CN114262300A

CN114262300A - Preparation method of 2-ethoxy-4, 6-difluoropyrimidine

Info

Publication number: CN114262300A
Application number: CN202111530126.6A
Authority: CN
Inventors: 王焕挺; 陈阿明; 何建兵; 郑小兵; 李明
Original assignee: Zhejiang Weifeng Pharmaceutical Co ltd
Current assignee: Zhejiang Weifeng Pharmaceutical Co ltd
Priority date: 2021-12-15
Filing date: 2021-12-15
Publication date: 2022-04-01

Abstract

The invention discloses a preparation method of 2-ethoxy-4, 6-difluoropyrimidine, which comprises the following steps: A) urea is used as a raw material, ethyl isourea sulfate is prepared, and cyclization reaction is carried out to obtain 2-ethoxy-4, 6-dihydroxypyrimidine; B) taking the 2-ethoxy-4, 6-dihydroxypyrimidine prepared in the step A) as a raw material, reacting with trifluoromethanesulfonic anhydride to generate an intermediate with trifluoromethanesulfonyl, and reacting with a fluorinating agent for fluorination to obtain 2-ethoxy-4, 6-difluoropyrimidine. The invention adopts urea as an initial raw material, prepares the intermediate 2-ethoxy-4, 6-dihydroxypyrimidine through a one-pot two-step method, does not need separation and purification in the middle, has simple operation, stable yield and high conversion rate of the raw material, utilizes the property of easy separation of trifluoromethanesulfonyl to activate the intermediate into ester when preparing a finished product, then substitutes the intermediate at low temperature through potassium fluoride, and prepares the product through the one-pot two-step method.

Description

Preparation method of 2-ethoxy-4, 6-difluoropyrimidine

Technical Field

The invention belongs to a preparation method of a drug intermediate, and particularly relates to a preparation method of 2-ethoxy-4, 6-difluoropyrimidine.

Background

2-ethoxy-4, 6-difluoropyrimidine is an important pyrimidine compound and an important intermediate of a plurality of medicaments. In particular to a key intermediate for synthesizing triazolopyrimidine sulfonamide-type medicament diclosulam and the like. At present, 2-ethoxy-4, 6-disubstituted pyrimidine compounds are generally prepared by firstly preparing an intermediate 2-ethoxy-4, 6-dihydroxypyrimidine, then chlorinating by phosphorus oxychloride to obtain 2-ethoxy-4, 6-dichloropyrimidine, and then substituting by potassium fluoride at a temperature of over 160 ℃ to obtain a final product. Moreover, when the generated chloride is replaced by potassium fluoride, the reaction can be completed only at a very high temperature, and the industrial production difficulty is high.

Disclosure of Invention

Aiming at the problems in the prior art, the invention aims to develop a new synthesis method and provide a preparation method of 2-ethoxy-4, 6-difluoropyrimidine, which is based on urea as a raw material and has the advantages of simple operation, high yield and mild reaction conditions.

The invention is realized by the following technical scheme:

the preparation method of 2-ethoxy-4, 6-difluoropyrimidine comprises two steps:

step A), urea is used as a raw material, ethyl isourea sulfate is prepared, and cyclization reaction is carried out to obtain 2-ethoxy-4, 6-dihydroxypyrimidine;

the process route is as follows:

step B) taking the 2-ethoxy-4, 6-dihydroxypyrimidine prepared in the step A) as a raw material, reacting with trifluoromethanesulfonic anhydride to generate an intermediate with trifluoromethanesulfonyl, and reacting with a fluorinating agent for fluorination to obtain 2-ethoxy-4, 6-difluoropyrimidine;

the process route is as follows:

。

further, step a) comprises the steps of:

A1) adding diethyl sulfate and urea into the reaction kettle in sequence, heating to 75-85 ℃, and stirring for reaction for 5-6 h;

A2) after the reaction is finished, cooling to 25-35 ℃;

A3) adding methanol into the reaction system, stirring and dissolving, then cooling to-5 ℃, adding liquid sodium methoxide into the reaction kettle, and continuing stirring for 0.5-1 h;

A4) then adding diethyl malonate into the reaction kettle, and stirring and reacting for 6-7h at the temperature of 20-25 ℃;

A5) after the reaction is finished, heating and decompressing to recover the methanol and the ethanol, and then adding water to dissolve the obtained solid;

A6) adjusting the pH value to 2-3 by using an acid solution to generate white fixation, and washing and drying a solid phase after solid-liquid separation to obtain the 2-ethoxy-4, 6-dihydroxypyrimidine.

Further, the mass ratio of the urea to the diethyl sulfate to the diethyl malonate is 1: 2.1-3: 2.2-2.6, and the acid solution is a hydrochloric acid solution.

Further, step B) comprises the steps of:

B1) adding the 2-ethoxy-4, 6-dihydroxypyrimidine prepared in the step A), dichloromethane and triethylamine into a reaction kettle, and stirring for dissolving;

B2) cooling to 0-5 ℃, adding trifluoromethanesulfonic anhydride into the reaction kettle, and stirring for reaction for 0.5-1 h;

B3) then heating to 25-35 ℃, and stirring for 10-11h under the condition of keeping the temperature;

B4) after the reaction is finished, adding water into the reaction kettle for layering, extracting the water phase at least once by using dichloromethane, and combining the organic phases;

B5) washing the organic phase with saturated sodium bicarbonate solution and water in sequence, and then distilling and concentrating to recover dichloromethane and triethylamine to obtain light yellow oily matter;

B6) adding DMF into the light yellow oily matter for dissolving, adding a fluorinating agent, and stirring for reaction for 2-3h at the temperature of 60-70 ℃;

B7) after the reaction is finished, carrying out reduced pressure distillation to obtain a mixture of DMF and the product, and then carrying out rectification separation on the DMF and the product to obtain the 2-ethoxy-4, 6-difluoropyrimidine.

Further, the mass ratio of the 2-ethoxy-4, 6-dihydroxypyrimidine to the trifluoromethanesulfonic anhydride to the fluorinating agent is 1: 2.2-2.8: 0.8-1.2, and the fluorinating agent is potassium fluoride.

Further, in the step B6) and the step B7), barium sulfate powder is further added to the mixed solution after the DMF is dissolved, the barium sulfate powder is separated from the reaction solution by filtration after the reaction is completed and before the reduced pressure distillation, the separated barium sulfate powder is washed by at least one time of DMF solvent, and the washed solvent is mixed with the reaction solution.

The invention adopts urea as an initial raw material, prepares the intermediate 2-ethoxy-4, 6-dihydroxypyrimidine through a one-pot two-step method, does not need separation and purification in the middle, has simple operation, stable yield and high conversion rate of the raw material, utilizes the property of easy separation of trifluoromethanesulfonyl to activate the intermediate into ester when preparing a finished product, then substitutes the intermediate at low temperature through potassium fluoride, and prepares the product through the one-pot two-step method.

Detailed Description

The present invention will be further described in detail with reference to the following examples to better understand the technical solution.

EXAMPLE 1 preparation of 2-ethoxy-4, 6-dihydroxypyrimidine

(1) Adding 45kg of diethyl sulfate into a reaction kettle, then adding 20kg of urea, and heating to 75-85 ℃;

(2) stirring and reacting for 5-6 hours at 75-85 ℃;

(3) after the reaction is finished, cooling to 25-35 ℃;

(4) adding 70kg of methanol into the system, stirring and dissolving the mixture to be clear, and then cooling the mixture to-5 ℃;

(5) 120kg of liquid sodium methoxide was slowly added to the reaction kettle. After the addition is finished, continuously stirring for 0.5-1 h;

(6) then adding 45kg of diethyl malonate into the reaction kettle, heating to 20-25 ℃ after the addition is finished, and stirring for reaction for 6-7 hours;

(7) after the reaction is finished, heating and decompressing to recover methanol and ethanol;

(8) after distillation, 280kg of drinking water is added into the reaction kettle, and the obtained solid is dissolved;

(9) adding hydrochloric acid into the reaction kettle, and adjusting the pH =2-3 to generate a large amount of white products;

(10) discharging, centrifuging, washing with water, and drying to obtain white product 44.5kg with yield of 85.6% and purity of 99.0%.

Example 2: synthesis of 2-ethoxypyrimidine-4, 6-diylbis (2, 2, 2-trifluoroacetate)

(1) Adding 140kg of dichloromethane and 31kg of 2-ethoxy-4, 6-dihydroxypyrimidine into a reaction kettle, then adding 60kg of triethylamine, and stirring for dissolving;

(2) cooling to 0-5 ℃, adding 67.7kg of trifluoromethanesulfonic anhydride into the reaction kettle, and stirring at 0-5 ℃ for reaction for 0.5-1 h;

(3) heating to 25-35 ℃, and stirring for reaction for 10-11 h;

(4) after the reaction, 70kg of water was added to the reaction vessel, and the layers were separated. The aqueous phase was extracted once more with 20kg of dichloromethane and the organic phases were combined;

(5) the organic phase is washed by saturated sodium bicarbonate solution and water, and then methylene chloride and triethylamine are recovered by distillation and concentration, so that light yellow oily matter is obtained.

Example 3: synthesis of 2-ethoxy-4, 6-difluoropyrimidine

(1) Adding 120kg of DMF into the oily substance obtained in the last step, then adding 26.5kg of anhydrous potassium fluoride (powder), heating to 60-70 ℃, and stirring for reaction for 2-3 h;

(2) after the reaction of the raw materials is detected to be less than or equal to 0.5 percent, carrying out reduced pressure distillation to obtain a mixture of DMF and the product;

(3) the mixture is rectified to separate DMF and the product, and 27.4kg of the product is finally obtained, the yield is 86.2 percent, and the purity is 99.3 percent.

Claims

1. A preparation method of 2-ethoxy-4, 6-difluoropyrimidine is characterized by comprising the following steps:

A) urea is used as a raw material, ethyl isourea sulfate is prepared, and cyclization reaction is carried out to obtain 2-ethoxy-4, 6-dihydroxypyrimidine;

B) taking the 2-ethoxy-4, 6-dihydroxypyrimidine prepared in the step A) as a raw material, reacting with trifluoromethanesulfonic anhydride to generate an intermediate with trifluoromethanesulfonyl, and reacting with a fluorinating agent for fluorination to obtain 2-ethoxy-4, 6-difluoropyrimidine.

2. The process for preparing 2-ethoxy-4, 6-difluoropyrimidine as claimed in claim 1, wherein step a) comprises the steps of:

A2) after the reaction is finished, cooling to 25-35 ℃;

3. The method for preparing 2-ethoxy-4, 6-difluoropyrimidine as claimed in claim 2, wherein the mass ratio of urea to diethyl sulfate to diethyl malonate is 1: 2.1-3: 2.2-2.6.

4. The process for preparing 2-ethoxy-4, 6-difluoropyrimidine as claimed in claim 2, wherein the acidic solution is hydrochloric acid solution.

5. The process for preparing 2-ethoxy-4, 6-difluoropyrimidine as claimed in claim 1, wherein step B) comprises the steps of:

6. The method for preparing 2-ethoxy-4, 6-difluoropyrimidine according to claim 5, wherein the mass ratio of the 2-ethoxy-4, 6-dihydroxypyrimidine to the trifluoromethanesulfonic anhydride to the fluorinating agent is 1: 2.2-2.8: 0.8-1.2.

7. The process for preparing 2-ethoxy-4, 6-difluoropyrimidine of claim 5, wherein the fluorinating agent is potassium fluoride.

8. The process according to claim 5, wherein in steps B6) and B7), the mixed solution of DMF and barium sulfate powder is further added, the barium sulfate powder is separated from the reaction solution by filtration after the reaction is completed and before the distillation under reduced pressure, the separated barium sulfate powder is washed with DMF solvent at least once, and the washed solvent is mixed with the reaction solution.