CN106883185B

CN106883185B - Preparation method of 4-chloro-2-trifluoromethylpyrimidine

Info

Publication number: CN106883185B
Application number: CN201510935307.5A
Authority: CN
Inventors: 杨耀宇; 张飞
Original assignee: PORTON FINE CHEMICALS Ltd
Current assignee: PORTON FINE CHEMICALS Ltd
Priority date: 2015-12-15
Filing date: 2015-12-15
Publication date: 2021-07-09
Anticipated expiration: 2035-12-15
Also published as: CN106883185A

Abstract

The invention discloses a preparation method of 4-chloro-2-trifluoromethylpyrimidine (formula I), which is prepared by taking methyl trifluoroacetate and malonamide which are low in price and easy to purchase as raw materials.The method does not use expensive materials, has mild reaction conditions, simple equipment, low EHS risk and low cost, and is suitable for large-scale production.

Description

Preparation method of 4-chloro-2-trifluoromethylpyrimidine

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of an active drug intermediate for treating diseases related to arteriosclerosis, nephropathy, tumors, cardiovascular diseases, anxiety, depression and the like.

Background

4-chloro-2-trifluoromethylpyrimidine is an important medical intermediate, and the preparation methods reported at present are few. Among them, the target compound is obtained by cyclization with ethyl 3-oxopropionate using trifluoroacetamidine and ethyl trifluoroacetamidine as reported in document j, org, chem, 26, 4505, 1961, as shown in the following reaction scheme:

however, both the raw materials of the trifluoroacetamidine and the ethyl 3-oxopropionate do not have a large number of suppliers at home, and the synthesis of the trifluoroacetamidine is reported to be mainly obtained by the high-pressure reaction of trifluoroacetonitrile and ammonia gas, wherein the boiling point of the trifluoroacetonitrile is only-65 ℃, and the trifluoroacetonitrile belongs to a low-boiling-point high-toxicity substance and also has no large number of suppliers. The limitations of the starting materials make the synthesis of this compound difficult and the development of new synthetic methods very promising.

Disclosure of Invention

The invention discloses a preparation method of 4-chloro-2-trifluoromethylpyrimidine (formula I), which is prepared by taking methyl trifluoroacetate and malonamide which are low in price and easy to purchase as raw materials. The method does not use expensive materials, has mild reaction conditions, simple equipment, low EHS risk and low cost, and is suitable for large-scale production.

1. The invention discloses a preparation method of a compound shown in a formula I,

the method comprises the following steps:

a) reacting the compound shown in the formula V with sodium methoxide to prepare a reaction solution containing the compound shown in the formula IV; carrying out catalytic hydrogenation on a reaction liquid containing a compound shown in a formula IV to prepare a compound shown in a formula III; the method does not need to separate and purify the compound of the formula IV, and obtains the compound of the formula III by feeding the compound of the formula V in a one-pot method.

b) The compound of the formula III is subjected to demethylation reaction to prepare a compound of a formula II;

c) halogenating the compound of formula II in the presence of a halogenating agent to produce the compound of formula I.

2. The process as described in 1, step a) should be strictly controlled in the amount of sodium methoxide, otherwise both chlorides will be substituted by methoxy groups, the molar ratio of the amounts of sodium methoxide and compound of formula V being: 1.15-1: 1.

3. In the process according to claim 2, the molar ratio of the amounts of sodium methoxide and compound of formula V is preferably: 1.05:1.

4. The process as described in 1, the catalyst used for the catalytic hydrogenation in step a) being Pd/C.

5. The process as described in 1, the reagent used for the demethylation reaction in step b) is hydrobromic acid.

6. The process as described in 1, the halogenating agent in step c) being POCl 3.

7. The method as described in 1, wherein the compound of formula V is prepared by the following method, which is characterized by comprising the following steps:

d) preparing a compound VI from a compound shown in a formula VII and methyl trifluoroacetate in the presence of a condensing agent;

e) reacting the compound VI with a halogenating agent to prepare a compound V;

。

8. the process according to 7, wherein the condensing agent in step d) is sodium methoxide.

9. The method as described in 8, wherein the molar ratio of the sodium methoxide to the compound of formula VII is 2-3: 1.

10. In the process according to claim 9, the molar ratio of sodium methoxide to VII compound is preferably 2.2: 1.

11. The process as described in 7, the halogenating agent in step e) being POCl 3.

12. In the method of 7, triethylamine is required to be added as a base in the step e), and the triethylamine can accelerate the reaction to complete the reaction.

The specific implementation mode is as follows:

EXAMPLE 1 preparation of 2-trifluoromethyl-4, 6-dihydroxypyrimidine (VI)

Adding 500 mL of methanol into a reaction bottle, cooling to 0-5 ℃, adding 118.6 g of sodium methoxide, stirring until the mixture is basically clear, adding 102.1g of malonamide, stirring, heating to 35 ℃, adding 153.7g of methyl trifluoroacetate, stirring for 30 minutes after the addition is finished, and heating to 65-70 ℃ for refluxing for 15 hours. After the reaction is finished, cooling to 25-35 ℃, dropwise adding 100 mL of methyl tert-ether, cooling to 5-10 ℃ after dropwise adding, stirring, filtering, leaching a filter cake with methyl tert-ether, transferring the solid to a single-mouth bottle after filtering, and concentrating under reduced pressure. Adding water, stirring until the mixture is clear, adding concentrated hydrochloric acid to adjust the pH = 1-2, and filtering to obtain 95g of a filter cake. And adding 250 mL of ethyl acetate into the filter cake, heating to reflux, stirring, filtering, and concentrating under reduced pressure to constant weight to obtain 118.4g of off-white solid, wherein the yield is 65.8 percent and the HPLC is 94.3 percent.

EXAMPLE 2 preparation of 4, 6-dichloro-2-trifluoromethylpyrimidine (V)

Adding 144.1 g of phosphorus oxychloride into a reaction bottle, stirring, adding 36g of 2-trifluoromethyl-4, 6-dihydroxypyrimidine, stirring, cooling to 5-10 ℃, dropwise adding 55.4 mL of triethylamine, heating to 100-105 ℃ after dropwise addition, reacting for 4 hours, controlling the temperature to be 0-5 ℃ after the medium-controlled reaction is qualified, adding the reaction solution into ice water, stirring, adding dichloromethane, stirring for layering, adding dichloromethane into the water phase, extracting, combining organic phases, washing, filtering, and drying to obtain a crude product. The crude product was distilled and the product distilled off was collected as a colorless liquid 31.4g, yield 72.4%, HPLC 99.9%.

EXAMPLE 3 preparation of 4-methoxy-2-trifluoromethylpyrimidine (III)

Adding 100 mL of methanol into a reaction bottle, cooling to 0-5 ℃, adding 7.8 g of sodium methoxide in batches, and stirring for 10 minutes until the sodium methoxide is basically dissolved and clear for later use. And then adding 100 mL of methanol and 27.2 g of 4, 6-dichloro-2-trifluoromethylpyrimidine into another reaction bottle, dropwise adding the prepared sodium methoxide methanol solution at 10-20 ℃, stirring for 5 hours at 30-35 ℃, filtering the reaction solution after the raw materials react, leaching a filter cake with 50 mL of methanol, and combining the filtrates to obtain the 4-chloro-6-methoxy-2-trifluoromethylpyrimidine solution.

And (2) adding 2 g of 10% palladium carbon and 14 g of triethylamine into the 4-chloro-6-methoxy-2-trifluoromethylpyrimidine solution obtained in the previous step, replacing with nitrogen, introducing hydrogen under normal pressure, stirring for 15 hours at 25-35 ℃, controlling the reaction to be finished, filtering the reaction solution, and leaching a filter cake with 50 mL of methanol. The filtrate was concentrated under reduced pressure to constant weight to give 24 g of pale yellow solid, crude yield of two steps 107%.

EXAMPLE 4 preparation of 2-trifluoromethyl-4-hydroxypyrimidine (II)

To the reaction flask was added 40mL of hydrobromic acid, and 27.2 g of 4-methoxy-2-trifluoromethylpyrimidine was added with stirring. Heating to 60-70 ℃, stirring for 5 hours, cooling to 25-35 ℃ after the intermediate control reaction is qualified, filtering, dropwise adding a sodium hydroxide solution into the filtrate to adjust the pH to be = 2-3, separating out a solid, cooling to 5-10 ℃, stirring, filtering, drying a filter cake to constant weight, and obtaining 16.1 g of white powder solid, 95.9% of HPLC (high performance liquid chromatography), and the yield of 65.6%.

EXAMPLE 5 preparation of 4-chloro-2-trifluoromethylpyrimidine (I)

Adding 10 g of phosphorus oxychloride into a reaction bottle, stirring, adding 3.5 g of 2-trifluoromethyl-4-hydroxypyrimidine, and dropwise adding 2.2 g of triethylamine at 20-30 ℃. Heating to 100-105 ℃, stirring and reacting for 3 hours, cooling the reaction liquid to 0-5 ℃ after the intermediate control reaction is qualified, slowly dripping the reaction liquid into ice water, and stirring for 30 minutes at controlled temperature. Adding dichloromethane for extraction, standing for layering, adding dichloromethane into the water phase for extraction once, combining the organic phases, washing, and concentrating under reduced pressure to constant weight to obtain 3.4 g of brown yellow liquid, wherein the HPLC content is 97.9%, and the yield is 87%.

Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.

Claims

1. A process for the preparation of a compound of formula I,

the method is characterized by comprising the following steps:

a) reacting the compound shown in the formula V with sodium methoxide to prepare a reaction solution containing the compound shown in the formula IV; carrying out catalytic hydrogenation on a reaction liquid containing a compound shown in a formula IV to prepare a compound shown in a formula III;

c) halogenating the compound of formula II in the presence of a halogenating agent to obtain a compound of formula I,

e) reacting the compound VI with a halogenating agent to prepare a compound V;

the compound shown in the formula V in the step a) reacts with sodium methoxide at the temperature of 30-35 ℃, and a reagent used in demethylation reaction in the step b) is hydrobromic acid.

2. The process according to claim 1, wherein the molar ratio of the amounts of sodium methoxide and compound of formula V used in step a) is: 1.15-1: 1.

3. The process according to claim 2, wherein the molar ratio of the amounts of sodium methoxide and compound of formula V is preferably: 1.05:1.

4. The process of claim 1, wherein the catalyst used for the catalytic hydrogenation in step a) is Pd/C.

5. The process of claim 1 wherein the halogenating agent in step c) is POCl 3.

6. The process according to claim 1, wherein the condensing agent in step d) is sodium methoxide.

7. The process according to claim 1, wherein the molar ratio of sodium methoxide to compound of formula VII is 2-3: 1.

8. The process according to claim 1, wherein the molar ratio of sodium methoxide to VII compound is preferably 2.2: 1.

9. The process of claim 1, the halogenating agent in step e) being POCl 3.

10. The process of claim 1, wherein triethylamine is added as a base in step e).