HU188160B - Process for preparing 2-imidazolidinone-1-thiocarvoxylic acid amide - Google Patents

Abstract

The present invention relates to a process for the large-scale production of 2-imidazolidinone-1-thiocarboxylic acid of formula (I) by reacting a rodan of formula (IV) wherein Me is an alkali metal or ammonium and benzoyl chloride, to obtain the benzoyl isothiocyanate of formula (II). Reaction of 2-imidazolidinone, followed by basic hydrolysis of N-benzoyl-2-imidazolidinone-1-thiocarboxylic acid of formula (III), by reacting the rodan of formula (IV) and benzoyl chloride at 0-30 ° C. the resulting benzoyl isothiocyanate of formula (II) is reacted in the reaction mixture formed in its preparation without isolation with 2-imidazolidinone and then in the reaction mixture of the resulting N-benzoyl-2-imidazolidinone-1-thiocarboxylic acid, without isolation. Hydrolyzed at 0-30 ° C with an alkali metal hydroxide from a dipolar aprotic solvent and in a protic solvent. reaction medium. The compound of formula (I) is known as a pharmaceutical intermediate. Our process allows the preparation of the compound of formula (I) to be produced in a substantially better yield, in pure form, and in conditions which can be advantageously carried out in industrially acceptable conditions. NH N - CZ '11 0> 0' N = C = θ CH 1, - CH 1 x nh-c s N NH xc / I 0 Me-SCN IV -1-

Description

The present invention relates to an improved process for the preparation of 2-imidazolidinone lithiocarboxylic acid amide of formula (I) which is advantageously carried out under large-scale conditions.

The 2-imidazolidinone-1-thiocarboxylic acid amide of formula (I) is a known pharmaceutical intermediate which is useful, for example, in the preparation of 1- (5-nitro-2-thiazolyl) -2-imidazolidinone (Yarocen) against the gut worm Bilharzia.

In a known process for the preparation of a compound of formula I, the benzoyl chloride is reacted with a rhodanide of formula IV (wherein Ma is an alkali metal or ammonium), and the resulting benzoyl isothiocyanate of formula II is reacted with 2-imidazolidinone after isolation and the resulting N-benzoyl-2-imidazolidinone-thiocarboxylic acid amide (III) is also subjected to alkaline hydrolysis after isolation and purification. According to one embodiment of the first step of the synthesis [J. Chem. Soc. 56, 719 (1934)], benzoyl chloride and ammonium rhodanide are reacted in hot acetone at the boiling point of the reaction mixture; the reaction mixture is poured into water to give benzoyl isothiocyanate as an oil.

The above methods have several disadvantages. Benzoyl isothiocyanate, on the one hand, is formed in the form of a contaminated, difficult to clean oil. Purification of this compound is difficult and requires vacuum distillation. In addition, the isolated benzoyl isothiocyanate is a difficult-to-handle, highly unpleasant, odorous substance which, even in the presence of small amounts of water, is decomposed to highly toxic substances (COS, rhodanic acid, hydrogen cyanide) (Beilstein, Handbuch Der Org. Chemie, Vol. Page 222).

The isolated and thoroughly purified benzoyl isothiocyanate of formula (II) is then reacted with 2-imidazolidinone in dimethylformamide medium at 90 'Cos for 4 hours [Helv. Chim. Acta 49, 2443 (1966)]. In this way, N-benzoyl-2-imidazolidinone-l-thiocarboxylic acid amide (III) is obtained in a yield of 32%. In the third step of the synthesis, the compound of formula (III) is subjected to alkaline hydrolysis. According to the literature, the hydrolysis of 1,1-disubstituted-3-benzoylthioureas can only be carried out under vigorous heating under vigorous reaction conditions, even in moderate yields [J. Chem. Soc., 56, 408 (1934)]. The Helv. Chim. Acta 49, 2443 (1966), the N-benzoyl-2-imidazolidinone-1-thiocarboxamide (III) is hydrolysed with aqueous sodium hydroxide at boiling point. The resulting product is so contaminated that it needs to be purified by sublimation. Said publication reports a yield of 62%, the material purified by sublimation melts at 203-206 ° C.

The implementation of the three-step process described above on an industrial scale is difficult. The overall yield of the three steps is less than 20%, the process requires the purification of degradable, difficult to handle and environmentally hazardous substances (benzoyl isothiocyanate), and the resulting compound of formula (I) needs to be thoroughly purified by sublimation.

SUMMARY OF THE INVENTION It is an object of the present invention to overcome the above-mentioned drawbacks of the above methods for the production of an important pharmaceutical intermediate of formula (I) which can be advantageously carried out on a large scale.

The present invention relates to a process for the large-scale preparation of 2-imidazolidinone-1-thiocarboxylic acid amide of formula (I) by reacting a rhodanide of formula (IV wherein Me is an alkali metal or ammonium) with benzoyl chloride to give benzoyl isothiocyanate reaction of the imidazolidinone followed by basic hydrolysis of the resulting N-benzoyl-2-imidazolidinone-1-thiocarboxylic acid (III) by reaction of rhodanide (IV) with benzoyl chloride at 0-30 ° C. the resulting benzoyl isothiocyanate of formula (II) is reacted in its reaction mixture without isolation with the 2-imidazolidinone and then the N-benzoyl-2-imidazolidinone-1-thiocarboxylic acid amide (III) formed in the reaction mixture without isolation, At -30 ° C, it is hydrolyzed with an alkali metal hydroxide from a dipolar aprotic solvent and a protic solvent. horse in reaction medium.

The present invention is based on the discovery that the reaction of benzoyl chloride with ammonium rhodanide or alkali metal rhodanide under appropriate conditions produces a product of such purity that the isolation and purification of the benzoyl isothiocyanate of formula (II) is unnecessary.

The conditions and mechanism for the formation of aryl isothiocyanates are poorly understood in the literature, but there are numerous reports on the preparation of suitable alkyl isothiocyanates. It has been reported in the literature that the reaction of alkali metal thiocyanates and alkyl halides at low temperatures leads to kinetically controlled and clear alkyl thiocyanates. If the reaction is carried out at a higher temperature or the alkyl thiocyanate is subsequently heated, the reaction is obtained in a thermodynamically controlled, i.e., more stable, isomer, the alkyl isothiocyanate.

The reaction of alkali metal thiocyanates with aroyl halides results in the amide reactivity of the mesomeric thiocyanate isothiocyanate anion and both isomers are formed.

Surprisingly, it has been found that, unlike the formation of alkyl isothiocyanates, raising the temperature during the preparation of the benzoyl isothiocyanate, in particular boiling in the reaction medium, reducing the yield of the desired benzoyl isothiocyanate, and causing a substantial deterioration of the product quality. The higher reaction temperatures used in the literature are not uniform by thin layer chromatography and, besides the desired transformation, side reactions occur which are increasingly brought to the fore by increasing the temperature.

It has been found that when the reaction of the benzoyl chloride and the compound of formula IV is carried out at low temperatures between 0 ° C and 30 ° C, the side reactions are virtually completely suppressed and the desired benzoyl isothiocyanate is obtained in such pure form that without purification;

188 160

It can be further modified in the reaction mixture generated by your passenger.

Ammonium, sodium or potassium rhodanide may be used as the compound of formula IV. The reaction components are preferably reacted in equimolar amounts, but small amounts of one of the components can be used. The reaction is preferably carried out in dipolar aprotic media (e.g. acetone). The reaction temperature, as mentioned above, may be from about 0 ° C to about 30 ° C, preferably about room temperature, but at a temperature of from about 0 ° C to about 10 ° C, a high purity product is obtained. The reaction also takes place over a short period of time, some 3-4 hours, at the low temperature used.

The resulting benzoyl isothiocyanate is reacted with the 2-imidazolidinone in the reaction mixture formed during its preparation. The reaction may be carried out under heating, preferably at 50-60 ° C. Conveniently, the reaction mixture can be worked under reflux. The reaction takes place very quickly within 1-2 hours.

The N-benzoyl-2-imidazolidone-1-thiocarboxylic acid amide of formula (III) thus formed is subjected to basic hydrolysis in the reaction mixture without isolation. Contrary to the findings in the literature, it has now surprisingly been found that the benzoyl group can be cleaved even at low temperatures with excellent yields. The reaction may be carried out at a temperature of 0 to 30 'C, preferably at a temperature of 5 to 25' C. This is a very useful recognition in practice since it is known in the literature [Bér. 46, 1908 (1913)] that the 2-imidazolidinone ring is decomposable in alkaline media and decomposes on formation of carbon dioxide and ethylenediamine and its derivatives under various heating conditions. This fact is supported by the finding that 2-imidazolidinone-1-thiocarboxylic acid (I) obtained by alkaline boiling of the compound of formula (III) had to be subjected to sublimation purification [Helv. Chim. Acta. 49, 2443 (1966)].

The gentle hydrolysis employed in the process of the present invention avoids the side reactions outlined above and yields a highly purified product in very good yield. The process does not require any recrystallization purification to provide the product directly as a pharmaceutical intermediate, m.p. 204-207C.

The alkaline hydrolysis is preferably carried out in a reaction medium consisting of a dipolar aprotic solvent and a protic solvent. Preferably the dipolar aprotic solvent is acetone, while the protic solvent is preferably lower alkanol, preferably methanol and / or water. In a preferred embodiment of the process of the invention, the alkaline hydrolysis may be carried out in a mixture of acetone, methanol and water in a ratio of 1: (0.2-1.5): 1, preferably 1: 1: 1. The dipolar aprotic solvent, especially acetone, is already used in the first step of the synthesis for the preparation of the benzoyl isothiocyanate (II) and thus in the reaction mixture containing the N-benzoyl-2-imidazolidinone-1-thiocarboxylic acid (III) to be hydrolyzed. The protic solvents are preferably introduced into the system by addition of methanol and an aqueous solution of alkali metal hydroxide. In our process, hydrolysis occurs in a glazed reaction medium at a temperature of 0 to 30 ° C in a short period of time, within a few hours, in very good yield. Upon hydrolysis, the sodium benzoate formed with the compound of formula (I) remains in solution and can be recovered from the mother liquor after isolation of the 2-imidazolidinone-1-thiocarboxylic acid amide of formula (I).

The alkaline hydrolysis may be carried out with sodium or potassium hydroxide.

The advantages of the process of the present invention are summarized below:

- The process can be carried out on an industrial scale with excellent yields; the total yield of 2-imidazolidinone or benzoyl chloride is 74-77%, compared to 15-20% of the yield in the literature.

- The process is very environmentally and occupationally friendly as there is no need to isolate and purify the benzoyl isothiocyanate, which is difficult to handle and transforms into highly toxic decomposition products.

By eliminating the isolation of intermediates of formulas II and III, the process can be carried out in a single apparatus, which greatly improves capacity utilization and economy.

By suppressing the side reactions, a very high purity product is obtained and sublimation purification that is difficult to achieve on an industrial scale is eliminated.

- The single-device method is very favorable for solvent management, significantly less energy is required to regenerate solvents and solvent loss is also reduced.

The following non-limiting Examples illustrate the invention without further limiting it.

Example 1

To a solution of 14.1 g (0.185 mol) of ammonium rhodanide and 84 ml of acetone is added dropwise at 20 ° C 26 g (0.185 mol) of benzoyl chloride and the reaction mixture is stirred for 2 hours at room temperature. 15 g (0.174 mol) of 2-imidazolidinone are then added portionwise at 20 ° C and the reaction mixture is refluxed for 2 hours at 55-60 ° C. The reaction mixture was cooled to 20-30 ° C, methanol (84 ml) was added, and a solution of 11.4 g of sodium hydroxide in 84 ml of water was added dropwise from a dropping funnel at 20-30 ° C over half an hour. The reaction mixture was stirred at room temperature for 5 hours, cooled for 2 hours, then the crystalline crystalline 2-imidazolidinone-1-thiocarboxylic acid amide was filtered off and washed with water. 18.7 g of product are obtained, m.p. 204 'C, yield 73.9%.

Example 2

14.1 g (0.185 mol) of ammonium rhodanide and 26 g (0.185 mol) of benzoyl chloride were reacted at 0-5 C

188 160 were added as described in Example 1, then 16 g (0.185 mole) of 2-imidazolidinone was added to the reaction mixture containing benzoyl isothiocyanate and proceeded as in Example 1 below. 20.6 g of 2-imidazolidinone 1 -tiokarbonsavamidot obtained ⁵ Yield: 76.35%, m.p .: 206 ° C;

Example 3 ^F 10

14.1 g (0.185 mole) of ammonium rhodanide and 26 g (0.185 mole) of benzoyl chloride are reacted at 0-5 ° C in the same manner as in Example 2, and 16 g (0.185 mole) of 2-imidazolidinone are added thereto. the mixture was heated at ¹⁵ visszafolya- lake cooling for 1.5 hours at 55-60 ° C. The reaction mixture was cooled to 10-20 ° C, methanol (80 ml) followed by a solution of sodium hydroxide (11.4 g) in water (80 ml) was added and the reaction mixture was stirred at 5-15 ° C for 5 hours. The reaction mixture was cooled and the crystalline product precipitated was filtered and washed. Yield: 20.8 g (77.4%) of 2-imidazolidinone-1-thiocarboxylic acid, m.p.

Example 4 kg of ammonium rhodanide is dissolved in 451 L of acetone and then 140 kg of benzoyl chloride is added at 20 ° C over 4 hours. After this was stirred for ³⁰ at room temperature for 2 hours and 86 kg of 2-imidazolidinone was added and the mixture was heated at 55-60 ° C for 2 hours.

The mixture was cooled and 20-30 ° C in 454 1 of methanol and 61.5 kg of sodium hydroxide in ³⁵ 1 water 454 is added to the reaction mixture over 1 hour. After stirring for 5 hours at room temperature, the reaction mixture was cooled to 0-5 ° C for 2 hours, and the crystalline 2-imidazolidinone-1-thiocarboxylic acid amide was filtered off and washed with water to make it alkaline. 108-110 kg of 2-imidazolidinone-1-thiocarboxylic acid amide are obtained. Yield: 74.5-76%, m.p. 206 ° C.

Claims (4)

Patent claims A process for the large-scale preparation of 2-imidazolidinone-1-thiocarboxylic acid amide of formula (I) by reacting a rhodanide of formula (IV) wherein Me is an alkali metal or ammonium) with benzoyl isothiocyanate of formula (II). reaction of the imidazolidinone followed by basic hydrolysis of the resulting N-benzoyl-2-imidazolidinone-1-thiocarboxylic acid amide III, characterized in that the reaction of rhodanide IV with benzoyl chloride is carried out at 0-30 ° C. the benzoyl isothiocyanate of formula (II) is reacted with 2-imidazolidinone without isolation and the resulting N-benzoyl-2-imidazolidinone-l-thiocarboxylic acid amide (III) in the reaction mixture without isolation; Hydrolysis at 30 ° C with an alkali metal hydroxide reaction of dipolar aprotic solvent and protic solvent medium. 2. The process of claim 1 wherein the dipolar aprotic solvent is acetone. 3. The process according to claim 1, wherein the protic solvent is a lower aliphatic alkanol, preferably methanol, and / or water. 4. The process according to any one of claims 1 to 3, wherein the mixture of dipolar aprotic solvent and protic solvent is 1: (0.2-1.5): 1, preferably 1: 1: 1 acetone-methanol-water. 1 figure