The invention relates to the new monohydrate of N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi ne (cimetidine), a histamine-H.sub.2 receptor antagonist which is called N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi ne H (cimetidine H) as well as to a process for the preparation of same, which comprises pouring a hot, homogeneous aqueous solution of N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi ne, optionally containing also methylamine, onto ice and separating the N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi ne monohydrate.

This invention relates to the new monohydrate of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-}ethyl-N"-cyanoguanidi 
ne (cimetidine), a histamine H-2 receptor antagonist, as well as to a 
process for preparing same. In this description, this new monohydrate is 
named 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne H (cimetidine H). 
Several modifications of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne have been described in the literature. According to the published German 
patent application No. 2,742,531 the modification A, which is most useful 
for pharmaceutical purposes, is formed by crystallization from anhydrous 
media, while modification B or C, respectively, separates from a solvent 
containing water. 
Similar statements are contained in another publication [Gazz. Chim. Ital. 
109, 535/1979]. The main conclusion of the latter is that the separation 
of the individual modifications from an aqueous medium is accidental and 
cannot be controlled. 
From the processes known for the preparation of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne, those described in the Belgian patent No. 804,144 have practical 
importance. These are as follows: 
(a) the reaction ethanolic methylamine of 
N-cyano-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-S-methylisothiou 
rea; 
(b) the reaction of 4-[2-(aminomethyl)-thiomethyl]-5-methyl-imidazole with 
N-cyano-N',S-dimethylisothiourea in acetonitrile by boiling for a long 
time; 
(c) the reaction of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-thiourea with 
lead cyanamide in a mixture of dimethylformamide and acetonitrile. 
All these processes are carried out in anhydrous media. According to the 
process (b), the product is obtained with a yield of only 20% after 
purifying with column chromatography [J. Med. Chem. 20, 901/1977]. The 
yield of the process (c) (i.e. 40%) also falls below the effectivity 
required in the last step of a reaction sequence. Another disadvantage of 
process (c) is the use of a lead reagent. 
Although process (a) seems to be problem-free concerning the yield, the 
carrying out of the reaction and working up of the reaction mixture is 
rather problematic. According to the Belgian Pat. No. 804,144 [Example 1 
(c) (ii)], the reaction takes place at room temperature with a large 
excess of methylamine in ethanol, the mixture is then evaporated and the 
residue recrystallized from a mixture of isopropanol and petroleum ether. 
The inconveniences of this method can be summarized as follows. Methyl 
mercaptan, arising from the condensation reaction, does not pass out from 
the system in the course of the reaction carried out at room temperature 
and as a consequence, the simultaneous leaving of both gases proceeds 
during evaporation so violently that the binding of these gases cannot be 
solved. 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne as the reaction product appears as an evaporation residue containing all 
contaminations and side products. These cannot be removed in the way 
described in the Example cited from the Belgian Pat. No. 804,144; thus, 
the recrystallisation does not result in a product of the required 
quality. 
When preparing 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne in anhydrous media, the recrystallisation and purification to a certain 
but not satisfying degree of the compound can be solved by the 
recrystallisation from an anhydrous organic solvent. This leads to 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne A which is the most useful modification for pharmaceutical purposes. 
During our experiments aimed to improve the chemical preparation of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne, it was found that in case of the reaction of 
N-cyano-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-S-methylisothiou 
rea hydrate (prepared by the method disclosed in Hungarian patent 
application Ser. No. 899/80) with methyl amine in aqueous media, 
temperature conditions could be found under which the evolution of methyl 
mercaptan became smooth; thus, the destruction (annihilation) of same by 
chemical transformation (burning, oxidation with hypochlorite) could be 
accomplished more favourably in comparison to the abrupt gas evolution. 
Namely, the leaving of methyl mercaptan is retarded by methylamine 
(because of a loose salt formation) at or even above room temperature, 
while on heating in ethanolic media the methylamine reactant also steps 
out to a significant extent. On the contrary, when an aqueous medium is 
used, methyl mercaptan can be eliminated at temperatures (at about 
50.degree.-60.degree. C.) far below the boiling point. Thus, methylamine 
can be used in a lower excess, i.e. more economically: 2 to 5 moles of it 
are satisfying for the rapid and complete transformation, as opposed to 
the 10 moles required according to the literature. 
The advantages of the process carried out in an aqueous medium concern not 
only the safety and protection of the environment. Additional advantages 
are the decrease in the amount of methylamine used and the fact that the 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne obtained is purer. 
Namely, S,S'-bis-[2-(N-cyano-N'-methyl)-guanidinoethyl-disulphide appears 
as a side product in the reaction. The preparation of this compound is 
described in the published German patent application No. 2,944,257 (though 
with a not satisfying purity). The contamination with disulphide of 
cisteamine hydrochloride, used for the precursor of the synthesis, is not 
necessary for the appearance of this compound as impurity. The formation 
of this substance can be formulated from bis-(2-aminoethyl)-disulphide 
(contaminating the cisteamine), methyl N-cyanoimidodithiocarbonate and 
methylamine however, according to our discovery it can also arise from 
splitting of the C-S bond in the side chain of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne. The interchange of various nucleophils in Mannich type compounds is 
well known. It was found that the above contamination, crystallizing 
together with the desired product from organic solvents, can be removed 
even by crystallisation from water, or by a reaction carried out in water 
and by washing thoroughly out the methylamine with water before drying. On 
the basis of our experiments, the amount of the contaminating side product 
considerably increases when the reaction is realized by boiling with the 
methylamine solution or when the drying is performed in the presence of 
methylamine. This can be proved by thin layer chromatography on Kieselgel 
60F 254 adsorbent, by development with ethyl acetate-acetone-water 5:4:1 
system and by evaluation with UV densitometry of the spot appearing with 
0.45 R.sub.f value. 
The preparation with aqueous methylamine of N-methyl-N'-{2-[( 
5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidine is favourable 
both for carrying out the reaction as well as for obtaining a substance 
with higher purity. During the practical verification of these advantages, 
it was aimed to develop a simple process for obtaining 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne from the aqueous reaction mixture as well as for the preparation of 
modification A. 
It was found that when the homogeneous, aqueous solution containing 
optionally also methylamine is poured onto ice, the main bulk of the 
substance crystallizing out is not the amorphous modification B, but a new 
monohydrate of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne, i.e. the modification H. The modification A can be obtained from this 
modification H by means of a simple recrystallization. 
It should be noted that the modification H is slowly transformed to 
modification A during storage, too. This spontaneous transformation can be 
accelerated by increasing the temperature. 
Thus, this invention relates to the new monohydrate of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne as well as to a process for the preparation of same, which comprises 
pouring a homogeneous aqueous hot solution of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne, optionally containing also methylamine, onto ice and separating the 
obtained 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne monohydrate from the solution. 
When the solution containing 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne is cooled relatively slowly, the modification B crystallizes out. When 
the reaction mixture cools to 20.degree. or a lower temperature without 
the beginning of crystallization, then the modification H separates from 
the solution. An effective way for obtaining the modification H consists 
in pouring a hot aqueous solution of 
N-methyl-N'-{2-(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidin 
e, optionally containing also methylamine, onto ice. The ice is used in an 
amount approximating the weight of the solution. The solution is poured 
onto the ice at a considerably high rate. The modification H of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne is easily recognized for it forms a well-settling precipitate, which can 
conveniently be washed out on the filter. The high dry substance content 
of the modification H gives the possibility of the direct 
recrystallisation to modification A of the product filtered out, without 
drying. 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne H obtained from the solution and containing not more than 30% of water 
is suitably transformed to the modification A by recrystallisation from an 
alcohol, favourably from isopropanol. The X-ray diagram and the infrared 
spectrum of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne H are shown in the enclosed FIGS. 1 and 2 respectively. 
The infrared examinations were accomplished in such a way that a sample of 
1 mg was homogenized with 300 mg of KBr and pellets were prepared. The 
spectra were taken up with the pellets on a Nicolet 7000 FT-IR 
spectrophotometer. The X-ray diffraction studies were performed on a Zeiss 
HZG 4/c X-ray diffractometer. The exposures were made with Cu tube (40 kV, 
20 mA, Ni filter) at a rate of 1.degree./min of the goniometer and at a 
rate of 1 cm/min of the paper. The characteristic bands and the lattice 
planes calculated on the basis of the X-ray diagrams are given in Example 
1. 
The investigation results of the X-ray diffractions of the known 
modifications B and C, which can be obtained from aqueous media, are 
different from case to case because of the amorphous appearance of the 
products. Oppositely, the modification H is in all cases identical 
concerning X-ray diffraction and can be prepared in a stable crystal form. 
The practical importance of the modification H consists in that it is a 
well-settling, sand-like precipitate which can be filtered rapidly, washed 
well and after suction or centrifugation, it contains not more than 30-35% 
of moisture. 
As contrasted to the favourable properties of the modification H, the 
modification B is a precipitate with a large surface adsorbing a large 
amount of the solution and thus its dry substance content is 20 to 33% in 
a filter-wet state. The washing out and drying of this precipitate is not 
simple. 
Further details of the invention are given in the following non-limiting 
Examples.

EXAMPLE 1 
Preparation of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne H 
N-cyano-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-S-methylisothiour 
ea monohydrate (14.35 g; 0.05 mole) is suspended in distilled water (50 
ml), stirred and heated. At a bath temperature of 50.degree. C., aqueous 
methylamine solution (18.5 ml containing 411 g/liter of methylamine, i.e. 
0.245 mole equal to 4.9 equivalents) is added. The evolving gas is led to 
an equipment for destruction (annihilation). The reaction mixture is kept 
in a bath of 50.degree.-55.degree. C. for 2.5 hours. Initially, the 
mixture becomes considerably thinner, then, in most cases, 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne begins to precipitate without appearing of a complete solution. The 
mixture becomes thicker and eventually the stirring is stopped. After 2.5 
hours the mixture is rapidly heated to 90.degree. C. and stirred at this 
temperature for 30 minutes. The solution should not contain undissolved 
material. The solution is poured without cooling onto stirred ice (70 g). 
A clear solution of 0.degree. to 10.degree. C. is formed which becomes 
turbid and granular, and well-settling crystals separate. The solution is 
kept in a refrigerator for 2 hours, then filtered and washed with 
distilled water (2.times.10 ml). The wet weight of this precipitate is 
14.8 g. After drying at 40.degree. C., the dry weight of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne H is 12.27 g (90.82%); m.p. 73.degree.-75.degree. C. 
The characteristic bands of the infrared spectrum are: 3502, 3388, 3302, 
3042, 2940, 2153, 1594, 1573, 1369, 1258, 1061, 1000, 960, 723, 639, 478 
cm.sup.-1. It is further characteristic that no peak is observed at 1200 
cm.sup.-1 ; at 1180 cm.sup.-1, where the most extensive sign is found with 
the aqueous modifications known so far, a very weak absorption can only be 
seen. 
The values of distance of the X-ray diffraction lattic planes are: 5.861; 
4.287; 4.168; 3.743; 3.689; 3.630; 3.424; 3.317; 3.328; 3.195; 3.150; 
2.803; 3.724 R. 
EXAMPLE 2 
Preparation of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne H. 
The substance (10 g) obtained according to Example 1 is dissolved in water 
(50 ml) and the hot solution is poured onto ice (75 g) while stirring to 
yield 9.85 g (98.5%) of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne H; m.p. 73.degree. C. 
On the basis of the Karl-Fischer's determination, its water content is 6.5% 
(the theoretical value is 6.67%). The N content found is 31.30% (calcd. 
31.09%). 
EXAMPLE 3 
Preparation of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne A 
(a) 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne H (23.5 g) is dissolved in isopropanol (100 ml), decolourized with 
carbon (0.5 g), filtered and set aside at -5.degree. C. for 10 hours 
following the separation of the precipitate. After filtration 20.96 g 
(95.5%) of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne A are obtained. 
(b) The filter-wet product obtained according to Example 1 (14.8 g 
containing 12.27 g of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne H) is dissolved in isopropanol (45 ml), decolourized with carbon, 
filtered and dried to give 10.52 g (91.86%) of 
N-methyl-N'-{2-[(5-methylimidazol-4-yl)-methylthio]-ethyl}-N"-cyanoguanidi 
ne A.