Process for the preparation of 5-arylhydantoins.

(42) Date of commencement of the patent: 15. 2. 1994 (45) Date of issue: 25.10.1994

<td>(56) Documents:</td><td>(73) Patent owner:</td>

<td>EP-A2 / A3 79021</td><td>CHEMIE LINZ SOCIETY MBH A-402I LINZ, UPPER AUSTRIA (AT).</td>

<td></td><td>(72) Inventor:</td>

<td></td><td>HENDEL TOLFRAM OR. LEONDING, UPPER AUSTRIA (AT). KLOIMSTEIN ENGELBERT ING. EFERDING, UPPER AUSTRIA (AT). FITZINGER KLAUS LINZ, UPPER AUSTRIA (AT). VIEHBÖCK ANTONIA LINZ, CBERÖSTERREICH (AT). HAIDINGER KURT LINZ, UPPER AUSTRIA (AT).</td>

(54) PROCESS FOR PREPARING ARYLHYDANTOINES (57) A process for preparing 5-arylhydantoins by reacting allantoic acid alkyl esters with an aryl compound in concentrated inorganic acid at temperatures from room temperature to 150 ⁰ C with or without a phase mediator.

CQ

AT 398 199

MR 6078018

AT 398 199 Β

Arylhydantoins are valuable intermediates for the preparation of enantiomerically pure arylamino acids, which are used, for example, in pharmacy.

Processes for the preparation of arylhydantoins have been known for a long time.

For example, according to EK Harvill et al., J. Org. Chem. 9, 26 (1944), 5- (4-hydroxyphenyl) -hydantoln be prepared by reacting p-hydroxybenzaldehyde with potassium cyanide and ammonium carbonate in aqueous, alcoholic solution. However, cyanides are toxic and are only used in technical processes when it is unavoidable.

From GB-A-2 012 756 it can be seen that 5-arylhydantoins can be obtained by reacting urea with an alpha-aryl-alpha-hydroxyacetic acid.

The alpha-aryl-alpha-hydroxy acid is prepared by reacting glyoxylic acid with an aryl compound in an aqueous medium in the presence of an alkali metal hydroxide, but difficult to be separated isomeric mixtures, so that this reaction generally succeeds only with low yields.

GB-A-20 53 206 discloses the preparation of 5-arylhydantoins by reacting allantoin with an aryl derivative in a hot, acidic medium. For the implementation, however, allantoin must first be prepared.

According to GB-A-1 572 316, 5- (4-hydroxyphenyl) -hydantoin can be prepared from simple starting materials, namely from glyoxylic acid, urea and phenol in aqueous, acidic solution. However, it has been found that the product of this reaction is relatively heavily contaminated by its isomeric 5- (2-hydroxyphenyl) hydantoin, which is poorly soluble.

According to EP-A-0 474 112, glyoxylic acid methyl ester methyl hemiacetal is reacted with urea and an aryl compound in a one-pot process to produce 5-arylhydantoins of good purity.

The long reaction times of 20 hours and more are not sustainable for a technical procedure.

Unexpectedly, it has now been found that 5-arylhydantoins are obtained in a 2-stage reaction starting from simple, non-toxic starting materials in high purity, when reacted in a first reaction step a Glyoxylsäurealkylesteralkylhemiacetal with urea to Allantoinsäurealkylester, this isolated and then in a 2nd reaction stage react with an aryl compound, wherein the reaction times are surprisingly very short in both stages.

The invention therefore provides a process for the preparation of 5-arylhydantoins of the general formula

CH-CO

<img file="AT398199B_D0001.tif" />

NH in the Ri, R2 and R3 are independently hydrogen, alkyl, alkoxy, hydroxy, halogen or acylated amino groups, which is characterized in that a Allantoinsäurealkylester of the general formula

<img file="AT398199B_D0002.tif" />

CH H₂N - C-HN

<img file="AT398199B_D0003.tif" />

il il

AT398 199 B in which FL is an alkyl group having 1 to 6 C atoms, in concentrated, inorganic acid at temperatures from room temperature to 150 ° C with or without a phase mediator with an aryl compound of the general formula

<img file="AT398199B_D0004.tif" />

III in the Ri, R₂ and R3 have the meaning given above, is reacted.

In the general formula I, Ri, R₂ and R3 is independently hydrogen, an alkyl, alkoxy, hydroxy, halogen or acylated amino group. Alkyl or alkoxy groups are to be understood as meaning groups having 1 to 6, preferably 1 to 3, C atoms, for example methyl, ethyl, propyl, iso-propyl, hexyl groups, halogen, fluorine, chlorine or bromine. Acylated amino groups are amino groups which are substituted by acyl groups having 1 to 8 C atoms, preferably by the acetyl group. Preferably, Ri, R₂ and R3 are independently hydrogen, hydroxy, alkoxy or halogen groups. Most preferably Ri is hydrogen and R is₂ and R3 are independently hydrogen, hydroxy or alkoxy groups.

In the general formula II, R4. an alkyl group having 1 to 6 carbon atoms. By alkyl group is meant a straight-chain or branched alkyl group, for example a methyl, ethyl, propyl, isopropyl, isopentyl, hexyl group, preferably a methyl, ethyl or isopropyl group.

The preparation of compounds of the formula II can be carried out by reacting a Glyoxylsäurealkylesteralkyliaciacetals with urea in the presence of an alkyl alcohol and a mineral acid. The preparation of the allantoic acid methyl ester from methyl glyoxylate methyl hemiacetal and urea in the presence of inorganic acid and methanol is disclosed, for example, in EP-A-0 460 412. This reaction is generally completed within a few hours.

In general formula III, Ri, R₂ and R3 is the meaning given in the general formula I. Very particularly preferred compounds of the general formula III are benzene, phenol, dihydroxybenzene, anisole or gujacol.

To carry out the reaction according to the invention, the compound of the formula II and the compound of the formula III are initially charged in an inorganic acid.

In general, 1 to 6, preferably 1 to 3, moles of the compound of the formula III are employed per mole of the compound of the formula II. However, in individual cases it may be advantageous to use the compound of formula III in deficit.

As inorganic acids mineral acids such as hydrochloric acid, sulfuric acid, or mixtures of such acids are used. The amount of acid depends on the type of compound III, which is difficult to dissolve in the acid in some cases. In order to increase the solubility of the compound III in the acid, a phase mediator, for example a liquid, organic acid such as acetic acid, propionic acid, if necessary acetic acid is optionally used.

The reaction mixture is stirred at temperatures of about room temperature to 150 ° C., preferably at temperatures of 60 to 100 ° C., more preferably from 70 to 90 ° C. Optionally, the reaction is carried out under pressure using conventional pressures of from 0.3 to 2 MPa.

This forms the 5-arylhydantoin of the formula I. The course of the reaction can be monitored by means of conventional methods, for example gas chromatography, thin-layer chromatography. The reaction takes place in a surprisingly short time and is in some cases already finished after 2 hours.

The position in the aryl ring of the formula III in which the allantoic acid alkyl ester of the formula II reacts depends on the nature of the substituents Ri, R₂ and R3 and their respective positions in the aryl ring of the formula III. As is known, the nature of a substituent in an aryl ring causes the charge density distribution in the molecule and the position of a substituent in the aryl ring, depending on the strength of the inductive or mesomeric effect, that position in which a further substituent is introduced by a reaction. For substituents in the aryl ring which are not hydrogen, the position of the reaction center in the aryl ring depends on the strength of the respective inductive or mesomeric effect of the individual substituents. It has been found that in the case that in the formula III Ri is a hydroxy group and R₂ and R3 is hydrogen, the reaction proceeds predominantly in the para position. In individual cases, in which the position of the reaction center can not be predicted with certainty, a preliminary test suffices, after which the

AT398 199B washed warm water and slurried in 375 ml of water wet and stirred for 2 hours under reflux. After cooling, filtration and washing with water, the precipitate was dried at 80 ° C. in vacuo.

In this case, 79.7 g, that is 63% of theory, D, L-5- (4-hydroxyphenyl) -hydantoin with a purity of 99.4% and a melting point of 267'C were obtained. The proportion of isomeric 5- (2-hydroxyphenyl) hydantoin was 0.2%. Based on Glyoxylsäuremethylestermethylhemiacetal the yield over both reaction stages A) and B) was 55% of theory.

The isomeric purity of the prepared compound was determined by high pressure liquid chromatography:

Data system: Hewlett-Packard Chemstation column: Phenyl Bondapak 10 μm, Fa. Waters Temperature: room temperature Mobile phase: water - acetonitrile 88:12 Flow rate: 0.6 ml / min

Detector: UV, 254 nm

Under these conditions, the retention times for 5- (4-hydroxyphenyl) -hydantoin were about 9 minutes and those for the isomeric 5- (2-hydroxyphenyl) -hydantoin about 11 minutes.

Example 2

A mixture of 23.8 g of allantoic acid methyl ester (125 mmol), 50 g of benzene (0.64 mol) and 50 g of concentrated sulfuric acid was heated at 80 ° C. for two hours. After that the reaction was over. The reaction mixture was cooled to room temperature, adjusted to pH 4 with 50% sodium hydroxide solution and extracted with ethyl acetate, the organic phase was dried and evaporated. The residue was recrystallized from water.

In this case, 10.5 g, which is 47.7% of theory, D, L-5-phenylhydantoin having a melting point of 151 · Cerhalten.

Example 3

A mixture of 83.4 g of allantoic acid methyl ester (0.44 mol), 146.45 g of pyrocatechol (1.33 mol) and 250 ml of HCl 36% was heated with vigorous stirring for 2.5 hours at 80 ° C. After that the reaction was over. The clear solution was cooled, with no crystallization. The reaction solution was adjusted to pH 4.4 by addition of 50% sodium hydroxide solution and evaporated, the remaining residue was extracted exhaustively with ethyl acetate in a Soxhlet extractor, the ethyl acetate phase was concentrated and the product was crystallized.

In this case, 61.8 g, that is 67% of theory, D, L-5- (3,4-dihydroxyphenyl) hydantoin having a melting point of 231 to 233 · C were obtained.