FI73208B - FOERFARANDE FOER FRAMSTAELLNING AV 4-SUBSTITUERADE IMIDAZOLFOERENINGAR. - Google Patents

Description

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(Fl) (21) Patent application - Patentansökning 771291 (22) Application date - Ansöknmgsdag 22.04.77

National Board of Patents and Registration (23) Start date - Giltighetsdag 22.04.77

Patent- och registerstyrelsen (41} Has become public_ BI) Vll offentlig 23.08.78 (44) Date of publication and of publication. - 29 05 87

Ansökan utlagd och utl.skriften publicerad y 3 '' (86) Kv. application - Int. trap (32) (33) (31) Privilege claimed - Begärd priority 22.02.77 USA 771044 (71) Smithkline Corporation, 1500 Spring Garden Street, Philadelphia, Pennsylvania, USA (72) Joseph James Lewis, West Chester, Pennsy1 van ia,

The present invention relates to a process for the preparation of 4-substituted imidazole compounds, which compounds are prepared by the following process: The present invention relates to a process for the preparation of substituted imidazole compounds which are useful intermediates in the preparation of compounds having pharmacological activity. More particularly, the invention relates to a process for the preparation of 4- (thio or amino) methylimidazoles of the formula

1 2 __CH0R

R

. 1 2 wherein R is hydrogen or lower alkyl, R is -SCH 9 CH 2 NH 2,

^ NCN

-SCH2CH2NHC

"^ ^ νη (: η3 6 7 6 7 or -NR R, where R and R are each hydrogen, lower alkyl or together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine or morpholine ring, and R is hydrogen , lower alkyl, trifluoromethyl, benzyl, amino 2 73208 4 4 or -SR, wherein R is lower alkyl, phenyl, benzyl or chlorobenzyl, which process is characterized in that the compound of formula 1 © 5 RX CH-P (R3)

^ 2 3 NN

X H X® E3 13 5 wherein R and R are as defined above, R is lower alkyl or phenyl and X is halogen, are reacted together. 2 with a compound of formula R -H, wherein R is as defined above, in an organic solvent such as methanol, ethanol, propanol, butanol, acetone, acetone triil, dimethylformamide or dimethyl sulfoxide at a temperature at ambient temperature and between the reflux temperature of the solvent, and under basic conditions provided by a base having a pKa value greater than 12.

The above process can be described by the following reaction scheme: R3_ ^ CH2P (R5) 3 r1 ^ C »2r2 N N ~ _> N N © P (R5) 3

γ / nB X® ^ H

R3 r3

I II

In formula I, R 1 is preferably phenyl and X is preferably chlorine or bromine.

2

In formula II, R is preferably

^ jj.NCN

-SCH2CH2NH2 or -SCH2CH2NCH

The term "lower alkyl" as used in this specification means a group containing 1 to 4 carbon atoms.

According to the process of the invention, displacement of the triple-substituted phosphonium group (-P (R5) 3) in the compound of formula I is effected by reacting a compound of formula I with a compound R H under basic conditions, i.e. 2 H, i.e. the compound R H is in the form of its anion R 1. Anion 2 can be formed in situ by reacting a compound of formula R H with a strong base. Bases that can be used in the process of the invention include e.g.

2

those capable of removing a proton of formula R H

2 0 2 to form the anion R, wherein R is as defined above. Such bases are those having a pKa value greater than 12, for example, alkali metal alkoxides such as sodium methoxide or ethoxide or metal hydrides such as sodium hydride, which are most suitable. When 2 2 R H is itself sufficiently basic, for example when R H is piperidine, no other base needs to be added. In cases 2 where RH is very volatile, such as when Rz is -NR ° R, where R ° and R are both hydrogen or 2 the other is hydrogen, it is preferred that RH is a metalate, e.g. in the form of sodium or lithium metalate, such as sodium 2 amide. Preferably, a small excess of R H is present.

The reaction is carried out in an organic solvent, the most suitable of which are methanol, ethanol, propanol, butanol, acetone, acetonitrile, dimethylformamide and dimethyl sulfoxide. The reaction is carried out at a temperature which is between the return of the ambient temperature and the cooling temperature of the solvent used in the reaction, namely between about 25 ° C. 200 ° C, with a temperature range of about 65 ° C to about 100 ° C being most preferred, with a reaction time of about 20 minutes to about 24 hours, preferably about 20 minutes to about 3 hours.

Preferably, the reaction mixture is worked up by diluting with water and removing the trialkyl or triphenylphosphine by-product by filtration. Extraction of the filtrate when necessary, followed by evaporation, affords compounds of formula II. It is often desirable to convert compounds of formula II to the corresponding salts, preferably the hydrochloride salts. Such salts are prepared by treating a solution of an imidazole of formula II with an acid or an acidic solution, for example an ethereal or ethanolic solution of hydrogen chloride, and crystallizing the salt formed from a suitable solvent.

The 4- (trisubstituted phosphonium) methylimidazoles of the formula I are prepared by reacting a trisubstituted β-acylvinylphosphonium halide, preferably a bromide or chloride of the formula

O

5 ® li 1

| R> 3P

15 wherein R, R and X are as defined above, to react with a compound of formula R3 H2N2 · nh wherein R3 is as defined above except for hydrogen, by the method described in Zbiral, Synthesis 11: 775 (1974) , and Zbiral and Hugl, Phosphorus, 2:29 (1972). When R 3 is hydrogen, the corresponding 4- (tri-substituted phosphonium) methylimidazoles of formula I are also prepared by reacting trichloroacetamidine or formamidine sulfinic acid with triphenyl-β-acylvinylphosphonium halide. The formamidine sulfinic acid process uses a base, preferably a non-nucleophilic base such as a tertiary amine.

5 73208

To prepare new trisubstituted β-acylvinylphosphonium halides, a halovinyl alkyl ketone such as chlorovinyl methyl ketone is treated with a trialkyl or triphenylphosphine. When R 1 is hydrogen, trisubstituted β-formyl vinylphosphonium halides are prepared by oxidizing a β-haloallyl alcohol such as β-chloroallyl alcohol and treating the product thus obtained with a trialkyl or triphenylphosphine.

The present invention provides an inexpensive, efficient and high yield process for the preparation of certain imidazoles which are useful as intermediates in the preparation of pharmacologically active compounds. Another advantage of this process in converting compounds of formula I to compounds of formula II is that the trisubstituted phosphines formed during the reaction, 5 P (R) 2, can be easily removed from the reaction mixture and returned to the reaction or otherwise used.

The imidazole compounds of formula II prepared by the process of the invention are useful as intermediates in the production of pharmacologically active compounds, especially histamine α1-antibodies, for example N-cyano-N'-methyl-N "- [2- (5-R'-imidazolylmethylthio) ethyl / guanidine and N-methyl-N '- / 2- (5-R-imidazolylmethylthio) ethyl / thiourea Histamine H2 antibodies act at histamine β-receptors which, like Black et al., Nature 236: 385 (1972J_ / have been described can be defined as histamine receptors which are not inhibited by "antihistamines" such as mepyramine but by burimamide. Inhibition of histamine β-receptors is useful in that it prevents the biological effects of histamine which are not inhibited by "antihistamines"). Histamine H2 antibodies are useful, for example, as inhibitors of gastric acid secretion.

The conversion of compounds of formula II to pharmacologically active guanidine and thiourea products can be performed in a number of different ways. When R 1 is -SCH 2 CH 2 NH 2 and R 2 is hydrogen, lower alkyl, trifluoromethyl, benzyl or amino, the 4- (2-aminoethyl) thiomethylimidazole compound of formula II is treated with methyl isothiocyanate according to the corresponding N-methyl-N'- To give [2- (5-R, -imidazolylmethylthio) ethyl] thioureas. Reaction of the same 4- (2-aminoethyl) thiomethylimidazole compound with N-cyano-N ', S-dimethylisothio-73208 urea affords the corresponding N-cyano-N'-methyl-N "- [2- (5- R (imidazolylmethylthio) ethyl / guanidines and guanidine products are also prepared by reacting 4- (2-aminoethyl) thiomethylimidazole with dimethyl N-cyanoimidothiocarbonate followed by administration of the resulting N-cyano-N, - / 2- (5- R'L-imidazolylmethylthio) ethyl-S-methylisourea reacts with methylamine.

.NCN

S

-SCH2CH2NHC

NsNHCH3 guanidine products are prepared directly by the process of the invention.

When R 1 is -SCH 2 CH 2 NH 2 and R is -SR, where R is the same as above, the compounds of formula II are treated with a reducing agent, for example Raney nickel, to give the corresponding 4- (2-aminoethyl) thiomethyl-3-imidazoles in which R is hydrogen and which are then converted to guanidine and thiourea products as described above. When R2 is

NOT

-SCH2CH2NHC

Ns> sNHCH3 3 4 and R is -SR, treatment with a reducing agent directly yields the guanidine product.

When R 1 is -NR 2 R 2 and R 2 is -SR 2 where R 1 is the same as above, the -SR group of the compounds of formula II is removed as described above, and the products thus obtained are then treated with a system. with 4- (2-aminoethyl) thiomethylimidazole compounds

O

wherein R is hydrogen and which compounds are converted to guanidine and thiourea products as previously described.

When R is -NR R 'and R is hydrogen, the compounds of formula II are treated with cysteamine to give 4- (2-aminoethyl) thiomethyl-73208 liimidazoles, which are then converted to guanidine and thiourea products as described above.

These thiourea and cyanoguanidine products prepared from compounds of formula II are described in U.S. Patent Nos. 3,950,333 and 3,950,353.

The following examples illustrate the invention.

Example 1

Sodium metal (25.3 g, 1.1 mol) was dissolved in 2 liters of ethanol. 2-Methyl pseudothiourea sulfate (278.3 g, 1.0 mol) was added and the mixture was stirred for 1/2 hour. 411 g (1.0 mol) of triphenyl-β-acetylvinylphosphonium bromide were then added, and the mixture was heated under reflux for 18 hours, after which the mixture was cooled and filtered. The filter cake was washed with 200 ml of ethanol. The filtrate and ethanol washings were combined, and the combination was evaporated under reduced pressure to leave a brown residue. 500 ml of chloroform was added to the residue, and the mixture was stirred for a few minutes and then filtered. The filter cake was washed three times with 150 ml portions of chloroform and dried to give 364 g (75%) of [(2-methylthio-5-methylimidazolyl) -4-methyl] triphenylphosphonium bromide, m.p. 223-225 ° C.

Cysteamine (12.23 g, 0.13 mol) was dissolved in 100 ml of methanol, and 46.5 ml of 25% w / v sodium methoxide solution was added to the solution. After stirring the solution at ambient temperature for 10 minutes, a solid phosphonium salt was added thereto, and the mixture was heated under reflux for 20 minutes. The solution was diluted with twice the volume of ice water and then stirred. The precipitated triphenylphosphine was removed by filtration. The filtrate was extracted with three 100 ml portions of chloroform, and the chloroform extracts were dried and evaporated to dryness to give 19 g (86%) of 4- (2-aminoethyl) thiomethyl-5-methyl-2-methylthioimidazole as a viscous oily substance.

Treatment of 4- (2-aminoethyl) thiomethyl-5-methyl-2-methylthioimidazole with ethanolic hydrogen chloride gave the corresponding dihydrochloride salt, m.p. 165 ° C (ethanol-ethyl acetate).

8 73208

Example 2

Sodium metal (2.3 g, 0.1 mol) was dissolved in ethanol, and 9.5 g (0.1 mol) of acetamidine / hydrochloride was added to the solution with stirring. After 10 minutes, 41.1 g (0.1 mol) of triphenyl-β-acetylvinylphosphonium bromide was added, and the mixture was heated under reflux for 17 hours. The mixture was filtered and the filtrate evaporated to dryness to give a brownish solid which was extracted by heating with 300 ml of chloroform. 100 ml of ethyl acetate were added, and the precipitate was collected by filtration and washed with 100 ml of acetone. 36 g (80%) of [(2,5-dimethylimidazolyl) -4-methyl] triphenylphosphonium bromide, m.p. 239-240 ° C.

When an equivalent amount of / (2,5-dimethylimidazolyl) -4-methyl-7-triphenylphosphonium bromide is used in place of / (2-methylthio-5-methylimidazolyl) -4-methyl / triphenylphosphonium bromide in the process of Example 1, 4- (2-aminoethyl-yl) thiomethyl-2,5-dimethyl-imidazole ·

Example 3 (a) Trichloroacetamidine (1.62 g, 0.1 mol) was dissolved in 20 ml of dry dimethyl sulfoxide, and 4.1 g (0.1 mol) of triphenyl-6-acetylvinylphosphonium bromide in 40 ml of dimethyl sulfoxide was added in one portion. while confusing. The exothermic reaction mixture gradually turned pale in color and was heated at 100 ° C for 10 minutes. Evaporation of the solvent gave [(5-methyl-73208] imidazolyl) -4-methyl / triphenylphosphonium bromide.

Alternatively and more suitably, the phosphonium bromide is prepared using trichloroacetamidine according to the following method:

Triphenyl-3-acetylvinylphosphonium bromide (8.0 g, 0.019 mol) was dissolved in as little dry acetonitrile as possible (about 100 mL), and 4.0 g (0.25 mol) of trichloroacetamidine was added in one portion. The resulting mixture was stirred at room temperature, and the crystallized material was filtered off to give [(2-trichloromethyl-5-methylimidazolyl) -4-methyl] triphenylphosphonium bromide, m.p. 155-157 ° C.

This phosphonium salt (15.0 g, 0.027 mol) was added to 150 ml of methanol, and the resulting mixture was heated under reflux for 3 hours. The mixture was concentrated to a volume of about 15 mL and the solid was filtered off to give [(2-methoxycarbonyl-5-methylimidazolyl) -4-methyl] triphenylphosphonium bromide, m.p. 168-170 ° C, yield 89%.

The phosphonium salt prepared above is heated to its melting point (about 170 ° C) and maintained at this temperature until gas evolution is complete. After cooling, the solid product is triturated with chloroform to give [(5-methylimidazolyl) -4-methyl] triphenylphosphonium bromide, m.p. 238-239 ° C, 70% yield.

A mixture of triphenyl-8-acetylvinylphosphonium chloride (36 g, 0.01 mol) and trichloroacetamidine (16.1 g, 0.1 mol) in 200 ml of methanol was stirred for 1 hour. The solution was heated to reflux, then cooled and the methanol evaporated to leave [(2-methoxycarbonyl-5-methylimidazolyl) -4-methyl] triphenylphosphonium chloride. Heating this phosphonium chloride at 170 ° C until gas evolution ceases, followed by cooling and trituration with chloroform affords [(5-methylimidazolyl) -4-methyl] triphenylphosphonium chloride, m.p. 225-227 ° C, 65% yield.

(b) Formamidine sulfinic acid (11.0 g, 0.1 mol) was suspended in 250 ml of dry dimethyl sulfoxide, and 2.4 g (0.1 mol) of sodium hydride was added to the suspension. After completion of the hydrogen evolution, 36.5 g (0.1 mol) of triphenyl-3-acetylvinylphosphonium chloride were added, and the mixture was stirred at ambient temperature for 1 hour and then heated at 100 ° C for 10 minutes. After cooling, the dimethyl sulfoxide was evaporated, the residue was dissolved in 300 ml of a 1: 1 mixture of chloroform and methanol, and the solution was filtered. The filtrate was evaporated to dryness, and the residue was recrystallized from a mixture of chloroform and acetone to give 20 g (50%) of [(5-methylimidazolyl) -4-methyl] triphenylphosphonium chloride, m.p. 223-225 ° C.

Alternatively and more suitably, [(5-methylimidazolyl) -4-methyl] triphenylphosphonium chloride and bromide is prepared using formamidine sulfinic acid according to the following procedure:

Triphenyl-3-acetylvinylphosphonium chloride (3.65 g, 0.01 mol) and formamidine nitric acid (1.1 g, 0.01 mol) were dissolved in 50 ml of dimethyl sulfoxide. 1,8-Bis- (dimethylamino) naphthalene ("proton fungus") (2.14 g, 0.01 mol) was added and the mixture was heated to 80 ° C. After cooling, evaporation of dimethyl sulfoxide, precipitation of inorganic salts with chloroform, filtration, evaporation to dryness and recrystallization from a mixture of chloroform and acetone, a substantially quantitative yield of (5-methyl-iridazolyl) -4-methylphenyl / triphenyl / triphenyl) triphenyl was obtained.

Triphenyl-8-acetylvinylphosphonium bromide (20.6 g, 0.05 mol) and formamidine sulfinic acid (6.0 g, just over 0.05 mol) were dissolved in 100 mL of dimethyl sulfoxide. 1,5-Diazabicyclo [5.4.0] undec-5-ene (DBU) (7.6 g, 0.05 mol) was added dropwise with stirring. The mixture was kept at 80 ° C for 20 minutes and the dimethyl sulfoxide was evaporated. The residue was taken up in chloroform, and the inorganic salts were removed by filtration. The filtrate was evaporated to dryness, and the residue was recrystallized from a mixture of chloroform and acetone to give [(5-methylimidazolyl) -4-methyl] triphenylphosphonium bromide in 80% yield.

11 73208

Example 4

Triphenyl-8-acetylvinylphosphonium bromide (4.11 g, 0.01 mol) was added in one portion to a stirred suspension of 1.1 g (0.01 mol of formamidinesulfinic acid in 20 ml of dimethyl sulfoxide and 0.25 g of sodium hydride). The mixture was stirred at ambient temperature for 1 hour and then for a second hour at 80 [deg.] C. A solution of 0.99 g (0.01 mol of the sodium salt of cysteine prepared by adding two equivalents of sodium methoxide to cysteamine dihydrochloride in 10 ml of methanol) was stirred. , and the resulting mixture was heated at 70-80 ° C for 4 hours, diluted with twice the volume of water, and the triphenylphosphine was removed by filtration, the filtrate was extracted with 100 ml of toluene and two 100 ml portions of chloroform. MgSO 4) and evaporated to dryness to give 4- (2-aminoethyl) thiomethyl-5-methylimidazole, the dihydrochloride salt having a melting point of 189-192 ° C.

Example 5 Using the salt of 2- (4-chlorobenzyl) pseudothiourea of the following 2-substituted pseudothioureas: 2-benzylpseudothiourea instead of 2-methylpseudothiourea sulphate in the process of Example 1, the following triphenylphosphonium bromine compounds are obtained:

(T2-benzylthio-5-methylimidazolyl) -4-methyl / triphenylphosphonium bromide, m.p. 193-194 ° C

: [72- (4-chlorobenzyl) thio-5-methylimidazolyl) -N-methyl] triphenylphosphonium bromide, m.p. 197-198 ° C.

Reaction of these triphenylphosphonium bromides with cysteamine as described in Example 1 affords the following imidazole compounds: 4- (2-aminoethyl) thiomethyl-2-benzylthio-5-methylimidazole 4- (2-aminoethyl) thiomethyl-2- (4-chlorobenzyl) thio-5-methyl-imidazole.

12 73208

Example 6

To a solution of 9.25 g (0.1 mol) of β-chloroallyl alcohol in 100 ml of benzene is added an equivalent amount of aqueous chromium and sulfuric acid solution (Jones reagent), and the mixture is stirred at ambient temperature for 1 hour. After filtration, the layers are separated and the organic phase is washed with water. Triphenylphosphine (26.2 g, 0.1 mol) is added to the benzene solution, and the mixture is heated to reflux. The precipitate formed on cooling is collected by filtration and dried to give β-formylvinylphosphonium chloride.

When an equivalent amount of β-formylvinylphosphonium chloride is reacted with formamidine sulfinic acid according to the procedure described in Example 3, (imidazolyl-4-methyl) triphenylphosphonium chloride is obtained.

reaction of (imidazolyl-4-methyl) triphenylphosphonium chloride with cysteamine in the presence of sodium ethoxide or sodium hydride as described above affords 4- (2-aminoethyl) thiomethylimidazole, dihydrobromide m.p. 178-179 ° C.

Similarly, the triphenylphosphonium group of (imidazolyl-4-methyl) triphenylphosphonium chloride is displaced by reacting the chloride with other nucleophiles using the method of the invention.

Example 7

Tri-n-butylphosphine (20.2 g, 0.1 mol) is added to a solution of 10.4 g (0.1 mol) of chlorovinyl methyl ketone in 250 ml of benzene, and the mixture is heated under reflux for 1 hour. The mixture is cooled and the precipitate is collected by filtration and dried to give tri-n-butyl-β-acetylvinylphosphonium chloride.

Triethyl 3-acetylvinylphosphonium chloride is prepared as described above using triethylphosphine instead of tri-n-butylphosphine.

73208

Reaction of an equivalent amount of tri-n-butyl-8-acetylvinylphosphonium chloride or triethyl-β-acetylvinylphosphonium chloride with formamidine sulfinic acid according to the procedure described in Example 3 affords (5-methylimidazolyl) -4-methyl) -tri-n-butyl-tri-n-butyl (5-methylimidazolyl) -4-methyl / triethylphosphonium chloride.

Reaction of 1- (5-methylimidazolyl) -4-methyl-tri-n-butylphosphonium chloride or / (5-methylimidazolyl) -4-methyl-triethylphosphonium chloride with cysteamine in the presence of sodium methoxide or sodium hydride, as described above, affords 4- (2-aminoethyl) thiomethyl-5-methylimidazole having a melting point of the dihydrochloride salt of 189-192 ° C.

Example 8

Sodium amide (0.39 g, 0.01 mol) was dissolved in 40 ml of liquefied ammonia, and 4.11 g (0.01 mol) of / (5-methylimidazolyl) -4-methyl / triphenylphosphonium bromide was added to the solution. The suspension was stirred at -40 ° C for 1 hour, after which it was allowed to warm to room temperature with the ammonia evaporating.

Triphenylphosphine was removed from the residue with benzene, and the remaining solids were taken up in water and extracted with chloroform. Drying and evaporation of the chloroform extracts gave 4-aminomethyl dihydrochloride m.p. 240-242 ° C (dec.) With 1-5-methylimidazole in 70% yield. This amine was heated to reflux along with one molar equivalent of cysteamine in acetic acid. Treatment with hydrochloric acid afforded 4- (2-aminoethyl) thiomethyl-5-methylimidazole dihydrochloride, m.p. 189-192 ° C.

Example 9 / (5-Methyl-2-methylthioimidazolyl) -4-methyl-1-triphenylphosphonium bromide (4.83 g, 0.01 mol) was added to 20 ml of piperidine, and the mixture was stirred at room temperature for 30 minutes, then heated to reflux for 1 hour. hour, after which it was cooled and filtered. The filtrate was evaporated under reduced pressure and chromatographed on a silica gel column using chloroform / methanol as the eluent to give 5-methyl-2-methylthio-4-piperidinomethylimidazole. Treatment with hydrochloric acid and refluxing the dihydrochloride salt formed with one molar equivalent of cysteamine in acetic acid afforded 4- (2-aminoethyl) thiomethyl-5-methyl-2-methylthioimidazole dihydrochloride, m.p. 165 ° C.

14 73208

By the same method, using pyrrolidine instead of piperidine, 5-methyl-2-methylthio-4-pyrrolidinomethylimidazole is prepared ·

In a similar manner, using morpholine instead of piperidine, 5-methyl-2-methylthio-4-morpholinomethylimidazole is prepared, m.p.

79 ° C (dec.).

Conversion of these pyrrolidine and morpholine compounds to the dihydrochloride salts and treatment with cysteamine in acetic acid affords 4- (2-aminoethyl) thiomethyl-5-methyl-2-methylthioimidazole hydrochloride.

Example 10

Dimethylamine (0.5 g, 0.01 mol) was dissolved in 35 ml of tetrahydrofuran, and the solution was cooled in an ice bath and stirred while 5 ml (0.01 mol) of 2M butyllithium in hexane solution was added dropwise. After stirring for 15 minutes in the cold, 3.93 g (0.01 mol) of [(5-methylimidazolyl) -4-methyl] triphenylphosphonium chloride was added thereto, and the solution was allowed to warm to room temperature. After stirring the solution for 2 hours at room temperature, the solvents were evaporated and the residue was treated with 50 ml of water. Filtration yielded diphenylphosphine. The aqueous filtrate was extracted with chloroform, dried and evaporated to give 4- (N, N-dimethylaminoethyl) -5-methylimidazole, m.p. 92-94 ° C. This amine was heated to reflux with one molar equivalent of cysteamine in acetic acid, and treatment of the product with hydrochloric acid gave 4- (2-aminoethyl) thiomethyl-5-methylimidazole dihydrochloride, m.p. 189-192 ° C.

By the same procedure, but using methylamine instead of dimethylamine, 4- (N-methylaminomethyl) -5-methylimidazole is prepared. In a similar manner, using butylamine and dibutylamine, 4- (N-butylaminomethyl) -5-methylimidazole and 4- (N, N-dibutylaminomethyl) -5-methylimidazole are prepared. Refluxing these intermediates with cysteamine according to the method described above and treatment with hydrochloric acid affords 4- (2-aminoethyl) thiomethyl-5-methylimidazole dihydrochloride, m.p. 189-192 ° C.

Example 11 N-Cyano-N'-methyl-N "-mercaptoethylguanidine (1.58 g, 0.01 mol) was dissolved in 15 ml of methanol, and 2.3 ml of 73208 sodium methoxide in methanol was added to the solution. After stirring the solution for 5 minutes at room temperature, A suspension of 3.93 g of [(5-methylimidazolyl) -4-methyl] triphenylphosphonium chloride in 10 ml of methanol was added and the solution was heated to reflux, an equal volume of water was added and most of the methanol was removed. Filtration and washing with water gave triphenylphosphine. The filtrate was treated with charcoal, then filtered and concentrated. Filtration gave N-cyano-N'-methyl-N "- [2- (5-methyl-4-imidazolylmethylthio) ethyl] guanidine. , sp. 141-142 ° C.

Example 12

A mixture of 6.6 g (0.03 mol) of 4- (2-aminoethyl) thiomethyl-5-methyl-2-methylthioimidazole and 6.6 g of a 50:50 nickel-aluminum alloy in 50 ml of formic acid was heated at reflux for 3 hours. The metals were removed by filtration and the filtrate was evaporated to dryness. The residue was dissolved in ethanol, and the ethanol solution was saturated with hydrogen sulfide and filtered. The filtrate was saturated with hydrogen chloride. Addition of ethyl acetate caused precipitation of 4- (2-aminoethyl) -thiomethyl-5-methylimidazole as the dihydrochloride salt, m.p. 189-19 2 ° C.

Similarly, the 2-substituted thio group is removed from the other 3 imidazole compounds where R is a substituted thio group and prepared above.

7.75 g of potassium carbonate were added to a solution of 14.6 g of 4- (2-aminoethyl) thiomethyl-5-methylimidazole dihydrochloride in 120 ml of water. The solution was kept at ambient temperature for 15 minutes, and 5.15 g of methyl isothiocyanate was added thereto. After refluxing for 1/2 hour, the solution was slowly cooled to 5 ° C. The product was collected and recrystallized from water to give N-methyl-N '- [2- (5-methyl-4-imidazolylmethylthio) ethyl] thiourea, m.p. 150-152 ° C.

16 73208

Example 13 Using (2-methylthio-5-methylimidazolyl) -4-methyl / triphenylphosphonium bromide instead of the phosphonium compound used in the process of Example 11, N-cyano-N'-methyl-N "- [2- (2-methylthio-5 The 2-methylthio group is removed by heating under reflux to a mixture of the compound and a 50:50 nickel-aluminum alloy in formic acid and carrying out the work-up according to the procedure described in Example 12 to give N-cyano-N'-methyl. - [2- (5-methyl-4-imidazolylmethylthio) ethyl] guanidine, m.p. 141-o 142 C.

Example 14 (a) A solution of 17.0 g of 4- (2-aminoethyl) thiomethyl-5-methylimidazole and 11.2 g of N-cyano-N ', S-dimethylisothiourea in 500 ml of acetonitrile, heated to reflux for 24 hours. The mixture was concentrated and the residue was chromatographed on a silica gel column with acetonitrile as eluent. Recrystallization of the resulting product from a mixture of acetonitrile and ether afforded N-cyano-N'-methyl-N '- [2- (5-methyl-4-imidazolylmethylthio) ethyl] guanidine, m.p. 141-142 ° C.

(b) A solution of 23.4 g of 4- (2-aminoethyl) thiomethyl-5-methylimidazole in ethanol was slowly added at ambient temperature to a solution of 20.0 g of dimethyl N-cyanoimidodithiocarbonate in ethanol while stirring. Filtration afforded N-cyano-N '- [2- (5-methyl-4-imidazolylmethylthio) ethyl] -5-methylisothiourea, m.p. , 148-150 ° C. The filtrate was concentrated under reduced pressure, and the mixture was triturated with cold water to give a solid which was collected by filtration and recrystallized twice from a mixture of isopropanol and ether, m.p. 148-150 ° C.

17 73208 A solution of 75 ml of 33% methylamine in ethanol was added to a solution of 10.1 g of N-cyano-N '- [2- (5-methyl-4-imidazolylmethylthio) ethyl] -5-methylisothiourea. mlrssa ethanol. The reaction mixture was allowed to stand at ambient temperature for 21/2 hours. After concentrating the mixture under reduced pressure, the residue was recrystallized twice from a mixture of isopropanol and petroleum ether to give N-cyano-N'-methyl-N "- (1 -) - (5-methyl-4-imidazolylmethylthio). ethyl / guanidine, melting point 141-143 ° C.

Claims (6)

1. wherein R is hydrogen or lower alkyl, R is - NCN -SCH_CHONHC NHCH3 6 7 6 7 or -NR R, wherein R and R 'are each hydrogen, lower alkyl or together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine or morpholine ring, and 3 R is hydrogen, lower alkyl, trifluoromethyl, benzyl, amino 4 4 or -SR, wherein R is lower alkyl, phenyl, benzyl or chlorobenzyl, characterized in that the compound of formula 1 ® 5 R. >> CH ~ P (R ~ *) ^) Ύ NN IY XH X ® R3 13 5 in which R and R denote a sauna as above, R is lower alkyl or phenyl and X is halogen, is reacted with 2 2 of a compound of formula R -H, wherein R is as defined above, in an organic solvent such as methanol, ethanol, propanol, butanol, acetone, acetonitrile, dimethylformamide or dimethylsulfoxide. at ambient temperature and the reflux temperature of the solvent and under basic conditions provided by a base with a pKa value greater than 12. 19 73208 A process for the preparation of 4- (thio or amino) methylimidazoles of formula 18 73208 Process according to Claim 1, characterized in that 4- (2-aminoethyl) thiomethyl-5-methyl-2-methylthioimidazole is prepared. Process according to Claim 1, characterized in that 4- (2-aminoethyl) thiomethyl-5-methylimidazole is prepared. Process according to Claim 1, characterized in that sodium methoxide or sodium hydride is used as the base. A process according to claim 1, characterized in that the reaction is carried out at a temperature between about 25 ° C and about 200 ° C, with a reaction time between about 20 minutes and about 24 hours. A process according to claim 5, characterized in that the reaction is carried out at a temperature between about 65 ° C and about 100 ° C, with a reaction time between about 20 minutes and about 3 hours. : Patentkrav