CN111303045A - Production process of 2-ethoxy-4, 6-difluoropyrimidine - Google Patents

Abstract

The invention discloses a synthetic method of 2-ethoxy-4, 6-difluoropyrimidine, which comprises the following steps: (1) reacting urea and diethyl sulfate in an organic solvent at the temperature of 60-120 ℃ to prepare an intermediate I; (2) synthesizing an intermediate II by the intermediate I and diethyl malonate; (3) the intermediate II is chlorinated to obtain an intermediate III; (4) the intermediate III reacts with a fluoro reagent at the temperature of 80-120 ℃ for 6 hours, and then the target product 2-ethoxy-4, 6-difluoropyrimidine is obtained through separation and purification, and the structure is

Description

Production technology of 2-ethoxy-4,6-difluoropyrimidine

technical field

The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of 2-ethoxy-4,6-difluoropyrimidine.

Background technique

2-Ethoxy-4,6-difluoropyrimidine is an important pyrimidine compound and an important intermediate for many drugs. In particular, it is the key intermediate for the synthesis of triazolopyrimidine sulfonamides such as diclofenac.

There are some related reports at home and abroad about the synthesis of 2-ethoxy-4,6-disubstituted pyrimidines. The starting materials were all based on 2-ethoxy-4,6-dihydroxypyrimidine, and some halogenation reaction conditions were optimized to improve the yield. As for the synthesis of 2-ethoxy-4,6-dihydroxypyrimidine, the current mainstream synthesis process is based on O-ethylisourea sulfate as the initial raw material for subsequent synthesis and technical route improvement. For industrial production, in order to further reduce costs and improve production efficiency, it is necessary to develop a lower-cost production process for large-scale production.

SUMMARY OF THE INVENTION

The purpose of this invention is to develop a kind of new technical route, provide a kind of new preparation method of 2-ethoxy-4,6-difluoropyrimidine based on urea as initial raw material, and develop a kind of low cost and high yield .

The technical scheme for realizing the object of the present invention is as follows: a preparation method of 2-ethoxy-4,6-difluoropyrimidine has the following steps: (1) urea and diethyl sulfate are heated at 60-120° C. Reaction in organic solvent to prepare intermediate IO-ethyl isourea hydrogen sulfate; (2) intermediate IO-ethyl isourea hydrogen sulfate to prepare intermediate II 2-ethoxy-4,6-dihydroxypyrimidine; (3) ) Intermediate II 2-ethoxy-4,6-dihydroxypyrimidine undergoes chlorination under basic conditions to obtain intermediate III 2-ethoxy-4,6-dichloropyrimidine; (4) Intermediate III 2-ethoxy The target product 2-ethoxy-4,6-difluoropyrimidine was obtained by separation and purification after -4,6-dichloropyrimidine reacted with fluorinated reagent at 80-120℃ for 6 hours.

The mol ratio of urea described in above-mentioned steps (1) and dimethyl sulfate is 1: 0.5～1: 1.5;

The organic solvent described in the above-mentioned steps (1) is one or more mixtures in ethyl acetate, tetrahydrofuran, toluene, 1,2-dichloroethane and acetonitrile;

The reagent described in above-mentioned steps (2) and O-ethyl isourea sulfate reaction is diethyl malonate;

The mol ratio of O-ethylisourea sulfate and diethyl malonate described in the above step (2) is 1:0.5～1:1.5;

The reaction temperature described in the above-mentioned step (2) is 60～150 ℃;

The chlorination reagent described in above-mentioned steps (3) is phosphorus oxychloride;

The alkali described in above-mentioned steps (3) is triethylamine;

The mol ratio of 2-ethoxy-4,6-dihydroxypyrimidine and phosphorus oxychloride described in the above step (3) is 1:1～1:3;

The molar ratio of 2-ethoxy-4,6-dihydroxypyrimidine to pyridine described in the above step (3) is 1:2～1:5;

The fluorination reagent described in above-mentioned steps (4) is potassium fluoride;

The mol ratio of 2-ethoxy-4,6-dichloropyrimidine and potassium fluoride described in the above step (4) is 1:2～1:5;

Compared with the prior art, the present invention has obvious positive effects: the present invention adopts urea as the initial raw material, has good production safety, stable yield, high conversion rate of raw materials, convenient post-processing, and effectively reduces 2-ethoxylate after comprehensive investigation. The production cost of base-4,6-difluoropyrimidine, the final product is white crystal, the purity is more than 99%, the yield of each step is basically more than 80%, and the total yield can reach more than 61% after four steps; the present invention The solvent used in the process can be recovered, which further reduces the production cost and is suitable for industrial production.

Detailed ways

The following descriptions are only preferred embodiments of the present invention, and therefore do not limit the protection scope of the present invention.

Embodiment 1: the present embodiment is the preparation of O-ethyl isourea hydrogen sulfate, and the concrete method is as follows:

Add urea (129g, 2.148mol) and diethyl sulfate (280g, 1.818mol) into a 1000ml reaction flask and stir well, react at 80°C for 6 hours, stop the reaction when sampling and analysis to urea≤0.5%. The excess diethyl sulfate in the reaction system was removed by distillation under reduced pressure, and the remaining solid obtained was washed and purified with ethyl acetate to obtain the product O-ethylisourea hydrogen sulfate 301.5g, the yield was 75.5%, and the purity was 99.2% (HPLC);

Embodiment 2-5;

The method of each embodiment is basically the same as that of embodiment 1, and the difference is shown in Table 1;

Table 1 Other conditions affect

Example 2 3 4 5 washing solvent tetrahydrofuran Toluene Acetonitrile Xylene product (g) 290.1 368.8 272.9 347.2 yield 72.6% 92.3% 68.3% 86.9% Purity (HPLC) 98.9% 99.5% 99.8% 99.7%

Embodiment 6: This embodiment is the preparation of 2-ethoxy-4,6-dihydroxypyrimidine, and the specific method is as follows:

93.5g of O-ethylisourea hydrogen sulfate (0.5mol) with a purity of 99.5% and 250g of anhydrous methanol were added to a 1000mL reaction flask, the system was cooled to -5°C, and 200g of 27wt concentration was added dropwise with stirring. % sodium methoxide solution, and react at room temperature for 0.5h after the dropwise addition. 87.6 g of diethyl malonate was added by slow dropwise addition (about 20 min) at -5 °C, and the reaction was performed at 20 °C for 6 h after the dropwise addition. Sampling and analysis to stop the reaction when O-ethylisourea hydrogen sulfate is less than or equal to 0.5%. The methanol in the reaction system was recovered by distillation under reduced pressure, and then water was added to the system to fully dissolve, cooled to below 5°C, and 30 g of hydrochloric acid with a concentration of 36.5% was added dropwise under stirring to adjust the pH to 2. After the solid was fully separated, filter and wash with water. , and dried to obtain 69.2 g of 2-ethoxy-4,6-dihydroxypyrimidine white crystals with a yield of 88.7% and a purity of 99.4% (HPLC).

Embodiment 7: This embodiment is the preparation of 2-ethoxy-4,6-dichloropyrimidine, and the specific method is as follows:

In a 1000mL reaction flask, 157g of 2-ethoxy-4,6-dihydroxypyrimidine with a purity of 99.4% (1mol) was dissolved in 1,2-dichloroethane (300mL), and trichloroethylene was slowly added to the system. Phosphorus 340 g (2.2 mol). 205 g (2 mol) of triethylamine with a purity of 98.5% was added to the reaction system under stirring. During the process of adding triethylamine, attention was paid to controlling the rate of addition and the temperature of the reaction system so that the temperature of the reaction solution did not exceed 50°C. After the addition was completed, the reaction system was reacted at 85° C. for 3 h, and the reaction was stopped when 2-ethoxy-4,6-dihydroxypyrimidine ≤ 0.5% was sampled and analyzed. Cooled to room temperature, slowly added an appropriate amount of ice water, stirred for 0.5h, left to stand for layers, the organic phase was washed once with brine, dried, and fractionated to obtain 174.2g of the product, yield 90.7%, purity 98.7% (HPLC).

Embodiment 8-12;

The method of each embodiment is basically identical with embodiment 7, and difference is shown in Table 2;

Table 2 Other conditions affect

Example 8 9 10 11 11 12 Amount of POCl₃ 2mol 2.5mol 2.2 2.2 2.2 2.2 temperature reflex 85℃ 85℃ 75℃ 95℃ 85℃ 85℃ Reaction time 3h 3h 3h 3h 2.5h 4h product (g) 166.7 174.0 158.8 173.2 164.5 172.6 yield 86.8% 90.6% 82.7% 90.2% 85.7% 89.9% Purity (HPLC) 98.3% 99.1% 99.4% 98.7% 98.2% 98.5%

Embodiment 13: This embodiment is the preparation of 2-ethoxy-4,6-difluoropyrimidine, and the specific method is as follows:

In a 1000 mL reaction flask, 400 mL of sulfolane, 147.2 g (2.5 mol) of anhydrous potassium fluoride with a purity of 98.5% was added, and the mixture was heated to 200° C. and stirred for 1 h. Then it was cooled to 80°C, 194.5 g (1 mol) of 2-ethoxy-4,6-dichloropyrimidine with a purity of 98.7% was added, the temperature was raised to 160°C, and the reaction was stirred for 3 hours. Sampling and analysis to stop the reaction when 2-ethoxy-4,6-dichloropyrimidine is less than or equal to 0.5%, the product is distilled off under reduced pressure, and the product is refractionated to obtain 132.3g, the yield is 82.7%, and the purity is 99.1% (HPLC) . White crystals may form on cooling.

Examples 14-19;

The method of each embodiment is basically the same as that of embodiment 13, and the difference is shown in Table 3;

Table 3 Other conditions affect

Example 14 15 16 17 18 19 Amount of KF (mol) 2.2 3 2.5 2.5 2.5 2.5 Response time (h) 3 3 2.5 4 3 3 Reaction temperature (℃) 160 160 160 160 150 170 product (g) 126.1 131.8 115.1 132.6 85.8 127.4 yield 78.8% 82.4% 71.9% 82.9% 53.6% 79.6% Purity (HPLC) 98.3% 99.0% 99.1% 98.2% 98.4% 98.6%

Claims (11)

1. A synthetic method of 2-ethoxy-4, 6-difluoropyrimidine is characterized in that: the method takes urea as an initial raw material, prepares ethyl isourea sulfate, obtains 2-ethoxy-4, 6-dihydroxypyrimidine through cyclization, performs chlorination reaction under alkaline conditions, and obtains a target product, namely 2-ethoxy-4, 6-difluoropyrimidine through fluorination.

2. The method of synthesizing 2-ethoxy-4, 6-difluoropyrimidine of claim 1, wherein: the reagent used for preparing the ethyl isourea sulfate from urea is diethyl sulfate.

3. The method of synthesizing 2-ethoxy-4, 6-difluoropyrimidine of claim 2, wherein: the mol ratio of urea to diethyl sulfate is 1: 0.5-1: 1.5.

4. The method of synthesizing 2-ethoxy-4, 6-difluoropyrimidine of claim 2, wherein: the reaction temperature is 60-120 ℃.

5. The method of synthesizing 2-ethoxy-4, 6-difluoropyrimidine of claim 1, wherein: the reagent for obtaining the 2-ethoxy-4, 6-dihydroxypyrimidine by the reaction of the ethyl isourea sulfate is diethyl malonate.

6. The method of synthesizing 2-ethoxy-4, 6-dihydroxypyrimidine according to claim 5, wherein: the molar ratio of the ethyl isourea sulfate to the diethyl malonate is 1: 0.5-1: 1.5.

7. The method of synthesizing 2-ethoxy-4, 6-dihydroxypyrimidine according to claim 6, wherein: the reaction temperature is 60-150 ℃.

8. The method of synthesizing 2-ethoxy-4, 6-difluoropyrimidine of claim 1, wherein: the 2-ethoxy-4, 6-dihydroxypyrimidine is subjected to chlorination reaction under an alkaline condition, and a chlorination reagent is phosphorus oxychloride.

9. The method of synthesizing 2-ethoxy-4, 6-difluoropyrimidine of claim 1, wherein: the 2-ethoxy-4, 6-dihydroxypyrimidine is subjected to chlorination reaction under an alkaline condition, and the base is triethylamine.

10. The method of synthesizing 2-ethoxy-4, 6-difluoropyrimidine of claim 1, wherein: the fluorinating agent for the fluorination reaction is potassium fluoride.

11. The method of synthesizing 2-ethoxy-4, 6-difluoropyrimidine of claim 1, wherein: the organic solvent used in the whole reaction process is one or a mixture of ethyl acetate, tetrahydrofuran, toluene, 1, 2-dichloroethane and acetonitrile.