CH631168A5 - Process for preparing substituted imidazole compounds. - Google Patents

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 the formula R<2>-H. The symbols used in the general formulae I and II are defined in Claim 1. <IMAGE>

Description

631168

2nd

PATENT CLAIMS 1. Process for making a compound of formula

The invention relates to a process for the preparation of substituted imidazole compounds of the formula r1 chjr2

y

II

II

B

10th

ch2 r '

Y

h wherein R1 represents hydrogen or lower alkyl, R2 represents -NR6R7, where R6 and R7 separately represent hydrogen or lower alkyl or have such a meaning that together with the nitrogen atom to which they are connected they form a piperidine, pyrrolidine or morpholine ring , and R3 is hydrogen, lower alkyl, trifluoromethyl, benzyl, amino or -SR4, wherein R4 is lower alkyl, phenyl, benzyl or chlorobenzyl, which comprises the step that a compound of formula

® 5 CHjPtR3 ^

rn «ß

wherein R1 is hydrogen or lower alkyl, preferably Me-15thyl, R2 is -NR6R7, where Re and R7 are separately hydrogen or lower alkyl or have such a meaning that together with the nitrogen atom to which they are connected they form a piperidine Form pyrrolidine or morpholine ring, and R3 is hydrogen, 20 lower alkyl, trifluoromethyl, benzyl, amino or -SR4, where R4 is lower alkyl, preferably methyl, or phenyl, benzyl or chlorobenzyl.

Substituted imidazole compounds of this type are useful intermediates for the preparation of pharmacologically active compounds.

The process for the preparation of substituted imidazole compounds is characterized according to the invention in that a compound of the formula in which R1 and R2 are as defined above, R5 is lower alkyl or phenyl and X is halogen, in an organic solvent under basic conditions with a compound of the formula R2- H is reacted, wherein R2 has the meaning given above.

2. The method of claim 1, wherein R5 is phenyl.

3. The method of claim 2, wherein R3 is -SR4, where R4 is methyl.

4. The method of claim 2, wherein R3 is hydrogen.

5. The method of claim 1, wherein methoxide or sodium hydride is used to bring about the basic conditions.

6. The method according to claim 1, wherein the solvent used is methanol, ethanol, propanol, butanol, acetone, acetonitrile, dimethylformamide or dimethyl sulfoxide.

7. The method of claim 1, wherein the reaction in the temperature range of 25 ° C to 200 ° C is carried out for a period of 20 minutes to 24 hours.

8. The method according to claim 7, wherein the reaction is carried out in the temperature range from 65 ° C to 100 ° C for a period of 20 minutes to 3 hours.

9. A process for the preparation of a compound of the formula II in which R1 is hydrogen or lower alkyl and R2 is -SCH2CH2NH2, characterized in that a compound of the formula II in which R2 is -NR6R7 is prepared by the process according to claim 1 and then the compound obtained reacted with cysteamine under acidic conditions.

30th

35

® 5

ch2p (r3) 3

m

Y \ *

r "

40 wherein R1 and R3 are as defined above, R5 is lower alkyl or phenyl and X is halo, preferably chloro or bromo, is reacted in an organic solvent under basic conditions with a compound of the formula R2-H, R2 being the above has the meaning mentioned.

The process described allows the preparation of 4- (thio or amino) methylimidazoles by replacing the trisubstituted phosphonium group of a 4- (trisubs. Phos-phonium) methylimidazole compound according to the equation

45

50

55

K

v p

+ P (R).

60 The meaning of the term “lower alkyl” in this description includes one to four carbon atom-containing groups.

According to the method described, a trisub

©

65 substituted phosphonium group [-P (R5) 3] of the compound of formula I by replacing a compound of formula I with R2H under basic conditions, i.e. is reacted with R2H in the form of its anion R29. The

3rd

631168

Anion can be formed by a reaction in situ of a compound of formula R2H with a strong base. An example of bases which can be used successfully are those bases which allow the proton to be removed from a compound of the formula R2H to form the anion R29, where R2 has the meaning given above. Such bases, which have a pKa of more than 12, are alkali metal alkoxides such as sodium methoxide or ethoxide, or the metal hydrides, preferably sodium hydride. If R2H is per se sufficiently basic, for example piperidine, no further base has to be used. If R2H is very volatile, for example if R6 and / or R7 are hydrogen, use as R2H of a metalate, for example sodium or lithium metalate, in particular sodium amide, is preferred. R2H is preferably used in excess.

The reaction is carried out in an organic solvent, with solvents such as methanol, ethanol, propanol, butanol, acetone, acetonitrile, dimethylformamide and dimethyl sulfoxide being preferred. The reaction is preferably carried out in the temperature range approximately between room temperature and the reflux temperature of the solvent used, namely in the temperature range between approximately 25 ° C. and approximately 200 ° C., advantageously between approximately 65 ° C. and approximately 100 ° C., for approximately 20 minutes to approximately 24 Hours, advantageously for about 20 minutes to about 3 hours.

The reaction mixture is preferably diluted with water and the trialkyl or triphenylphosphine by-product is removed by filtration. The filtrate is extracted, if necessary, to give the compound of formula II after evaporation. If desired, the compound of formula II thus obtained is converted into the corresponding salts, preferably into the corresponding hydrochloride salts. These salts are obtained by treating a solution of the imidazole of formula II with an acid or an acidic solution, for example with a solution of hydrochloric acid in ether or in ethanol, and by crystallizing the salt from a suitable solvent.

The 4- (trisubst. Phosphonium) methylimidazole compounds of the formula I can be obtained by a trisubstituted .beta.-acylvinylphosphonium halide, preferably bromide or chloride, of the formula in which R 1, R 5 and X have the meaning defined above, with a compound of the formula

»N

wherein R3, with the exception of hydrogen, has the meaning defined above, is reacted according to the method described by Zbiral in Synthesis 11: 775 (1974) and by Zbiral and Hugl in Phosphorus 2:29 (1972). If hydrogen is used as R3, the corresponding 4- (trisubst. Phosphonium) methylimidazole compounds of the formula I can be prepared by reacting trichloroacetamidine or formamidinesulfinic acid with a triphenyl β-acyvinylphosphonium halide. When carrying out the process with formamidine sulfinic acid, a base, preferably a non-nucleophilic base, advantageously a tertiary amine, is used.

5 The trisubstituted β-acylvinyl-phosphonium halides, which are not previously known, are obtained by treating a halovinyl alkyl ketone, preferably chlorovinyl methyl ketone, with a trialkyl or triphenylphosphine. If hydrogen is used as R1, the tri-io substituted β-formylvinylphosphonium halides are obtained by oxidation of a β-haloallyl alcohol, preferably β-chloro-allyl alcohol, and by treatment of the product obtained with a trialky or triphenylphosphine.

According to the process described, imidazole compounds which can be used as intermediates for the production of pharmacologically active compounds can be prepared at low cost, with high efficiency and with a high yield. Another advantage of the process described is that the trisubstituted phosphines of formula P (R5) 3, which are formed during the reaction to convert the compound of formula I to that of formula II, are easily removed from the reaction mixture and returned to the Reaction can be recycled or otherwise used.

If -S4 is used as R3, where R4 has the meaning defined above, the -SR4 group of the compound of the formula II is removed and the products thus obtained are treated with cysteamine, the 4- (2-amino-ethyl) Obtained thiomethylimidazole compounds with hydrogen as 30 R3 and subsequently converted into the corresponding guanidine and thiourea products.

When hydrogen is used as R3, the compounds of formula II are treated with cysteamine to give the 4- (2-aminoethyl) thiomethylimidazoles and convert them to the corresponding guanidine and thiourea products.

These thiourea and cyanoguanidine products prepared from the 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

0.39 g (0.01 mol) of sodium amide was dissolved in 40 ml of liquid 45 ammonia and 4.11 g (0.01 mol) of [(5-methylimide-azolyl) -4-methyl] triphenylphosphonium bromide were added. The resulting suspension was stirred at -40 ° C for one hour and then allowed to warm gradually to room temperature with evaporation of the ammonia. The triphenylphosphine 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 a 70% yield of 4-aminomethyl-5-methylimide-55 azole. (Melting point of the dihydrochloride salt: 240-242 ° C with decomposition.)

This amine was refluxed with a molar equivalent of cysteamine in acetic acid and hydrochloric acid to give 4- (2-aminoethyl) thiomethyl-5-60 -methylimidazole dihydrochloride.

Example 2

4.83 g (0.01 mol) of [(5-methyl-2-methylthioimidazolyI) -4 - methyljtriphenylphosphonium bromide were stirred in 20 ml of 65 piperidine at room temperature for 30 minutes, then refluxed for one hour, cooled and filtered. The filtrate was evaporated under reduced pressure and on a silica gel column with

631168

Turning chloroform / methanol as eluant chromatographed, whereby 5-methyl-2-methyl-4-piperidinomethyl-imidazole was obtained. After treatment with hydrochloric acid and subsequent reflux treatment of the resulting dihydrochloride salt with a molar equivalent of cysteamine in acetic acid, 4- (2-aminoethyl) thiomethyl-5-methyl-2-methylthioimidazole dihydrochloride was obtained.

According to the same procedure, but using pyrrolidine instead of piperidine, 5-methyl-2-methylthio-4-pyrrolidinomethylimidazole was obtained.

In a similar manner, but using morpholine instead of piperidine, 5-methyl-2-methylthio-4-morpholinomethylimidazole was obtained. (Melting point: 79 ° C under decomp.)

The conversion of these pyrrolidine and morpholine compounds into the corresponding dihydrochloride salts and treatment with cysteamine in acetic acid gives 4- (2-amino-ethyl) thiomethyl-5-methyl-2-methylthioimidazole dihydrochloride.

Example 3

0.5 g (0.01 mol) of dimethylamine were dissolved in 35 ml of tetra-hydrofuran, then stirred and cooled in an ice bath with the dropwise addition of 5 ml (0.01 mol) of 2M butyl-lithium in hexane and with stirring. After Um4

Stir the mixture in the cold for 15 min., 3.93 g (0.01 mol) of [(5-methylimidazolyl) -4-methyl] triophenylphosphonium chloride was added and the solution was allowed to warm to room temperature. After stirring j for two hours at room temperature, the solvents were evaporated and the residue was treated with 50 ml of water to give diphenylphosphine after filtering. The aqueous filtrate was extracted with chloroform, dried and evaporated to give 4- (N, N-di-io methylaminomethyl) -5-methylimidazole, which melts at 92-94 ° C. This amine was then refluxed with a molar equivalent of cysteamine in acetic acid and treated with hydrochloric acid to give 4- (2-aminoethyl) thiomethyl-5-methylimidazole idihydrochloride 15.

According to the same process, but using methylamine instead of dimethylamine, 4- (N-methylaminomethyl) -5-methylimidazole was obtained. 4- (N-ButylaminomethyI) -5-methylimidazole and 4- (N, N-Dibutylaminomethyl) -5-methylimidazole were obtained in the same manner, but using butylamine and dibu-20-tylamine. After reflux treatment of these intermediates with cysteamine according to the above procedure and after treatment with hydrochloric acid, 4- (2-amino-25 ethyl) thiomethyl-5-methylimidazole dihydrochloride was obtained.