CN117903117A

CN117903117A - Preparation method of KRAS G12C inhibitor divarasib

Info

Publication number: CN117903117A
Application number: CN202311734048.0A
Authority: CN
Inventors: 梁永宏; 黄建宜
Original assignee: Yunnan Wanhong Pharmaceutical Technology Co ltd
Current assignee: Yunnan Wanhong Pharmaceutical Technology Co ltd
Priority date: 2023-12-15
Filing date: 2023-12-15
Publication date: 2024-04-19

Abstract

The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of a KRAS G12C inhibitor divarasib. The synthetic method comprises the following reaction steps: the preparation method comprises the steps of reacting raw material 2-amino-4-bromo-5-chloro-3-fluorobenzamide (1) with bis (1H-imidazol-1-yl) methyl thioketone (11) to obtain compound 7-bromo-6-chloro-8-fluoro-2-mercaptoquinazolin-4-ol (2), carrying out methylation and halogenation reaction and substitution reaction with (S) -3-methylpiperazine-1-tert-butyl formate to obtain a key intermediate compound (5), carrying out coupling reaction with halide, oxidizing, reacting with (S) - (1-methylpyrrolidine-2-yl) methanol, deaminating protecting group, and finally reacting with acryloyl chloride to obtain a target compound divarasib (10).

Description

Preparation method of KRAS G12C inhibitor divarasib

Technical Field

The invention belongs to the field of pharmaceutical chemical synthesis, and relates to a novel preparation method of a KRAS G12C inhibitor divarasib.

Background

The KRAS gene is the most common oncogene in human cancers, with G12C mutations in KRAS genes found in a variety of solid tumors, with G12C mutations in KRAS genes found in 12% to 14% of non-small cell lung cancers, and G12C mutations in KRAS genes found in 4% of colorectal cancers, as well as other solid tumors. It is important for cancer therapy to inhibit KRAS proteins once certain critical sites have undergone specific mutations that lead to the development of cancer disease. For a long time, tumors harboring mutations in the KRAS gene have been treated with chemotherapy in combination with PD-1 inhibitors,

Up to now, a total of 3 KRAS G12C inhibitors were approved by the united states Food and Drug Administration (FDA), accelerated approval or entered into clinical trials. The method comprises the following steps: sotorasib (sotoracicb): a full-ball KRAS G12C inhibitor for use in the second line treatment of patients with locally advanced or metastatic non-small cell lung cancer having a KRAS G12C mutation. Adagrasib (adaglazeb): the global second KRAS G12C inhibitor was approved by the FDA in the united states at month 12 of 2022, with Adagrasib having somewhat stronger data at stage 2 than Sotorasib, and the third was Divarasib (GDC-6036). Divarasib (GDC-6036) is a small molecule targeting agent which is screened, has high-efficiency selective inhibition capability on protein translated by KRAS gene G12C mutation, has the action mechanism approximately the same as Sotorasib, adagrasib, and can irreversibly lock the mutated KRAS in an inactive state, close an oncogenic signal and inhibit tumor growth. In vitro experiments demonstrated Divarasib potency, 5 to 20 times greater than sotorasib and adagrasib, designed to work only with KRAS G12C protein, selectivity up to 50 times. Related studies have shown that Divarasib produces a safe and durable anti-tumor response with tolerability in a variety of solid tumor patients with KRAS G12C mutations, potentially becoming a KRAS G12C inhibitor for the next agent to combat solid tumors.

Disclosure of Invention

In view of the above, the preparation of KRAS G12C inhibitor divarasib is very important. The inventor solves the technical problem of the compound through experimental study, and the reaction route is as follows:

The invention comprises the following steps:

(a) The compound (1) is taken as a raw material and reacts with the compound (11) to obtain the compound (2)

(B) Methylation of the compound (2) to give the compound (3)

(C) Halogenation of Compound (3) gives Compound (4)

Wherein R ₁ = OTf, cl, br

(D) The compounds (4) and (12) are under the action of alkali. Substitution reaction to give compound (5)

(E) The compound (5) reacts with the compound (13) under the catalysis of zinc to obtain a compound (6)

(F) The compound (6) is oxidized to give a compound (7)

(G) Reacting the compound (7) with (14) under basic conditions to give the compound (8)

(H) Deamination of compound (8) under acidic conditions gives compound (9)

(I) Finally, the reaction with acryloyl chloride gives the target compound divarasib (10)

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.

Example 1

Step A

The compound 2-amino-4-bromo-5-chloro-3-fluorobenzamide (1.33 g,5 mmol) was dissolved in THF (15 ml), warmed to 40℃and NaH (0.47 g) was added in portions, stirred for 10 minutes at 40℃and bis (1H-imidazol-1-yl) methylthioketone (1.25 g,7 mmol) was added in portions, and the temperature was raised to 60℃after the addition and reacted for 0.5 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, and the pH was adjusted to 5-6 with dilute hydrochloric acid, followed by concentration to remove tetrahydrofuran. At this time, a large amount of solids precipitated. The solid was filtered and dried to give the compound 7-bromo-6-chloro-8-fluoro-2-mercaptoquinazolin-4-ol (1.23 g, 80% yield). LC-MS (ESI): m/z=309.5 [ m+h ] ⁺ step B

The compound 7-bromo-6-chloro-8-fluoro-2-mercaptoquinazolin-4-ol (1.8 g,5.85 mmol) was dissolved in methanol (30 mL), sodium methoxide (0.445 g) and methyl iodide (0.68 mL) were added and reacted at room temperature for 0.5 hours. After completion of the reaction, water (5 mL) was added to the reaction solution, stirred for 10 minutes, and a solid was obtained by filtration, and after drying, the compound 7-bromo-6-chloro-8-fluoro-2- (methylthio) quinazolin-4-ol (1.37 g, yield 72%) was obtained. LC-MS (ESI): m/z=323.6 [ m+h ] ⁺

Step C

The compound 7-bromo-6-chloro-8-fluoro-2- (methylthio) quinazolin-4-ol (1.11 g,3.42 mmol) was dissolved in phosphorus oxychloride (8 mL), followed by the addition of DIEA (884 mg,6.84 mmol) and heating to 90 ℃ for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and excess phosphorus oxychloride was removed. Then, it was dissolved in ethyl acetate, washed with saturated brine and water in this order, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product which was used directly in the next step (1.17 g, yield 100%). LC-MS (ESI): m/z=342.0 [ m+h ] ⁺ step D

7-Bromo-4, 6-dichloro-8-fluoro-2- (methylthio) quinazoline (0.94 g,2.75 mmol), (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.52 g,2.6 mmol) and K ₂CO₃ (0.76 g,5.5 mmol) were dissolved in NMP (5 mL), stirred at 80℃for 1 hour, and then 12.5: 12.5mLH ₂ O was added. The solid was collected by filtration to give the compound (S) -4- (7-bromo-6-chloro-8-fluoro-2- (methylthio) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.26 g, 91% yield), LC-MS (ESI): m/z=505.8 [ m+h ] ⁺

Step E

The compound (S) -4- (7-bromo-6-chloro-8-fluoro-2- (methylthio) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.89 g,1.76 mmol) was dissolved in THF (4 mL) at-70.+ -. 5 ℃, i-PrMgClxLiCl (1.14M in THF, 1.56g,1.84 mmol) was added and the corresponding mixture stirred for 30 min. Then, znCl2 solution (1 g,1.88 mmol) was added at-70.+ -. 5 ℃. After complete addition, the reaction mixture was heated to-10℃and then NaTFA (652 mg,4.8 mmol) was added in portions. The mixture was heated to 50deg.C, then a solution of the compound 6-bromo-N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (0.79 g,1.6 mmol) in THF (8 mL) was added. The mixture was stirred for about 15 minutes, then a solution of palladium chloride (PI-cinnamyl) dimer (4 mg,0.008 mmol) and (R, R) -CHIRAPHITE (15.4 mg,0.018 mmol) in THF (1.6 mL) was added and the reaction mixture was stirred until complete conversion was achieved. The reaction mixture was cooled to 20℃and quenched by the addition of aqueous trisodium citrate (6 g,20% w/w) and toluene (4 mL). The reactor was rinsed with THF (4 mL) and the biphasic mixture was stirred for 15 minutes. After phase separation, aqueous trisodium citrate (6 g,20% w/w) was added and the biphasic mixture was stirred for 15 minutes. After phase separation, water (2 mL) was added and the biphasic mixture was stirred for 15 minutes. After phase separation, water, THF and 2-Me-THF were replaced with toluene (4 mL) at constant volume under vacuum. The solution was then filtered through a charcoal filter at 50.+ -. 2 ℃ and the reactor and filter were rinsed with toluene (4.2 g) and the reaction volume was concentrated to about 3mL under vacuum. The reactor was cooled to 20℃and n-heptane (0.54 g) and 0.8mg of seed crystal were added and the suspension was aged for 1h. N-heptane (6 g) was then added over 2 hours and the resulting suspension stirred for at least 12 hours. The crystals were filtered off and washed three times with 5mL toluene/n-heptane (1:1) to give the crude product. The crude product can be recrystallized from toluene/n-heptane following the crystallization procedure described above to yield the compound (S) -tert-butyl 4- ((S) -7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (methylthio) quinazolin-4-yl) -3-methylpiperazine-1-carboxylate (1.06 g, 72% yield). LC-MS (ESI): m/z=841.4 [ M+H ] ⁺

Step F

The compound (S) -4- ((S) -7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (methylthio) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.9 g,1.05 mmol), (S) - (-) -1,1' -bi-2-naphthol (0.031 g,0.105 mmol), dichloromethane (304 mL), ti (OiPr) ₄ (3.27 mL,0.055 mmol) and water (3.86 mL) was added to a multi-necked flask and stirred under nitrogen at 20 ℃ for 1h. T-butyl peroxide (70% aqueous solution, 1.18 mmol) was added in one portion at 21 ℃; after the temperature had risen to about 40 ℃, the mixture became completely homogeneous. The mixture was allowed to reach normal room temperature, stirred for 1.5h and filtered. The filter cake was rinsed twice with isopropyl acetate (3 mL each) and the filter cake was air dried for more than 6h in the filter to give the compound (3S) -4- ((7S) -7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (methylsulfinyl) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.72 g, 80% yield). LC-MS (ESI): m/z=857.4 [ m+h ] ⁺

Step G

(S) - (1-methylpyrrolidin-2-yl) methanol (0.72 g,6.28 mmol) was dissolved in tetrahydrofuran (100 mL) and sodium hydride (0.5 g,12.5 mmol) was added, after stirring for 10min, (3S) -4- ((7S) -7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (methylsulfinyl) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (2.16 g,2.52 mmol) was added. The reaction mixture was stirred at 0 ℃ for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel to give tert-butyl (S) -4- ((S) -7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3-methylpiperazine-1-carboxylate (1.51 g, 66% yield). LC-MS (ESI): m/z=908.4 [ m+h ] ⁺.

Step H

(S) -4- ((S) -7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (2.88 g,3.17 mmol) was dissolved in trifluoroacetic acid (30 mL) and stirred at 50℃for 4 hours. After the reaction was completed, the reaction system was concentrated under vacuum. The residue was dissolved in dichloromethane (15 mL) and the PH was adjusted to 9 with N, N-diisopropylethylamine. Concentrated under vacuum, and the residue was directly purified by reverse phase chromatography to give 6- ((S) -6-chloro-8-fluoro-4- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (1.08 g, 60% yield) as a yellow solid. LC-MS (ESI): m/z=568 [ M+H ] ⁺

Step I

6- ((S) -6-chloro-8-fluoro-4- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-7-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (0.42 g,0.73 mmol) and N, N-diisopropylethylamine (0.48 g,3.75 mmol) were dissolved in dichloromethane (20 mL), acryloyl chloride (59.73 mg,0.66 mmol) was added at-78℃and stirred at-78℃for 25 min. The reaction was quenched with water and extracted with dichloromethane. The organic layers are mixed together. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was directly purified by reverse phase chromatography to give the title compound divarasib (45.67 mg, yield 10%). LC-MS (ESI): m/z=622.06 [ m+h ] ⁺

Example 2

(S) -4- (7-bromo-6-chloro-8-fluoro-2- (methylthio) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester was prepared in analogy to example 1 step A, B, C, D.

Step E

(S) -4- (7-bromo-6-chloro-8-fluoro-2- (methylthio) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.51 g,1 mmol), meOH (0.5 ml), CH ₂Cl₂ (4.5 ml) and AlCl ₃ (0.5 mmol) were mixed and stirred at room temperature for 1min. Then, iodobenzene diacetate (1.0 equivalent) was added, and the solution was stirred at room temperature. After disappearance of the sulfide species (TLC check), the solvent was removed under reduced pressure. The crude product was purified by column chromatography to give (3S) -4- (7-bromo-6-chloro-8-fluoro-2- (methylsulfinyl) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.47 g, 90% yield). LC-MS (ESI): m/z=521.8 [ M+H ] ⁺

The next four steps were carried out in the same manner as in example 1 to obtain the objective compound divarasib.

Example 3

Step E

(S) -4- (7-bromo-6-chloro-8-fluoro-2- (methylthio) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.46 g,0.919 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (634.63 mg,3.68 mmol) was added at 0deg.C for 1 hour at room temperature, and LCMS monitored for completion of the reaction. The reaction solution was poured into a saturated aqueous sodium sulfite solution, stirred for 0.5 hours, then the layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The residue was filtered, concentrated and purified by column to give (S) -tert-butyl 4- (7-bromo-6-chloro-8-fluoro-2- (methylsulfonyl) quinazolin-4-yl) -3-methylpiperazine-1-carboxylate (0.211 g, 43% yield) as a white solid. LC-MS (ESI): m/z=537.8 [ M+H ] ⁺

The examples are only for illustrating embodiments of the present invention, but the present invention is not limited to the above examples only. The invention is capable of numerous modifications and adaptations without departing from the spirit and scope of the invention as defined by the appended claims and their equivalents.

Claims

1. A preparation method of a KRAS G12C inhibitor divarasib is characterized by comprising the following specific steps of

(1) The compound 7-bromo-6-chloro-8-fluoro-2-mercaptoquinazolin-4-ol (2) is obtained by reacting the starting material 2-amino-4-bromo-5-chloro-3-fluorobenzamide (1) with bis (1H-imidazol-1-yl) methylthioketone (11)

(2) Methylation reaction again gave the compound 7-bromo-6-chloro-8-fluoro-2- (methylthio) quinazolin-4-ol (3)

(3) Then halogenating to obtain the compound 7-bromo-6-chloro-8-fluoro-4-halo-2- (methylthio) quinazoline (4)

(4) Substitution reaction of 7-bromo-6-chloro-8-fluoro-4-halo-2- (methylthio) quinazoline (4) with (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (12) under the action of base to obtain (S) -4- (7-bromo-6-chloro-8-fluoro-2- (methylthio) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (5)

(5) Coupling of (S) -4- (7-bromo-6-chloro-8-fluoro-2- (methylthio) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (5) with 6-bromo-N, N-bis (4-methoxybenzyl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine (13) to give the compound (S) -4- ((S) -7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (methylthio) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (6)

(6) (S) -4- ((S) -7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (methylthio) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (6) is oxidized to give the compound (3S) -4- ((7S) -7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (methylsulfinyl) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (7)

(7) (3S) -4- ((7S) -7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (methylsulfinyl) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (7) is reacted with (S) - (1-methylpyrrolidin-2-yl) methanol (14) to give the compound (S) -4- ((S) -7- (6- (bis (4-methoxybenzyl) amino) -4-methyl-3- (trifluoromethyl) pyridin-2-yl) -6-chloro-8-fluoro-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazolin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (8)

(8) Then the deamination protecting group is carried out to obtain 6- ((S) -6-chloro-8-fluoro-4- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) quinazoline-7-yl) -4-methyl-5- (trifluoromethyl) pyridine-2-amine (9)

(9) Finally, the reaction with acryloyl chloride gives the target compound divarasib (10).

2. The method of claim 1 wherein in step (1), the solvent is selected from one or more of diethyl ether, acetonitrile, THF, DMF, DME, 1, 4-dioxane, H ₂ O, NMP, DMA, DMSO, benzene, toluene. The reaction temperature is selected from 50-120 ℃ and the reaction time is selected from 0-24h.

3. The preparation method of KRAS G12C inhibitor divarasib as claimed in claim 1, wherein in step (2), the reaction temperature is selected from 0-200 ℃, the reaction time is 1-20h, the solvent is selected from one or more of diethyl ether, dimethyl sulfoxide, water, methanol, dimethylformamide or other organic solvents, the methylation reagent is selected from one or more of methyl triflate, dimethyl sulfoxide, methyl cobalt trioxide, methyl iodide, methyl halide, formaldehyde and formic acid mixed solution, grignard reagent, methyl zinc reagent or methyl ketone reagent, the catalyst is selected from one or more of metal oxides such as potassium hydroxide, sodium iodide, copper iodide, cesium carbonate or other alkaline catalysts, and the purification can be selected from column passing, beating or recrystallization.

4. The method for preparing KRAS G12C inhibitor divarasib of claim 1, wherein in step (3), the reaction temperature is selected from 50-120 ℃, the time is selected from 0-10h, the solvent is selected from one or more of ethanol, acetone, methanol, dichloromethane, water, formonitrile, N-dimethylformamide, dimethyl sulfoxide, N-diisopropylethylamine, the halogenating agent is selected from one of halogen acid, phosphorus trihalide, phosphorus pentahalide, thionyl chloride, and the purification can be selected from filtration, filter cake washing, column passing, beating, or recrystallization.

5. The method of claim 1, wherein in step (4), the reaction temperature is selected from 10-200 ℃, the time is selected from 0-72h, and the solvent is selected from one or more of N, N-Dimethylformamide (DMF), dichloromethane, etc. The alkaline agent is one or more selected from sodium carbonate, potassium carbonate, triethylamine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium hydride, etc. The purification can be carried out by washing filter cake, column passing, beating or recrystallization during filtration.

6. The method for preparing KRAS G12C inhibitor divarasib of claim 1, wherein in step (5), the catalyst is one or more of copper-catalyzed coupling reaction, nickel-catalyzed coupling reaction, and zinc-catalyzed coupling reaction, the temperature is selected from 10-200 ℃, the reaction time is selected from 0-72H, and the solvent is one or more of diethyl ether, acetonitrile, THF, DMF, DME, 1, 4-dioxane, H ₂ O, NMP, DMA, DMSO, benzene, and toluene.

7. The method of claim 1, wherein in step (6), the reaction temperature is selected from 25-70 ℃ and the time is selected from 0-24h, and the solvent is selected from one or more of methanol, dichloromethane, ethanol, water, formonitrile, N-dimethylformamide, dimethyl sulfoxide, and the like. The oxidant is one or more selected from tert-butyl peroxide, hydrogen peroxide, oxygen, N ₂O₄、NaIO₄ and the like. The catalyst is one or more selected from aluminum oxide, ti (OiPr) ₄, selenic acid, selenium dioxide, etc. The purification can be carried out by washing filter cake, column passing, beating or recrystallization during filtration.

8. The method for preparing KRAS G12C inhibitor divarasib of claim 1, wherein in step (7), the reaction temperature is selected from 10-200 ℃, and the solvent is selected from one or more of acetonitrile, THF, 1, 4-dioxane, H ₂ O, DMSO, DCM, and 1, 2-dichloroethane. The purification can be carried out by washing filter cake, column passing, beating or recrystallization during filtration.

9. The method for preparing KRAS G12C inhibitor divarasib of claim 1, wherein in step (8), the reaction temperature is selected from 0-100 ℃, and the solvent is selected from one or more of diethyl ether, acetonitrile, THF, DMF, DME, 1, 4-dioxane, H ₂ O, NMP, DMA, DMSO, benzene, toluene, chlorobenzene, anisole, xylene, DCM, and 1, 2-dichloroethane. The acid is one or more selected from trifluoroacetic acid, acetic acid, hydrochloric acid, sulfuric acid, etc. The purification can be carried out by washing filter cake, column passing, beating or recrystallization during filtration.

10. The method of claim 1, wherein in step (9), the temperature is selected from the group consisting of below 0deg.C, usually under ice cooling, and the reaction solvent is selected from the group consisting of dichloroethane, dichloromethane, diethyl ether, carbon tetrachloride, and toluene. The base is selected from one of triethylamine, pyridine, N-diisopropylethylamine, na ₂CO₃、NaHCO₃、K₂CO₃, naOH and KOH.