SU625609A3 - Method of producing derivatives of 1-tret alkyl-3(2,5-dihydro-5-oxo-3-furanyl)-urea - Google Patents

Claims (3)

This invention relates to a process for the preparation of new compounds, derivatives 1-tert. skkil-3- (2,5-dihydro-5-oxo-3-furanyl) -urea of the formula K, -HH-C NHTt / "R, 0 / where K | is a hydrogen atom or an alkyl; RJ is a hydrogen atom or a methyl, provided that one of the radicals R, or R, is a hydrogen atom, RJ is tert-butyl or tert-amyl. These compounds have valuable biologically active properties. The reaction of tertiary alkyl isocyanate with triethylamine is known to produce urea derivative l. However, in this way we can get urea derivatives from 4-amino-2-5H-furanones, t. they are not basic organic amines, but are neutral vinyl amides. Therefore, they must first be converted into salts, which easily react with tert-alkyl isocyanates. The purpose of the invention is the synthesis of new compounds - derivatives of 1-tert.alkln-3- (2,5-DIHYDRO-5-oxo-3 furanyl) -urea, having biological activity. The proposed method consists in that the 4-amino-2- | 5H-furanone derivative of the formula AND jN Hj L g where R and RJL have the above meanings, is reacted with an isocyanate of the formula C-0 where RJ has the above value, in the presence of a strong base in the environment of an organic solvent. Tetrahydrofuran is used as an organic solvent. Potassium t-butoxide, sodium hydride, sodium methoxide, lithium N-isopropyl cyclohexylamine, etc. are preferably used as the strong base. The compound of formula ill is obtained from 2,4-furandion with phenylhydrazine, followed by catalytic hydrogenation of the resulting 4- (2-phenylhydrazino) -2-G5H-furanone. The preferred catalyst for hydrogenation is Rene nickel, which provides a fast and complete breakdown of the hydrazine group. Other catalysts, such as palladium on carbon, may be used, however, they act slower and require pH adjustment to achieve the desired effect. Phenylhydrazine is usually preferred to other substituted hydrazines. Example. IM - (2, 5-DIHIDRO-2-methyl-5-oxo-3-furanyl) - N- (1,1-dime, til) -urea. A, 5-methyl-4- (2-phenylhydrazino) -2 -2H-furanone. In a stirred solution of 200 g (1.39 mol) of ethyl propionyl acetate in 500 ml of CHjCe Cc by cooling in an ice bath, 222 g (1.39 mol) of bromine are added dropwise. The mixture was allowed to warm to room temperature, then it was stirred in air for 16 hours. The solution was poured into ice-water, the organic layer was separated, dried with magnesium sulfate and evaporated. Ethyl 4-bromopropionyl acetate is obtained. This compound is added dropwise with stirring to 1 liter of 2.5N. Potassium hydroxide cooled from -10 to 0 ° C. The mixture is stirred at this temperature for 3 hours, then poured into a mixture of ice and 500 ml of 6N hydrochloric acid so that the temperature does not exceed 0 ° C. The resulting solution contains 5-methyl-2,4-furandione, which can be isolated by repeated extraction using a large amount of ether. The ether solution is evaporated, the residue is recrystallized from double (in terms of the amount of residue) amount of isopropyl acetate, cooled to -10 C. Get 5-methyl-2,4-furadione, so pl. 120.5-122 ° C. Yield 20%. To the above solution was added 150 g (1.39 mol) of phenylhydrazine. The mixture is stirred at room temperature for 16 hours, then cooled d. The solid product is filtered off, washed with water and dried, then it is stirred for 5-10 minutes with hot toluene and allowed to cool to room temperature. The orange crystals are filtered and washed inside with cold toluene, then with pentane. 127 g of 5-methyl-4- (2-phenylhydrazino) -2-5h-furanone are obtained, m.p. 147-149С (with decomposition). The compound is dimorphic and has mp. 158-160 C (with decomposition). Yield 45%. Found,%: C 64.56; H -5.91; N 13.40 C, H ,, fViO, Calculated,%: C 64.68, -H 5.93; N13.72 B. 4-amino-5-methyl-2-5H-furanone. A mixture of 51.0 g (0.25 mol) of 5-methyl- -4- (2-phenylhydrazino) -2-5H-furanone, 200 ml of alcohol and 2 teaspoons of Rene nickel is hydrogenated in a shaker at an initial pressure of 3 atm. 16-60 hours The catalyst is filtered off and the filtrate is evaporated to remove the alcohol. The residue is triturated with ether. Crystals are obtained, which are filtered, washed and dried. 25.0 g of 4-amino-5-methyl-2-5n-furanone are obtained, m.p. 150-152 ° C. Yield 88%. B. N- (2,5-dihydro-2-methyl-5-oxo-3-furanyl) - (1,1-dimethylethyl) -urea. 1. To a stirred solution of 77.9 g (0.69 mol) of 4-amino-5-methyl-2-5H-furanone in 1400 ml of anhydrous tetrahydrofuran was added 105.0 g (0.93 mol) of potassium t-butoxide, then 75.0 g (0.76 mol) of tert-butyl isocyanate are then quickly added dropwise at. The mixture is stirred for 2 hours. Then 90 ml of glacial acetic acid are added dropwise at 25 ° C, 1150 ml of water are added, the tetrahydrofuran is removed by evaporation. The solid product is filtered off, washed with water, dried and recrystallized from 900 ml of acetonitrile. 73.9 g of N / - (2, 5-dihydro-2-methyl-5-oxo-3-furanyl) (1,1-dimethylethyl) urea are obtained, m.p. 204-206 ° С (with decomposition). Yield 50%. 2. In a stirred solution of 0.24 g (0.006 mol) of 56% sodium hydride in mineral oil, 20 ml of anhydrous tetrahydrofuran and 1.1 g (0.01 mol) of 4-amino-5-methyl-2- | 5n -furanone 1.0 g (0.01 mol) tert-butyl isocyanate was added. The mixture was stirred for 4 hours at room temperature, after which 1 ml of glacial acetic acid was added. The mixture is poured into water. The precipitate is filtered off, washed with water, dried and recrystallized from acetonitrile, to obtain 0.55 g of N- (2, .5-dihydro-2-methyl-5-oxo-3-furanyl) -N-Ch1 g of 1-dimethylethyl) -urea m.p. 207-208 ° C (with decomposition). The spectrum is identical to the IR spectrum of the compound obtained in example 1, part B 1. 3. Replaced sodium hydride in example 1, part B 2 0.9 g (0.11 mol) of methoxide sodium is obtained. 0.5 g of crude - (2, 5-dihydro-2-methyl-5-oxo-3-furanyl) (1,1-dimethylethyl) urea, m.p. 196-198s (with decomposition). The IR spectrum is identical to the IR spectrum obtained in Example 1, part B 1. EXAMPLE 2.H - (1,5-dihydro-2-methyl-5-oxo-3-furanyl) -hj - (1,1-dimethylpropyl) -urea. Proceed in a similar manner as described in Example 1, part B 1, using tert-amyl isocyanate instead of tert-butyl isocyanate. N - (2,5-dihydro-2-methyl-5-oxo-3-furanyl) -Y- (1,1-dimethylpropyl) -urea is obtained, m.p. 140141 ° C. Found,%: C 58.51; H 8.09; M 12.35 ScN. ,, NjO, Calculated,%: C 58.39; H 8.02; N12.3 Example 3. M- (2,5-d ihydro-2-ethyl-5 -oxo-3-furanyl) -N - (1 g1-dime tylethyl) -urea. A. 5-Ethyl-4- (2-phenylhydrazino) -2-BN-furanone. To a stirred solution of 35.6 g (0.33 mol) of phenylhydrazine and 90 ml of glacial acetic acid in 150 ml of ethanol and 360 ml of water were added 38.4 g (0.3 mol) of 5-ztil-2.4- furandion. The mixture is heated under reflux for half an hour, then it is allowed to cool to room temperature. The mixture is evaporated until the alcohol is removed. The yellow crystals are filtered off from the water mixture, to obtain 50.8 g of 5-ethyl-4- (2- -phenylhydrazino) -2-5H-furanone, m.p. 181-182 ° C. The yield is 78%. The same product is obtained, starting from a crude solution of 5-ethyl-2,4-furandione, prepared analogously to example 1, part A. A. 4-amino-5-ethyl-2-5H-furanone. A mixture of 21.8 g (0.1 mol) of 5-ethyl-4- (2-phenylhydrazino) -2-5H-furanone, 200 ml of alcohol and 2 teaspoons of Rene nickel is hydrogenated in a shaker at an initial pressure of hydrogen of 3 atm. about 16 hours The catalyst is filtered off, the filtrate is evaporated to remove the alcohol. The residue is triturated with ether, the crystals are filtered, washed and dried. 9.3 g of 4-amino-5-ethyl-2-5n1-furan are obtained, m.p. 143-145,5 ° C. Yield 73%. Found,%: C B6.85; H 6.46; N11.20 CeHyNO, Calculated,%: C 56.68; H 7.14; N 11.0 B. Kj - (2, 5-dihydro-2- ethyl 5-ox-3-furanyl) -N- (1,1-dimethylethyl) -urea. The reaction is carried out analogously to the example of part B, except that 4-amino-5-ethyl-2-5N-fur non is used instead of 4-amino-5-methyl-2-Bn-furan. Get N- (2,5-DIGIDRO-2-ETHYL-5-oxo-3-furanyl) -M - (1,1-dimethylethyl) -urea, so pl. 142-144 C. Example 4.N - (2,5-DIHIDRO-4-methyl-5 oxo-furanyl) -N - (1,1-dimethylethyl) -urea. A. 3-methyl-4- (2-phenylhydrazino) -2 - BN-furanone. Proceed as described in Example 3, Part A using 3-methyl-2,4-α-furandione. 3-methyl-4- (2-phenylhydrazino) -2-5H-furanone is obtained, mp 201-202 ° C. Found,%: C 64.89; H 5.72; N13.76 C ,, H, afViOi Calculated,% tC 69; H 5.92; N13.72 V. 4-amino-3-methyl-2-5n-furanone. 1. Proceed as described in example 3, part B using 3-methyl-4- (2-phenylhydrazino) -3-5H-furanone. 4-amino-3-methyl-2-BN-furanone is obtained, m.p. 21B-216 C. Found,%: C 53.24; H 6.21; N12.00 CsHjNOz Calculated: C 53.09; H 6.24; M 12.39 2. A mixture of 7.2 g (0.035 mol) of 3-methyl-4- (2-phenylhydrazino) -2-5H-furanone , 200 ml of alcohol, B ml of concentrated hydrochloric acid and 0.5 g of 10% palladium on carbon are hydrogenated in a Parr shaker at an initial hydrogen pressure of 3 atm for 20 hours. Over the next 2 hours, hydrogen uptake is no longer observed. The catalyst was removed by filtration, the filtrate was evaporated. The residue is dissolved in a small amount of water, the solution is cooled in an ice-bath, to obtain crystals with m.p. 180-200 ° C. Chromatography on silica gel (100-200 mesh) using a mixture of toluene: ethyl acetate: methanol in a ratio of 60:20:20 as an eluting liquid yields a fraction, which is recrystallized from acetonitrile. Get 0.5. g of crystals T.PL. 214-215 ° C. B. N-, 2,5-dihydro-4-methyl-5-oxo-3-furanyl) -N- (1,1-dimethylethyl) -urea. Proceed as described in Example 1, Part B using 4-amino-3-methyl-2-5H-furanone. Get N - (2,5- -dihydro-4-methyl-5-oxo-3-furanyl) - - N - (1,1-dimethylethyl) -urea, so pl. 244 C (with decomposition). Found,%: C 56.58; H 7.47; N 12.98 C, oHi6 Calculated,%: C 56.59; H 7.60; N 13.20 Example 5. N - (2,5-dihydro-4-α-methyl-5-oxo -3-furanyl) - N- (1,1-dimethylethyl) -urea. A. 3-methyl-4- (2-p-chlorophenylhydrazino) -2-5H-furanone. To a stirred mixture, 19.7 g (0.11 mol) of p-chlorophenylhydrazine hydrochloride, 15.0 g (0.11 mol) of sodium acetate trihydrate, 120 ml of water, 50 ml of alcohol and 30 ml of glacial acetic acid are added to 11.4 g (0.1 mol) 3.4 furandion, the mixture is boiled under reflux for half an hour, then cooled to room temperature, evaporated to remove the alcohol, after which the yellow product precipitates. Bgo filtered, washed with water, dried. 19.5 g of a yellow solid are obtained, which is recrystallized from toluene. 18.5 g of 3-methyl-4- (2-p-chlorophenylhydrazino) -2-5H-furanone are obtained, m.p. 152-154, 5 p. Output 8B%. Found,%: C 55.46; H 4.53; N11 with H "ceN, Oi Sacchslvno, 55.35; H 4.65; N11 B. 4-amino-3-mtil-2-5H-furano 3-M9TIL-4- (2-p-chlorophenylhydraeno) - 2- SHJ-furanone is hydrogenated as described in Example 4, Part B. The resulting 4-amino-3-methyl-2-5n} -furanone is then converted into N - {2,5-dihydro-4-methyl-5-oxo-3- furanyl) -N- (1,1-dimethylene) -urea, as described in example 4, part B. Claim 1. The method of obtaining derivatives of 1-tert-alkyl-3- (2,5-dihydro-5-oxo - -3-furanyl) -urea of the formula About Uj-HH-CW TR. where D, is a hydrogen atom or alkyl C - Rj is a hydrogen atom or methyl, etc. provided that one of the radicals B or Kj is a hydrogen atom; D-tert-butyl or t-amyl, characterized in that the 4-amino-2-5H-furanone derivative of the formula LR / 0 (l) is reacted with an isocyanate of the formula RjN-C 0 (HI) in the presence of a strong base in a medium organic solvents. 2. Method POP1, characterized in that potassium t-butoxide, sodium hydride or sodium methoxide is used as a strong base. 3. Method POP1, characterized in that tetrahydrofuran is used as an organic solvent. Sources of information taken into account in the examination: 1. Thei hetmerW.3ynthettc Methods of Organic Chemi strv, 18, 544, p. 241. 24.03.76 when D, and Rj is a different hydrogen atom or methyl, H | - t, butyl or t.amil. 25.01.77 at 8 - a hydrogen atom or alkyl C, -C, RI - a hydrogen atom or methyl, provided that one of the radicals R, or H - an atom of hydrogen, RJ - tert.butyl or tert.amil.