IE43549B1

IE43549B1 - New process for the preparation of hydantoin derivatives

Info

Publication number: IE43549B1
Application number: IE200776A
Authority: IE
Original assignee: Philagro Sa
Priority date: 1975-09-11
Filing date: 1976-09-08
Publication date: 1981-03-25
Also published as: DD126533A5; CH615921A5; IE43549L; FR2323688A1; SU660593A3; GB1504840A; BR7605842A; CA1068284A; FR2323688B1

Abstract

1504840 1 - Carbamoyl - 3 - (3,5 - dichlorophenyl)hydantoins PHILAGRO 8 Sept 1976 11 Sept 1975] 37227/76 Heading C2C Compounds (I) where R is C 1-4 alkyl or C 2-4 alkenyl are made by cyclizing compounds (III), suitably at up to 100‹ C. with an organic acid anhydride. 2 - [3 - (3,5 - Dichlorophenyl) - 1 - isopropylcarbamoylureido]acetic acid is made by reacting glycine with isopropyl isocyanate, cyclizing the resulting 2-(3-isopropylureido)acetic acid, reacting the formed 3-isopropylhydantoin with 3,5 - dichlorophenyl isocyanate and treating the resulting 1 - (3,5 - dichlorophenyl)carbamoyl- 3-isopropylhydantoin with NaOH.

Description

THIS INVENTION relates to a new process for the preparation of hydantoin derivatives of the general formula: > wherein R represents an alkyl radical containing 1 to 4 carbon atoms or an alkenyl radical containing 2 to 4 carbon atoms.

The l-carbamoyl-3-(3,5-dichlorophenyl)hydantoins of general formula I,in particular l-isopropylcarbamoyl-3Q (3,5-dichlorophenyl)hydantoin, possess valuable fungicidal properties, and are described and claimed in the Specification of British Patent 1312536.

A process described and claimed in British Patent Specification 1312536 for the preparation of hydantoin - derivatives of general formula I involves the reaction of an isocyanate of the general formula: R - N = C = 0 II (wherein R is as hereinbefore defined) with 3-(3,5dichlorephenyl)hydantoin, which is itself obtained by the ) cyclisation of 3-(3,5-dichlorophenyl)ureidoacetic acid either in an aqueous acid medium or in an organic medium in the presence of a dehydrating agent.

It has now been found, and it is this which forms the subject of the present invention, that the hydantoin derivatives of general formula I, more especially those in which R represents an alkyl radical, can be obtained in good or excellent yields by the cyclisation of an acid of the general formula: III wherein R is as hereinbefore defined, e.g. 2—£3-(3,5— dichlorophenyl)-l~isopropylcarbamoyl-ureido]acetic acid.

Compounds of general formula III are described and claimed in Patent Specification No. 43426.

In general, the cyclisation Ϊ3 carried out with the aid of an anhydride of an organic acid, such as acetic anhydride, optionally in an organic solvent, and at a temperature between ambient temperature and 1OO°C., for example 15 to 25°C. The solvent used is preferably a polar organic solvent such as, for example, dimethylformamide or N-methylpyrrolid-2-one. In the absence of such a solvent, the acid anhydride, e.g. acetic anhydride, is used in excess and the excess serves as a solvent. The acids of general formula III can be obtained by the action of an inorganic base, e.g. sodium hydroxide, potassium hydroxide or ammonia, - 3 in aqueous organic solution, e.g. a mixture of ethanol and water, on a hydantoin derivative of the general formula: wherein R is as hereinbefore defined. The reaction is generally carried out at a temperature' between 20 and 80°C.

The hydantoin derivatives of general formula IV can be obtained by the action of 3,5-dichlorophenyl isocyanate on a hydantoin of the general formula: H 0=J-N —R wherein R is as hereinbefore defined.

Tiie, hydantoin derivatives of general formula V can be obtained by cyclisation of an acid of the general formula: r-nh-co-nh-ch2-cooh VI (wherein R is as hereinbefore defined) ih an organic medium, such as chlorobenzene, in the presence of a dehydrating agent, e.g. sulphuric acid. - li 4 3 5 4 9 Tha acids of the general formula VI can be obtained by the action of an isocyanate of general formula II on glycine.

The following Examples illustrate the process of the invention for the preparation of hydantoin derivatives of general .formula I.

EXAMPLE 1 2-[3-(3,5-Dichlorophenyl)-1-isopropylcarbamoylureido]acetic acid (34.8 g.) is added to acetic anhydride (180 cc.) and the reaction mixture is stirred at a temperature of about 20°C. for 17 hours. The product gradually passes into solution during this period. The reaction mixture is then poured into water (two litres), whilst stirring, after which the suspension obtained is cooled with ice-water. The precipitate which forms is filtered off, washed with water (2 x 150 cc.) and dried under reduced pressure. l-Isopropylcarbamoyl-3-(3,5dichlorophenyl )hydantoin (33 g.), melting at 135°C., is thus obtained. 2-[3-(3,5-Dichlorophenyl)-1-isopropylcarbamoy1ureido3acetic acid can be obtained in the following manner: ION Sodium hydroxide (80 cc.) and water (50 cc.) are added gradually to a suspension of 1-(3,5-diehlorophenyl)carbamoyl-3-isopropylhydantoin (16.5 g.) in ethanol - 5 435 48 (80 cc.). The reaction mixture Is heated ro about 60°C-, whilst stirring. It is then poured into water (1 litre) and the suspension obtained is filtered in the presence of decolourizing charcoal. The limpid filtrate is then poured, whilst stirring, into a mixture of hydrochloric acid (d - 1.19; 100 cc.) and crushed ice (300 g.). The mixture is then extracted with diisopropyl ether (300 cc. followed by 100 cc.). The organic solution is dried and concentrated to dryness under reduced pressure. The oily residue obtained (14 g.) is crystallized from a mixture of diisopropyl ether (100 cc.) and petroleum ether (b.p. 35-60°C.; 100 cc.). 2-[3-(3,5-Dichlorophenyl)-lisopropylcarbamoyl-ureidojacetic acid (12 g.), melting with decomposition at 175°C., is thus obtained. 1-(3,5-Dichlorophenyl)carbamoyl-3-isopropylhydantoin can be prepared in the following manner: A solution of 3,5-dichlorophenyl isocyanate (71.5 g.) in acetone (250 cc.), and triethylamine (38.4 g.) are added successively, whilst stirring, to a solution of 3-isopropylhydantoin (56.8 g.) in acetone (250 cc.). The temperature of the reaction mixture rises gradually from 25°C. to 50°C. over the course of 20 minutes and then again drops, whilst a copious precipitate forms. The reaction mixture is stirred for a further 5 hours at a temperature of about 20°C. The precipitate is filtered - 6 ‘4 3 3 4 3 off, washed with acetone (2 x 50 cc.) and. then dried under reduced pressure. 1-(3,5-Dichlorophenyl)carbamovl3-isopropylhydnntoin (100 g.), melting at 200°C., is thus obtained. 3-Isopropylhydanfcoin can be prepared in the following manner: A suspension of 2-(3-isopropylureido)acetic acid (66 g.) in chlorobenzene (250 cc.) is heated at 90°C., and sulphuric acid (d = 1.83; 6 cc.) is then added to this suspension. The reaction mixture is heated gradually to about 110°C., with constant stirring. The water formed is separated off by azeotropic distillation. The distillation is stopped when the temperature of the vapours roaches 126°C. The reaction mixture is cooled, and potassium carbonate (10 g.) and distilled water (20 cc.) are added successively, tho water being added with appropriate precautions. After the evolution of carbon dioxide has ceased, potassium carbonate (20 g.) is again added and stirring is continued for one hour. The reaction mixture is diluted with methylene chloride (300 cc.), the aqueous phase is decanted and the organic phase is dried over anhydrous sodium sulphate. After filtration and concentration under reduced pressure, 3-isopropylhydant,oin (50.8 g.), melting at 86°C., is obtained. - 7 2-{3-Isopropylureido)acetic acid can be prepared in the following manner: A solution of glycine (75.1 g.) in H sodium hydroxide solution (one litre) is heated at 36°C. A solution of isopropyl isocyanate (76.5 g.) in acetone (100 cc.) is then added dropwise, whilst stirring. A rise in temperature from 36°C. to 50°C. is observed in the course of the addition. The reaction mixture is stirred for a further 30 minutes after the end of the LO addition. Crushed ice (500 g.) and water (250 cc.) are then added, and the mixture is acidified by adding 5N hydrochloric acid (200 cc.) with stirring. The : precipitate is filtered off, and dried. 2-(3-Isopropylureido)acetic acid (70 g.), melting at 178°C., is thus obtained. A second crop (4ft g.) of 2-(3-isopropylureido)~ acotic acid, melting at 178°C., is obtained by concentrating the filtrate.

EXAMPLE 2 2-[3-(3,5-Dichlorophenyl)-1-isopropylcarbamoyl3 ureidojacetic acid Oft.8 g.) is added to acetic anhydride (150 cc.)· The suspension obtained, is stirred for 2 hours at a temperature of about 20°C., during which period the product gradually dissolves. After two hours, the solution obtained is poured into water (1 litre) whilst stirring. ί The precipitate which forms is filtered off, washed with ώ ΰ a S water (2 χ 150 cc.) and dried under reduced pressure. l-Isopropylcarbamoyl-3-(3,5-dichlorophenyl)l·/dantoin (33 g.), melting at 135°C., is thus obtained. Yield: 100%.

EXAMPLE 3 2-[3~(3,5-Dichlorophenyl)-1-isopropylcarbamoyluioidojacetic acid (34.8 g.) is added to acetic anhydride (50 cc.) in solution in N-methylpyrrolid-2-one (100 cc.). After stirring for 1 hour 30 minutes at a temperature of about 20°C., the solution obtained is poured into water (1 litre) whilst stirring. The precipitate which forms is filtered off, washed with water (2 x 150 cc.) and dried under reduced pressure. l-Isopropylcarbamoyl-3(3,5-dichlorophenyl)hydantoin (33 g.), melting at 135°C., is thus obtained. Yield: 100%.

Claims

1. Process for tho preparation of a l-carbamoyl-3-(3,5-dichlorophenyl)hydantoin of the gencra-l formula: COJSH-R (wherein R represents an alkyl radical containing 1 to 4 carbon atoms or an alkenyl radical containing 2 to 4 carbon atoms) which comprises the cyclisation of an acid of the general formula: wherein R is as hereinbefore defined.

2. ' Process according to claim 1 in which the cyclisation is carried out at a temperature between ambient temperature and 100°C. with an anhydride of an organic acid.

3. Process according to claim 2 in which the organic acid anhydride is acetic anhydride. - 10

4. Process according to any one of claims 1 to 3 in which the cyclisation is carried out in the presence of a polar organic solvent.

5. Process according to claim 4 in which the 5 polar organic solvent is N-methylpyrrolid-2-one.

6. Process according to any one of the preceding claims in which the cyclisation of the acid is carried out at 15 to 25°C.

7. Process according to any one of the io preceding claims in which the acid cyclized is of general formula III depicted in claim 1 wherein R represents an alkyl radical containing 1 to 4 carbon atoms.

8. Process according to any one of claims 1 to 6 in which the acid cyclized is 2-[3-(3,5-dichlorophenyl)-!)5 isopropylcarbamoyl-ureido]acetic acid.

9. Process for the preparation of 1-carbamoyl3-(3,5-dichlorophenyl)hydantoins as claimed in claim 1 , substantially as hereinbefore described with especial reference to Example 1, 2 or 3.

10. l-Carbamoyl-3-(3,5-dichlorophenyl)hydantoins of the general formula specified in claim 1 when prepared by the process claimed in any one of the preceding claims.

11. l-Isopropylcarbamoyl-3-(3,5-dichlorophenyl)hydantoin when prepared by the process claimed in claim 8 or 9.