methanol as eluant to yield 5-methyl-2-methylthio-4piperidinomethylimidazole. Treating with hydrochloric acid and reflexing the resulting dihydrochloride salt with one molar equivalent of cysteamine in acetic acid gave 4-(2-aminoethyl)thiomethyl - 5 - methyl - 2 - methylthioimidazole dihydrochloride.

By the same procedure, using pyrrolidine in place of piperidine, 5-methyl-2-methylthio4-pyrrolidinomethylimidazole is prepared.

Similarly, using morpholine in place of piperidine, 5 - methyl - 2 - methylthio - 4morpholinomethylimidazole is prepared.

Converting these pyrrolidine and morpholine compounds to the dihydrochloride salts and treating with cysteamine in acetic acid gives 4 - (2 - aminoethyl)thiomethyl - 5methyl - 2 - methylthioimidazole dihydrochloride.

EXAMPLE 3.

Dimethylamine (0.5 g., 0.01 mole) was dissolved in 35 ml. of tetrahydrofuran, stirred and cooled in an ice bath while 5 ml. (0.01 mole) of 2M butyl lithium in hexane were added dropwise with stirring. After stirring the mixture for 15 minutes in the cold, 3.93 g. (0.01 mole) of [(5-methylimidazolyl) - 4methyl] triphenylphosphonium chloride were added, and the solution was allowed to warm to room temperature. After stirring for two hours at room temperature, the solvents were evaporated, and the residue was treated with 50 ml. of water. Filtration yielded diphenyl phosphine. The aqueous filtrate was extracted with chloroform, and the extract was dried and evaporated to afford 4-(N,N-dimethylaminomethyl) - 5 - methylimidazole. This amine was then refluxed with a molar equivalent of cysteamine in acetic acid and treated with hydrochloric acid to give 4-'(2-amino- ethyl)thiomethyl - 5 - methylimidazole di hydrochloridz.

By the same procedure, using methylamine in place of dimethylamine, 4-(N-methyl- aminomethyl) - 5 - methylimidazole is prepared. In the same way, using butylamine and dibutylamine, 4 - (N - butylaminomethyl)5 - methylimidazole and 4 - (N,N - dibutylaminomethyl) - 5 - methylimidazole are prepared. Refluxing these intermediates with cysteamine by the above procedure and treating with hydrochloric acid gives 4- (2-amino- ethyl)thiomethyl) - 5 - methylimidazole dihydrochloride.

EXAMPLE 4.

N - Cyano - N' - methyl - N" - mercaptoethylguanidine (1.5'8 g., Q.01 mole) was dissolved in 15 ml. of methanol, and 2.3 ml. of sodium methoxide (0.01 mole) in methanol were added. After stirring at room temperature for five minutes, a suspension of 3.9o3 g.

of [(5 - methylimidazolyl) - 4 - methyl] - triphenylphosphonium chloride in 10 ml. of methanol was added. The solution was heated to reflux. An equal volume of water was added, and most of the methanol was removed by evaporation. Filtration and water washing afforded triphenylphosphine. The filtrate was treated with charcoal, and it was filtered and concentrated. Filtration gave N-cyano-N'methyl - N" - [2 - (5 - methyl - 4 - imid azolylmethylthio) ethyl] guanidine.

EXAMPLE 5.

Using [(2 - methylthio - 5 - methylimidazolyl) - 4 - methyl]triphenylphosphonium bromide in place of the phosphonium compound in the procedure of Example 4 gives N - cyano - N' - methyl - N" - [2 - (2methylthio - 5 - methyl - 4 - imidazolylmethylthio)ethyl] guanidine. The 2-methylthio group is removed by refluxing a mixture of the compound and 50:50 nickel-aluminum alloy in formic acid and working up by the procedure of Example 12 of Application No.

44439/76 (Specification No.) (Serial No.

1,570,212) to give N-cyano-N'-methyl-N" [2 - (5 - methyl - 4 - imidazolylmethylthio)ethyl] guanidine.

WHAT WE CLAIM IS: .1. A process for preparing a compound of the formula:

(where R1 is hydrogen or lower alkyl; R2 is

or NR'R' (where R3 and R7 are each hydrogen, lower alkyl or together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine or morpholine ring); and R3 is hydrogen, lower alkyl, trifluoromethyl, benzyl, amino or SR4 (where R4 is lower alkyl, phenyl, benzyl or chlorobenzyl) which comprises reacting a compound of the formula:

(where R1 and R3 are as hereinbefore defined; RS is lower alkyl or phenyl; and X is halo) with a compound of the formula R2-H (where R2 is as hereinbefore defined) under basic conditions.

2. A process according to claim 1, in which R6 is phenyl.

3. A process according to claim 1, in which R2 is

4. A process according to claim 3, in which R5 is phenyl.

5. A process according to claim 1, in which R2 is -NR6R7 and R6 and R7 are each hydrogen, lower alkyl or together with the nitrogen atom to which they are attached form a piperidine, .pyrrolidine or morpholine ring.

6. A process according to claim 2, in which R2 is

and R3 is hydrogen.

7. A process according to claim 1, in which sodium methoxide or sodium hydride are used to provide the basic conditions.

8. A process according to claim 1, in which the reaction is carried out in an organic solvent.

9. A process according to claim 1, in which the reaction is effected in methanol, ethanol, propanol, butanol, acetone, acetonitrile, dimethylformamide or dimethylsulfoxide as solvent.

10. A process according to claim 1, in 'which the reaction is carried out at a temperature of from 25 C to 2000C for from 20 minutes to 24 hours.

11. A process according to claim 10, in which the reaction is carried out at a temperature of 65"C to 100"C for from 20 minutes to 3 hours.

12. A process according to claim 3, substantially as hereinbefore illustrated in Example 4 or Example 7.

T A process according to daim 1, substantially as hereinbefore illustrated in any one of the Examples.

14. A compound of the formula I, as defined in claim 1, whenever prepared by a process according to any one of claims 1 to 13.

15. A compound of the formula

where R1 and R3 are as defined in claim 1, whenever prepared by a process according to any one of claims 1 to 4 and 6 to 12.

16. N - Cyano - N' - methyl - N" - [2 (5 - methyl - 4 - imidazolylmethylthio)ethyl]- guanidine whenever prepared by a process according to any one of claims 1 to 4 and 6 to 12.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. bromide in place of the phosphonium compound in the procedure of Example 4 gives N - cyano - N' - methyl - N" - [2 - (2methylthio - 5 - methyl - 4 - imidazolylmethylthio)ethyl] guanidine. The 2-methylthio group is removed by refluxing a mixture of the compound and 50:50 nickel-aluminum alloy in formic acid and working up by the procedure of Example 12 of Application No. 44439/76 (Specification No.) (Serial No.

WHAT WE CLAIM IS: .1. A process for preparing a compound of the formula:

(where R1 is hydrogen or lower alkyl; R2 is

2. A process according to claim 1, in which R6 is phenyl.

3. A process according to claim 1, in which R2 is

4. A process according to claim 3, in which R5 is phenyl.

6. A process according to claim 2, in which R2 is

and R3 is hydrogen.

15. A compound of the formula