GB2079276A

GB2079276A - 4-Methyl-5-[(2-aminoethyl) thionethyl]imidazole Production

Info

Publication number: GB2079276A
Application number: GB8119385A
Authority: GB
Original assignee: Sogo Pharmaceutical Co Ltd
Current assignee: Sogo Pharmaceutical Co Ltd
Priority date: 1980-07-02
Filing date: 1981-06-23
Publication date: 1982-01-20
Also published as: DE3125990A1; JPH0113469B2; GB2079276B; JPS5714576A

Abstract

The present invention relates to a process for producing 4-methyl-5-[(2- aminoethyl)thiomethyl]imidazole of formula (3): <IMAGE> characterized by reacting 4-methyl-5- hydroxymethylimidazole of formula (1): <IMAGE> with a 2,2-disubstituted thiazolidine of formula (2): <IMAGE> wherein R1 and R2 each represent an alkyl group or phenyl group or R1 and R2 together form a ring. Compound of above formula (3) has been produced from cysteamine or 2-aminoethanethiol sulfuric acid in the prior art. According to the present invention, problems such as unstability of cysteamine and byproduction of sulfuric acid from 2- aminoethane-thiol sulfuric acid can be solved by using compound of above formula (2) in place of said compound. According to the process of the present invention, a high reactivity can be obtained, the purification of the product can be effected quite easily and the intended product can be obtained at low costs.

Description

SPECIFICATION Process for Producing Imidazole Derivatives The present invention relates to a new, valuable process for producing 4-methyl-5-t(2- aminoethyl)thiomethyljimidazole of formula (3):

Imidazole derivative of above formula (3) has an important use as an intermediate in the synthesis of cimetidine which is an important medicine of formula (4):

cimetidine of above formula (4) is effective as a histamine H2-acceptor inhibitor and it is particularly valuable in the medical treatment of gastric ulcer and duodenal ulcer.

4-Methyl-5-[(2-aminoethyl)thiomethyljimidazole intended in the present invention has been produced in the prior art exclusively by reacting 4-methyl-5-hydroxymethylimidazole with cysteamine (see the specification of Japanese Patent Laid-Open No. 42661/1972). Recently, however, another process has been developed wherein 4-methyl-5-L(2-aminoethyl)thiomethyllimidazole is synthesized from 4-methyl-5-hydroxymethylimidazole and 2-aminoethanethiol sulfuric acid (see the specification of Japanese Patent Application No.159895/1978).

However, cysteamine used in the former process is apt to be oxidized by air. In addition, in the former process, the contamination with by-products and reduction in yield are unavoidable. The latter process has a serious defect that very troublesome separation step of by-produced sulfuric acid is indispensable.

The object of the present invention is to overcome the above serious defects of both processes.

After intensive investigations made for the purpose of obtaining a starting compound usable in place of cysteamine or 2-aminoethanethiol sulfuric acid, the inventors have found that 2,2-disubstituted thiazolidine of above formula (2) is suitably used for this purpose. The present invention has been completed on the basis of this finding. The present invention provides a process for producing 4 methyl-5-[(2-aminoethyl)thiomethyljimidazole according to the following reaction formula:

wherein R1 and R2 each represent an alkyl group or phenyl group or R1 and R2 together form a ring.

The 2,2-disubstituted thiazolidines used as starting material in the present invention are difficultly oxidized by air, since the sulfur atom thereof is in the form of the thioether bond. A ketone by-produced by the reaction can easily be removed by reduced pressure concentration. The 2,2-disubstituted thiazolidines can be used as the starting compound very advantageously, since a process for producing the 2,2-disubstituted thiazolidines from monoethanolamine hydrogen sulfate, a ketone and a hydrosulfide at low costs has been developed recently (see the specification of Japanese Patent Application No. 158130/1979). It has also been found that cysteamine used as the starting material in the prior art can be obtained easily by hydrolyzing the 2,2-disubstituted thiazolidine (see the specification of Japanese Patent Application No. 83922/1979).

In the process of the present invention, the above hydrolysis step can be omitted, while the 2,2disubstituted thiazolidine, as starting material instead of cysteamine is used. The effects obtainable by the process of the present invention are not limited to the only increase in efficiency by the omission of said step but an increase in yield or improvement in quality is invited. Thus, the effects are quite remarkable. By employing the process of the present invention, the defects of the conventional processes can be overcome.

It has been found that the reaction of the 2,2-disubstituted thiazolidine with 4-methyl-5hydroxymethylimidazole proceeds sufficiently even in water-free glacial acetic acid. According to this finding, the 2,2-disubstituted thiazolidine is reacted with 4-methyl-5-hydroxymethylimidazole and whereby the ring thereof is opened. Thus, it can be said that the reaction according to the present invention is utterly a new chemical reaction.

The reaction according to the present invention is, surprisingly, not a hydrolysis reaction. The reaction is fundamentally different from the process wherein the 2,2-disubstituted thiazolidine is once converted to cysteamine and then it is reacted with imidazole.

In the process of the present invention, 4-methyl-5-hydroxymethylimidazole in the form of its salt with, for example, a mineral salt or the free base may be reacted with the 2,2-disubstituted thiazolidine in the form of the free base or a salt with, for example, a mineral acid.

As the 2,2-disubstituted thiazolidines, there may broadly be used, for example, 2,2- dimethylthiazolidine, 2-methyl-2-ethylthiazolidine, 2-methyi-2-isobutylthiazolidine, spirocyclohexane1,2'-thiazolidine and 2-methyl-2-phenylthiazolidine. Among them, 2,2-dimethyfthiazoliffine and 2methyl-2-ethylthiazolidine are particularly preferred.

As solvents, acidic solvents generally used in the organic synthesis may be used. Among them, acetic acid and hydrohalogenic acids are particularly preferred.

The reaction time which varies depending on the other conditions are generally 1-1 0 hours.

After completion of the reaction, the product is concentrated to dryness under reduced pressure and dispersed in isopropyl alcohol or acetone. The resulting dispersion is cooled and subjected to the filtration to obtain 4-methyi-5-L(2-aminoethyl)thiomethylSimidazole dihydrohalide.

The present invention will be illustrated by way of the following examples and referential examples of cimetidine synthesis.

Example 1 4.5 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 4.6 g of 2,2-dimethylthiazolidine hydrochloride were added to 25 cc of acetic acid. They were allowed to react under reflux for 2 hours.

Acetic acid was removed under reduced pressure. 50 cc of isopropyl alcohol was added to the residue to obtain a dispersion. The dispersion was cooled, subjected to the filtration and dried to obtain 5.9 g (yield: 81.2%) of 4-methyl-5-[(2-am inoethyl)thiomethyljimidazole dihydrochloride as white crystals.

The product coincided with the reference standard in the thin layer chromatography and l.R.

Example 2 4.5 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 5.0 g of 2-methyl-2ethylthiazolidine hydrochloride were added to 25 cc of acetic acid. They were allowed to react under reflux for 2 hours. Acetic acid was removed under reduced pressure. After the dispersion in 50 cc of isopropyl alcohol followed by cooling, filtration and drying, 5.9 g (yield: 81.2%) of 4-methyl-5-[(2- aminoethyl)thiomethyljimidazole dihydrochloride was obtained as white crystals.

Example 3 4.5 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 5.9 g of 2-methyl-2 isobutyithiazolidine hydrochloride were added to 80 cc of concentrated hydrochloric acid. They were allowed to react under reflux for 2 hours. Water was sufficiently removed under reduced pressure. After the dispersion in 50 cc of isopropyl alcohol followed by cooling, filtration and drying, 4.7 g (yield: (14.8%) of 4-methyl-5-t(2-aminoethyl)thiomethyljimidazole dihydrochloride was obtained as white crystals.

Example 4 4.5 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 5.8 g of spirocyclohexane-1 ,2'- thiazolidine hydrochloride were added to 60 cc of 48% hydrobromic acid solution. They were allowed to react under reflux for 2 hours. Water was sufficiently removed under reduced pressure. After the dispersion in 50 cc of acetone followed by cooling, filtration and drying, 5.4 g (yield: 74.4%) of 4 methyl-5-L(2-aminoethyl)thiomethyljimidazole dihydrochloride was obtained as white crystals. The product coincided with the reference standard in the thin layer chromatography and l.R.

Example 5 4.5 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 5.4 g of 2-methyl-2 phenylthiazolidine were added to 80 cc of concentrated hydrochloric acid. They were allowed to react under reflux for 2 hours. Water was sufficiently removed under reduced pressure. After the dispersion in 50 cc of acetone followed by cooling, filtration and drying, 4.7 g (yield: 64.8%) of 4-methyl-5-1(2- aminoethyl)thiomethyljimidazole dihydrochloride was obtained as white crystals.

Referential Example 4-Methyl-5-[(2-aminoethyl)thiomethyl] imidazole 4.6 g of 2-methyl-2-ethylthiazolidine hydrochloride was added to 30 cc of acetic acid. 4.5 g of 4methyl-5-hydroxymethylimidazole hydrochloride was added thereto and the whole was allowed to react under reflux for 10 hours. Acetic acid was removed under reduced pressure. After the dispersion in 50 cc of isopropyl alcohol followed by cooling, filtration and drying,7.0 g (yield: 95.9%) of 4-methyl 5-[(2-aminoethyl)thiomethyljimidazole dihydrochloride was obtained as white crystals.

N-Cyano-N'-[2( (4-methyl-5-imidazolyl)methylthio)ethyli-o-ethylisourea 4.9 g of 4-methyl-5-[(2-aminoethyl)thiomethyljimidazole dihydrochloride obtained as above was added with a solution comprising 40 cc of water, 2.8 g of potassium carbonate, 2.9 g of O-ethyl-Smethylcyanothioimidocarbonate and 40 cc of ethanol. They were allowed to react at 600C for two hours. Ethanol was removed under reduced pressure and the remainder was cooled, filtered and dried to obtain 4.8 g (yield: 89.7%) of N-cyano-N'-L2-((4-methyl-5-imidazolyl)methylthio)ethyll-O- ethylisourea as white crystals.

N-Cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (Cimetidine) 4.0 g of N-cyano-N'-[2-((4-methyl-5-imidazolyl) methylthio)ethylj- 0-ethylisourea was added with 45 cc of ethanol and 45 cc of water and then 56 cc of 40% aqueous monomethylamine solution under cooling to below 50C with ice. The mixture was stirred overnight under cooling and then concentrated to dryness under reduced pressure. The resulting solid was added with 20 cc of acetonitrile. After cooling followed by filtration and drying, 3.0 g (yield: 78.9%) of cimetidine, i.e. N-cyano-N'-methyl-N" [2-((4-methyl-5-imidazolyl)methylthio)ethyljguanidine, was obtained.

Claims

1. A process for producing 4-methyl-5-[(2-aminoethyl)thiomethyljimidazole of formula (3):

characterized by reacting 4-methyl-5-hydroxymethylimidazole of formula (1):

with a 2,2-disubstituted thiazolidine of formula (2):

2. A process according to Claim 1, wherein the 2,2-disubstituted thiazolidine of formula (2):

wherein R1 and R2 each represent an alkyl group or phenyl group or R, and R2 together form a ring is selected from the group consisting of 2,2-dimethylthiazolidine, 2-methyl-2-ethylthiazolidine, 2-methyl- 2-isobutylthiazolidine, spirocyclohexane- ,2'-thiazolidine and 2-methyl-2-phenylthiazolidine.