SU620211A3 - Method of obtaining derivatives of 5-fluoruracil - Google Patents

Description

one

This invention relates to a process for the preparation of novel 5-fluorouracil derivatives, which can be used in medicine.

The reaction of acylation of heterocyclic amines by isocyanates or carbamyl halides is known to form the corresponding amides 1 and C2l.

The purpose of the invention is new derivatives of 5-fluorouracle having valuable headlamp macologic properties.

The goal is achieved based on a known reaction method for the preparation of 5-fluorouracil derivatives of general formula I

ABOUT

ABOUT ,

Kg

where K is aklkl with 1-7 carbon atoms, aryl with 6-1O carbon atoms, alicyclic group with 5-10 carbon atoms,

R ,, j has the same meaning as R or is hydrogen.

The method consists in that 5-fluorine uracil is reacted with an isocyanate of the general formula P

RjNCO

where R has the abovementioned or carbamoyl halide of the general form

s.

iKiRzN-COX

where R and have the indicated meanings,

X is halogen

in an organic solvent at a temperature from room temperature to the boiling point of the reaction mixture.

The organic solvent used is preferably an animetype oxide, dimethylformamide, dimethylacetamide.

The acylation reaction using a carbamoyl halide is preferably carried out using an acid acceptor such as triethylamine, pyridine, potassium carbonate, sodium bicarbonate, sodium hydride. The group of suitable isocyanates that may be used for carrying out such a reaction includes dianat methyl isobutyl isocyanate, ethyl isocyanate, n-propyl isocyanate isopropyl isocyanate, n-butyl isocyanate, isopropyl isocyanate, tert-butyl isocyanate and-pentilizotsianat, n -geksilizotsianat, fe- nilizotsianat, O- tolyl isocyanate, rt-toli isocyanate, oL-naphthyl isocyanate, (b-naphthyl isocyanate, cyclopentyl isocyanate, cyclohexyl isocyanate, and 1,2,3,4-tetrahydro-1-naphthyl isocyanate, the use of alkyl isocyanates is particularly preferred, where carbon. carbamoyl halide group, which can be used according to the proposed method includes 14, N -dimeti№karbamoilhlorid, N, N -dietilkarbamoilhlorid, N, N-diizoprrpilkarbamoilbromid N, N -ditsiklogeksilkarbamoilbromid and N, M -difenilkarbamoilhlorid. In a preferred embodiment, the reaction mixture was It should be filtered or evaporated in vacuo, the resulting crude product should be purified by washing, per- crystallization or by other methods. Example 1. 10.4 g (O, 08 mol) of B-fluorouracil is dissolved in 10 O ml of dimethyl sulfoxide, then 14.3 g (0.12 mol) of phenyl adipyanate is added and stirred at room temperature for 1 hour. The reaction mixture is filtered and receive a fine precipitate. This (hzadok is suspended in hot ethanol and filtered again. 16.2 (81.4%) 5-fluoro-1-phenylcarbamoyluracil is obtained, mp 280 C (decomposition), Found,%: C 52.83; H 3.19; F 7.64} N 16.43. Si V Calculated,%: C 53, O2; H 3.24; F 7.63; N 16.86; Example 2. 1О, 4 g ( O, 08 mol) 5-fluorouracil and 10, O g (O, 176 mol). Methyl isocyanate is mixed in 1OO ml d of methyl sulfoxide and subjected to stirring at room temperature for 5 hours. Dimethyl sulfoxide and excess methyl ethionic ionate are removed from the reaction mixture. The residue obtained is washed with chloroform and dried in vacuo; 15 are obtained. , 8 g (86.1%) of 5-fluoro-1-methylcarbamoyluracil. This product is recrystallized from ethyl acetate to obtain white crystals, melting at 277 ° C (with decomposition). Calculated,%: C 38.51; H 3, 23; F 10.155 N 22.46. Found: C 38.23; H 3.22; P 10.10; N 22.31. Example 3. 13.0 g (0.10 mol) 5 -fluorouracil is dissolved in 80 ml of dimethylacetamide, after which 9.4 g (0.11 mol) of N-propyl izdanate are added to the solution at room temperature and the mixture is stirred for 8 hours. The reaction mixture is evaporated: to the volume of 50 ml by removing Dimetylacetamide and excess n-propyl isocyanate 6 vacuum. After cooling, the residue is poured into ZOO ml of water, and the precipitate formed is filtered off. This precipitate is washed with water and ether, respectively, and then dried. As a result, 17.2 g (80.1%) of 5-fluoro-2- (i-propylcarbamoyl) uradil are obtained. This product is recrystallized from ethanol to obtain a white crystalline product, melting at 285 ° C (with decomposition), which is characterized by the presence of absorption bands in the infrared region of the spectrum at the following frequencies; 3400, 3300, 3180, 3080 (M), 2970, 2870, 2810, 1720, (VS), 168O (S), 1525 (S), 1455, 1330, 1270 (S), 1213, 109O, 1035, 1005, 935, 845, 786 and 755 cmH Calculated,%: C 44.65; H 4.65; F 8.84; N 19.53. Found,%: C 44.61; H 4.76; F 8.67; N 19.81. Example 4. 13.0 g (0.1O mol) of 5-fluoroucrypt is dissolved in 70 ml of dimethylformamide, after which 11.9 g (0.12 mol) of n-butyliso-nanoate are added to the solution at this temperature same temperature (ature, the solution is stirred for 24 hours. The reaction mixture is concentrated to a residual volume of 4O ml by removing dimethylformamide and excess inbutyl isocyanate in a vacuum. The residue is poured into ZOO ml of water, and the resulting precipitate is heated. Then the precipitate is washed and dried, then 16 are obtained , 6 g (72.3%) of 1- (n-butylcarbamoyl) -5-fluorouracil. This product is ethyl alcohol is obtained and white crystals are obtained, melting at 283 ° C (with decomposition), which are characterized by polo: absorption in the infrared region of the spectrum at the following frequencies: 3270, 3080, 1950, 2810, 2780, 1715 "1740 (S ), 1685, 1660, 1500; 1540, 148C 1332, 1270, 1205, 1090, 1085, 900,

770 and 750 cm: -.

Calculated,%: C 47.16 | H 5.24 jF 8.30}

N 18.34.

SdN.2RMzOz

Found%: C 47.29 | H 5,32} F 8D8; N 18.80.

Example 5. 13.0 g (0.10 mol) of 5-fluorouracil is suspended in 60 ml of dimethylacetamide, after which it is added to the suspension at room temperature.

14.0 g (0.11 mol) of i-hexyl isocyanate and the mixture is stirred at 50 ° C for 8 hours. After the reaction mixture is concentrated in vacuo, the residue is poured into 400 ml of water and the resulting precipitate is filtered off. The precipitate is washed and dried, and 19.3 g (75.0%) of 5-ft or-1- (n-hex or carbamoyl) uracil are obtained.

3Tot product is recrystallized from ether and white crystals are obtained; they are crystallized at 283 ° C (with decomposition), which are characterized by infrared absorption bands: 3320, 3230, 3080, 2920, 2850, 1720, 1740, 1680, 1660, 1510, 1445, 1240, 1282, 120О, 109О, 1О42, 802, 77О and 750 cm

Compound

Claims (4)

1-Etsh1carbamoyl-5-fluorouracil 5-Fluoro-1- (isopropylcarbamoyl-ethylate1-1- (tpe T-Butylcarba moyl) -5-fluorourazsh1 1-Cycloexylcarbamoyl-5-fluorouracil 1- (14, N-dimethymexylcarbamoyl-5-fluorouracil 1- (14, N-dimethymexylcarbamoyl-5-fluorouracil 1- (14, N-dimethyl) 5-fluoropyracil 1- (N, M-Diphenylcarbamoyl) -5 4-gorradal 5-Fluoro-1 - (& tolylcarbamoyl) -uracil Formula of the Invention A method for producing p {5-derivatives of 5-fluorouracil of general formula O NUNC: Calculated,%: C 51, .3 "; H 6,23} P 7.39; N16.34, Il l6 3 ° 3 Found: C, 51.19; H, 6.37} F, 7.27} N 16.60. Example 6 1.3 g (0.01 mol), 5-Foraracil was dissolved in 20 ml of dim & tyl acetamide and then Oj48 g (0.01 mol) of sodium hydride solution was added to the solution. A solution of 1.36 g (0.01 mol) of N, N-diethylcarbamoyl chloride in 5 ml of tamide diethyl chloride is added dropwise to the mixture at 30 ° C. After stirring at 30 ° C for 5 hours, the reaction mixture is filtered and the filtrate is evaporated in vacuo. The residue is extracted with 30 ml of chloroform and the extract is concentrated to dryness, to obtain 2.14 g of a crude product. This product is washed with diethyl ether to obtain 1.73 g (5.5%) of 1- (N; N-diethylcarbamoyl) -5-fluorouradyl, melting at 157-160 C. Calculated,%: C 47.16} H 5.28 jF 8.29} N 18.33. C9H12 3 . Found,%: C, 47.23} H, 5.27} F8.29} N 18, O9. Other compounds listed in the table were prepared in a similar manner. Melting point, C 286 286 287 286 194 256 280 where R is an alkyl with 1-7 carbon atoms, aryl with e-1O carbon atoms, an alkylic group with 5-10 carbon atoms, R 2 has the meaning of R, a hydrogen atom ,. characterized in that the 5-fluoroure sludge is treated with an isocyanate of the general formula I Ki-N (iO or carba 1 halogenide general formula w KiKjN-eox where R, Rj have the indicated meanings, X is a halogen atom, in an organic solvent in the temperature range from room temperature to the boiling point of the reaction mixture. 2. The method according to claim 1, in which is used as an organic solvent, dimetypsulfoxide, dimethylformamide, dimethylacetamide. 3. The method according to paragraphs. 1 and 2, that is, with the fact that, in the case of using a carbamoyl halide of the general formula (3), the process is carried out in the presence of an acid-binding agent cBJt. 4. A process according to claim 3, characterized in that triethylamine, pyridine, potassium carbonate, sodium bicarbonate, sodium hydride are used as an acid binding agent. Sources of information taken during examination: 1. Author's certificate No. 224521, cl. 12p 7/01, 1968. 2.Certificate of certificate number 322053 | cl. 12p 7/01, 1972.