Furazidin, also known under generic name furagin and chemical names 1- [3- [2- (5-nitrofuryl) prop-2-enylidene] amino] imidazolidin-2, 4- dione and 1- [3- (5-nitro-2-furyl) allylideneamino] hydantoin, shown by the formula I, is the biologically active substance with a wide spectrum of antibacterial activity against Gram-positive and Gram-negative bac- teria as well as against bacteria resistant to sulphonamides and some antibiotics.

I Furazidin is commonly used in the treatment of acute and chronic urinary tract infections (among others in prostatitis and cystitis) and in long-term prevention the recurrence of these infections. It is more po- tent antibacterial agent than nitrofurantoin, another medicinal sub- stance from nitrofurane derivatives group, and is devoid of side effects typical for nitrofurantoin, such as gastro-intestinal disturbances (vomiting, nausea, abdominal pains, diarrhoea).

The process for the preparation of furazidin, disclosed in J. Pharm. Soc. Japan 75,117 (1955) involves a reaction between 3- (5- nitro-2-furyl) acrolein and 1-aminohydantoin or a reaction between 3- (5- nitro-2-furyl) acrolein and semicarbazideacetic acid derivative followed by the formation of hydantoin ring: Main problems in the first of the said known processes are con- nected with the preparation of starting material, namely 1- aminohydantoin. It is usually obtained in a multistep synthesis process.

In the first step of the known method of 1-aminohydantoin preparation the reaction between hydrazine and chloroacetic acid is carried out. The resulting acid is esterificated and transformed into hydrochloride, which is treated with potassium cyanate to form aminocarbonylhydrazinacetic acid ester, the latter subsequently undergoing cyclisation to aminohy- dantoin. The disadvantage of this method is low yield, usually not ex- ceeding 20-30% (Ber. 31,164 (1898)). Different subsequent modifi- cations of this method, described for example in the Acta Polonia Pharmaceutica 16,1, (1959) and Przemysl Chemiczny 11,306, (1955) do not give rise to significant yield increase.

Another process for the preparation of 1-aminohydantoin, dis- closed in J. Pharm. Pharmacol. 11,108, (1959) consists in a reaction between benzaldehyde and semicarbazide. The resulting semicarbazone is reacted with ethyl chloroacetate in the presence of sodium ethanolate in ethanol to form benzylideneaminohydantoin. After heating of the latter in a mineral acid solution, 1-aminohydantoin and initial benzal- dehyde are obtained. Overall yield of this process is about 70%. Al- though this process is more effective than the first one, its disadvantage is the low purity of the product obtained, especially on a large-scale.

This product can not be purified by crystallisation. When such 1- aminohydantoin is used in the synthesis of furazidin, particularly on a large scale process, a low purity product containing high amounts of unremovable impurities is obtained.

The second of the mentioned above processes for the preparation of furazidin, consisting in the reaction between 3- (5-nitro-2-furyl)- acrolein (nitrofurylacrolein) with semicarbazideacetic acid derivative involves similar difficulties as in case of 1-aminohydrazine preparation from hydrazine and chloroacetic acid, i. e. the reactions for preparing starting semicarbazideacetic acid are non-selective and give poor yields.

This increases process costs and decreases the final product quality.

Known processes for the preparation of furazidin, described above, are multistep processes, frequently of low overall yield and/or give a product of unsatisfactory purity.

The aim of the invention is to provide a simplified process for the preparation of furazidin, giving increased overall process yield and im- proved final product purity.

This aim has been achieved by using another starting materials and, optionally, by carrying the synthesis in such a manner so as to move the reaction equilibrium towards the formation of furazidin by removal of carbonyl compound formed as a by-product from the reaction medium. Furthermore, the reaction equilibrium is moved towards the formation of the furazidin because the latter precipitates from the re- action medium during the course of the reaction.

According to the invention, the process for the preparation of 1- [3- (5-nitro-2-furyl-2-propenylidene] amino]-2, 4-imidazolidinodione (furazidin) of the formula I is based on the reaction of 3- (5-nitro-2- furyl) propenal with aminohydantoin derivative of general formula II, II where R is phenyl, tolyl, 5-nitro-2-furyl, furyl or Cl-C6 alkyl, and R, is hydrogen atom, or R and R, are both methyl groups or R and R, together with carbon atom to which they are attached, form cyclic system of 5 or 6 carbon atoms. The reaction is carried out in the presence of mineral acid or sulphonic acid of the formula R3SO3H, where R3 is methyl, trifluoromethyl or tolyl, in aqueous solution or in a mixture of water with a water-miscible organic solvent, at reflux temperature of the re- action medium, optionally while removing the formed carbonyl by- product by distillation. Then, after cooling the reaction mixture, the precipitate of the final product is separated from the solution, washed and dried.

The process according to the invention is performed to a high de- gree of conversion, usually over 80%. The insoluble in water reaction product is collected by filtration, washed to a neutral filtrate and then boiled several times with alcohol to remove residual organic starting materials. Good results can be obtained by the crystallisation of the raw product from dimethylformamide. Both main starting materials are used in stoichiometric amounts or in a small excess (up to 10%) of the

cheaper one. As the starting materials have limited solubility in reac- tion medium, an intensive stirring is usually required. Depending on the aminohydantoin derivative used, heating of the reaction mixture at re- flux temperature is carried out for a period of 1 to 6 hours. To estimate the reaction progress, the content of the carbonyl by-product in the distillate is determined; this is easy due to the separation of the organic and water phase in the distillate. If new portions of the distillate do not contain carbonyl compound, the reaction can be regarded as terminated.

The progress of the reaction can also be estimated by determination of the reaction mixture composition by Thin Layer Chromatography (TLC) or High Performance Liquid Chromatography (HPLC).

The preferred aminohydantoin derivative is benzylidene-1- aminohydantoin or isopropylidene-1-aminohydantoin, and especially preferred is 5-nitro-2-furfurylidene-1-aminohydantoin (nitrofurantoin).

As a mineral acid sulphuric acid or hydrochloric acid is prefera- bly used, in the concentration range from O. 1N to 1. 5N, preferably O. 5N to 1.2N. Instead of a mineral acid a sulphonic acid of the formula R3S03H where R3 is methyl, trifluoromethyl, phenyl or tolyl can be used successfully.

As a water-miscible organic solvent a Cl-C4 alcohol, such as methanol, ethanol, iso-propanol, etc., or glycol is preferably used.

1- [ [3- (5-nitro-2-furyl)-2-propenylidene] amino}-2, 4-imidazolidi- nedione (furazidin) obtained by the process according to the invention is of high purity and doesn't contain impurities typical for known meth- ods.

The process according to the invention is illustrated by the fol- lowing examples.

Example 1.

A mixture of 20 g (0.12 mol) of 3- (5-nitro-2-furyl) propenal and 22.5 g (0.1 mol) of 5-nitro-2-furfurylidene-1-aminohydantoin (nitrofurantoin) in 500 ml of water containing 10 ml of concentrated sulphuric acid was heated at reflux temperature with vigorous stirring.

After 30 minutes the distillation of 5-nitrofurfural formed in the reac- tion together with water was started. The reaction was carried out until disappearance of 5-nitrofurfural in the new portions of the distillate.

The reaction mixture was cooled, the obtained yellow precipitate fil-

tered off, washed with water until obtaining neutral filtrate. Then the precipitate was boiled with 100 ml of ethanol, filtered and filtrates dis- carded. The precipitate was dried on air. 19.75 g of the compound of the formula I were obtained (yield 79%). Melting point 267°C (decomposition).

Results of the elemental analysis: C = 45.55%; H = 3.02%; N = 21. 26% Example 2.

A mixture of 10 g (0.06 mol) of 3- (5-nitro-2-furyl) propenal and 10 g (0.05 mol) of benzylidene-1-aminohydantoin in 200 ml of water containing 20 ml of concentrated hydrochloric acid was heated with stirring and the formed benzaldehyde was distilled off together with water. The process was carried out for about 60 minutes. After cooling the mixture the obtained product was filtered off, washed with water to a neutral reaction and dried. The precipitate was heated to a tempera- ture of 70°C together with 50 ml of dimethylformamide, cooled, the precipitate obtained was collected by filtration and washed with etha- nol. 10.5 g of the compound of the formula I were obtained after dry- ing. Yield 84%, melting point 265°C (decomposition).

Example 3.

Starting from 10 g of 3- (5-nitro-2-furyl) propenal and 9.7 g of cyclohexylideneaminohydantoin and proceeding in the same manner as in Example 1 and using 4 g of toluenesulphonic acid instead of sulphuric acid 10.4 g of the compound of the formula I were obtained. Yield 83%, melting point 262°C (decomposition).

Example 4.

A mixture of 10 g of 3- (5-nitro-2-furyl) propenal and 7.8 g of iso- propylidene-1-aminohydantoin in 200 ml of water containing 5 ml of concentrated sulphuric acid was kept at reflux temperature for 35 min- utes, then cooled and proceeding in the same way as in Example 1, 10.4 g of the compound of the formula I were obtained. Yield 84%.

Example 5.

A mixture of 10 g of 3- (5-nitro-2-furyl) propenal and 9.7 g of 2- furfurylidene-1-aminohydantoin in 200 ml of water containing 2.5 ml of concentrated sulphuric acid was heated at reflux temperature with stir- ring and distilling off furfural formed till to its disappearance in new

portions of the distillate. Proceeding in the same way as in Example 1, the compound of the formula I was obtained with 72% yield.

Example 6.

A mixture of 20 g of 3- (5-nitro-2-furyl) propenal and 22.5 g of 5- nitro-2-furfurylidene-1-aminohydantoin (nitrofurantoin) in 500 ml of water containing 120 ml of propanol and 10 ml of concentrated sul- phuric acid was maintained at reflux temperature for 30 minutes and, proceeding in the same way as in Example 1, the compound of the for- mula I was obtained with 88% yield. Melting point 262°C (decomposition).