CS213375B2 - Method of making the new derivatives of imidazole - Google Patents

Abstract

New thiols: <IMAGE> (in which R is an alkyl group containing up to 4 carbon atoms) are useful as intermediates in the synthesis of antihistamines, which act as H2-receptor blockers. The thiols may be prepared by reacting the corresponding chloromethyl imidazole with an acid metal sulphide under non-oxidising conditions.

Description

The present invention relates to a process for the preparation of novel thiol derivatives of imidazoles. The method of the invention is derived from. known methods - for the production of thioalcohols, which - is described. - - in - Houben-Weyl 'Methoden der organischen - Chemie', Volume IX, pages 7 to - 11,1955. This method is not directly applicable due to the high volatility of the compounds of formula I (formula below), because it provides a mixture of compounds of formula I and their disulfides. The compounds of the formula I can be obtained in high yield - (above 90% of theory) - only by reducing the temperature to 0 to 5 ° C. dropwise addition of a solution of the compound of formula (II) (below), and blowing the reaction mixture continuously with dry hydrogen sulfide.

Process for producing imidazole derivatives of the general formula I .......

. R

Those (I) wherein -R represents a lower alkyl radical having at most 4 carbon atoms in the chain, and their salts with inorganic and organic acids, according to the invention, consist in the fact that the compound of formula (II) is: - · - - -

wherein R is as defined for Formula I. - and X represents a halogen atom, reacted with an acid sulphide of the formula -MeHS, where Me - represents sodium, - potassium; - - calcium, arnotum, - barium or - strontium. The reaction is carried out in a lower alcohol - at a temperature between -0 - 20 ° C while purging - with hydrogen sulphide gas. The resulting imidazole derivatives are optionally converted into salts with inorganic acids by acidification with an alcoholic solution of the corresponding acids.

Other acid sulfides may also be used, which - however - at the present time - are not economically interesting, - which - limits - their - applicability. Since virtually all of the acid sulfides are soluble to the extent that the compounds of formula (II) are also soluble, preferably in absolute methanol, ethanol, or propanol. Other alcohols, such as iso213373 propyl alcohol, amyl alcohol or allyl alcohol, may also be used. However, the yield is generally 10 to 16% lower than that of methanol or ethanol. Other solvents, such as dimethylsulfoxide (DMSO), are unsuitable because they either have a respiratory effect or dissolve a significant amount of air oxygen, which can lead to the formation of disulfides.

The compounds of formula (I) are unstable at elevated temperature in a basic environment because they oxidize very rapidly to disulfide compounds. So you ^r · prevent oxidation, the reaction is carried out under purging with dry hydrogen sulfide · at temperatures between 0 and J-20 ° C.

Acid metal sulfides are known to be very volatile and to be easily hydrolyzed by exposure to atmospheric moisture and can be oxidized by atmospheric oxygen. Therefore, it is advantageous to work. with freshly prepared potassium or sodium sulphide. These compounds can generally be prepared from potassium or sodium alkoxide in absolute alcohol by reaction with dry hydrogen sulfide in gaseous form. The compounds of formula (I) in the form of the free bases are very volatile and therefore. · ..Se? They are preferably isolated in the form of salts with inorganic or organic acids. These. the salts are obtained, for example, simply by acidifying the reaction medium with an alcoholic solution of the corresponding acids. For isolation, a solution of gaseous hydrogen chloride in isopropyl alcohol (35% solution), 96% sulfuric acid in isopropyl alcohol (40% solution) and glacial acetic acid in butanol (50% solution) proved the best.

The process of the present invention produces the following novel compounds:

4 (S) -methyl-5 (4) -imidazole-ethanethanol in the form of the hydrochloride,

4 (S) -ethyl-5 (4) -imidazole-methanthiol in the form of sulfate and 14 (5) -butyl-5 (4) -imidazole-methanthiol in the form of acetate.

The compounds of the formula (I) serve as intermediates in the synthesis of various antihistamines. Which are known as Hz-receptor blockers.

. The novel compounds are suitable for the preparation of cimetidine and its derivatives by reaction with the novel N-cyanoazomethine derivatives described in Czechoslovak Patent No. 213,376.

. The following examples are given to illustrate the invention. However, these examples do not limit the invention in any way.

Example -I: ./. . :

4 (S) -Methyl-5 (4) -imidazole-methanethiol hydrochloride

Dissolve 5.86 g (0.15 mol) of dassic acid in 100 ml of absolute methanol. This solution is then saturated with hydrogen sulfide at temperature. 6 to 5 ° C. At the same temperature, a solution of 10.0 g (0.06 mol) of 4 (S) -chloromethylimidazole hydrochloride in 50 ml of absolute methanol was added dropwise in a stream of hydrogen sulfide over 2 hours. After the dropwise addition, it is stirred for a further 30 minutes and the precipitated inorganic salt is then added. suction with suction filter. The filtrate is acidified with 10 ml of a 34% solution of hydrochloric acid in isopropyl alcohol, then 0.5 is added. . g. activated carbon and filtered. The filtrate was evaporated to a small volume and diluted. with 30 to 40 ml of isopropyl ether, followed by crystallization. 6.8 to 9.5 g (90-95% of theory) of melting point 226 DEG-227 DEG C. are obtained. IC (KBr): 3100-2600, 1630, 820 · cm -1.

NMR (DMSO-d 6) δ in ppm: 2.31 (s, 3H), 3.86 (s, 2H), 9.00 (s, 1H). _{Rf =} 0.50, on a silica gel plate, eluted with dichloromethane, methanol and formic acid in a ratio of 8: 2: 0.5 and induced by iodine vapors.

For C 5 H 9 ClN 2 S calculated:>

36.47% · C · 5.50% H · 17.01% N · 19.47% 7;

found:

% H, 16.48;% N, 20.02.

Example 2

4 (S) -methyl-5 (4) -imidazole methanol methanol hydrochloride

Dissolve 5.0 g (0.21 mol) of sodium in 100 ml of ethanol. The solution is saturated with hydrogen sulfide while cooling (to 0 to 5 ° C). To this solution was added 25.5 g (0.10 mol) of N, N-bromomethyl-S, N-methylimidazole dissolved in 50 ml of absolute ethanol, while purging with hydrogen sulphide for 2 hours. The mixture is then stirred for an additional 30 minutes and the inorganic salt is sucked off on a suction filter. The filtrate was acidified with 20 ml of a 34% solution of hydrochloric acid in isopropanol, added 0.5 g of activated carbon, and filtered.

The filtrate was evaporated to about 40 ml and diisopropyl ether was added to the warm solution until crystallization began. After cooling to 0 ° C, filtration is performed and the precipitate is washed with a 1: 1 mixture of methanol and isopropyl ether. Melting point 225-226 ° C (from methanol) is obtained in a yield of 93-97%.

IC (KBr): 3100-2600, 1630, 820 cm -1. NMR (DMSO-d 6): δ in ppm: 2.31 (s, 31H), 3.86 (s, 2H), 9.00 (S, 1H).

NMR (CD 3 OD): 2.33 (s, 3H), 3.85 (s, 2H), 8.80 (s, 1H).

For C5H9CIN2S calculated:

% C, 36.47;% H, 5/50;% N, 17.01;

found:

H, N, 16.68; S, 20.00.

Rf ~ 0.5 with methylene chloride, methanol and formic acid at a ratio of 8.0: 2.0: 0.5.

Example 3

4 (S) -ethyl-5 (4) -imidazole methanethiol sulfate

The procedure is the same as described in Example 2, but 6.5 g of calcium sulfide is dissolved in 100 ml of butanol and 8.0 g of 4 (5) -ethyl-5, (4) bromomethylimidaisole are added. Acidification is carried out with 40% sulfuric acid in isopropyl alcohol. The title compound is obtained in a yield of 88-90% and has a melting point of 208-210 ° C IC (KBr): 3-200-200, 1635, 915, 820 cm -1.

For: C6H12N2O4S2 calculated:

% C, 29.99;% H, 5.04;% N, 11.55;

found:

% H, 5.26;% N, 11.80;% S, 26.35;

Example 4

4 (S) -Butyl-5 (4) -imidazole methanethiol acetate acetate

The procedure is as described in Example 2, but starting with 6 g of 4 (5) -butyl-5- (4-bromomethylimidazole) and 10 g of ammonium sulfide, both of which are dissolved in isopropyl alcohol at 4. The acidification was carried out with a 50% glacial acetic acid in butanol solution to give the title compound, m.p. 126-128 ° C, yield 85-90%.

IC (KBr): 3150-2600, 1635, 910, 820 cm -1

For: C10H18N2O2S calculated:

% C, 52.15%;% H, 7.14;% N, 12.16;

found:

% H, 12.01;% N, 13.65%.

Claims (6)

Process for the preparation of novel imidazole derivatives of the general formula I R j ^H (I) wherein R represents a lower alkyl radical having up to 4 carbon atoms in the chain, and salts thereof with inorganic and organic acids, characterized in that the compound of formula II R N - / w · (II), wherein R has the same meaning as given in the general formula. I and X are halogen, reacted with an acid sulfide of the formula MeHS wherein Me is sodium, potassium, calcium, ammonium, barium or strontium, the reaction being carried out in a lower alcohol at a temperature between 0 to 20 ° C with hydrogen sulfide gas purging whereupon the resulting imidazole derivatives are optionally converted into salts with inorganic or organic acids by acidification with an alcoholic solution of the corresponding acids. 2. A process according to claim 1 for the preparation of 4- (5) -methyl-5- (4) -imidazole-methanethiol, characterized in that a compound of the formula II wherein R is methyl is used as the starting material; 1. 3. A process according to claim 1 for the preparation of 4, (5) -ethyl-5, (4) -imidazolmethanethiol, wherein the starting material is a compound of formula II wherein R is ethyl, X is as defined in 1. 4. The method of item 1 for producing 4 ( (5) -Butyl-5 (4) -imidazole-methanethiol, characterized in that the compound of formula (II) in which R is butyl is used as the starting material, X is as defined in point 1. ; 5. The process of claim 1, wherein the acidic sulfide of the metal of formula (MeHS) is freshly prepared potassium or sodium acid sulfide. 6. A process according to claim 1 or 5, wherein the lower alcohols used are meehamol, ethanol or isopropyl alcohol.