SU537074A1 - The method of obtaining derivatives of 6-fortimin - Google Patents

Description

one

This invention relates to an improved process for the preparation of 6-fluorothymine derivatives, which can be used in the pharmaceutical industry.

A known method for the preparation of 6-fluorothymine is that, in the first stage, the interaction of 2,4,6-trifluoro-5-methylpyrimidine with sodium benzylate in anhydrous toluene is obtained to obtain 2,4-dibenzyloxy-5-methyl-6-fluoropyrimidine in the second stage, catalytic hydrogenation of the intermediate product in methanol is carried out in the presence of Pd / C. The yield of 6-fluorothyne based on the starting trifluoropyrimidine is 59% (63 and 95% at each stage).

The disadvantages of this method are the low yield of the product (the reduced yield of b-fluorothyne is related to non-crystallized products), as well as the by-production of 2fluor-4,6-dibenzyloxy-5-methylpyrimidine and 2,4,6-tribenzyloxy-5- in the first alkoxylation stage. methylpyrimidine, hardly separated by recrystallization. In addition, the removal of benzyl groups is accompanied by side processes of hydrogenation of a multiple bond of the C-ring and reductive elimination of the fluorine atom. For these reasons, the yield of pure 6-fluorothymine by a known method does not exceed 40% based on the initial 2,4,6-trfluoro-5-methylpyrimidine.

In order to eliminate these drawbacks, simplify the process and increase the yield of the product according to the proposed method, 6-fluoromethine derivatives are obtained, formula (I)

OR

SNS

L l

EO N F

where R is a hydrogen atom, alkali metal, alkaline earth metal, ammonium cation, ethanolamine, chloroethylamine, ethyleneimine;

treatment of 2,4,6-trifluoro-5-methylpyrimidine with aqueous alkali at a molar ratio of reagents of 1: 2.5-3 at 70-100 ° C, followed by separation of the target product in free form by successive acidification of the solution to a pH of 2-3 and freezing or isolation of the desired product as a salt. It is preferable to use alkali metal hydroxide as alkali.

The method allows to increase the yield of target products up to 64-88%, in addition, it is one-step.

The preparation of 6-fluorothymine salts of general formula (I) is carried out either by direct hydrolysis of 2,4,6-trifluoropyrimidine in the presence of alkalis, or by the interaction of stoichiometric amounts of 6-fluorothymine and bases of organic and inorganic origin in a suitable solvent.

Example 1. Kaliev salt of 6-fortimin.

7.2 g (0.005 gmol) of 2,4,6-trifluoro-5-methylpyrimidine are added dropwise to a solution of 10.6 g (0.019 g-mol) KOH in 45 ml of water with vigorous stirring for 10-15 minutes. The temperature of the reaction mass rises to 60 ° C. The mixture is stirred for 50 minutes at 80-85 ° C, cooled to -10 ° C and left at this temperature for 3 hours. The crystalline product is filtered off, washed with a small amount of ice water, alcohol, ether, and dried in vacuum (1 mm) at 100 ° C. Obtain 6.2 g (71%) of the monopotassium salt of b-fortimin in the form of colorless crystals, so pl. 300 ° C (from methanol).

Found,%: C 32.93; H 2.81; F 10.40; N 15.19.

CsHiFKNzOa

Calculated,%; C 32.82; H 2.75; F 10.37; N 15.32.

UV spectrum. In methanol: Hmaco 275 nm (Ige 3.80); Yamin 243 nm (Igs 3.23);

0.1 M KOH: 1 max 273 nm (Ige 3.78), Lmsh 243 nm (Ige 3.25).

IR spectrum (CM-i): 3500, 3100, 2950, 2750, 1650; 1500, 1400, 1380, 1350, 1330, 1250, 1195, FROM 1120, 1050, 1030, 1000, 950, 900, 845, 780, 770, 750, 730, 690, 640, 480, 420 (suspensions in perfluoroprotein and petroleum jelly).

Similarly, the sodium salt of 6-fluorothymine is obtained.

Paragraph 2. 6-fluorothymine.

Synthesis of 6-fluorothyne potassium or sodium salt is carried out according to the procedure described in Example 1, but after the completion of the reaction, the hot reaction mass is not cooled, but quickly acidified with concentrated HCl to a pH of 2-2.5 (not lower) and to avoid hydrolysis to 5-methyl-barbituric acid, rapidly cooled to (-10 - (- 15) ° C and kept at this temperature for 3-4 hours. The precipitate is filtered off, washed on the filter with a small amount of ice water, alcohol, ether and dried in vacuum over PgOs 4.6 g (64%) of 6-fluorothymine are obtained in the form of colorless crystals, i.e. decomposition. 210-215 ° C (from methanol); data 210 ° C.

The analysis sample is dried under vacuum at 100 ° C over PrO3.

Found,%: C 41.81; H 3.54; F 13.81; N 19.31.

CsHsFNaOs

Calculated,%: C 41.67; H 3.49; F 13.19; N 19.44.

The resulting 6-fluorothyne is chromatographically homogeneous. R / 0.25 (Silufol UV 254,

chloroform — ethyl acetate — methanol 4: 2: 1), 0.67 (Whatman paper No. 1, propanol — water 7: 3), 0.75 (Whatsand LI, butanol-acetic acid — water 5: 2: 3).

UV spectrum. In water: Hmax 258 nm (Ige 4.00), Lmin 228 nm (Ige 3.60);

0.1 M KOH: Hmax 273 nm (Ige 4.23), Amine 241 nm (Ige 3.61); 0.1 M HC1: Lmax 255 nm (Ige 4.08), CMIN

228 nm (Ige 3.62).

IR spectrum (cm-1): 3060, 2940, 2790, 2780, 1680, 1630, 1600, 1520, 1480, 1440, 1420, 1380, 1360, 1300, 1290, 1250, 1230, 1190, 1155, 1135,

1090, 1040, 950, 900, 830, 780, 770, 760, 720, 695, 685, 550, 470 (suspensions in perfluorvazelin and petroleum jelly).

NMR-i F (internal standard CeFe): C -F-92.3 M. d. (Singlet).

The aqueous solution after crystallization of 6-fluorothymine from the reaction mass is evaporated in vacuo at 0 ° C to dryness. The colorless residue is treated with boiling absolute methanol, the undissolved precipitate is filtered off, the filtrate is evaporated in vacuo to 50-60 ml, the hot solution is filtered and the filtrate is neutralized with 1M sodium methoxide solution. After cooling, the colorless crystals of the 6-fluorothymine potassium salt

filtered off, washed with ether and dried in vacuum. An additional 0.5-0.7 g (6-8%) of 6-fluorothymine monopotassium salt is obtained. The conversion of the potassium salt to 6-fluorithymip is carried out by acidification of its aqueous

or an alcoholic solution (or suspension in water or in alcohol) aqueous or alcoholic HC1 to a pH of 2-2.5, followed by freezing of 6-fluorothymine, as described above.

Example 3. Monoethanolamine salt of 6-fluorothymine.

When heated, 0.5 g (0.0035 gmol) of 6-fluorothymine is dissolved in 25 ml of absolute methanol and then 0.25 g (0.004 g mol) of monoethanolamine in 10 ml of methanol is added to the solution at 20-25 ° C. The mixture is stirred for 20 minutes, evaporated in vacuo to dryness, the residue is suspended in 30 ml of anhydrous ether, the precipitate is filtered off, washed with ether and dried in vacuum over PaOg.

Obtain 0.6 g (88%) of the monoethanolamine salt of 6-fluorothymine in the form of colorless crystals, t. Decomposed. 225-230 ° C (from methanol).

Found,%: C 40.79; H 6.03; F 9.08; N 20.03.

CsHsFHsOs CsHrNO

Calculated,%: C 40.93; H 5.91; F 9.20; N 20.11.

UV spectrum. In methanol: 1 max 275 nm (Ige 4.26); in water:. „ax 273 nm (Ige 4.24).

IR spectrum (cm-1): 3500,3150,3060, 2900, 2780, 2650, 1640, 1520, 1490, 1370, 1330, 1250, 1185, FROM 1050,1020, 990, 960, 910, 850, 780 , 740, 700, 540, 510, 420 (in perfluorovazelin and liquid paraffin).

Claims (2)

1. A process for the preparation of b-fluorothymine derivatives of general formula (I) Cli th X ..L  M where R is a hydrogen atom, alkali metal or alkaline earth metal, ammonium cation, ethanolamine, chloroethylamine, ethyleneimine; using 2,4,6-trifluoro-5-methylpyrimidine, characterized in that simplify the process and increase the yield of the target product; 2,4,6-trifluoro-5-methylpyrimidine is treated with aqueous alkali at a molar ratio of reagents of 1: 2.5-3 at 70-100 ° C, followed by separation of the target product in free form by successive acidification to pH 2-3 and freezing or isolation of the target product in the form of salt. 2. A method according to claim 1, characterized in that an alkali metal hydroxide is used as the alkali. Sources of information taken into account in the examination: 1. Etzold S., Barwolft D. Synthes und Reaktivitat von 6-Fluorthymin. - J. pract. Chem., 313, 602, 1971 (prototype).