CH643246A5 - METHOD FOR PRODUCING N-cyano-N'-methyl-N '' - (2 - (((5-methylimidazol-4-yl) methyl) thio) ethyl) guanidine. - Google Patents

Description

643246

PATENT CLAIM Process for the preparation of N-cyano-N'-methyl-N "- <2 - {[(5-methylimidazol-4-yl) -methyl] -thio | -ethyl> -guani-din, characterized in that chlorodiacetyl is converted into the corresponding ethylene ketal hemiketal by means of ethylene glycol, then by reaction with N-cyano-N'-methyl-N "- (2-mercaptoethyl) guanidine in N-cyano-N'-methyl-N" - [2- ( butane-2,3-dionyl) thioethy] guanidine ethylene ketal hemiketal of the formula I.

OH NCN

I II

CH2SCH2CH2NH-C-NHCH5

CH, —C C

* / \ I

o o '

"j OOHgCHgOH

(I)

is transferred, from which corresponding a-diketone is obtained by acid hydrolysis, which by condensation with formaldehyde and ammonia in N-cyano-N'-methyl-N "- <2 - [[(5-methylimidazol-4-yl) methyl ] -thio} -ethyl) -guani-din is transferred.

OH

GH, —C —é —I

V \> i

^ J 0CH2CH20H

NCN

CH2SCH2CH2ira-G-NHCH5

(I)

20th

The process relates to the preparation of N-cyano-N'-methyl-N "- <2 - {[(5-methylimidazol-4-yl) methyl] thio} ethyl) guanidine (hereinafter cimethidine) by Condensation of N-cyano-N'-methyl-N "- [2- (butane-2,3-dio-nyl) thioethyl] guanidine, formaldehyde and ammonia.

It is known that cimethidine can be obtained by the reaction of 5-methyl-4 - [(2-aminoethyl) thiomethyl] imidazole and N-cyano-N ', S-dimethylisothiourea (US Pat. No. 3,876,647, DE-OS 2 344 779); of N-cyano-N "- <2 - {[(5-methyl-imidazoI-4-yl) methyl] thio} ethyl> -S-methylisothio-urea and methylamine (US Pat. No. 3,876,647, DE -OS 2 344 779); of N'-methyl-N "- <2 - {[(5-methylimidazol-4-yl) methyl] thio} ethyl) thiourea and lead cyanamide (U.S. Patent 3,876,647 , DE-OS 2 344 779); of N ', S-dimethyl-N "- <2 - {[(5-methylimidazol-4-yl) methyl] thio} ethyl) isothio urea and cyanamide (BE-PS 832 665) and of 5 -Methyl-4-chloromethylimidazole and N-cyano-N'-methyl-N "- (2-mercaptoethyl) guanidine (NL-OS 7 510 344) can be prepared.

Cimethidine inhibits gastric acid and pepsin secretion and has therapeutic efficacy in the treatment of duodenal and benign gastric ulcer, recurrent ulceration and stoma ulceration, reflux oesophagitis, and other conditions in which a decrease in gastric acid secretion is desired .

It has now been found that cimethidine can be easily and with a good yield by the condensation of N-cyano-N'-methyl-N "- [2- (butane-2,3-dionyl) thioethyl] guanidine, formaldehyde and ammonia The process is characterized in that chlorodiacetyl is converted into the corresponding ketal hemiketal by means of ethylene glycol, which by reaction with N-cyano-N'-methyl-N "- (2-mercaptoethyl) guanidine in ketal hemiketal general formula I.

is transferred, from which corresponding a-diketone is obtained by hydrolysis, which is converted into cimethidine by condensation with formaldehyde and ammonia.

According to an advantageous embodiment of the process according to the invention, chlorodiacetyl is converted into corresponding ketal hemiketal using ethylene glycol in benzene in the presence of catalytic amounts of p-toluenesulfonic acid. The latter is then mixed with N-cyano-N'-methyl-N "- (2-mercaptoethyl) guanidine in a lower alcohol, N, N'-dimethylformamide or sodium hydride in the presence of 1-3 equivalents of sodium or sodium hydride The precipitate obtained is filtered off with suction and the mother liquor is evaporated to dryness The ketal hemiketal of the formula I obtained is separated from the residue by crystallization from a suitable solvent or column chromatography and then in acetone at 55-57 ° C. for 2-4 hours After the solution has been evaporated to dryness under reduced pressure, 4-6 equivalents of 25% aqueous or ethanolic ammonia and 1-1.5 equivalents of formaldehyde are added, and the resulting mixture is stirred it is evaporated to dryness for 10-20 hours at 0-5 ° C., and the residue becomes 25 by crystallization from a suitable solvent or column chro matography cimethidine isolated. The advantages of this process are a low number of reaction steps and simplicity of manufacture.

The process is illustrated by the following examples, which, however, in no way limit this invention.

example 1

35 A solution of 4.82 g (0.04 mol) of chlorodiacetyl, 5.5 g (0.088 mol) of ethylene glycol and a catalytic amount of p-toluenesulfonic acid in 250 ml of anhydrous benzene is boiled under reflux for 10 hours. The crude product is obtained by evaporating the solution to dryness under reduced pressure, from which pure chlorodiacetyl-ethylene-ketal-hemiketal with a melting point of 99-101 ° C. is obtained after purification (crystallization, column chromatography).

45 Example 2

0.484 g (0.021 mol) of sodium are dissolved in 60 ml of isopropanol and 1.11 g (0.007 mol) of N-cyano-N'-methyl-N "- (2-mercaptoethyl) guanidine are added. After stirring for 30 minutes at room temperature, 1 , 59 g of 50 (0.007 mol) of chlorodiacetyl-ethylene-ketal-hemiketal are added and the mixture is stirred for 5 hours at the boiling point of the solution, the resulting precipitate is filtered off with suction, the mother liquor is evaporated to dryness under reduced pressure and the residue is purified after 55 (crystallization, column chromatography) N-cyano-N'-methyl-N "- [2- (butane-2,3-dionyl) thioethyl] guanidine-ethylene ketal hemiketal in the form of white hygroscopic crystals with an mp. Get <120 ° C.

60

Example 3

Analogously to the process described in Example 2, 0.92 g (0.021 mol) of 55% sodium hydride, 1.11 g (0.007 mol) of N-cyano-N'-methyl-N "- (2-mercaptoethyl) -65 guanidine and 1.59 g (0.007 mol) of chlorodiacetylethylene ketal hemiketal in 20 ml of N, N'-dimethylformamide at 20-25 ° C for 30 hours N-cyano-N'-methyl-N "- [2- (butane-2 , 3-dionyl) -thioethyl] -guanidine-ethyIenketal-hemiketal obtained.

Example 4

Analogously to the process described in Example 2, 0.31 g (0.007 mol) of 55% sodium hydride, 1.11 g (0.007 mol) of N-cyano-N'-methyl-N "- (2-mercaptoethyl) guanidine and 1 59 g (0.007 mol) of chlorodiacetylethylene ketal hemiketal in 50 ml of acetonitrile at the boiling point of the mixture N-cyano-N'-methyl-N "- [2- (butane-2,3-dionyl) thioethyl] guanidine - Preserved ethylene ketal hemiketal.

Example 5

Analogously to the process described in Example 2, 0.161 g (0.007 mol) of sodium, 1.11 g (0.007 mol) of N-cyano-N'-methyl-N "- (2-mercaptoethyl) guanidine and 1.59 g (0.007 Mol) chlorodiacetyl-ethylene-ketal-hemiketal in 20 ml of ethanol at room temperature N-cyano-N'-methyl-N "- [2- (butane-2,3-dionyl) -thioethyl] -guanidine-ethylene ketal-hemiketal obtained.

3,643,246

Example 6

A mixture of 0.35 g (0.001 mol) of N-cyano-N'-methyl-N "- [2- (butane-2,3-dionyl) thioethyl] guanidine-ethylene-ketal-hemiketal, 50 ml of acetone and 15 ml of 1% sulfuric acid are heated for 2-4 hours at 55-57 ° C. and then evaporated to dryness under reduced pressure, the residue is dissolved in 2 ml of water or ethanol at 0-5 ° C 0.5-0.7 ml (0.007-0.009 mol) of 25% aqueous or ethanolic ammonia solution and then subsequently 0.08-0.12 ml (0.001-0.0015 mol) of 40% formaldehyde are added dropwise and during The reaction solution is then evaporated to dryness under reduced pressure, and the residue is, after purification (crystallization, Kols column chromatography), N-cyano-N'-methyl-N "- <2 - {[( 5-methylimidazol-4-yl) -methyl] -thio} -ethyl) -guanidine obtained with a mp. 140-142 ° C.