FI84912B - FOERFARANDE FOER FRAMSTAELLNING AV 2-GUANIDINOTIAZOLDERIVAT. - Google Patents

Description

8491 2

The present invention relates to a novel process for the preparation of 2-guanidinothiazole derivatives of general formula (I).

H, N N — 7r ^ s-Y

for the preparation of 2-guanidinothiazole derivatives and salts thereof according to the formula wherein Y represents a formula (II) ^ nh2 -c (II)

^ NH

or a group of formula (III) -CH2-CH2-CN (III). These compounds are important intermediates for the preparation of famotidine (chemically N-sulfamyl-3- (2-guanidinothiazol-4-ylmethylthio) propionamidine), which has been shown to be an excellent drug in the treatment of gastric and duodenal ulcers.

The compounds prepared according to the invention are known from the literature. Chronologically, a nitrile of formula (I) wherein Y represents a group of formula (III) is prepared from a compound of formula (VIII)

^ .CN

From the aminonitrile 4-step pathway according to XT 'H2N s (viii) in reasonable yield according to U.S. Patent 4,283,408.

According to EP 87,874, an isothiourea of formula (I) in which Y represents a group of formula (II) is obtained in a yield of more than 90% by subjecting h2n of formula (V) to n -

Jk 1 \ -HX (V>

H 2 N

wherein X is halogen to react with a thiourea in an alcohol.

However, the disadvantage of this method is that the chloromethyl compound used as a starting material is an allergenic substance which irritates the skin and mucous membranes.

The isothiourea obtained as above is then reacted with 3-chloropropionitrile in the presence of sodium hydroxide in aqueous alcohol under cooling to give the nitrile in 89.8% yield. This method is cumbersome, time consuming and laborious because the product must be isolated by extraction, azeotropic drying and recrystallization from a solvent mixture.

Researchers at Yamanouchi Co. have tried to eliminate the disadvantages of the above methods by developing another method disclosed in EP patent application 128,736. The dichloroacetone is condensed with the amidinothiourea below 0 ° C for several days to give the formula (VI)

OH

H * (VI)

Jv, Λ y · HCl

Thiazole according to H2N n xsx in 96.4% yield. The thiazoline thus obtained is heated with thiourea in an alcohol to give a compound of formula (I) wherein Y represents a group of formula 3 84912 (II) in 75.0% yield (83.8% based on thiourea), and then is converted with 3-chloropropionitrile in the presence of an aqueous alkali in a mixture of isopropanol and water to give a nitrile of formula (I) in which Y represents a group of formula (III) in 79.2% yield. Thus, the total yield of the compound of formula (I) (Y is a group of formula (II)) is 72.3%, the total yield of the compound of formula (I) (Y is a group of formula (III)) is 57.2% based on amidinothiourea.

The reaction of the thiazoline of formula (VI) with a thiourea is also carried out in an aqueous medium. An aqueous solution of the compound obtained in situ is diluted with isopropanol and then converted with 3-chloropropionitrile in the presence of sodium hydroxide under cooling to give a compound of formula (I) wherein Y is a group of formula (III) in 83.5% yield based on formula (VI). thiazoline and dichloroacetone and amidinothiourea used as starting materials in 80.5% yield, respectively.

The main disadvantage of the above process is that the technological processing is cumbersome and time-consuming, the cyclization requires cooling throughout the reaction cycle, and the thiazoline compound of formula (VI) thus obtained is quite unstable. According to our studies, this thiazoline derivative is very unstable at room temperature.

The intermediate skin irritant chloromethyl compound of formula (V) wherein X is chlorine is disclosed for the first time in BE patent 866,156, according to which dichloroacetone is reacted with an amidinothiourea with stirring in an acetone solution overnight at room temperature. However, this publication does not disclose a pure chloromethyl compound obtained by recrystallization from alcohol. According to our assays, this yield is less than 80%. Other manufacturing methods are not described in the literature or are similar to the above method or variations thereof.

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Thus, it is an object of the present invention to provide a process in which the famotidine intermediates of general formula (I) can be prepared in a single vessel, without the need to isolate other unsuitable intermediates.

The present invention is based on the finding that S-alkylation carried out by reacting dihaloacetone with an amidinothiourea of formula (IV) H2N NH2 I (IV) and then cyclization can be effected selectively using an iodide catalyst in a solvent medium, wherein the general formula (V) the halomethyl compound separates in crystalline form from the reaction mixture. Water and thiourea are then added, after which this compound can be converted to another target product, i. to a compound of general formula (I) in which Y represents a group of formula (II) and which differs from the reaction mixture in pure crystalline state.

It has further been found that the isolation of all other intermediates can be eliminated in the preparation of a compound of formula (I) wherein Y represents a group of formula (III). Thus, after dilution with water, removal of acetone and addition of alcohol, acrylonitrile and sodium hydroxide, the mercaptan compound of formula (VII) h2n n-t ^ sh (vii) 1 I \ η2νΛν '^ 5 / formed in situ can be easily S-cyanoethylated in an alkaline medium. The nitrile product thus obtained differs from the reaction mixture in crystalline form.

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There are also new and surprising elements associated with the above observation. Indeed, such a degree of selectivity could not be expected in both crystallization and S-alkylation using an iodide catalyst in an acetone medium. This is well supported by the fact that without the iodide catalyst in the reaction of dichloroacetone and amidinothiourea and the subsequent reaction with thiourea, the yields were 25-35% lower compared to the yield based on our observation, although the only difference is catalysis.

In addition, the selective value of the iodide catalysis was also proved in the case of 2-amino-4-chloromethylthiazole hydrochloride of the formula (IX) N- (IX) J - (IX) J 1 -He Reaction of thiourea with dichloroacetone in a 1: 1 molar ratio gives a compound of formula (IX) in 58.5% yield and subsequent reaction with thiourea yields a compound of formula (X) nh 2 ΐ N - ^ S ^ NH (χ)

Ä) '2 HCl

η2νγ xsx in 22.2% yield [J. Am. Chem. Soc. 68, 2156 (1946)]. Compared to these yields, the compound of formula (IX) is obtained in 86% yield using the iodide catalysis used in our experiments.

It is also known that at least 3 main steps are required for the cyclization of a compound of formula (IV). Although it can be expected that the first stage, i.e. S-alkylation 6 84912 is only accelerated by iodide catalysis, it is also surprising that in addition to the improvement in selectivity, the formation of the whole thiazole is accelerated.

Accordingly, the present invention provides a novel process for the preparation of 2-guanidinothiazole derivatives of general formula (I) and their salts, wherein Y represents a group of formula (II) or (III), which process comprises cyclizing an amidothiourea of formula (IV) 1,3- with dihaloacetone in a solvent, especially acetone. According to the invention, the cyclization is carried out in the presence of a solvent-soluble iodide catalyst, in particular sodium iodide, and the halogen derivative of formula (V) in which X represents halogen is reacted without isolation with thiourea in the presence of water to give a compound of formula (I) in which Y represents and which, if desired, is S-cyanoethylated with acrylonitrile in the presence of an alkaline aqueous alkanol medium to give a compound of formula (I) wherein Y represents a group of formula (III).

According to a preferred embodiment of the process according to the invention, 1 to 10 mol%, in particular 4 to 6 mol%, of iodide catalyst are used.

In the process of the invention, a compound of formula (I) in which Y represents a group of formula (II) is formed at 20® to 60 ° C and the compound thus obtained is S-cyanoethylated at a pH of 11 to 13 at 20® to 50 ° C. .

In the process according to the invention, the amidinothiourea of the formula (IV) is added portionwise to a suitable dihaloacetone, in particular dichloroacetone, in a solvent, in particular acetone, which also contains sodium iodide. To the crystalline suspension thus obtained, water and thiourea are added, and after boiling and cooling, the compound of formula (I) thus obtained, wherein Y represents a group of formula (II), is filtered, washed with aqueous acetone and dried.

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When it is desired to obtain a nitrile, i.e. a compound of formula (I) wherein Y represents a group of formula (III), then when boiling with thiourea in water, acetone is continuously distilled off from the reaction mixture at the same time as water is added portionwise. The aqueous solution thus obtained is cooled, diluted with alcohol and then the desired amount of acrylonitrile and aqueous sodium hydroxide solution are added. The nitrile thus formed is filtered off, washed and dried.

The advantages of the process according to the invention are as follows: a) Due to the iodide catalysis, cyclization lasting several days at 0 ° C as well as isolation of unstable intermediates is unnecessary.

b) The resulting skin irritant product of formula (V) may be further modified without isolation in the same vessel.

c) The solvent system used causes the compounds of formula (I) and their salts to be separated in a pure state with the impurities remaining in the mother liquor.

d) Much simpler and cheaper acrylonitrile can be used to prepare the nitrile instead of the 3-chloropropionitrile reported in the literature.

e) Using the process of the invention, a compound of formula (I) wherein Y represents a group of formula (III) may also be prepared from an in situ formed isothiourea derivative of formula (I) wherein Y represents a group of formula (II).

f) Due to the low working time and the excellent yields, the process according to the invention can be used very well on an industrial scale. The use of the space is also very advantageous: in a 1 m3 working space, 240 kg of a compound of formula (I) in which Y represents a group of formula (II) or 100 to 160 kg of a compound of formula (I) in which Y represents III).

8 84912

The process according to the invention is illustrated in more detail by the following non-limiting examples.

Example 1 Preparation of S- (2-guanidinothiazol-4-ylmethyl) isothiourea dihydrochloride di monohydrate (compound of formula (I) wherein Y represents a group of formula (II))

Example 1.1 11.8 g (0.1 mol) of amidinothiourea are added over 2 hours to a stirred solution of 12.7 g (0.1 mol) of 1,3-dichloroacetone and 0.75 g (0.005 mol) of sodium iodide in 92 ml: in acetone. Stir for a further 2 hours, then add 9.2 g of water and, after a short boil, form a solution. To this solution is added 7.6 g (0.1 mol) of thiourea, after which the mixture is boiled for one hour. The reaction mixture containing the oily reaction product is allowed to cool with stirring. The crystal suspension thus formed is cooled to 0 ° C, then filtered, washed twice with acetone and dried to give the title compound, m.p.

209-213 ° C (dec.), Yield 27.86 g (85%) with an active ingredient content of 98% as determined by potentiometric titration.

Example 1.2 35.4 g (0.3 moles) of amidinothiourea are added portionwise over 1 hour to a stirred solution of 38.1 g (0.3 moles) of 1,3-dichloroacetone and 2.25 g (0.015 moles) at 30-36 ° C. ) sodium iodide in 240 ml acetone. The crystal suspension thus obtained is stirred at the same temperature for a further hour, then 30 ml of water and 24 g (0.315 mol) of thiourea are added, after which the mixture is heated under reflux with stirring for 1 hour. The mixture is allowed to cool to room temperature, the crystalline product is filtered and washed twice with 40 ml of 90% acetone to give the title compound, m.p. 210-214 ° C (dec.), Yield 88.02 g (89.7%) of active ingredient content 98.2% as determined by potentiometric titration.

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Example 1.3 127.0 kg (500 moles) of 1,3-dichloroacetone in a 50% by weight acetone solution are pumped into a 1000 liter reactor. 257 kg of acetone and 3.75 kg (25 moles) of sodium iodide are added, followed by 60.5 kg of amidinothiourea (purity 97.6%, 500 moles) portionwise to the reaction mixture over 1.0 to 1.5 hours with stirring. The desired internal temperature of 30 to 40 ° C is maintained by running cold industrial water in the jacket. The reaction mixture is stirred for 1 hour, then 50 l of water and 41.2 kg of thiourea (purity 97%, 525 mol) are added and the mixture is boiled with stirring for 1 hour. The reaction mixture is then allowed to cool slowly to room temperature over 2-3 hours, the suspension is centrifuged, the product is washed in a centrifuge with an 8: 1 mixture of acetone and water and dried to give the title compound, m.p. 209-214 ° C (dec.), Yield 148.3 kg (90.0%) with an active ingredient content of 97.5%.

Example 2 Preparation of 3- (2-guanidinothiazol-4-ylmethylthio) propionitrile (compound of formula (I) wherein Y is a group of formula (III))

Example 2.1 20 ml of 10 N sodium hydroxide solution (40%) are added portionwise to a solution containing 32.78 g (0.1 mol, 98%) of S- (2-guanidinothiazol-4-ylmethyl) isothiourea dihydrochloride monohydrate (prepared according to Examples 1.1, 1.2 or 1.3) and 8.0 g (0.15 mol) of acrylonitrile in 100 ml of water and 40 ml of isopropanol. Stir for 2 hours, then add 30 ml of water and cool on ice, then filter the precipitated product, wash with water, then with isopropanol and dry to give the title compound, m.p. 127-129 ° C, yield 22 g (91%) of active ingredient at 99.0% as determined by potentiometric titration with hydrochloric acid.

10 84 91 2

Example 2.2 65.8 g (0.20 mol) of the product prepared according to Example X.1 are mixed with a mixture of 16 g (0.30 mol) of acrylonitrile, 80 ml of water and 60 ml of alcohol. 43 ml (0.43 mol) of 10N sodium hydroxide solution are added, stirred for 2 hours, filtered at 15-20 ° C, washed with water and then with alcohol and dried to give the title compound, yield 45.4 g (94%), m.p. 127-128 ° C. The active ingredient content is 99.1% as determined by titration.

Example 2.3

A solution of 38.1 g of 1,3-dichloroacetone and 2.25 g of sodium iodide in 240 ml of acetone is treated with 35.4 g of amidinothiourea with stirring as described in Example 1.2. 120 ml of water and 24 g of thiourea are added, then 220 ml of acetone are distilled off from the reaction mixture. 90 ml of ethanol, 24 g of acrylonitrile and 63 ml of 10 N sodium hydroxide solution are poured into the cooled residue. Stir for an additional 2 hours and cool to below 20 ° C, then filter the mixture, wash the precipitate with water, then alcohol and dry to give the title product, m.p. 127-128 ° C, yield 62.1 g (84.8%). The content of the active ingredient is 98.9%.

Claims (3)

A process for the preparation of 2-guanidinothiazole derivatives of the general formula (I) h2n n - and salts thereof, wherein Y represents a group of the formula (II) (II) -C2HN or a group of the formula (III) -ch2-ch2-cn (III ) by cyclizing an amidinothiourea of the formula (IV) H2V NH2 av, h2n ^ n ^ s with 1,3-dihaloacetone in a solvent, preferably acetone, characterized in that the cyclization is carried out in the presence of a solvent-soluble iodide catalyst, preferably sodium iodide. , followed by isolating without isolation the halogen derivative of formula (V) 8491 2 Η, Ν N— λ- Λ \ · ΗΧ CV) Η2 merk /, wherein X represents halogen, with thiourea in the presence of water to give a compound of formula (I) wherein Y represents a group of formula (II) and which, if desired, is S-cyanoethylated with acrylonitrile in the presence of an alkaline aqueous alkanol medium to give the formula a compound of formula (I) wherein Y represents a group of formula (III). Process according to Claim 1, characterized in that 1 to 10 mol%, in particular 4 to 6 mol%, of iodide catalyst are used. Process according to Claim 1 or 2, characterized in that a compound of general formula (I) in which Y represents a group of formula (II) is formed at 20 ° C to 50 ° C. Il i3 8491 2