CS268693B2 - Method of 2-guanidinothiazole's derivative production - Google Patents

Abstract

Produced 2-guanidino- 4-amidino- thiomethyl thiazole has formula (I). Cpd. (I) is obtd. by cyclisation of amidino-thiourea of formula (II) with 1,3-dihaloacetone, in an organic solvent, followed by reacting the cyclisation prod. of formula (III) (where X is halide ion), with thiourea in the presence of water, with heating, and conversion of obtd. dihydrohalide of (I) into a free base. Cyclisation is conducted in presence of catalyst comprising alkali metal (pref. sodium) iodide, using aliphatic 3-6C ketone (pref. acetone) or aliphatic 2-4C nitrile as solvent, in which the catalyst is dissolved. The reaction temp. is 20-40 deg.C. Prod. of cyclisation (III) is reacted with thiourea directly in the reaction mixt. obtd. at cyclisation stage. Alkali metal iodide (catalyst) is taken in amt. 4-6 mol.%. The yield of (I) is 85-90% and the content of biologically active substance is up to

Description

The invention relates to a novel process for the preparation of a 2-guanidinothiazole derivative of the formula I

and its salts · These compounds are important intermediates for the preparation of famotidine N-sulfamyl-3- (2-guanidinothiazol-4-ylmethylthio) propionamidine) which has been shown to be an excellent drug in the treatment of gastric duodenal ulcers · Compounds prepared according to the invention known from literature ·

According to the authors of European Patent Specification No. 87,274, the isothiourea of formula I was obtained in a yield of over 90% by reaction of a compound of formula V

(V) wherein X is halogen, with thiourea in alcohol.

The disadvantage of this procedure, however, is that the starting chloromethyl compound is an allergen that irritates the skin and mucous membranes.

The isothiourea obtained above was reacted with chloropropionitrile in the presence of sodium hydroxide in aqueous alcohol with cooling to give the nitrile in 89.8% yield. This process is very time consuming and labor intensive as the product must be isolated using extraction, azeotropic drying and recrystallization from a solvent mixture ·

Researchers at Yamanouchi Co · have tried to overcome the shortcomings of the above methods and have developed a different process, which is described in European Patent Application No. 128,736 · Dichloroacetone was condensed for several days at a temperature below 0 ° C am amidinothiourea to thiazoline of formula VI

The thiazoline thus prepared was heated with thiourea in alcohol to give the compound of formula I in 75% yield (83.8% calculated for thiourea. This compound was converted with 3-chloropropionitrile). in the presence of aqueous alkali in 9mA isopropanol and water, the nitrile of the compound of formula I in 79.2% yield, thus the total yield of the compound of formula I is 72.3% of the nitrile compound of formula I, which is 57.2%.

The reaction of the thiazoline of formula VI with thiourea was also carried out in an aqueous medium.

The aqueous solution of the compound obtained was diluted with isopropanol and then converted with 3-chloropropionitrile in the presence of sodium hydroxide while cooling to the nitrile compound of formula I, in 83.5% calculated for thiazoline of formula VI and 80.5% calculated for starting material. dichloroacetone and amidinothiourea.

The greatest disadvantage of the above method is that the process is complex and lengthy cyclization requires cooling throughout the reaction and the thus obtained thlazoline compound of formula VI is completely unstable. It has now been found that this thiazoline derivative is very unstable at room temperature.

The skin irritant intermediate * is a chloromethyl compound of the formula V * in which * X is chlorine was first described in Belgian * 866 * 156 according to which dichloroacetone was reacted with aeidinothiourea with stirring in acetone solution overnight at room temperature. However, the yield of pure chloro-stearyl compound obtained by recrystallization * from alcohol was not reported. According to our findings, this yield is less than 80%. Methods for preparation other than equivalent or similar to the above procedure are not described in the literature.

It is an object of the present invention to provide a process in which the intermediates of formula (X) famotidine can be prepared in a single container, thereby rendering the isolation of other intermediates of unsuitable properties unnecessary.

The invention is based on the finding that the S-alkylation carried out by the reaction of dihaloacetone with an amidinothiourea of formula IV

and subsequent cyclization, may be performed selectively using an iodide catalyst in a solvent environment. Thus, after the addition of water and thiourea, this compound can be converted to one of the resulting products, i.e. the compound of formula I, which is separated from the reaction mixture in a pure crystalline state.

New and surprising elements are also included in the above finding. Indeed, it was not expected that such a degree of selectivity could be achieved in both cyclization and S-alkylation using an iodide catalyst in acetone. This is duly substantiated by the fact that in the reaction of dichloroacetone with an amidinothiourea carried out without the iodide catalyst, followed by reaction and thiourea, the yields obtained were 25 to 35% lower than the yield of the reaction based on our knowledge, although the only difference was catalysis.

The role of the iodide catalyst in enhancing selectivity has also been proven in the case of 2-amino-4-chloromethylthiazole hydrochloride of formula IX

a compound known from the literature. Reaction of the thiourea with dichloroacetone in a 1: 1 molar ratio gave the compound of formula IX in 58.5% yield and the following reaction with the thiourea gave the compound of formula X

(X)

HCl

CS 268693 82 in 22.2% yield of ní / □ ♦ A.. Che®. Soc. 68, 2156 (1946)]. In contrast to these yields, the compound of formula IX was obtained in a yield of 86% of nines using the iodide catalysis found in our experiments.

It is also known that the cyclization of a compound of formula IV comprises at least three basic steps. Since it can be expected that the first step, i.e. S-alkylation, is only accelerated by iodide catalysis, it is surprising that, in addition to increasing the selectivity of ee, it also achieves an acceleration of the overall thiazole formation.

The invention therefore provides a novel process for the preparation of a 2-guanidinothiazole derivative of the formula

AND

and its 901I. The method consists in ee cyclizing the amidinothiourea of formula IV

(IV)

1,3-dihaloacetone in a solvent, preferably acetone, and in the presence of an iodide catalyst soluble in the solvent, preferably in the presence of Bodium iodide. The halogenated derivative of the formula V thus obtained

НХ (V) in which X is halogen, ee is reacted with thiourea in the presence of water without prior isolation.

According to a preferred embodiment of the process according to the invention, the iodide catalyst is used in an amount of 1 to 10 mol%, preferably in an amount of 4 to 6 mol%.

In the process of the invention, the compound of formula I is formed at a temperature between 20 ° C and ° C. The amidinothiourea of formula IV is added in portions to a suitable dihaloacetone, preferably dichloroacetone, in a solvent, preferably acetone, which also contains sodium iodide. Water and thiourea are added to the crystals thus formed, and after cooking and cooling, the compound of formula I thus prepared is filtered off, washed with aqueous acetone and dried.

The advantages of the process according to the invention can be summarized as follows.

a) Oxygen iodide catalysis becomes unnecessary for cycling for several days at temperatures below 0 ° C and isolation of unstable intermediates.

b) The obtained product of formula V, which acts as an irritant to the skin, can be further transformed without prior isolation in the same vessel.

c) The solvent system used ensures the separation of the compound of formula I and their salts in the pure state, while the impurities remain in the crystallization liquor.

d) Due to the low consumption of working time and excellent yields, the process according to the invention is very well applicable for industrial applications. Volume consumption is also advantageous: 240 kg of the compound of formula I can be prepared in a working volume of 1 m < 3 >

The process according to the invention will be explained in more detail in the following non-limiting examples.

Example 1

Right S- (2-guanidinothiazol-4-yl-methyl) -isothiourea dihydrochloride monohydrate

Example 1Л

While stirring, the solution containing 12.7 g (0.1 mol) of 1,3-dichloroacetone and 0.75 g (0.005 aol) of sodium iodide in 92 ml of acetone is added to 11.8 g (0.1 mol) of water for 2 hours. olu) anidinothioaceans · The reaction mixture is stirred for a further 2 hours, 9.2 g of water are added and after a short period of boiling ее forms a solution · 7.6 g (0.1 aol) of thiourea are added to this solution ее then the mixture is heated to The reaction mixture containing the oily product is allowed to cool with stirring. The crystalline suspension thus formed is cooled to 0 ° C, filtered off and washed twice with acetone and dried. 209 DEG-213 DEG C. (dec.) In a yield of 27.86 g (85%), containing 98% of active ingredient, as determined by potentiometric titration.

Example 1.2

From stirred stirring, a solution containing 38.1 g (0.3 mol) of 1,3-dichloroacetone and 2.25 g (0.015 mol) of sodium iodide in 240 ml of acetone in portions of 35 is added over one hour at 30 to 36 ° C. 4 g (0.3 mol) of amidinothiourea. The crystalline suspension thus obtained was stirred for an additional hour at the same temperature, after which the mixture was heated to reflux after the addition of 30 ml of water and 24 g (0.315 mol) of thiourea with stirring for a further hour. The mixture is then allowed to cool to room temperature, the crystalline product is filtered off and washed twice with 40 ml of 90% acetone. M.p. 210 DEG-214 DEG C. (dec.) In a yield of 83.02 g (89.7%) containing 98.2% of active ingredient as determined by potentiometric titration.

Example 1.3

127.0 kg (500 moles) of 1,3-dichloroacetone are pumped into a 1000 L reactor in 50 wt% acetonic solution. After addition of 257 kg of acetone and 3.75 kg (25 moles) of sodium iodide, the reaction mixture is added portionwise over a period of 1.0 to 1.5 hours while stirring, 60.5 kg of amidothiourea having a purity of 97.6% (500 moles). . The required internal temperature of 30 to 40 ° C is maintained by the jacket through the cold industrial water flow. The reaction mixture is stirred for an additional hour, then 50 liters of water and 41.2 kg of thiourea of 97% purity (525 moles) are added and the mixture is heated to boiling for one hour with stirring. The temperature of the reaction mixture is slowly cooled to room temperature over 2 to 3 hours, the suspension is centrifuged, the product is washed in a centrifuge with 8: 1 acetone / water and dried. 209 DEG-214 DEG C. (dec.) In a yield of 148.3 kg (90.0%) with an active ingredient content of 97.5%.

Claims (2)

OBJECT OF THE INVENTION A process for the preparation of a 2-guanidinothiazole derivative of the formula I H _? N (I) iiirta Its salts characterized in that ae cyclizes the amidinothiourea of the formula IV 1,3-dihaloacetone in a solvent, preferably acetone, and in the presence of an iodide catalyst soluble therein, preferably in the presence of sodium iodide, and without prior isolation, the thus obtained halogenated derivative of the formula V (V) in which X is halogen is left react with thiourea in the presence of water. 2. Process according to claim 1, in an amount of 1 to 10 mol%, preferably 4 to 6 mol%. The method according to claim 1, wherein the iodide catalyst is used