DE1670561C3 - Process for the production of 5,5-diphenylhydantoin - Google Patents

Description

The invention relates to a new process for the preparation of the pharmacologically important compound 5,5-diphenylhydantoin.

From German Auslegeschrift 1,209,117 a method for the preparation of 5,5-diphenylhydantoin by heating to at least 90 ⁰ C of benzoin with urea in a molar ratio of 1.5 to 3 moles of urea to 1 mole benzoin in aqueous alkali metal hydroxide while blowing is a strong LufL-> troms known. Copper sulphate and potassium bromate have also been tried as oxidizing agents in the production of 5,5-diphenylhydantoin from benzil or benzilic acid and urea, originally based on benzoin.

However, these known methods have considerable disadvantages. The use of air as an oxidizing agent encounters difficulties insofar as large amounts of gas must be enforced and the yield of the reaction depends on the flow rate is subject to high fluctuations (cf. German Auslegeschrift 1209 117 Column 1, line 50f and patent specification 32 313, of the Office for Inventions and Patents in East Berlin, Line 9ff.), In some cases, the air flow must also be be preheated.

The use of copper sulfate and potassium bromate as an oxidizing agent is uneconomical; on the one hand, the price of both oxidizers) is sensitive On the other hand, one needs of these oxidizing agents even when using equivalent amounts Due to their high molecular weights, very large amounts are used.

It has now been found that sulfur in aqueous suspension is an excellent oxidizing agent. The effect of sulfur as a dehydrogenating agent in an aqueous medium at a relatively low temperature was surprising in that sulfur usually only develops its dehydrogenating effect above its melting point.
The invention thus provides a process for the preparation of 5,5-diphenylhydantoin by heating benzoin with excess urea in the presence of an oxidizing agent in an aqueous alkaline medium, which is characterized in that the oxidizing agent used is elemental sulfur in an amount of 0.5 to 4 gram atoms per mole of benzoin used and in a reaction medium consisting of water or mixtures of water with water-miscible organic solvents at a temperature between 60 ° C and the boiling point

point of the reaction mixture works.

The advantage of the method according to the invention lies in its astonishing simplicity and in its good quality Reproducibility achievable high yield of pure product.

Is preferably carried out using from 1 to 3 mol of urea per MoI benzoin and at an alkali concentration of I0bis40 ° / ₀ in the reaction medium. The use of potassium hydroxide is preferred. The temperature of the reaction mixture must

range from 6O ⁰ C and the boiling point of the reaction mixture, preferably between 80 and 100 "C. The reaction time is between 1 and 4 hours, the amount of sulfur is preferably from 1 to 4 gram atoms of sulfur per mole.

Benzoin. Higher concentrations of sulfur lead to a reduction in yield. The implementation is in aqueous Medium carried out, but mixtures of water with water-miscible organic are also suitable Solvents, preferably alcohols, as solvents.

The parts mentioned in the examples are parts by weight.

Example I.

25 parts of benzoin were mixed with 20 parts of urea in a solution of 35 parts of potassium hydroxide in 125 parts Water for 4 hours at 93 ° C in the presence of 11.3 parts of elemental sulfur with stirring Brought reaction. Then the

equal volume of water and diluted by 6.8 parts of insoluble residue with mp. 32O ⁰ C was filtered off. Acidification with hydrochloric acid gave 27.8 parts of 5,5-diphenylhydantoin with a melting point of 282 to 285 ° C. (Yield 94 ° / ₀ of the theory.) Purification was

by recrystallization from 500 parts of ethanol and gave 24 parts of 5,5-diphenylhydantoin with m.p. up to 296 ° C (81 ° / "of theory).

Example II

25 parts of benzoin were as in Example I with

20 parts of urea and 7.6 parts of sulfur in aqueous potassium hydroxide solution (25% strength) was reacted for 3 hours at 90 ⁰ C. After dilution and filtration, 26 parts of crude product were precipitated with hydrochloric acid (melting point 283 to 287 ° C,

87 ° / ₀ of theory). Recrystallize from ethanol gnb

21 parts of 5,5-diphenylhydantoin with mp. 290-292 ⁰ C (71 ° / ₀ of theory).

Example III

25 parts of benzoin, 20 parts of urea, 35 parts of potassium hydroxide in 150 parts of water / methanol (120:30) and 11.3 parts of sulfur were ^{kept at 90 °} C. for 4 hours. 6.3 parts of an insoluble residue was filtered off and after dilution obtained by acidifying a crude product having a mp. 283-286 ⁰ C, which gave, after recrystallization from ethanol, 20.5 parts of 5,5-diphenylhydantoin mp. 291-293 ° C ( 69% of theory).

Example IV

25 parts of benzoin, 20 parts of urea, "35 parts of potassium hydroxide, 150 parts water and 15,2Teile sulfur were held for 4 hours at 90 ° C. After filtering and acidifying the reaction mixture a crude product 284 left with mp. 287 ^G to C, and after recrystallization 24.5 parts (83 ⁰ Z ₀ of theory). 5,5-Diphenylhydantoin (melting point 291 to 293 "C) are obtained from ethanol.

Example V

25 parts of benzoin, 20 parts of urea, 35 parts of potassium hydroxide, water and ISOTeile 3,8Teile sulfur gave 24.4 parts of colorless 5,5-diphenylhydantoin with melting point 293-297 ^r C after 4 hours at 90 ^c C. after filtration and acidification ( 82.2% of theory). After recrystallization from ethanol, 20 parts of 5,5-diphenylhydantoin (68% of theory) with a melting point of 292 ° to 298 ° C. were obtained. 1.2 parts with a melting point of 266 to 272 = C. were obtained from the mother liquor by evaporation.

Example Vl

The batch corresponds to Example V, but was ^{kept at 90 °} C. for only 1 hour. The crude yield of colorless 5,5-diphenylhydantoin betrue 2 to 4.3 parts (81.7 ° / ₀ of theory) of mp. 293-298 C. After Umkristallisieiung Athanoi from the pure yield was 19.8 parts (66.7 ⁰ Z _{0 of} the theory) with melting point 293 to 297 ° C.

Example VII

25 parts of benzoin, 20 parts of urea, 35 parts of potassium hydroxide, 150 parts of water and 3.42 parts of sulfur were ^{kept at 100 °} C. for 2 hours. After filtering and acidifying the reaction mixture, 23.8 parts (80% of theory) of a colorless crude product with a melting point of 293 to>K'C could be obtained. Oas product was of high purity and yielded, after recrystallization from ethanol, 22.6 parts of (76 °, '"of theory) of 5,5-diphenylhydantoin of mp. 294-298 C. ^J

Example viii

25 parts benzoin, 20 parts urea, 35 parts ca-

La liumhydroxyd in 150 parts of water were ^{reacted with 11.4 parts of sulfur at 6O 0} C for 4 hours.

Working up according to Example I produced 27.9 parts

raw 5,5-diphenyl hydantoin (94 ^IJ / ₀ of theory) with

M.p. 286 to 290C. Recrystallization from ethanol gave 22.3 parts Reinproduki with mp. 293 ^ 297 bi C (75 ^o / _o of theory).

Example IX

25 parts of benzoin, 20 parts of urea, 35 parts of potassium hydroxide were in 150 parts of a mixture * of 100 parts of methanol and 50 parts of water in the presence of \ 8 parts of sulfur for 1 hour Boiled under reflux (temperature 78 C). The clear reaction solution was then, as in the example I, diluted water. The resulting precipitate was filtered off and the filtrate according to Example I acidified. 23.2 parts of colorless 5,5-diphenylhydantoin (78% of theory) with melting point were obtained.

293 to 297 ° C.

Example X

The approach corresponds to Example IX, but was in

150 parts of a mixture of 75 parts of Athanoi and 75 parts of water carried out. The work-up was 23.8 parts colorless 5.5 TJiphein! Hydantoin (80 "" theory) of mp. 293-297 C.

Claims (3)

Patent claims: 1. A process for the preparation of 5,5-diphenylhydantoin by heating benzoin with excess urea in the presence of an oxidizing agent in an aqueous alkaline medium, characterized in that the oxidizing agent used is elemental sulfur in an amount of 0.5 to 4 gram atoms per mole of benzoin and operates in a group consisting of water or mixtures of water with water-miscible organic solvent reaction medium at a temperature between 60 ⁰ C and the boiling point of the reaction mixture. 2. The method according to claim 1, characterized in that the urea in an amount from 1 to 3 moles per mole of benzoin is used. 3. The method according to claim 1 or 2, characterized in that the reaction medium has an alkali concentration of 10 to 40 ^fl / ₀ .