Synthesis of 2,4,5-trifluorophenylacetic acid

Abstract

This invention discloses a method for synthesizing 2,4,5-trifluorophenylacetic acid, comprising reacting a compound of formula II with a nitro compound in a first reaction, followed by a second reaction with a borohydride to obtain a compound of formula III; the compound of formula III then undergoes a third reaction with a nitrite to synthesize 2,4,5-trifluorophenylacetic acid. This synthetic method uses readily available raw materials, is simple to operate, low in cost, and has a short route. It is also environmentally friendly, safe, and reliable, significantly improving the feasibility of industrial production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for synthesizing 2,4,5-trifluorophenylacetic acid. Background Technology

[0002] The DPP-4 inhibitor sitagliptin is widely used in the treatment of diabetes due to its safety, efficacy, and few side effects, and has a broad market prospect. 2,4,5-trifluorophenylacetic acid, as a key intermediate in the synthesis of sitagliptin, is in huge demand.

[0003] Chinese patent CN1749232A discloses a method for preparing 2,4,5-trifluorophenylacetic acid. Using 1,2,4-trifluorobenzene as a raw material, a chloromethylation reaction is carried out in the presence of paraformaldehyde and chlorosulfonic acid or zinc chloride and hydrochloric acid to generate 2,4,5-trifluorobenzyl chloride. Then, 2,4,5-trifluorobenzyl chloride is reacted with sodium cyanide and tetramethylammonium chloride in an ethanol solution. Finally, the resulting 2,4,5-trifluorophenylacetonitrile is hydrolyzed in an aqueous sodium hydroxide solution to obtain the target product, 2,4,5-trifluorophenylacetic acid. The reaction route is shown below: .

[0004] This route is currently the industrialized method, which has the advantage of low cost, but it requires the use of highly toxic cyanide, posing significant safety risks in production.

[0005] Chinese patent CN101092345A discloses a method for preparing 2,4,5-trifluorophenylacetic acid. This method uses 1,2,4-trifluorobenzene as a starting material, first reacting it with paraformaldehyde, zinc chloride, and hydrochloric acid to obtain 2,4,5-trifluorochlorobenzyl. Then, under high pressure and with the aid of sodium tetracarbonyl cobalt catalysis, it undergoes a carbonylation reaction with carbon monoxide to finally generate the target product, 2,4,5-trifluorophenylacetic acid. The reaction route is shown below: .

[0006] The sodium tetracarbonyl cobalt catalyst used in this process is expensive and difficult to prepare, and both it and another reactant, carbon monoxide, are highly toxic.

[0007] Chinese patent CN102584565A discloses a process for preparing 2,4,5-trifluorophenylacetic acid. Using 1,2,4-trifluorobenzene as the starting material, it undergoes a Friedel-Crafts alkylation reaction with chloroacetonitrile under Lewis acid catalysis, followed by hydrolysis to obtain 2,4,5-trifluorophenylacetic acid. The reaction route is shown below: .

[0008] The process route is simple, but the Friedel-Crafts alkylation step has a low yield.

[0009] Chinese patent CN101244994A discloses a process for preparing 2,4,5-trifluorophenylacetic acid. Using 1,2,4-trifluorobenzene as a raw material, it first undergoes a Friedel-Crafts acylation reaction with acetyl chloride, followed by a Willgerodt-Kindler rearrangement reaction with excess sulfur, dimethylamine hydrochloride, and sodium acetate in N,N-dimethylformamide. Finally, it is hydrolyzed in sodium hydroxide solution to obtain 2,4,5-trifluorophenylacetic acid. The reaction route is shown below: .

[0010] The process has mild reaction conditions, but it is prone to producing a large number of byproducts during the rearrangement reaction stage, and the use of sulfur will lead to the generation of a large amount of wastewater.

[0011] Patent text WO2008078350A2 discloses a method for synthesizing 2,4,5-trifluorophenylacetic acid. Using 1,2,4-trifluorobenzene as a raw material, it undergoes a Friedel-Crafts acylation reaction with dichloroacetyl chloride under aluminum trichloride catalysis to obtain 2,4,5-trifluoro-α,α-dichloroacetophenone; subsequently, it undergoes a rearrangement catalyzed by sodium hydroxide and acidification with hydrochloric acid to obtain 2,4,5-trifluoromandelic acid; then, it undergoes a hydroxychlorination reaction with thionyl chloride in dichloromethane to generate 2,4,5-trifluoro-α-chlorophenylacetic acid; finally, it is reduced in a formic acid / triethylamine / water system under palladium / carbon catalysis to obtain 2,4,5-trifluorophenylacetic acid. The reaction route is shown below: .

[0012] The process involves lengthy reaction steps, with poor yields in the last three steps, resulting in a low overall yield. It also requires the use of expensive palladium / carbon catalysts, leading to high costs.

[0013] Chinese patent CN101429115A discloses a synthetic process for 2,4,5-trifluorophenylacetic acid. Using 2,4,5-trifluorochlorobenzyl as a raw material and dibromoethane as an initiator, a Grignard reagent is prepared by reacting magnesium filings with tetrahydrofuran under nitrogen protection. Carbon dioxide is then introduced into the reaction, and the mixture is hydrolyzed to finally obtain 2,4,5-trifluorophenylacetic acid. The synthetic route is shown below: .

[0014] This process has extremely stringent environmental requirements in the preparation of Grignard reagents and subsequent reactions, requiring strict anhydrous and oxygen-free conditions, and also results in low yields.

[0015] US Patent 2004077901A1 discloses a synthetic process for 2,4,5-trifluorophenylacetic acid. Starting with 2,4,5-trifluorobromobenzene, it first undergoes an exchange reaction with isopropyl magnesium chloride in tetrahydrofuran to generate 2,4,5-trifluorophenyl magnesium bromide; subsequently, it undergoes a coupling reaction with allyl bromide to obtain 2,4,5-trifluoroallylbenzene; finally, under ruthenium trichloride catalysis, 2,4,5-trifluorophenylacetic acid is obtained by oxidation with sodium periodate in an acetonitrile and water system. The synthetic route is shown below: .

[0016] The reaction process of this method requires strict control of anhydrous and oxygen-free conditions, and the sodium periodate oxidant and ruthenium trichloride catalyst used are expensive.

[0017] In summary, the current industrial preparation of 2,4,5-trifluorophenylacetic acid faces numerous problems: the process generates a large amount of waste, requires the use of highly toxic reactants, posing safety hazards; the atom utilization rate is low and the catalyst consumption is large, making industrialization difficult; the catalysts and oxidants used are costly, some process conditions are demanding, there are many byproducts, and the yield is not ideal. Summary of the Invention

[0018] The purpose of this invention is to provide a method for synthesizing 2,4,5-trifluorophenylacetic acid, so as to solve at least one aspect of the problems and defects mentioned in the background art.

[0019] To achieve the above objectives, the present invention provides the following technical solution: The method for synthesizing 2,4,5-trifluorophenylacetic acid includes reacting a compound of formula II with a nitro compound in a first reaction, followed by a second reaction with a borohydride to obtain a compound of formula III. The compound of formula III then undergoes a third reaction with nitrite to synthesize 2,4,5-trifluorophenylacetic acid. The compound of formula II has the following structure: ; The compound of formula III has the following structure: .

[0020] As a further embodiment of the present invention, the temperature of the first reaction is -10 to 40 °C, preferably 0 to 25 °C.

[0021] As a further embodiment of the present invention, the first reaction time is 0.5 to 3 hours, preferably 1.0 to 2.0 hours.

[0022] As a further embodiment of the present invention, the nitro compound is selected from at least one of nitromethane and nitromethane, preferably nitromethane.

[0023] As a further embodiment of the present invention, the molar ratio of the nitro compound to the compound of formula II is (0.75~2.5):1, preferably (1.1~1.5):1.

[0024] As a further embodiment of the present invention, a catalyst and a first solvent are used in the first reaction.

[0025] As a further embodiment of the present invention, the catalyst is selected from at least one of hydroxides, carbonates and acetates.

[0026] As a further embodiment of the present invention, the hydroxide is selected from at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0027] As a further embodiment of the present invention, the carbonate is selected from at least one of sodium carbonate and potassium carbonate.

[0028] As a further embodiment of the present invention, the acetate includes ammonium acetate.

[0029] As a further embodiment of the present invention, the catalyst is sodium hydroxide.

[0030] As a further embodiment of the present invention, the molar ratio of the catalyst to the compound of formula II is (0.75~2.5):1, preferably (1.2~1.5):1.

[0031] As a further embodiment of the present invention, the first solvent is selected from at least one of methanol, water and ethanol, preferably methanol and water in a volume ratio of (2.5~3.5):1.

[0032] As a further embodiment of the present invention, the second reaction temperature is -10~40℃, preferably 25~40℃.

[0033] As a further embodiment of the present invention, the second reaction time is 0.5 to 8 hours, preferably 0.5 to 3 hours.

[0034] As a further embodiment of the present invention, the borohydride is selected from at least one of sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, and tetramethyltriacetoxyammonium borohydride, preferably sodium borohydride.

[0035] As a further embodiment of the present invention, the molar ratio of the borohydride to the compound of formula II is (1.0~2.0):1, preferably (1.2~1.5):1.

[0036] As a further embodiment of the present invention, a second solvent is used in the second reaction. The second solvent is selected from at least one of dimethyl sulfoxide, N,N-dimethylformamide, and acetic acid, preferably dimethyl sulfoxide and acetic acid in a volume ratio of (4.5~5.5):1.

[0037] As a further embodiment of the present invention, the third reaction temperature is 20~100 ℃, preferably 40~65 ℃.

[0038] As a further embodiment of the present invention, the third reaction time is 6 to 24 hours, preferably 8 to 12 hours.

[0039] As a further embodiment of the present invention, the nitrite is selected from at least one of sodium nitrite and potassium nitrite.

[0040] As a further embodiment of the present invention, the molar ratio of the nitrite to the compound of formula III is (0.5~3.5):1, preferably (2.0~3.0):1.

[0041] As a further embodiment of the present invention, a third solvent is used in the third reaction, the third solvent being selected from at least one of dimethyl sulfoxide, N,N-dimethylformamide, and water, preferably dimethyl sulfoxide and water in a volume ratio of (6.5~7.5):1.

[0042] As a further embodiment of the present invention, the compound of formula II is obtained by reacting the compound of formula I with phosphorus oxychloride via a fourth reaction, and the compound of formula I has the following structure: .

[0043] As a further embodiment of the present invention, the reaction concentration of compound I in the fourth reaction is (0.5~2.5) mmol / mL, preferably (0.5~1.0) mmol / mL.

[0044] As a further embodiment of the present invention, the fourth reaction temperature is 20~80 ℃, preferably 40~60 ℃.

[0045] As a further embodiment of the present invention, the fourth reaction time is 8 to 24 hours, preferably 8 to 12 hours.

[0046] As a further embodiment of the present invention, the molar ratio of phosphorus oxychloride to the compound of formula I is (0.5~2.0):1, preferably (0.8~1.5):1.

[0047] As a further embodiment of the present invention, a fourth solvent is used in the fourth reaction, the fourth solvent being selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, and N-methylpyrrolidone, preferably N,N-dimethylformamide.

[0048] As a further embodiment of the present invention, the synthesis method includes: reacting a compound of formula I with phosphorus oxychloride in a formylation reaction, washing the product to remove the solvent, condensing it with nitromethane in a nitral condensation, reducing it with sodium borohydride, and finally oxidizing and hydrolyzing it with sodium nitrite to generate 2,4,5-trifluorophenylacetic acid.

[0049] As a further embodiment of the present invention, the synthesis method specifically includes the following steps: S1. Dissolve the compound of formula I in N,N-dimethylformamide, add phosphorus oxychloride and react to obtain the compound of formula II; S2-1. Nitromethane and compound II are mixed in methanol, then an aqueous sodium hydroxide solution is added and stirred. After the reaction is complete, the mixture is acidified and extracted with ethylene glycol dimethyl ether to obtain intermediate I. S2-2. Dissolve intermediate I in dimethyl sulfoxide and acetic acid, add sodium borohydride and react to obtain compound III; S3. Compound of formula III and sodium nitrite were stirred and reacted in dimethyl sulfoxide and water. After the reaction was completed, the mixture was acidified and extracted with ethylene glycol dimethyl ether to obtain 2,4,5-trifluorophenylacetic acid.

[0050] Compared with the prior art, the present invention has the following beneficial effects: This invention provides a synthetic method for preparing 2,4,5-trifluorophenylacetic acid from a compound of formula I. The raw materials are readily available, the process is simple, the cost is low, and the route is short. It eliminates the drawbacks of using highly toxic raw materials and expensive catalysts in existing processes, making the process route more green, environmentally friendly, safe, and reliable. At the same time, thanks to the excellent reaction selectivity and high yield, the raw material recovery is simpler, the difficulty of waste treatment is greatly reduced, and the feasibility of industrial production is significantly improved. Detailed Implementation

[0051] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention; that is, the described embodiments are merely some embodiments of the invention, and not all embodiments.

[0052] Therefore, the following detailed description of embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0053] Example 1 The synthetic method for 2,4,5-trifluorophenylacetic acid, and the synthetic reaction route are as follows: ; Includes the following steps: S1. Synthesize 2,4,5-trifluorobenzaldehyde, with the following structural formula: ; In a three-necked flask, 100 mmol of 1,2,4-trifluorobenzene was dissolved in 100 mL of N,N-dimethylformamide, and 100 mmol of phosphorus oxychloride was added. The mixture was reacted at 40 °C for 12 hours. After the reaction was complete, the reaction solution was poured into 100 mL of water and extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was removed by distillation. Subsequently, the crude product was purified by vacuum distillation at -0.100 MPa and 90 °C to obtain 14.72 g of 2,4,5-trifluorobenzaldehyde with a purity of 99%. S2. Synthesize 1,2,4-trifluoro-5-(2-nitroethyl)-benzene, with the following structural formula: ; S2-1. At 0 °C, 110 mmol of nitromethane and 100 mmol of 2,4,5-trifluorobenzaldehyde were mixed in 30 mL of methanol. Over 30 minutes, an aqueous solution of sodium hydroxide (prepared from 4.8 g of sodium hydroxide and 12 mL of water) was added to the stirred solution, and stirring was continued at 0 °C for 1 hour. The mixture was diluted with 30 mL of water, and 10 mL of concentrated hydrochloric acid was added. A solid precipitated out. The solid was extracted three times with ethylene glycol dimethyl ether, and the combined organic layers were washed with water, saturated sodium bicarbonate aqueous solution, and brine and concentrated to obtain a solid. The solid was recrystallized with a small amount of ethanol to obtain 19 g of intermediate I. S2-2. Intermediate I was dissolved in 30 mL of dimethyl sulfoxide and 6 mL of acetic acid, and the temperature was controlled at 25±2 °C. 24 mmol of sodium borohydride (total 120 mmol) was added every 20 minutes. The resulting solution was stirred for another 0.5 hours, diluted with 100 mL of ethyl acetate, washed with water and saturated sodium bicarbonate and sodium chloride solutions, dried, concentrated, and recrystallized to obtain 17.4 g of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene with a purity of 98%. S3, Synthesis of 2,4,5-trifluorophenylacetic acid Dissolve 50 mmol of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene and 100 mmol of sodium nitrite in 100 mL of a dimethyl sulfoxide / water mixture (V 二甲基亚砜 V 水 The mixture was stirred at 65 °C for 12 h (ratio = 7:1). After the reaction was completed, an equal volume of water was added to the reaction mixture, and the mixture was acidified with 5 mL of concentrated hydrochloric acid. The aqueous layer was extracted three times with ethylene glycol dimethyl ether, the concentrated organic layer was combined, and recrystallized to obtain 8.3 g of 2,4,5-trifluorophenylacetic acid with a purity of 99%.

[0054] Example 2 The difference from Example 1 is as follows: In step S1, the amount of N,N-dimethylformamide used should be adjusted to 50 mL; The other steps were the same, and 12.8 g of 2,4,5-trifluorobenzaldehyde with a purity of 99% was obtained.

[0055] Example 3 The difference from Example 1 is as follows: In step S1, the amount of N,N-dimethylformamide used should be adjusted to 150 mL; The other steps were the same, and 14.4 g of 2,4,5-trifluorobenzaldehyde with a purity of 99% was obtained.

[0056] Example 4 The difference from Example 1 is as follows: In step S1, the amount of phosphorus oxychloride was adjusted to 80 mmol; The other steps were the same, yielding 13.1 g of 2,4,5-trifluorobenzaldehyde with a purity of 99%.

[0057] Example 5 The difference from Example 1 is as follows: In step S1, the amount of phosphorus oxychloride was adjusted to 150 mmol; The other steps were the same, and 13.44 g of 2,4,5-trifluorobenzaldehyde was obtained with a purity of 99%.

[0058] Example 6 The difference from Example 1 is as follows: In step S1, the reaction temperature is adjusted to 25 °C; The other steps were the same, yielding 9.92 g of 2,4,5-trifluorobenzaldehyde with a purity of 99%.

[0059] Example 7 The difference from Example 1 is as follows: In step S1, the reaction temperature is adjusted to 60 °C; The other steps were the same, yielding 12.16 g of 2,4,5-trifluorobenzaldehyde with a purity of 99%.

[0060] Example 8 The difference from Example 1 is as follows: The amount of nitromethane used in step S2-1 is adjusted to 150 mmol; The other steps were the same, yielding 16.4 g of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene with a purity of 98%.

[0061] Example 9 The difference from Example 1 is as follows: The amount of nitromethane used in step S2-1 is adjusted to 200 mmol; The other steps were the same, yielding 15.17 g of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene with a purity of 98%.

[0062] Example 10 The difference from Example 1 is as follows: In step S2-1, the amount of sodium hydroxide used should be adjusted to 100 mmol. The other steps were the same, yielding 14.35 g of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene with a purity of 98%.

[0063] Example 11 The difference from Example 1 is as follows: In step S2-1, the amount of sodium hydroxide used is adjusted to 150 mmol; The other steps were the same, yielding 16.81 g of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene with a purity of 98%.

[0064] Example 12 The difference from Example 1 is as follows: In step S2-1, the amount of sodium hydroxide used is adjusted to 200 mmol; The other steps were the same, yielding 16.4 g of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene with a purity of 98%.

[0065] Example 13 The difference from Example 1 is as follows: In step S2-1, the feeding and reaction temperature are adjusted to 25 ℃; The other steps were the same, yielding 13.3 g of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene with a purity of 96%.

[0066] Example 14 The difference from Example 1 is as follows: In step S2-1, the feeding and reaction temperature are adjusted to 40 ℃; The other steps were the same, yielding 8.61 g of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene with a purity of 95%.

[0067] Example 15 The difference from Example 1 is as follows: In step S2-2, the amount of sodium borohydride used is adjusted to 100 mmol; The other steps were the same, yielding 16.6 g of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene with a purity of 98%.

[0068] Example 16 The difference from Example 1 is as follows: In step S2-2, the amount of sodium borohydride used is adjusted to 150 mmol; The other steps were the same, yielding 17.01 g of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene with a purity of 98%.

[0069] Example 17 The difference from Example 1 is as follows: In step S2-2, the reaction temperature is adjusted to 40 ℃; The other steps were the same, yielding 13.94 g of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene with a purity of 98%.

[0070] Example 18 The difference from Example 1 is as follows: In step S2-2, the reaction temperature is adjusted to 0 ℃; The other steps were the same, yielding 9.22 g of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene with a purity of 98%.

[0071] Example 19 The difference from Example 1 is as follows: In step S3, the amount of sodium nitrite is adjusted to 50 mmol; The other steps were the same, yielding 7.79 g of 2,4,5-trifluorophenylacetic acid with a purity of 99%.

[0072] Example 20 The difference from Example 1 is as follows: In step S3, the amount of sodium nitrite used is adjusted to 150 mmol; The other steps were the same, yielding 8.07 g of 2,4,5-trifluorophenylacetic acid with a purity of 99%.

[0073] Example 21 The difference from Example 1 is as follows: In step S3, the reaction temperature is adjusted to 25 °C; The other steps were the same, yielding 6.46 g of 2,4,5-trifluorophenylacetic acid with a purity of 99%.

[0074] Example 22 The difference from Example 1 is as follows: In step S3, the reaction temperature is adjusted to 40 °C; The other steps were the same, yielding 7.22 g of 2,4,5-trifluorophenylacetic acid with a purity of 99%.

[0075] Example 23 The difference from Example 1 is as follows: In step S3, the reaction temperature is adjusted to 80 °C; The other steps were the same, yielding 6.84 g of 2,4,5-trifluorophenylacetic acid with a purity of 99%.

[0076] As can be seen from Examples 1 to 7, in step S1, the reactant concentration and reaction temperature both have a certain impact on the yield of 2,4,5-trifluorobenzaldehyde, with temperature having the most significant effect, and 40~60℃ being the optimal reaction temperature.

[0077] As can be seen from Examples 1 and 8-18, in step S2, the amount of sodium hydroxide and sodium borohydride has little effect on the yield of 1,2,4-trifluoro-5-(2-nitroethyl)-benzene, while the reaction temperature has the greatest effect on the yield. The product yield obtained at the reaction temperature shown in Example 1 is the highest.

[0078] As can be seen from Examples 1 and 19-23, in step S3, the amount of sodium nitrite has little effect on the yield of 2,4,5-trifluorophenylacetic acid, while the reaction temperature has a greater effect.

[0079] The above description is merely an example and illustration of the structure of the present invention. Those skilled in the art can make various modifications or additions to the specific embodiments described, or use similar methods to replace them, as long as they do not deviate from the structure of the invention or exceed the scope defined in the claims, all of which should fall within the protection scope of the present invention.

Claims

A method for synthesizing 1,2,4,5-trifluorophenylacetic acid, characterized in that, This includes reacting a compound of formula II with a nitro compound in a first reaction, followed by a second reaction with a borohydride to obtain a compound of formula III; The compound of formula III then undergoes a third reaction with nitrite to synthesize 2,4,5-trifluorophenylacetic acid. The compound of formula II has the following structure: ； The compound of formula III has the following structure: 。 2. The synthesis method according to claim 1, characterized in that, The temperature of the first reaction is -10 to 40 °C; And / or, the nitro compound is selected from at least one of nitromethane and nitromethane; And / or, the molar ratio of the nitro compound to the compound of formula II is (0.75~2.5):

1.

3. The synthesis method according to claim 1, characterized in that, The first reaction uses a catalyst and a first solvent; The catalyst is selected from at least one of hydroxides, carbonates, and acetates; And / or, the catalyst is selected from at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide; And / or, the catalyst is selected from at least one of sodium carbonate and potassium carbonate; And / or, the catalyst comprises ammonium acetate; And / or, the catalyst is sodium hydroxide; And / or, the molar ratio of the catalyst to the compound of formula II is (0.75~2.5):1; And / or, the first solvent is selected from at least one of methanol, water and ethanol; And / or, the first solvent comprises methanol and water in a volume ratio of (2.5~3.5):

1.

4. The synthesis method according to claim 1, characterized in that, The second reaction temperature is -10~40℃; And / or, the borohydride is selected from at least one of sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, and tetramethyltriacetoxyammonium borohydride; And / or, the borohydride is sodium borohydride; And / or, the molar ratio of the borohydride to the compound of formula II is (1.0~2.0):

1.

5. The synthesis method according to claim 1, characterized in that, The second solvent is used in the second reaction; The second solvent is selected from at least one of dimethyl sulfoxide, N,N-dimethylformamide, and acetic acid; And / or, the second solvent comprises dimethyl sulfoxide and acetic acid in a volume ratio of (4.5~5.5):

1.

6. The synthesis method according to claim 1, characterized in that, The third reaction temperature is 20~100 ℃; And / or, the nitrite is selected from at least one of sodium nitrite and potassium nitrite; And / or, the molar ratio of the nitrite to the compound of formula III is (0.5~3.5):

1.

7. The synthesis method according to claim 6, characterized in that, The third reaction uses a third solvent, which is selected from at least one of dimethyl sulfoxide, N,N-dimethylformamide, and water; And / or, the third solvent comprises dimethyl sulfoxide and water in a volume ratio of (6.5~7.5):

1.

8. The synthesis method according to claim 1, characterized in that, The compound of formula II is obtained by reacting the compound of formula I with phosphorus oxychloride via a fourth reaction, and the compound of formula I has the following structure: 。 9. The synthesis method according to claim 8, characterized in that, The concentration of compound I in the fourth reaction is 0.5~2.5 mmol / mL; And / or, the fourth reaction temperature is 20~80 °C; And / or, the molar ratio of phosphorus oxychloride to the compound of formula I is (0.5~2.0):

1.

10. The synthesis method according to claim 8, characterized in that, The fourth reaction uses a fourth solvent, which is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, and N-methylpyrrolidone. And / or, the fourth solvent is N,N-dimethylformamide.

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