FR2508447A1 - PROCESS FOR THE PREPARATION OF CIMETIDINE - Google Patents

Abstract

THE PRESENT INVENTION RELATES TO A NEW PROCESS FOR THE PREPARATION OF CIMETIDINE. IT CONSISTS OF REACTING THE COMPOUND: (CF DRAWING IN BOPI) WITH METHYLAMINE IN SOLUTION, THE REACTION TAKING PLACE IN AN AQUEOUS MEDIUM AT A TEMPERATURE BETWEEN 30C AND THE BOILING POINT OF THE SOLUTION.

Description

The present invention relates to a process for the preparation of

  cimetidine (Histamine-H-2 receptor blocking drug) by the reaction of the compound of formula I below:

  H 3 C CH 2 -S-CH 2 -CH 2 -NH-C-S-CH 3 ()

  3, there is NCN H or its hydrate or hydrohalide with methylamine, followed-if desired by separation of the product obtained

of the reaction mixture -

  Many of the methods of preparing cimetidine are of practical importance and the processes described in Belgian Patent No. 804,144 deserve particular attention:

  a) the reaction of N-cyano-N '- (Z) -methylimidazole

  4-methylthio-ethyl-5-methylisothiocarbamide of formula I with methylamine in alcohol;

  b) the reaction of 4-methyl-5 (2-aminoethyl) thio-

  methyl-imidazole with N-cyano-N ', S-dimethyl-

  isothiocarbamide by prolonged boiling in acetonitrile; c) reaction of N-methyl-N'-2- (1,5-methylimidazol-4-yl) methylthio-ethyl-7-carbamamide with

  lead cyanamide in a mixture of

formamide and acetonitrile.

  According to the method b) the product is obtained

  purification by chrcmatography with only one

  20% e Med Chem 20, 901 (1977) 7, as well as the efficiency of process c) (40%) do not meet the requirements

  synthesis in its last stage. Similarly, the use of

  of a reagent containing lead in the last

step is very unfavorable.

  If the process according to variant (a) does not

  no problem, at least as far as the return is concerned

  However, it is not the same with regard to

  According to the Belgian patent Example 1 (c), point (ii) 7, the operation of the reaction mixture is carried out in the presence of a large excess of methylamine in an alcoholic medium, and then the mixture is evaporated. mixed

  reaction and the residue is crystallized from a mixture of

  This process has the following drawbacks: during this reaction carried out at ambient temperature, the methyl mercaptan is not extracted, so that during the evaporation of the reaction mixture, the gaseous release is so tumultuous that gas adsorption is not possible Cimetidine, ie the desired product, is obtained as an evaporation residue which also contains all the impurities and by-products of Because these impurities and by-products can not be separated by the method described in Belgian Patent No. 804,144, the quality

  crystallized product leaves something to be desired.

  It has therefore been the object of the present invention to improve the reaction of the compound of formula I with the methylamine so as to obtain a more pure finished product and so that methyl mercaptan is formed regularly and under simpler conditions. experimentally the temperature range in which the formation of methylmercaptana occurs regularly during the reaction of the compound of formula I (or its hydrate or its hydrohalide) with aqueous methylamine This makes it possible to destroy this secondary product more easily by the chemical route (combustion, oxidation by

  hypochlorite) only if formed by a staged reaction.

  This is due to the fact that at room temperature and above

  above, methylamine forms spongy salts which

  If in alcoholic medium the methylamine reagent can be removed substantially by heating in an aqueous medium, which can be brought to 50-600 ° C, elimination of methylmercaptan is obtained. this way use a

  less excess of methylamine, which is economically very

  health; to get a complete and quick reaction he

  2 to 5 molar excess, while in the literature

  The present invention relates to a process for the preparation of cimetidine by the reaction of the compound of formula I or its monohydrate or its hydrohalide with methylamine in solution. This process is characterized in that The reaction takes place at a temperature between 30 ° C. and the boiling point of the solution and preferably between 40 and 60 ° C., in aqueous solution. If desired, the cimetidine formed can be separated from the mixture.

  reaction by a known method and dried by distillation.

  azeotropic solution in a butanol-water system.

  The compound of formula I which serves as raw material can be prepared according to the indications described

in the Belgian patent N 804 144.

  The corresponding hydrate can be obtained by melting the mixture of 14.8 g (0.1 mol) of 5-methyl-4-hydroxymethylimidazole hydrochloride and 11.3 g (0.1 mol) of cysteamine hydrochloride. and stirring this melt for 15 minutes at 160 ° C. After cooling, the mass is dissolved in 75 ml of water. To this solution is added successively 10.6 g (0.1 mol) of sodium carbonate, 50 ml. of ethanol and 14.6 g (0.1 mole) of N-cyanimido-dithiocarbonic acid ester. The reaction mixture is then boiled for one hour with constant stirring, and then, after cooling to room temperature.

  ambient, left stirring for 5-7 hours.

  The product which has been deposited is then filtered, washed with water

  and dried at room temperature Oh gets 23 g (makes

  80%) of N-cyano-N'-2- (5-methyl-imidazole) hydrate.

  4-γ 17-methylthio) -ethyl-S-methyl-isothiocarbamide melting at about 104 ° -106 ° C. The preparation of the halogenhydrates of the compound of formula I will be described in the preparation example

  monohydrochloride The procedure is as described for the preparation of

  hydrate ration, but only half of the sodium carbonate is used (ie 0.05 Mol) 22.05 g (a yield of 74.5%) of monohydrochloride is obtained

  N-cyano-N'- 2- (5-methyl-imidazol-4-yl-17-methylthio) -

  J-S-methyl-isothiocarbamide ethyl melting at 220-222 ° C.

  The reaction is carried out in aqueous medium with 2 to 5 mol equivalents of methylamine for 2 to 6 hours between and 60 ° C. The concentration of methylamine in this medium

  The reaction is advantageously between 2 and 6 Mol / l.

  The minimum concentration is determined as a function of the desired reaction rate and the maximum concentration according to the desire to have the lowest possible methylamine loss. If a homogeneous solution is not obtained during the reaction, this could indicate the It is therefore very advantageous, in order to have a homogeneous solution, to choose a temperature such that cimetidine is redissolved towards the end of the reaction. The appropriate temperature for this is order of 70 to 90 C It is undesirable to

  bring the temperature of the solution to the boiling point

  because it could encourage, among other things,

  detection of secondary products detectable by chromatography.

  You can isolate cimetidine if you want -

  from the aqueous solutions obtained at the end of the

  reaction, by crystallization using known methods.

The impurity of formula II

  CH 3 NH-C-NH-CH 2 -CH 2 -S-S-CH 2 -CH 2 -NH-C-NHCH (II)

NCN NCN

  accompanying cimetidine may be removed by water.

  It is also possible to transform the cimetidine obtained or its

  acid addition salt by methods known per se.

  The advantages of the process in an aqueous medium according to the present invention reside not only in its greater safety and better protection of the environment and not only in reducing the quantities of methylamine used, but also in the best quality of the finished product. During the reaction, 5-5'-bis- {2 (N-cyano-N'-methyl) -guanidoethyl disulfide 7 is formed as a by-product of formula II. The preparation of this product ( of insufficient purity) has been described in German Patent Publication No. 2,944,257. The presence of the compound of formula II as an impurity does not necessarily arise from the fact that cysteamine hydrochloride

  intermediate for synthesis is contaminated by disul-

  The compound of formula II can also be formed from cystamine hydrochloride, dimethyl ester.

  cyanidodithiocarbonic acid and methylamine.

  It is also known that this compound can also be formed by the breaking of the C-S bond of the cimetidine side chain. The exchange phenomenon of the different groups

  nucleophiles is very well known for Mannich derivatives.

  It has been demonstrated that by-product crystallized with the desired product from organic solvents can be removed either by crystallization in water or by conducting the reaction in an aqueous medium and washing thoroughly.

  to the water of methylanine before drying It was possible to demon-

  by chromatography (the by-product has a Rf of 0.45 on Kieselgel 60 F 254 by developing with the mixture ethyl acetate-acetone-water 5: 4: 1 and measuring at UV at 225 nm) that the proportion of the by-product of formula II

  increases considerably by boiling in the

  methylamine or by drying in the presence of methylamine.

  In addition to the foregoing, the invention also includes other arrangements which will emerge from

  the following description, which refers to examples

  implementation of the method according to the present invention.

  It should be understood, however, that these examples are given solely by way of illustration of the subject of the invention, of which they do not constitute any

way a limitation.

Example 1

  14.35 g (0.05 mol) of hydrate from

  N-cyano-N- (2- (5-methylimidazol-4-yl) 7-methylthio) ethyl)

  S-methylisothiocarbamide in 50 ml of distilled water, stirred and heated to 50 ° C., then 18.5 ml of an aqueous solution of methylamine at a concentration of 411 g / l (this corresponds to 0.245 mol is 4.9 times Ecpimolar) This reaction mixture is left for 2 hours and 1/2 at a temperature of 50-55 ° C., while the evolved gases are collected and sent for destruction. The reaction mixture is initially very fluid. but without the solution being completely clear, the desired product begins to settle The mixture becomes thick and it may even happen that the stirrer is blocked After these 2 1/2 hours the temperature is quickly raised to 80 C and This product is maintained at this temperature for 1/2 hour with stirring The solid product returns to solution The product is taken out of the heating bath and when the temperature of the mixture goes down by itself, at 60 C, a large precipitate is formed. the m The precipitates are then separated by vacuum filtration. The emulsions are carefully removed and the precipitate is washed with water, for example 3 times ml of water at 0 ° C. The technology of this operation will be the following: we stop the vacuum pump, we mix the substance on the filter with the washing water to obtain a paste

  homogeneous, then the vacuum pump is turned on again.

  The effectiveness of the washing is checked by taking samples of

  precipitates and subjecting it to chromatography.

  thin film under the conditions described above. By taking 300 gamma from the product (ie about 100 y of solid), the intensity of the by-product stain (Rf = 0.45) must not exceed 0.3%. We obtain 32.7 g

  (wrung product, wet) of N-cyano-N'-methyl-N "-_ 2- (Z 5-

  methylinidazol-4-yl 7-methylthio) -ethyl / guanidine, then, after heating to constant weight 11.77 g (93.33%) of the product containing 0.14% impurities at Rf 0.45 and which melts

at 142-144C.

Example 2

  The procedure is as described in Example 1, but the wet wrung product (35.8 g) is homogenized in a round bottom flask equipped with a stirrer with 35 ml of n-butanol. The solvent is then distilled under reduced pressure ( 4000 Pa or 30 mm Hg) The apparatus is cooled by ice The maximum temperature of the heating bath is 60 C; the azeotropic butanol-water mixture passes towards 30 C The distillate separates in 2 phases One recovers

  about 30 ml of butanol The distillation residue contained

  a small amount of butanol and less than 1% of water is recrystallized from 45 ml of isopropanol.

  drying, 10.21 g of cimetidine are obtained.

  Yield = 80.96% Melting point: 141-143 C.

Example 3

  3.05 g (0.01 mol) of N-cyano-N '- (2- (5-methylimidazol-4-yl) -methylthio) -ethyl-5-methylisothiocarbamide hydrochloride are reacted with 14 ml of 'a solution

  aqueous methylamine concentration: 3.43 Mol / l.

  The procedure is as described in Example 1 After cooling.

  washing and drying, 2.31 g (91.7%) of

  cimetidine melting point: 141-143C.

  As is apparent from the foregoing, the invention

  tion is not limited to those of its modes of implementation, of realization and of application which have just been described more explicitly; on the contrary, it embraces all the variants that may come to the mind of the technician in the field, without departing from the framework, nor

  of the scope of the present invention.

Claims (4)

  A process for the preparation of cimetidine by the reaction of the compound of formula I below: H 3 C, CH 2 -S-CH 2 -CH 2 -NH-C-S-CH 3   NCN H or its monohydrate or its hydrohalide with methylamine in solution, characterized in that the reaction takes place at a temperature between 30 C and the boiling point of the solution in an aqueous medium, said reaction being followed if desired by separating the cimetidine from the reaction mixture by known conventional routes and drying by azeotropic distillation.   Process according to Claim 1, characterized   in that the methylamine is in excess 1 to 4 times molar.   Process according to any one of the claims   cations 1 and 2 characterized in that the temperature during most of the reaction is included   between 40 and 600 ° C and preferably between 50 and 55 ° C.   Process according to any of the claims   cations 1 to 3, characterized in that the reaction time is 2 to 6 hours.