CN109761914B

CN109761914B - Method for preparing 5-trifluoromethyl uracil

Info

Publication number: CN109761914B
Application number: CN201910131345.3A
Authority: CN
Inventors: 刘志强; 李亚周; 陈振昌; 张红娟
Original assignee: Beijing Ribio Biotech Co ltd
Current assignee: Fujian Ruibo Technology Co ltd
Priority date: 2019-02-22
Filing date: 2019-02-22
Publication date: 2021-03-05
Anticipated expiration: 2039-02-22
Also published as: CN109761914A

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing 5-trifluoromethyl uracil. The method comprises the following steps: firstly, carrying out chlorination reaction on (5-iodouracil) and phosphorus oxychloride to obtain 2, 4-dichloro-5-iodopyrimidine; then carrying out trifluoromethylation reaction on the 2, 4-dichloro-5-iodopyrimidine and a trifluoromethylation reagent to obtain 2, 4-dichloro-5-trifluoromethylpyrimidine; and finally, reacting the 2, 4-dichloro-5-trifluoromethylpyrimidine with acetic acid to obtain a product. The invention adopts chlorination reaction, trifluoromethylation reaction and hydrolysis reaction, so as to synthesize the key intermediate trifluoromethyluracil of the trofluvudine with high yield, low cost and low pollution.

Description

Method for preparing 5-trifluoromethyl uracil

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing 5-trifluoromethyl uracil.

Background

Trifluthymidine is a kind of spectral antiviral medicine, and has the effect of inhibiting herpes simplex virus, herpes zoster virus, etc. and also has the effect of inhibiting HSV-I, HSV-II, CMV, varicella virus and some adenovirus. 5-trifluoromethyl uracil (TFU) is a key intermediate in the synthesis of the anticancer drug trofluthymidine. The main methods for synthesizing TFU reported in the literature at present are: (1) 2-trifluoromethyl acrylic acid and urea are used as main raw materials, 5, 6-dihydro-5-trifluoromethyl uracil is obtained by ring closure in acetic anhydride, and then the 5, 6-dihydro-5-trifluoromethyl uracil is obtained by oxidative dehydrogenation. The method has high temperature of ring-closing reaction, low yield, large pollution and high cost, and limits large-scale industrialization (Akiko Chemistry Letters,1984, 1595-; (2) thymine is used as a main raw material, a key intermediate 5-trichloromethyl-2, 4-dichloropyrimidine is obtained through hydroxyl chlorination and methyl free radical chlorination, and then the target product is obtained through fluorination and hydrolysis. The method has the main advantages that the cost is low, but 5-methyl-2, 4-dichloropyrimidine cannot be chlorinated completely, so that the content of raw materials in a final product is higher and cannot reach the medicinal standard. This impurity is also involved in the subsequent reaction to 2' -deoxythymidine and is difficult to remove (Journal of Fluorine Chemistry,1996, 93-95). (3) Uracil and trifluoroiodomethane or sodium trifluoromethane sulfinate are used as main raw materials, and a target product is obtained through one-step trifluoromethylation. The reaction route is short, but the yield is not ideal; trifluoroiodomethane is expensive and a gas, which is extremely inconvenient to store and use (US2014/135497a1, EP1947092a 1).

Therefore, a method for preparing 5-trifluoromethyl uracil with low cost, high yield and low pollution is urgently needed to be found.

Disclosure of Invention

The invention aims to provide a method for preparing 5-trifluoromethyl uracil.

The method for preparing 5-trifluoromethyl uracil provided by the invention is carried out according to a synthesis route diagram shown in figure 1, and comprises the following steps:

1) enabling a compound (5-iodouracil) shown in the formula I and phosphorus oxychloride to perform chlorination reaction to obtain a compound (2, 4-dichloro-5-iodopyrimidine) shown in the formula II;

2) carrying out trifluoromethylation reaction on the compound shown in the formula II and a trifluoromethylation reagent to obtain the compound shown in the formula III (2, 4-dichloro-5-trifluoromethylpyrimidine)

3) And (3) carrying out hydrolysis reaction on the compound shown in the formula III and an acetic acid aqueous solution or a formic acid aqueous solution to obtain the 5-trifluoromethyl uracil.

In step 1) of the above method, the molar ratio of the compound 5-iodouracil shown in formula I to the phosphorus oxychloride can be: 1:2-5.

The chlorination reaction is carried out under alkaline conditions.

The chlorination reaction is carried out in an organic solvent, and the organic solvent can be toluene, xylene, DMF and the like.

The specific operation of the chlorination reaction is as follows: mixing 5-iodouracil with triethylamine and an organic solvent, heating to 95-110 ℃, slowly dripping phosphorus oxychloride when the temperature in a reaction system reaches 90 ℃, keeping the temperature after the dripping of phosphorus oxychloride, and continuously stirring for reacting for 1-2 hours.

Wherein, the mol ratio of the 5-iodouracil to the triethylamine can be 1: 2-3.

In step 2) of the method, the trifluoromethylating agent may specifically be: (trifluoromethyl) Trimethylsilane (TMSCF)₃)。

The molar ratio of the compound shown in the formula II to the trifluoromethyl in the trifluoromethylating reagent can be 1: 2-4.

The trifluormethylation reaction is carried out in the presence of KF, trimethyl borate, CuI and 1, 10-Phen.

The reaction is carried out in an organic solvent, which may be: DMSO, DMF, toluene, and the like.

The molar ratio of the compound shown in the formula II to KF, trimethyl borate, CuI and 1,10-Phen (1, 10-phenanthroline) can be sequentially as follows: 1: 2.0-4.0, 1: 2.0-4.0, 1: 0.05-0.20, 1: 0.10-0.40.

The reaction is carried out under an inert atmosphere, wherein the inert gas specifically comprises: nitrogen or argon.

The reaction temperature can be 55-65 ℃, particularly 60 ℃, and the reaction time can be 2-3h, particularly 2 h.

In step 3), the ratio of the compound represented by formula III to acetic acid or formic acid may be: 1 g: 1.5-2.5mL, specifically 15.6 g: 30 mL.

The reaction is carried out in water.

The reaction temperature may be 100-120 ℃, and specifically may be 110 ℃.

The reaction time may be 5 to 6 hours, specifically 5 hours.

The invention adopts chlorination reaction, trifluoromethylation reaction and hydrolysis reaction, so as to synthesize the key intermediate trifluoromethyluracil of the trofluvudine with high yield, low cost and low pollution.

Drawings

FIG. 1 is a scheme showing the synthesis of 5-trifluoromethyluracil according to the present invention.

Detailed Description

The present invention will be described below with reference to specific examples, but the present invention is not limited thereto.

The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples are commercially available unless otherwise specified.

The compound represented by formula I (5-iodouracil) used as a raw material in the following examples was obtained from national health biotechnology, Inc., Baoji, under the trade name of 5-iodouracil.

Examples

1. Synthesis of 2, 4-dichloro-5-iodopyrimidine

A500 mL three-necked flask was charged with 5-iodouracil (23.8g), TEA (30.3g), and Tol (240mL), and heated to 100 ℃. Phosphorus oxychloride (33.7g) was slowly added dropwise when the internal temperature of the flask reached 90 ℃. After the addition was complete, the temperature was maintained and stirring continued for 1h, then cooled to room temperature, suction filtered, the filtrate was collected, the solid was washed with PE/EA-5/1, the filtrate and the washing liquid were combined, spin dried to give a crude product which was slurried with PE to give the product as 24.5g of an off-white solid in 89% yield. 274.8 m/z

2. Synthesis of 2, 4-dichloro-5-trifluoromethylpyrimidine

2, 4-dichloro-5-iodopyrimidine (24.5g), TMSCF were placed in a 500mL three-necked flask₃(25.5g), KF (10.4g), trimethyl borate (18.5g), CuI (1.7g), Phen (1.6g), DMSO (250mL) were heated to 60 ℃ under nitrogen blanket. After 2 hours of reaction, the temperature is reduced to room temperature, ethyl acetate (500mL) and water (300mL) are added for liquid separation, the organic phase is washed by 1N diluted hydrochloric acid (300mL), dried by sodium sulfate and spin-dried to obtain a crude product, and the crude product is pulped by petroleum ether to obtain 15.6g of a product with the yield of 81%. m/z is 217.0

3. Synthesis of 5-trifluoromethyluracil

A250 mL single-neck flask was charged with 2, 4-dichloro-5-trifluoromethylpyrimidine (15.6g), acetic acid (30mL), and water (15mL), and heated to 110 ℃. The reaction was carried out for 5 hours, and the mixture was concentrated to 30mL, and 120mL of toluene was added, and the mixture was concentrated to 100mL, and the mixture was stirred at room temperature and filtered by suction to obtain 11.7g of a product with a yield of 90.6%. m/z 181.0

Claims

1. A process for preparing 5-trifluoromethyluracil comprising the steps of:

1) carrying out chlorination reaction on the compound shown in the formula I and phosphorus oxychloride to obtain a compound shown in a formula II;

2) carrying out trifluoromethylation reaction on the compound shown in the formula II and a trifluoromethylation reagent to obtain a compound shown in a formula III;

3) carrying out hydrolysis reaction on the compound shown in the formula III and an acetic acid aqueous solution or a formic acid aqueous solution to obtain 5-trifluoromethyl uracil;

in the step 1), the chlorination reaction is carried out by: firstly, mixing a compound shown as a formula I with triethylamine and an organic solvent, heating to 95-110 ℃, slowly dripping phosphorus oxychloride when the temperature in a reaction system reaches 90 ℃, and keeping the temperature to continue stirring and reacting for 1-2 h after finishing the dripping;

in the step 1), the molar ratio of the compound shown in the formula I to the phosphorus oxychloride is as follows: 1: 2.2;

in the step 2), the trifluoromethylation reagent is: (trifluoromethyl) trimethylsilane TMSCF₃；

The molar ratio of the compound shown in the formula II to trifluoromethyl in the trifluoromethyl reagent is 1: 2-4;

the trifluromethylation reaction is carried out in the presence of KF, trimethyl borate, CuI and 1, 10-Phen;

the molar ratios of the compound shown in the formula II to KF, trimethyl borate, CuI and 1,10-Phen are as follows: 1: 2.0-4.0, 1: 2.0-4.0, 1: 0.05-0.20, 1: 0.10-0.40;

in the step 2), the reaction temperature is 60 ℃, and the reaction time is 2 h.

2. The method of claim 1, wherein: in the step 2), the reaction is carried out in an organic solvent, wherein the organic solvent is: DMSO, DMF, toluene;

the reaction is carried out under an inert atmosphere.

3. The method of claim 1, wherein: in the step 3), the mixture ratio of the compound shown in the formula III to acetic acid or formic acid is as follows: 1 g: 1.5-2.5 mL;

the reaction is carried out in water.

4. The method of claim 1, wherein: in the step 3), the reaction temperature is 100-120 ℃, and the reaction time is 5-6 h.