SU791753A1 - Method of preparing n1,n3-(tetrahydrofyryl-2)-5-fluorouracyl - Google Patents

Description

The invention relates to an improved process for the preparation of N, (tetrahydrofuryl-2) -5-fluorouracil, which has antitumor activity, and it can be used as an intermediate product for the synthesis of the known antitumor drug Ftorafur.

A method of producing N.Nj-bis (tetrahydrofuryl-2) -5-fluorouracil is known by reacting 5-fluorouracil with 2-halo-tetrahydrofuran in the presence of a base, the pH of which is measured in water whiche 6. The disadvantage of this method is the low yield of the desired product (the highest the yield indicated in the examples of the application, 72.2%). Another disadvantage of this method is the use of dimethylacetamide, dimethylformamide, tetrahydrofur, dioxane or triethylamine as a solvent (in the examples only dimethylacetamide and triethylamine ij are indicated.

Dimethyl / acetamide and dimethylformamide are high-boiling solvents (165 and 152 ° C, respectively), the removal of which requires removal in vacuum, tetrahydrofuran and dioxane require preliminary purification from

peroxide compounds. The use of an excess of triethylamine as a solvent reduces the yield of the target product to 30.1% (Example 4).

5 Another disadvantage of this method is the difficulty of isolating the target product using column chromatography on silica gel, which requires the use of a large number of solvents and makes the process low-tech.

Such purification is required due to the fact that the N formed in the reaction

5 N J-bis- (tetrahydrofuryl-2) -5-fluorouracil is chromatographically heterogeneous and contains impurities of 5-fluorouracil and N-f- (tetrahydrofuryl-2) -5-fluorouracil.

20 The aim of the invention is to simplify the process and increase the yield of the target product.

The goal is achieved by the described method H, (tetra25 rahydrofuryl-2) -5-fluorouracil, which consists in the fact that 5-fluorouracil is reacted with 2-chloro-tetrahydrofuran in a medium of ogene alkanes in a heterogeneous medium, in the presence of triethylamine.

D Methylene chloride is preferably used as haloalkanes.

Distinctive features of the method are carrying out the process in a heterogeneous environment in the environment of halogen-alkanes.

. At the same time, the resulting N, Nj-6HC (tetrahydrofuryl-2) -5-fluorouracil goes into solution.

For carrying out the process of 5-fluorouracil suspensions in a halogen alkane (e.g., methylene chloride), triethylamine and a solution of 2-chloro-tetrahydrofuran in the same gas are added. logalkane to create a heterogeneous environment. The heterogeneous medium provides a maximum excess of 2-chloro-tetrahydrofuran over 5-fluorouracil in the liquid phase and creates the best conditions for the formation of 1,3-bis (tetrahydrofuryl-2) -5-fluorouracil.

Carrying out the reaction in a heterogeneous environment made it possible to simplify the process and increase the yield from 72.2 to 92%.

The reaction is carried out for 2-3 hours at room temperature. At the end of the reaction, a precipitate of hydrochloride triethylamine is sucked off. Halogen-alkane, being a highly volatile substance, is easily distilled. 1,3-bis (tetrahydrofuryl-2) -5-fluorouracil is obtained chromatographically homogeneous and does not require brushing by means of column chromatography.

The 2-chlortetrahydrofuran used in this method can be obtained from 2,3-dihydrofuran and hydrogen chloride by chlorination of tetrahydrofuran or loved by another known method.

It is preferable to use in the reaction a ratio of 5-fluorouracil-2-chlorotetraidoidofuran-triztilamine 1: 3: 6.

To create a heterogeneous environment, it is preferable to use methylene chloride as a halogen alkane, since it is a highly volatile substance (so-called boiling point), it is easily distilled off, as a result, the remaining target product is not destroyed, as is the case during Long-term heating required for distilling dimethylacetamide , In methylene chloride, peroxide compounds do not accumulate during storage and therefore do not require cleaning before use. Methylene chloride is not combustible and less toxic than tetrahydrofuran and dioxane.

. Under this method, N, Nj-bis- (tetrahydrofuryl-2) -5-fluorouracil is obtained as an oil (it can easily be converted to 1- (tetrahydrofuryl-2) -5-fluorouracil without crystallization), an anticancer drug fluoroufur)

by heating for 2 hours with aqueous ethanol containing 20% water. In this way, 1- (tetrahydrofuryl-2) -5-fluorouracil can be obtained in 80% yield, calculated as 5-fluorouracil.

For a better understanding of the present invention, the following examples are given.

Example. To a suspension of 3.25 g (0.025 mol) of 5-fluorouracil in 100 ml of dry methylene chloride, 7.6 g (0.075 mol, 10, .4 ml) of triethylamine are added and a solution of 8.0 g (0.075 mol, 6, 8 ml) 2-chlortetrahydrofuran in 15 MP of methylene chloride. The reaction mixture is stirred for 2 hours, during which it turns from heterogeneous to homogeneous. The progress of the reaction is monitored by thin layer chromatography on silica gel in a 9: 1 chloroform-ethanol system. The spot of 5-fluorouracil on the chromatogram disappears (R.0,10) and the spot N, TJj-bis (tetrahydrofuryl-2) -5-fluoroacyl appears (, 90). Upon completion of the reaction, the precipitated precipitate of triethylamine hydrochloride salt is filtered off with suction, washed on the filter with methylene chloride. The mother’s solution was washed with water (twice 50 ml) and dried over anhydrous sodium sulfate. The solution is filtered off, the solvent is distilled off, and 10 ml of absolute ethanol is added to the remaining oil. The solution is kept for 3-5 hours for complete crystallization. The resulting crystals are filtered off with suction, washed with 1 ml of cold absolute ethanol, and dried over This gives 6.2 g (92%) of chromatographically pure N, N J bis (tetragshdrofuryl-2) - 5-fluorouracil in the form of colorless crystals, m.p. 87-89 ° C; , 90.

Found,%: C 53.50; H 5.59; 10.25.

Calculated,%: C 53.50; H 5.59; N 10.36,

277 nm (8700);

UV spectrum A

Max

 MU1-H. 241 nm.

PMR (DhMSO): 7.86 (9.1.6 th lH-f 7.0 Hz); 6.46 (m, 1.1-H); 5.92 (m, 1.1-H); 4.30-3.70 (m, 4, 4-H,); Z.itO-l ,, 8o (m, 8.2-N,, ZN,

).

Example2. To a suspension of 3.25 g (0.025 mol) of 5-fluorouracil in 100 M; 25 g (0.25 mol of 17.3 ml) of triethylamine are added in dry dichloroethane and a solution of 13.3 (0.125 mol, 11.2 ml) of 2- chlortetrahydrofuran. The reaction is carried out as in Example 1. 6.1 g (90%) of N, N-5-bis (tetrahydrofuryl-2) -5 - fluorouracil are obtained.

Example 3. To a suspension of 3.25 g (0.025 mol) of 5 Fluorouracil in 100 ml of carbon tetrachloride, 13.8 g (O, O75 mol) of tributylamine are added and 8.0 r (0, t) of 75 mol,

6.8 ml) 2-chlortetrahydrofuran. The reaction is carried out as in Example 1. 5.9 g (87%) of N, N5-BGCTtetrahydropyryl-2) -5-fluorouracil is obtained.

invention formula

Claims (2)

1. The method of obtaining M, M | -bis (tetrahydrofuryl-2) -5-ftyruracil by the interaction of 5: -fluorouracil with 2-chloro-tetrahydrofuran in the presence of triethylamine, which distinguishes f-. so that, in order to simplify the process and increase the yield of the final product, the reaction is carried out in a heterogeneous medium, S medium of halogen-alkanes. 2. A method according to claim 1 and 2, characterized in that methylene chloride is used as a halogen-alkane. Sources of information Taken into account in the examination 1. Published for Japan № 33682, cl. C 07 O 405/14, published 03.14.77.