阅读说明：本技术 2-溴-5-(三氟甲氧基)吡啶的制备方法 (Preparation method of 2-bromo-5- (trifluoromethoxy) pyridine ) 是由 刘德勇 张玉 孙鹏大 李宝华 陈德安 张治柳 董径超 于 2021-08-27 设计创作，主要内容包括：本发明公开一种2-溴-5-(三氟甲氧基)吡啶的制备方法,包括以下步骤：2-溴-5-羟基吡啶(化合物1)与二氟溴乙酸乙酯(化合物1A)在有机碱的存在下反应,生成化合物2；化合物2在碱性试剂存在下发生酯基水解反应,生成化合物3；化合物3与草酰氯在N,N-二甲基甲酰胺催化下羧基发生酰氯化,将其反应液浓缩后和2,2’-偶氮二异丁腈(AIBN)滴入2-巯基吡啶氮氧化物钠盐(化合物3A)的三氯溴甲烷溶液中,得到化合物4；将四氟硼酸银溶液滴入化合物4的溶液中,反应生成最终产物2-溴-5-(三氟甲氧基)吡啶。本发明的方法具有原料环保易得、条件温和、易操作、适合公斤级生产等优点。(The invention discloses a preparation method of 2-bromo-5- (trifluoromethoxy) pyridine, which comprises the following steps: reacting 2-bromo-5-hydroxypyridine (compound 1) with ethyl difluorobromoacetate (compound 1A) in the presence of an organic base to produce compound 2; the compound 2 undergoes ester group hydrolysis reaction in the presence of an alkaline reagent to generate a compound 3; performing acyl chlorination on the carboxyl group of the compound 3 and oxalyl chloride under the catalysis of N, N-dimethylformamide, concentrating a reaction solution, and dripping the concentrated reaction solution and 2,2' -Azobisisobutyronitrile (AIBN) into trichlorobromomethane solution of 2-mercaptopyridine nitrogen oxide sodium salt (compound 3A) to obtain a compound 4; and dripping the silver tetrafluoroborate solution into the solution of the compound 4 to react to generate a final product, namely 2-bromo-5- (trifluoromethoxy) pyridine. The method has the advantages of environment-friendly and easily-obtained raw materials, mild conditions, easy operation, suitability for kilogram-level production and the like.)

1. A preparation method of 2-bromo-5- (trifluoromethoxy) pyridine is characterized by comprising the following steps:

1) carrying out an alkylation reaction on the compound 1 and ethyl difluorobromoacetate in the presence of organic base to generate a compound 2;

2) the compound 2 undergoes ester group hydrolysis reaction in the presence of an alkaline reagent to generate a compound 3;

3) performing acyl chlorination reaction on the compound 3 and oxalyl chloride under the catalysis of N, N-dimethylformamide, concentrating the reaction solution, and dripping the concentrated reaction solution and 2,2' -azobisisobutyronitrile into trichlorobromomethane solution of 2-mercaptopyridine nitrogen oxide sodium salt to generate a compound 4;

4) dripping the silver tetrafluoroborate solution into the compound 4 solution for reaction to generate a compound 5, namely a final product 2-bromine-5- (trifluoromethoxy) pyridine;

the reaction formula is as follows:

2. the method according to claim 1, wherein in the step 1, the feeding molar ratio of the compound 1 to the ethyl difluorobromoacetate is 1: 1-1: 3.

3. The method according to claim 1, wherein in step 1, the solvent is one or more selected from tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform, acetonitrile and acetone.

4. The method of claim 1, wherein in step 1, the organic base is one or more of potassium tert-butoxide, sodium tert-butoxide, potassium ethoxide, sodium ethoxide, pyridine and triethylamine.

5. The method of claim 1, wherein in step 1, the reaction time is 12 to 24 hours.

6. The method of claim 1, wherein in step 1, compound 1 is reacted with ethyl difluorobromoacetate in a solution at 20 ℃ to 80 ℃ with stirring.

7. The process of claim 6, wherein compound 1 is reacted with ethyl difluorobromoacetate with stirring at 20 ℃ to 40 ℃.

8. The method according to claim 1, wherein in the step 2, the feeding molar ratio of the compound 2 to the alkaline agent is 1: 1-1: 2.

9. The method of claim 1, wherein in step 2, the solvent is selected from one or more of ethanol, methanol, isopropanol, 1, 4-dioxane, dichloromethane, chloroform, tetrahydrofuran, and water.

10. The method of claim 1, wherein in step 2, the alkaline reagent used in the reaction is sodium hydroxide or lithium hydroxide.

11. The method of claim 1, wherein in step 2, the reaction time is 6 to 24 hours.

12. The method of claim 1, wherein in step 2, compound 2 is reacted with the alkaline agent with stirring at a temperature of 0 ℃ to 80 ℃.

13. The method of claim 12, wherein the compound 2 is reacted with the alkaline agent with stirring at a temperature of 40 ℃ to 60 ℃.

14. The method of claim 1, wherein the reaction of step 3 operates as: oxalyl chloride was added to a solution of compound 3 and N, N-dimethylformamide.

15. The method of claim 14, wherein the oxalyl chloride is added dropwise at a temperature of-10 ℃ to 10 ℃ and the reaction temperature is-10 ℃ to 40 ℃.

16. The method of claim 1, wherein the reaction of step 3 operates as: the reaction concentrated solution of the compound 3 acyl chloride and 2,2' -azobisisobutyronitrile solution are added into trichlorobromomethane solution of 2-mercaptopyridine nitrogen oxide sodium salt.

17. The method of claim 16, wherein the reaction time is 1 to 5 hours.

18. The process of claim 16, wherein the reaction temperature is from 20 ℃ to 100 ℃.

19. The method of claim 16, wherein the concentrated reaction solution and 2,2' -azobisisobutyronitrile are added over a period of 1 to 6 hours.

20. The method of claim 17, wherein the reaction time is 2 to 3 hours.

21. The method of claim 19, wherein the dropping time is 2 to 4 hours.

22. The method according to claim 1, wherein in the step 3, the charging molar ratio of the compound 3 to the oxalyl chloride is 1: 1-1: 3.

23. The method according to claim 1, wherein in the step 3, the feeding molar ratio of the compound 3 to the N, N-dimethylformamide is 1: 0.1-1: 0.5.

24. The method according to claim 1, wherein in the step 3, the volume ratio of the compound 3 to the solvent is 1:2 to 1: 4.

25. The method according to claim 1, wherein in the step 3, the feeding molar ratio of the compound 3 to the 2,2' -azobisisobutyronitrile is 1:0.1 to 1: 0.5.

26. The method according to claim 1, wherein in the step 3, the feeding molar ratio of the compound 3 to the sodium salt of 2-mercaptopyridine nitrogen oxide is 1: 0.5-1: 1.

27. The method of claim 22, wherein the molar ratio of compound 3 to oxalyl chloride is from 1:1 to 1: 2.

28. The method of claim 25, wherein the compound 3 and 2,2' -azobisisobutyronitrile are fed in a molar ratio of 1:0.1 to 1: 0.3.

29. The method of claim 26, wherein the molar feed ratio of compound 3 to the sodium salt of nitroxide of 2-mercaptopyridine is 1:0.5 to 1: 0.8.

30. The method of claim 22, wherein in step 3, the reaction solvent is selected from one or more of dichloromethane, chloroform, toluene and ethyl acetate.

31. The method of claim 1, wherein the reaction of step 4 operates as: adding silver tetrafluoroborate into the low-temperature solution of the compound 4, and then heating for reaction.

32. The method of claim 31, wherein the solution of compound 4 is at a temperature of-70 ℃ to-40 ℃.

33. The process of claim 31, wherein the reaction temperature is from 0 ℃ to 80 ℃.

34. The process of claim 33, wherein the reaction temperature is from 0 ℃ to 40 ℃.

35. The method according to claim 1, wherein in the step 4, the feeding molar ratio of the compound 4 to the silver tetrafluoroborate is 1: 1-1: 3.

36. The method according to claim 1, wherein in the step 4, the solvent is one or more of dichloromethane, chloroform, toluene and ethyl acetate.

37. The method of claim 1, wherein in step 4, the reaction time is 4 to 12 hours.

38. The method according to claim 1, wherein in the step 4, the feeding molar ratio of the compound 4 to the silver tetrafluoroborate is 1: 1-1: 2.

39. The method of claim 37, wherein the reaction time is 4 to 8 hours.

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of 2-bromo-5- (trifluoromethoxy) pyridine.

Background

Fluorine-containing organic molecules are ubiquitous in medicine, agriculture, and materials science due to their unique physical properties and biological activities. Therefore, in recent years, a new synthesis method for introducing fluorine into an organic molecule has been widely studied, and the trifluoromethyl group has been particularly spotlighted for pharmaceutical research because of its high electronegativity (χ ═ 3.7), unique orthogonal conformation (relative to aromatic ring), high lipophilicity, and high metabolic stability. Due to the importance of heterocyclic structures in medical and agrochemical research and the widespread use of fluorine atoms and fluorinated groups, methods for preparing trifluoromethoxy-substituted heterocyclic structures are constantly being attempted.

2-bromo-5- (trifluoromethoxy) pyridine (formula I) is used as a synthetic drug (WO201144181) and a pesticide intermediate (WO2010040461), and the synthetic method thereof has been reported.

Patent (WO201144181) reports that 2-chloro-5-hydroxypyridine is used as a raw material to react with thiophosgene to generate 2-chloro-5- (trichloromethoxy) pyridine, then the 2-chloro-5- (trifluoromethoxy) pyridine is generated under the action of antimony trifluoride, and finally the 2-bromo-5- (trifluoromethoxy) pyridine is generated by reacting with trimethylbromosilane. The key raw materials of the route, namely antimony trifluoride and thiophosgene, are toxic and dangerous chemicals, are greatly limited in purchase and use, and are not suitable for large-scale production. The same starting materials and a similar three-step synthesis method as those in the above patent were also used in the literature (European Journal of Organic Chemistry, (31), 6043-6066) except that the second step was to use a pyridine solution of hydrogen fluoride as a fluorinating agent to produce 2-chloro-5- (trifluoromethoxy) pyridine, which is highly corrosive and is critical to equipment and operation. (route one)

The patent (WO200655187) uses 2-bromopyridine-5-boric acid as a starting material, generates 2-bromo-5-hydroxypyridine under the action of hydrogen peroxide, and then reacts with antimony pentafluoride to generate a final product, namely 2-bromo-5- (trifluoromethoxy) pyridine (route II). The antimony pentafluoride used as a fluorinating reagent is a dangerous chemical which has high toxicity and harm to the environment, is limited in purchase and use, and is not suitable for scale-up production.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a synthetic method of 2-bromo-5- (trifluoromethoxy) pyridine, which has the advantages of environment-friendly and easily-obtained raw materials, mild conditions, easy operation and suitability for kilogram-level production.

In order to solve the technical problems, the technical scheme provided by the invention is as follows:

a preparation method of 2-bromo-5- (trifluoromethoxy) pyridine specifically comprises the following steps:

1) carrying out an alkylation reaction on the compound 1 and ethyl difluorobromoacetate in the presence of organic base to generate a compound 2;

2) the compound 2 undergoes ester group hydrolysis reaction in the presence of an alkaline reagent to generate a compound 3;

3) performing acyl chlorination reaction on the compound 3 and oxalyl chloride under the catalysis of N, N-dimethylformamide, concentrating the reaction solution, and dripping the concentrated reaction solution and 2,2' -azobisisobutyronitrile into trichlorobromomethane solution of 2-mercaptopyridine nitrogen oxide sodium salt to generate a compound 4;

4) dripping the silver tetrafluoroborate solution into the compound 4 solution for reaction to generate a compound 5, namely a final product 2-bromine-5- (trifluoromethoxy) pyridine;

the reaction formula is as follows:

specifically, in the step 1, the feeding molar ratio of the compound 1 to ethyl difluorobromoacetate is 1: 1-1: 3.

Specifically, in the step 1, the solvent is one or more of tetrahydrofuran, 1, 4-dioxane, dichloromethane, chloroform, acetonitrile and acetone.

Specifically, in the step 1, the organic base is one or a combination of potassium tert-butoxide, sodium tert-butoxide, potassium ethoxide, sodium ethoxide, pyridine and triethylamine.

Specifically, in the step 1, the reaction time is 12 to 24 hours.

Specifically, in the step 1, the compound 1 and ethyl difluorobromoacetate are stirred and reacted in a solution at the temperature of 20-80 ℃.

Preferably, the compound 1 is reacted with ethyl difluorobromoacetate with stirring at 20 ℃ to 40 ℃.

Preferably, in the step 2, the feeding molar ratio of the compound 2 to the alkaline reagent is 1: 1-1: 2.

Specifically, in the step 2, the solvent is selected from one or more of ethanol, methanol, isopropanol, 1, 4-dioxane, dichloromethane, chloroform, tetrahydrofuran and water.

Specifically, in the step 2, the alkaline reagent used in the reaction is sodium hydroxide or lithium hydroxide.

Specifically, in the step 2, the reaction time is 6 to 24 hours.

Specifically, in the step 2, the compound 2 and the alkaline reagent are stirred and reacted at the temperature of 0-80 ℃.

Preferably, the compound 2 and the alkaline reagent are stirred and reacted at the temperature of 40-60 ℃.

Specifically, the reaction operation of step 3 is: oxalyl chloride was added to a solution of compound 3 and N, N-dimethylformamide.

Preferably, the dropping temperature of the oxalyl chloride is kept between 10 ℃ below zero and 10 ℃, and the reaction temperature is kept between 10 ℃ below zero and 40 ℃.

Specifically, the reaction operation of step 3 is: the reaction concentrated solution of the compound 3 acyl chloride and 2,2' -azobisisobutyronitrile solution are added into trichlorobromomethane solution of 2-mercaptopyridine nitrogen oxide sodium salt.

Preferably, the reaction time is from 1 to 5 hours,

preferably, the reaction temperature is 20 ℃ to 100 ℃.

Specifically, the dropping time of the concentrated reaction solution and 2,2' -azobisisobutyronitrile is 1 to 6 hours.

Preferably, the reaction time is 2 to 3 hours.

Preferably, the dropping time is 2 to 4 hours.

Specifically, in the step 3, the feeding molar ratio of the compound 3 to oxalyl chloride is 1: 1-1: 3.

Specifically, in the step 3, the feeding molar ratio of the compound 3 to the N, N-dimethylformamide is 1: 0.1-1: 0.5.

Specifically, in the step 3, the volume ratio of the compound 3 to the solvent is 1: 2-1: 4.

Specifically, in the step 3, the feeding molar ratio of the compound 3 to the 2,2' -azobisisobutyronitrile is 1: 0.1-1: 0.5.

Specifically, in the step 3, the feeding molar ratio of the compound 3 to the 2-mercaptopyridine sodium oxynitride salt is 1: 0.5-1: 1.

Preferably, the feeding molar ratio of the compound 3 to the oxalyl chloride is 1: 1-1: 2.

Preferably, the feeding molar ratio of the compound 3 to the 2,2' -azobisisobutyronitrile is 1:0.1 to 1: 0.3.

Preferably, the feeding molar ratio of the compound 3 to the sodium salt of 2-mercaptopyridine nitroxide is 1: 0.5-1: 0.8.

Preferably, in the step 3, the reaction solvent is selected from one or more of dichloromethane, chloroform, toluene and ethyl acetate.

Specifically, the reaction operation of step 4 is: adding silver tetrafluoroborate into the low-temperature solution of the compound 4, and then heating for reaction.

Specifically, the solution temperature of the compound 4 is-70 ℃ to-40 ℃.

Specifically, the reaction temperature is 0-80 ℃.

Preferably, the reaction temperature is from 0 ℃ to 40 ℃.

Specifically, in the step 4, the feeding molar ratio of the compound 4 to the silver tetrafluoroborate is 1: 1-1: 3.

Specifically, in the step 4, the solvent used is one or a combination of more of dichloromethane, chloroform, toluene and ethyl acetate.

Specifically, in the step 4, the reaction time is 4 to 12 hours.

Specifically, in the step 4, the feeding molar ratio of the compound 4 to the silver tetrafluoroborate is 1: 1-1: 2.

Preferably, the reaction time is 4 to 8 hours.

The technical idea of the invention mainly lies in that: the first step is that 2-bromo-5-hydroxypyridine (compound 1) and ethyl difluorobromoacetate (compound 1A) are subjected to an alkylation reaction to generate 2- ((6-bromopyridin-3-yl) oxo) -2, 2-difluoroacetate (compound 2), the second step is that the compound 2 hydrolyzes an ester group to obtain 2- ((6-bromopyridin-3-yl) oxo) -2, 2-difluoroacetic acid (compound 3), and the first two steps have the advantages of low reaction solvent demand, mild conditions and easy operation; the third step is that the compound 3 generates bromine through radical reaction after decarboxylation on the oxo-difluoroacetic acid group to generate 2-bromine-5- (bromine difluoro methoxyl) pyridine (compound 4), and the fourth step is that the compound 4 is reacted with silver tetrafluoroborate (AgBF)₄) To produce 2-bromo-5- (trifluoromethoxy) pyridine (compound 5) as a final product.

Compared with the prior art, the invention has the beneficial effects that:

1. compared with the prior art, the method has the advantages that in the first step, the easily-obtained 2-bromo-5-hydroxypyridine (compound 1) is selected as the starting raw material, and the 2- ((6-bromopyridine-3-yl) oxo) -2, 2-difluoroacetic acid (compound 2) is obtained through two-step reactions of oxygen alkylation and ester group hydrolysis, so that the reaction condition is mild, the reaction solvent consumption is small, the post-treatment is simple, and the total yield of the two-step reaction is more than 85%; and the third step is to carry out decarboxylation bromine-adding reaction on the oxo-difluoroacetic acid group, and the fourth step is to obtain the final product 2-bromo-5- (trifluoromethoxy) pyridine (compound 5) through the reaction of substituting bromine on the difluoro-bromomethyl group with fluorine, so that the difficulty of directly substituting carboxyl on the oxo-difluoroacetic acid group with fluorine is overcome, the pyridine solution of hydrogen fluoride with very strong corrosivity is avoided being directly used, the reaction yield is high, the conditions are mild, the method is suitable for kilogram-level production, and toxic dangerous chemicals such as thiophosgene, antimony trifluoride and the like are avoided being used in the whole reaction route.

2. Compared with the prior art, the method has the advantages of easily available raw materials, high reaction yield and mild conditions, avoids using toxic and highly corrosive fluorination reagents in the whole reaction route, and is suitable for kilogram-level production.

Detailed Description

The technical solutions of the present invention will be described clearly and completely below, and it should be apparent that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.

Example one

2-bromo-5- (trifluoromethoxy) pyridine

The first step is as follows: synthesis of ethyl 2- ((6-bromopyridin-3-yl) oxo) -2, 2-difluoroacetate

To a solution of 2-bromo-5-hydroxypyridine 1(5.0kg, 1.0eq) and ethyl difluorobromoacetate (compound 1A) (11.67kg, 2.0eq) in Tetrahydrofuran (THF) (10L) was added potassium tert-butoxide (t-BuOK) (4.83kg, 1.5eq) at 0 ℃ under a nitrogen atmosphere. The reaction mixture was heated to 20 ℃ and stirred for 16 hours. Indicating complete consumption of compound 1. Adjusting the pH value of the reaction by using concentrated hydrochloric acid to 5-6, and concentrating in vacuum. Diluting the concentrated solution with petroleum ether, and adding 1% HCl and saturated NaHCO₃The solution and the saturated NaCl solution were washed sequentially. The organic layers were combined, dried, filtered under reduced pressure and concentrated. To give ethyl 2- ((6-bromopyridin-3-yl) oxo) -2, 2-difluoroacetate (Compound 2) (8.35kg, 94.35% yield, pureDegree 96.13%) as a yellow oil.¹HNMR:(400MHz,CDCl3)δ1.34-1.47(m,3H)，4.33-4.50(m,2H)，7.38-7.67(m,2H)，8.33(s,1H)。LCMS:(M+H)⁺＝295.8。

The second step is that: synthesis of 2- ((6-bromopyridin-3-yl) oxo) -2, 2-difluoroacetic acid

Sodium hydroxide (NaOH) (1.26kg, 1.1eq) was added to a solution of compound 2(8.5kg, 1.0eq) in Tetrahydrofuran (THF) (17L) and water (1.7L) at 0 ℃, and the reaction mixture was heated to 20 ℃ and stirred for a further 16 hours. Monitoring showed complete consumption of compound 2. And (3) adjusting the pH value of the reaction to 3-4 by using concentrated HCl, and concentrating in vacuum. The concentrate was diluted with THF and filtered. The filtrate was concentrated under reduced pressure again to give 2- ((6-bromopyridin-3-yl) oxo) -2, 2-difluoroacetic acid (compound 3) (6kg, yield 76.37%, purity 97.94%) as an off-white solid.¹HNMR:(400MHz,CDCl₃)δ7.45-7.52(m,1H)，7.53-7.61(m,1H)，8.36(d,J＝2.80Hz,1H)。LCMS:(M+H)⁺＝267.8。

The third step: synthesis of 2-bromo-5- (bromodifluoromethoxy) pyridine

Compound 3(3kg, 1eq) and N, N-Dimethylformamide (DMF) (81.82g, 86.12mL, 0.1eq) were dissolved in dichloromethane (CH)₂Cl₂) To (24L), oxalyl chloride (1.70kg, 1.18L, 1.2eq) was added at 0 ℃. The mixture was stirred at 20 ℃ for 1 hour and concentrated in vacuo. The concentrate and 2,2' -Azobisisobutyronitrile (AIBN) (1.19mol, 0.1eq) were then dissolved in 27L of methylene Chloride (CH)₂Cl₂) In (b), trichlorobromomethane (BrCCl) was added dropwise to 2-thiopyridine 1-oxide sodium (compound 3A) (40% aqueous solution,. about.3.3 mol/L, 0.50eq) at 80 deg.C₃) (3.3L) in suspension. Monitoring after 120 minutes showed complete consumption of compound 3. With saturated NaHCO₃The reaction is slowly quenched, thenAnd then extracted with dichloromethane. The organic phase was washed with brine several times and anhydrous Na₂SO₄Drying, filtering, and vacuum concentrating. The concentrate was purified by silica gel chromatography with petroleum ether/ethyl acetate 99:1 to give compound 4(1.86kg, yield 53.26%, purity 97.3%) as a yellow oil. HNMR (400MHz, CDCl)₃)δ7.45-7.52(m,1H)，7.53-7.61(m,1H)，8.36(d,J＝2.80Hz,1H)。LCMS:(M+H)⁺＝303.6。

The fourth step: synthesis of 2-bromo-5- (trifluoromethoxy) pyridine

A solution of compound 4(3.5kg, 1eq) in Dichloromethane (DCM) (25L) was cooled to-70 ℃ and silver tetrafluoroborate (AgBF) was added₄) (2.70kg, 1.2 eq). The resulting mixture was slowly heated to 20 ℃ and after stirring for 4 hours, monitoring indicated complete consumption of compound 4. With saturated NaHCO₃The reaction was quenched slowly and then extracted with dichloromethane. The combined organic phases were washed with brine, anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. Final product 5(2.61kg, yield 91.13%, purity 97.63%) was obtained as a yellow oil.¹H NMR:(400MHz,CDCl3)δ7.45(dd,J1＝8.8Hz,J2＝2.4Hz,1H)，7.57(d,J＝8.8Hz,1H)，8.36(d,J＝2.8Hz,1H)。F NMR:(400MHz,CDCl3)δ-58.394。LCMS:(M+H)⁺＝241.8。

Example two

2-bromo-5- (trifluoromethoxy) pyridine

The first step is as follows: synthesis of ethyl 2- ((6-bromopyridin-3-yl) oxo) -2, 2-difluoroacetate

To a solution of 2-bromo-5-hydroxypyridine 1(2g,1.0eq) and ethyl difluorobromoacetate (compound 1A) (5.84g,2.5eq) in Tetrahydrofuran (THF) (4mL) was added potassium tert-butoxide (t-BuOK) (1.93g,1.5eq) at 0 ℃ under a nitrogen atmosphere. The reaction mixture was heated to 20 ℃ and stirred for 16 hours. Indicating complete consumption of compound 1. Adjusting the pH value of the reaction by using concentrated hydrochloric acid to 5-6, and concentrating in vacuum. Diluting the concentrated solution with petroleum ether, and adding 1% HCl and saturated NaHCO₃The solution and the saturated NaCl solution were washed sequentially. The organic layers were combined, dried, filtered under reduced pressure and concentrated. Ethyl 2- ((6-bromopyridin-3-yl) oxo) -2, 2-difluoroacetate (compound 2) (3.2g, 91.3% yield, 97.0% purity) was obtained as a yellow oil.¹HNMR:(400MHz,CDCl3)δ1.19-1.42(m,3H)，4.40-4.45(m,2H)，7.27-7.53(m,2H)，8.33(s,1H)。LCMS:(M+H)⁺＝295.8。

The second step is that: synthesis of 2- ((6-bromopyridin-3-yl) oxo) -2, 2-difluoroacetic acid

Sodium hydroxide (NaOH) (0.3g, 1.1eq) was added to a solution of compound 2(2g, 1.0eq) in Tetrahydrofuran (THF) (8mL) and water (1.6mL) at 0 ℃, and the reaction mixture was heated to 20 ℃ and stirred for a further 16 hours. Monitoring showed complete consumption of compound 2. And (3) adjusting the pH value of the reaction to 3-4 by using concentrated HCl, and concentrating in vacuum. The concentrate was diluted with THF and filtered. The filtrate was concentrated under reduced pressure again to give 2- ((6-bromopyridin-3-yl) oxo) -2, 2-difluoroacetic acid (compound 3) (1.77g, yield 95.7%, purity 97.9%) as an off-white solid.¹HNMR:(400MHz,CDCl₃)δ7.62-7.64(m,1H)，7.65-7.66(m,1H)，8.30(d,J＝2.80Hz,1H)。LCMS:(M+H)⁺＝267.8。

The third step: synthesis of 2-bromo-5- (bromodifluoromethoxy) pyridine

Mixing compound 3(2g, 1eq) with N, N-dimethyl formamideAmide (DMF) (0.06mL, 0.1eq) was dissolved in dichloromethane (CH)₂Cl₂) To (16mL) was added oxalyl chloride (1.13g, 0.79mL, 1.2eq) at 0 ℃. The mixture was stirred at 20 ℃ for 1 hour and concentrated in vacuo. The concentrate and 2,2' -Azobisisobutyronitrile (AIBN) (0.1eq) were then dissolved in 18mL of methylene Chloride (CH)₂Cl₂) In (b), trichlorobromomethane (BrCCl) was added dropwise to 2-thiopyridine 1-oxide sodium (compound 3A) (40% aqueous solution,. about.3.3 mol/L, 0.50eq) at 40 deg.C₃) (3mL) in suspension. Monitoring after 120 minutes showed complete consumption of compound 3. With saturated NaHCO₃The reaction was quenched slowly and then extracted with dichloromethane. The organic phase was washed with brine several times and with anhydrous Na₂SO₄Drying, filtering and vacuum concentrating the filtrate. The concentrate was purified by silica gel chromatography using petroleum ether/ethyl acetate 99:1 to obtain compound 4(1.44g, yield 62.2%, purity 97.6%).¹HNMR:(400MHz,CDCl₃)δ7.27-7.41(m,1H)，7.44-7.57(m,1H)，8.35(d,J＝2.80Hz,1H)。LCMS:(M+H)⁺＝303.6。

The fourth step: synthesis of 2-bromo-5- (trifluoromethoxy) pyridine

A solution of compound 4(2g, 1eq) in Dichloromethane (DCM) (15.4mL) was cooled to-70 ℃ and silver tetrafluoroborate (AgBF) was added₄) (1.93g,1.5 eq). The resulting mixture was slowly heated to 20 ℃ and after stirring for 4 hours, monitoring indicated complete consumption of compound 4. With saturated NaHCO₃The reaction was quenched slowly and then extracted with dichloromethane. The combined organic phases were washed with brine, anhydrous Na₂SO₄Drying, filtration and concentration in vacuo afforded final product 5(1.44g, 88.3% yield, 97.9% purity).¹H NMR:(400MHz,CDCl₃)δ7.45(dd,J1＝8.8Hz,J2＝2.4Hz,1H)，7.55(d,J＝8.8Hz,1H)，8.34(d,J＝2.8Hz,1H)。LCMS:(M+H)⁺＝241.8。

In summary, the above embodiments are merely preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalents, improvements, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention.