NO167387B - PROCEDURE FOR PREPARING 2-GUANIDINOTHIAZOLD DERIVATIVES. - Google Patents

Description

The present invention relates to a new process for the production of 2-guanidinothiazole derivative of formula (I)

as well as salts thereof.

This derivative is an important intermediate for the production of famotidine (chemical N-sulfamyl-3-(2-guanidino-thiazol-4-ylmethylthio)propionamide which has proven to be an excellent drug in the treatment of stomach and intestinal ulcers.

The compound produced according to the invention is known from the literature.

According to the authors of European patent specification 87 274, isothiourea of formula (I) was obtained in a yield of over 90% by reacting a compound of formula (III)

wherein X is halogen, with thiourea in alcohol.

A disadvantage of this method, however, is that the chloromethyl starting compound is an allergenic agent that irritates the skin and mucous membranes.

The isothiourea compound obtained in the above manner was reacted with 3-chloropropionitrile in the presence of sodium hydroxide in aqueous alcohol under cooling, forming the nitrile in 89.8% yield. This process is cumbersome as it requires a lot of time and labor as the product must be isolated using extraction, azeotropic drying and recrystallization from a solvent mixture.

The researchers at Yamanouchi Co. tried to eliminate the disadvantages of the above methods by developing another method described in European patent application 128 736. Dichloroacetone was condensed with amidinothiourea below 0° C for several days, forming the thiazoline of formula (iv)

in 96.4% yield. The thiazoline thus obtained was heated with thiourea in alcohol, forming the compound of formula (I) in 75.9% yield (83.8% as calculated for thiourea).

The most significant disadvantage of the above-mentioned method seems to be that the technological procedure is cumbersome and lengthy, the cyclization requires cooling throughout the reaction period and the thus obtained thiazoline compound of formula (IV) is relatively unstable. According to investigations carried out, this thiazoline derivative is very unstable at room temperature.

The skin-irritating chloromethyl intermediate compound of formula (IV) in which X represents chlorine was first described in Belgian patent document 866 156, according to which dichloroacetone was reacted with amidinothiourea by stirring in acetone solution overnight at room temperature. However, the yield of the pure chloromethyl compound obtained by recrystallization from alcohol is not stated. According to own regulations, this yield is less than 80%. Other production methods are not known from the literature, or are equivalent or variants of the above-mentioned method.

An aim of the present invention is to provide a method in which the intermediate product of formula (I) for famotidine can be produced in a single vessel, so that isolation of the other intermediate products which exhibit inappropriate properties becomes unnecessary.

The invention is based on the recognition that S-alkylation carried out by reacting a dihaloacetone with amidinothiourea of formula (II) and the subsequent cyclization can be selectively achieved using an iodide catalyst in a solvent, which leads to the separation of the halomethyl compound of general formula (III ) in crystalline form from the reaction mixture. After addition of water and thiourea, this compound can be transferred to the target product, i.e. the compound of formula (I), which separates out in a pure crystalline state from the reaction mixture.

New and surprising features are also involved in the above-mentioned realization. It could not be expected that such a degree of selectivity could be achieved in the cyclization using an iodide catalyst in an acetone medium. This is supported by the fact that without an iodide catalyst in the reaction of dichloroacetone with amidinothiourea, followed by reaction with thiourea, the yields obtained were 25 to 30% lower compared to the yield of the reaction based on this finding, although the only difference was in the catalysis.

The selectivity-enhancing role of iodide catalysis was additionally also confirmed in the case of 2-amino-4-chloromethyl-thiazole hydrochloride of formula (v)

a connection known from the literature. By reacting thiourea with dichloroacetone in a 1:1 molar ratio, the compound of formula (V) was obtained in 58.5% yield, and the subsequent reaction with thiourea resulted in the compound of formula (VI)

in a yield of 22.2% (J.Am. Chem. Soc. 68. 2156 (1946). In contrast to these yields, the compound of formula (V) was obtained in a yield of 86% using the iodide catalysis obtained in the present attempt.

It is also known that the cyclization of the compound of formula (II) involves at least three steps. As it can be expected that the first step, i.e. the S-alkylation, is only accelerated by the iodide catalysis, it is also surprising that in addition to the increase in selectivity, the whole thiazole chain is accelerated.

The present invention thus relates to a new process for the production of 2-guanidinothiazole derivative of formula (I), as well as salts thereof, characterized by cyclization of amidinothiourea of formula (II)

with a 1,3-dihaloacetone in a solvent, preferably in acetone, and in the presence of an iodide catalyst which is soluble in specified solvents, preferably sodium iodide, and reaction without isolation of the halogen derivative of formula (III) thus obtained

wherein X represents halogen, with thiourea in the presence of water.

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

In the method according to the invention, the compound of formula (I) is formed at a temperature between 20 and 60 C.

In the method according to the invention, the amidinothiourea compound of formula (u) is added portionwise to the suitable dihaloacetone, preferably dichloroacetone, in a solvent, preferably in acetone also containing sodium iodide. Water and thiourea are added to the crystal suspension thus formed, and after boiling and cooling, the thus obtained compound of formula (I) is filtered, washed with aqueous acetone and dried.

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

a) Due to the iodide catalysis, the performance of a cyclization that lasts for several days below 0° C, as well as the isolation of the unstable intermediates will become unnecessary.

b) The obtained skin-irritating product of formula (III) can be further transferred without isolation in the same reaction vessel. c) The solvent system used provides separation of the compounds of formula (I) and their salts in a pure state, while the impurities remain in the mother liquor.

d) Due to the modest working time and excellent yields, the method according to the invention is very applicable for industrial use. The volume utilization is also very advantageous: 240 kg of the compound of formula (I) can be produced in an operating volume of lm<3>.

The method according to the invention is illustrated in detail in the following examples.

Example 1

Preparation of S-(2-guanidinothiazol-4-yl-methyl)-isothiourea dihydrochloride monohydrate [compound of formula (I) in which Y is the group of formula (II)].

Example 1. 1

11.8 g (0.51 mol) of amidinothiourea was added to a stirred solution containing 12.7 g (0.1 mol) of 1,3-dichloroacetori and 0.75 g (0.005 mol) of sodium iodide in 92 ml of acetone. within 2 hours. After stirring for a further 2 hours, 9.2 g of water was added, and a solution was formed after boiling for a short time. To this solution was added 7.6 g (0.1 mol) of thiourea, after which the mixture was boiled for 1 hour. The reaction mixture containing the oily reaction product was allowed to cool while stirring. The crystal suspension thus formed was cooled to 0°C and then filtered, washed twice with acetone and dried to give the title product, mp 209-213°C (with cleavage), in a yield of 27.86 g (85%) with an active ingredient content of 98% as determined by potentiometric titration.

Example 1. 2

35.4 g (0.3 mol) of amidinothiourea was added portionwise to a stirred 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 at 30 to 36° C within 1 hour. The crystal suspension thus obtained was stirred at the same temperature for a further 1 hour, and after adding 30 ml of water and 24 g (0.315 mol) thiourea, the mixture was boiled under reflux and with stirring for 1 hour. The mixture was allowed to cool to room temperature, the crystalline product was filtered and washed twice with 40 ml of 90% acetone each time, forming the title product with melting point 210 - 214° C (under cleavage)

in a yield of 88.02 g (89.7%) with an active ingredient content of 98.2% as determined by potentiometric titration.

Example 1. 3

127.0 kg (500 moles) of 1,3-dichloroacetone in a 50% by weight acetone solution was pumped into a 1000 liter reactor. After adding 257 kg of acetone and 3.75 kg (25 mol) of sodium iodide, 60.5 kg of 97.6% purity amidinothiourea (500 mol) was added portionwise to the reaction mixture over 1.0 to 1.5 hours with stirring. The desired internal temperature of 30 to 40°C was maintained by the flow of cold water in the jacket. After stirring the reaction mixture for a further 1 hour, 50 liters of water and 41.2 kg of thiourea of 97% purity (525 mol) were added and the mixture was boiled with stirring for 1 hour. The temperature of the reaction mixture was then reduced to room temperature over 2 to 3 hours, the suspension was centrifuged, the product was washed in the centrifuge with an 8:1 mixture of acetone and water and was dried to give the title product, mp 209-214° C (under cleavage) in a yield of 148.3 kg (90.0%) with an active ingredient content of 97.5%.

Claims (2)

1. Process for the preparation of 2-guanidinothiazole derivative of formula (I) as well as salts thereof, characterized by cyclization of amidinothiourea of formula (II) with a 1,3-dihaloacetone in a solvent, preferably in acetone, and in the presence of an iodide catalyst which is soluble in specified solvents, preferably sodium iodide, and reaction without isolation of the halogen derivative of formula (III) thus obtained wherein X represents halogen, with thiourea in the presence of water. 2. Method according to claim 1, characterized in that the iodide catalyst is used in an amount of from 1 to 10 mol%, preferably in an amount of 4 to 6 mol%.