Preparation method of fiazonepan

Abstract

The invention discloses a preparation method of fiazonetin, and belongs to the technical field of medicinal chemistry. According to the route, 2-halo-3-methylpyrazine which is low in price and easy to obtain is used as a raw material and sequentially reacts with hydrazine hydrate and orthoester, and then a hydrogenation reduction reaction is performed to generate a compound 4; carrying out chiral resolution or chiral separation on the compound 4 and carrying out condensation reaction on the compound 4 and p-fluorobenzoyl halide to obtain an intermediate compound 5 or 5'and a new intermediate compound 6; reacting the compound 6 with a halogenating reagent to obtain a compound 7; carrying out Suzuki coupling reaction on the compound 7 and a compound 8 to obtain a compound, namely, the compound of the formula A, namely, non-azonepan; according to the route, the raw materials are simple, easy to obtain and low in cost; the reaction is simple, the preparation efficiency is high, and the reaction yield of each step can be higher than 90%; no harsh reaction conditions exist, and operation is safe; post-treatment is simple and convenient, and environmental pollution is low. The method is suitable for large-scale production; a high-chiral product can be obtained, the chiral purity value of a final product is as high as 99.5%, and the method has relatively good market value and profound practical significance. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of chemical medicines, and in particular relates to a preparation method of fezonetant. Background Art

[0002] Menopausal vasomotor syndrome (VMS) is mainly caused by the decrease or fluctuation of estrogen levels after menopause, which leads to unstable vasoconstriction function, thus causing characteristic symptoms, mainly including hot flashes and / or excessive sweating. During menopause, moderate to severe vasomotor syndrome can cause a gradual decrease in the production of estrogen and progesterone in women's bodies due to menopause. About 80% of menopausal women will experience hot flashes, including sweating, flushing and chills that last for several minutes, especially at night, which can interfere with sleep and affect mental state. Previously, the main treatment for menopausal VMS worldwide was hormone replacement therapy (HRT). Although it can significantly improve patient symptoms, a randomized, controlled trial conducted by the National Heart, Lung, and Blood Institute and the Women's Health Initiative (WHI) pointed out that this therapy increases patients' risk of cardiovascular disease, venous thromboembolism (VTE), breast cancer and endometrial cancer.

[0003] Fizonaitant, the Chinese chemical name is (4-fluorophenyl)-[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2],4]triazolo[4,3-a]pyrazine-7-(8H)-yl]methanone, and its structural formula is shown in Formula A:

[0004]

[0005] The synthesis route of fezonetam in the prior art is reported as follows:

[0006]

[0007] This method requires 2,4-dimethoxybenzyl (DMB) protection, ethylation, cyclization, DMB deprotection and acylation to obtain the product. The reaction is cumbersome, the atomic utilization is low, and it does not conform to the concept of green cleaning. In addition, the starting material and the 3-methyl-1,2,4-thiadiazole-2(3H)-carbohydrazide used in the cyclization step are not easy to obtain and are expensive, which is not conducive to large-scale industrial production.

[0008] Therefore, it is necessary to develop a method for synthesizing fezonetan with readily available raw materials, convenient operation, simple route, and green and clean properties to improve efficiency and promote industrial production. Summary of the invention

[0009] In order to solve the problems in the prior art, the present invention provides a new method for preparing fezonetant, which has the advantages of simple process, high yield, high applicability, low cost and green environmental protection.

[0010] In one aspect, the present invention provides a method for preparing the compound of formula A, fezonetam, and the reaction formula thereof is as follows:

[0011]

[0012] The following steps are involved:

[0013] 1. Compound 6 reacts with a halogenating agent to obtain compound 7;

[0014] 2. Compound 7 and compound 8 are subjected to Suzuki coupling reaction to obtain a compound of formula A;

[0015] Wherein, in step 1, X is a halogen, such as Cl, Br, I;

[0016] Wherein, the halogenating agent in step 1 is selected from N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), bromine, benzyltrimethylammonium tribromide, N-iodosuccinimide (NIS), iodine chloride, dibromohydantoin, preferably dibromohydantoin.

[0017] Wherein, in step 1, a base is added, and the base is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate or potassium hydroxide, preferably sodium bicarbonate.

[0018] Wherein, the solvent in step 1 is selected from one of amides, halogenated hydrocarbons, nitriles, alcohols, and ether solvents or any combination thereof. Preferably, the amide solvent is selected from dimethylformamide; the halogenated hydrocarbon solvent is selected from dichloromethane, carbon tetrachloride, dichloroethane or chloroform; the nitrile solvent is selected from acetonitrile or propionitrile; the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol or butanol; the ether solvent is selected from tetrahydrofuran or dioxane; the solvent used is preferably chloroform or dichloromethane.

[0019] Wherein, the reaction temperature in step 1 is 25-60°C, preferably 60°C;

[0020] Wherein, in step 2, a catalyst is used, and the catalyst is selected from Pd(dppf)Cl2, Pd(PPh3)4, PdCl2, Pd(OAc)2, Pd(PPh3)2Cl2, preferably Pd(dppf)Cl2; the molar amount of the catalyst is 5% to 10% of the molar amount of compound 7, preferably 5%;

[0021] Wherein, the solvent in step 2 is selected from any one of methanol, ethanol, dichloromethane, dichloroethane, chloroform, DMF, THF, acetonitrile and dioxane, preferably dioxane.

[0022] Wherein, a base is added in the reaction of step 2, and the base is selected from potassium acetate, potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, preferably potassium acetate.

[0023] Wherein, the reaction temperature in step 2 is 70-120°C, preferably 90°C.

[0024] In another aspect, the present invention provides a novel intermediate compound 5' and a novel intermediate compound 6 of fezonetant:

[0025]

[0026] On the other hand, the present invention also provides a method for preparing a non-zonetant intermediate compound of formula 6, comprising the following method:

[0027] The reaction formula of method (1) is as follows:

[0028]

[0029] The method comprises the following steps: compound 4 is subjected to chiral resolution or SFC chiral separation to obtain compound 5; and compound 5 is subjected to condensation reaction with p-fluorobenzoyl halide to obtain compound 6.

[0030] The reaction formula of method (2) is as follows:

[0031]

[0032] The method comprises the following steps: compound 4 reacts with p-fluorobenzoyl halide to obtain compound 5' through condensation reaction, and compound 5' is subjected to chiral resolution or asymmetric synthesis to obtain compound 6.

[0033] The chiral resolution or chiral separation in method (1) and method (2) can be achieved by conventional methods in the art, such as SFC resolution or chiral resolution reagents, wherein the chiral resolution reagents can be exemplarily selected from L-(+)-tartaric acid, D-(-)-citramalic acid, D-aspartic acid, L-aspartic acid, D-pyroglutamic acid, L-pyroglutamic acid, D-(-)-quinic acid, D-(-)-tartaric acid, (D)-(-)-mandelic acid, (L)-(+)-mandelic acid, (R)-(-)-1,1'-binaphthol phosphate, (S)-(-)-binaphthol phosphate, D (+)-10-camphorsulfonic acid, D(+)-camphorsulfonic acid, L(-)-camphorsulfonic acid, (+)-diacetyl-L-tartaric anhydride, (-)-di-p-toluoyl-L-tartaric acid, L-glutamic acid, D(+)-malic acid, L(-)-malic acid, (S)-(-)-α-methylbenzyl isocyanate D-glucuronic acid, L-(-)-acetylglutamic acid, (-)-acetylmandelic acid, L-(-)-dibenzoyltartaric acid, preferably L-(+)-tartaric acid, D-(-)-quinic acid, (-)-di-p-toluoyl-L-tartaric acid, L-(-)-dibenzoyltartaric acid.

[0034] Wherein, the p-fluorobenzoyl halide in method (1) and method (2) is selected from p-fluorobenzoyl chloride, p-fluorobenzoyl bromide, and p-fluorobenzoyl iodide, preferably p-fluorobenzoyl chloride.

[0035] Furthermore, the reaction solvent of the condensation reaction in method (1) and method (2) is selected from any one or more mixtures of halogenated hydrocarbons, alcohols, amides, ether solvents or water; the halogenated hydrocarbon solvent is selected from dichloromethane, carbon tetrachloride, and ethylene dichloride; the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, and butanol; the amide solvent is selected from dimethylformamide; and the ether solvent is selected from tetrahydrofuran and dioxane; preferably, it is a mixed solvent of water and dichloromethane;

[0036] Furthermore, in the condensation reaction in method (1) and method (2), a base is added, and the base is selected from one or any combination of sodium carbonate, sodium bicarbonate, N-methylmorpholine, triethylamine or DIPEA, preferably sodium bicarbonate;

[0037] Furthermore, the reaction temperature of the condensation reaction in method (1) and method (2) is 20 to 40°C, preferably 25°C.

[0038] In another aspect, the present invention provides a method for preparing an intermediate of the compound of formula 4, fezonetam:

[0039]

[0040] The steps include:

[0041] I. Compound 1 reacts with hydrazine hydrate to generate compound 2;

[0042] II. Compound 2 and orthoester undergo cyclization reaction to obtain compound 3;

[0043] III. Compound 3 is subjected to a hydrogenation reduction reaction to generate compound 4;

[0044] Wherein, in step I, X is a leaving group selected from halogen, preferably bromine.

[0045] Wherein, the solvent in step I is selected from one or any combination of aromatic hydrocarbons, halogenated hydrocarbons, alcohols, and amide solvents; the aromatic hydrocarbon solvent is selected from toluene and xylene, the halogenated hydrocarbon solvent is selected from dichloromethane, carbon tetrachloride, and dichloroethane, the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, and butanol, and the amide solvent is selected from dimethylformamide; the solvent used is preferably ethanol.

[0046] Wherein, the reaction temperature in step I is 80-120°C, preferably 90°C.

[0047] Wherein, the reaction time in step I is 12 to 18 hours, preferably 16 hours.

[0048] Wherein, in step II, the orthoester is selected from trimethyl orthoformate and triethyl orthoformate, preferably trimethyl orthoformate.

[0049] Wherein, the reaction temperature in step II is 80-130°C, preferably 100°C.

[0050] Wherein, the reaction time in step II is 2 to 5 hours, preferably 3.5 hours.

[0051] Wherein, the step III is carried out under the action of a catalyst, and the catalyst is selected from any one of palladium, palladium carbon, palladium trifluoroacetate, and palladium diacetate, preferably palladium carbon; the mass amount (g) of the catalyst is 0.1% to 12% of the mass amount (g) of compound 2, preferably 5 to 10%.

[0052] Wherein, the reaction temperature in step III is 35-60°C, preferably 50°C.

[0053] Wherein, the hydrogen pressure in step III is 0.5-10 MPa, preferably 0.8-1 MPa.

[0054] Wherein, the hydrogenation reduction reaction in step III is carried out in an organic solvent, and the organic solvent is selected from one or any combination of alcohol, amide or ether solvents; the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol or butanol, the amide solvent is selected from dimethylformamide, and the ether solvent is selected from tetrahydrofuran or dioxane; the solvent used is preferably ethanol.

[0055] Beneficial technical effects of the present invention:

[0056] 1. Compared with the expensive and difficult-to-obtain chiral raw materials in the prior art, the route of the present invention uses 2-halogenated-3-methylpyrazine as a raw material. There is currently no report on the use of this compound as a raw material to prepare fezonetant. At the same time, the raw material is simple and easy to obtain, low in cost, and more suitable for large-scale industrial production.

[0057] 2. The route of the present invention has simple reaction, high preparation efficiency, and the yield of each step can be higher than 90%. At the same time, the route has no harsh reaction conditions, safe operation, avoids expensive raw materials and reagents, low cost, simple post-processing, and less environmental pollution. It is suitable for large-scale production and has good market value and far-reaching practical significance.

[0058] 3. The route of the present invention can obtain a high-chirality product, and the chiral purity of the final product is as high as 99.5%. The chiral purity is high and is suitable for subsequent preparation production and commercialization.

[0059] 4. The new intermediate compound 5' and the new intermediate compound 6 of the present invention have stable properties and good reproducibility. The intermediate compound of the present invention is judged based on the method for producing subsequent API products or the resulting products. The new intermediate compound of the present invention has made a great contribution to the creative method for producing subsequent API products. The preparation method of the new intermediate compound of the present invention is simple to operate, has a high yield and good product quality. DETAILED DESCRIPTION

[0060] The beneficial effects of the present invention are now further described by the following examples. It should be understood that these examples are only for illustrative purposes and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by ordinary technicians in the field according to the present invention are also included in the scope of the present invention.

[0061] The novel synthesis method of fezonetant and the advantages of the method will be further described below in conjunction with the embodiments of the present invention.

[0062] Example 1

[0063]

[0064] (1) Dissolve 2-chloro-3-methylpyrazine (200.0 g, 1.6 mol) in 20 mL of ethanol and add hydrazine hydrate solution (500 g, 8 mol). Heat to 90°C and stir for 16 h. After the reaction is complete, concentrate to dryness under reduced pressure, slurry with a small amount of dichloromethane and filter. After vacuum drying, 180.2 g of yellow solid is obtained, which is directly used in the next step reaction with a yield of 94.3%. 1H NMR: (400MHz, CD3OD) δ7.99-7.96(d, 1H), 7.68-7.67(d, 1H), 4.90(s, 3H), 2.36(s, 3H), ms(ESI): 125[M+H] + .

[0065] Example 2

[0066]

[0067] The yellow solid (180.2 g, 1.45 mol) and trimethyl orthoformate (667.0 g, 6.3 mol) were added to a reaction kettle, heated to 100°C, stirred and reacted for 3.5 hours, the reaction liquid was cooled to room temperature, concentrated to dryness under reduced pressure, and methanol was evaporated to dryness to obtain 186.6 g of oily liquid with a yield of 95.8%, which was directly used for the next step. 1 H NMR: (400MHz, CD3OD) δ9.06 (s, 1H), 8.14-8.12 (d, 1H), 7.99-7.97 (d, 1H), 3.19-3.16 (s, 3H), ms (ESI): 135 [M+H] + .

[0068] Example 3

[0069]

[0070] Add the above 186.6g oily liquid and 10V of ethanol to the reactor, start stirring, add palladium carbon (18.6g, 10%), keep warm at 50℃, and maintain the hydrogen pressure at 0.5-1Mpa. Filter under reduced pressure, concentrate the filtrate to a small volume, filter and evaporate to dryness with toluene to obtain 190.4g of viscous liquid, with a yield of 98.9%. SFC chiral preparation obtained 124.3g of colorless viscous liquid, with a chiral purity of 99.5% and a yield of 65.3%. SFC conditions: chiral column: ChiralpakAS (250mm×30mm, 5um); mobile phase: supercritical CO2 / ethanol (0.05% DEA) = 70 / 30; flow rate: 60mL / min; detection wavelength: 220nm. 1 H NMR (CDCl3): δ4.66 (m, 1H), 4.33-4.21 (m, 2H), 3.47 (m, 1H), 3.23 (m, 1H), 2.72 (s, 3H), 1.69 (d, 3H). MS(ESI):237[M+H] + . 1HNMR: (400MHz, CD3OD) δ8.42 (s, 1H), 4.21-4.15 (m, 2H), 3.39-3.34 (m, 2H), 3.17-3.10 (m, 1H), 1.62-1.60 (d, 3H), ms (ESI): 139 [M+H] + .

[0071] Example 4

[0072]

[0073] Add the above 124.3g colorless viscous liquid, 5V of dichloromethane and 5V of water into the reactor and start stirring. Add sodium bicarbonate (151.2g, 2eq.), dropwise add p-fluorobenzoyl chloride (142.7g, 1eq.), and react at 25°C. Separate the liquids, wash the organic phase twice with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and perform rapid column chromatography to obtain 213.0g of off-white solid. Yield 91.0%. 1 H NMR: (400MHz, CDCl3) δ8.10 (s, 1H), 7.45-7.41 (m, 2H), 7.15-7.10 (m, 2H), 5.60 (s, 1H), 4 .51(s, 1H), 4.19-4.04(m, 2H), 3.51-3.42(t, 1H), 1.66-1.64(d, 3H), ms(ESI): 261[M+H] + .

[0074] Example 5

[0075]

[0076] Add the above 213.0g off-white solid, 3.2L chloroform, and sodium bicarbonate (137.5g, 2eq.) into a reactor and start stirring. Add NBS (145.6g, 1eq.) in batches and keep at 60°C for reaction. Cool to room temperature and add 10V water. Stir and stand for separation, wash the organic phase with water twice, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform rapid column chromatography to obtain 259.2g off-white solid with a yield of 93.4%. 1 H NMR: (400MHz, CDCl3) δ7.49-7.46(m, 2H), 7.19-7.15(m, 2H), 5.61(s, 1H), 4.64(s , 1H), 4.07-3.91(m, 2H), 3.52-3.46(t, 1H), 1.70-1.68(d, 3H), ms(ESI): 340[M+H] + .

[0077] Example 6

[0078]

[0079] The above 259.2g off-white solid, 2.5L of 1,4-dioxane, Pd(dppf)Cl2 (27.9g, 5% mol), potassium acetate (112.5g, 1.5eq.), 3-methyl-5-boric acid ester-1,2,4-thiadiazole (176.2g, 1.02eq.) were added to the reaction kettle, stirred, and protected with nitrogen. The reaction was kept at 90°C. The temperature was lowered, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. 244.3g off-white solid was obtained by rapid column chromatography, with a purity of 98.9% and a chiral purity of 99.5%. The yield was 89.2%. 1 H NMR: (400MHz, CDCl3) δ7.50-7.47(m, 2H), 7.20-7.15(t, 2H), 5.78(s, 1H), 4.95-4.91(dd, 1H), 4.62 (s, 1H), 4.31-4.24 (m, 1H), 3.57-3.51 (t, 1H), 2.74 (s, 3H), 1.76-1.75 (d, 3H), ms (ESI): 359.4[M+H] + .

[0080] Example 7

[0081]

[0082] Take the oily liquid (10 g, 0.075 mol) obtained in Example 2, add 10V of ethanol into the reaction kettle, start stirring, add palladium carbon (1.0 g, 10%), keep warm at 50°C for reaction, and maintain the hydrogen pressure at 0.5-1 MPa. Filter under reduced pressure, concentrate the filtrate to a small volume, filter it with toluene, and evaporate to dryness to obtain 9.9 g of viscous liquid, with a yield of 96.7%. 1 HNMR: (400MHz, CD3OD) δ8.42 (s, 1H), 4.21-4.15 (m, 2H), 3.39-3.34 (m, 2H), 3.17-3.10 (m, 1H), 1.62-1.60 (d, 3H), MS (ESI): 139 [M+H] + .

[0083] Example 8

[0084]

[0085] Add the above 9.9g (0.071mol, 1.0eq.) colorless viscous liquid, 5V of dichloromethane and 5V of water into the reactor and start stirring. Add sodium bicarbonate (12.0g, 0.14mol, 2.0eq.) and drop p-fluorobenzoyl chloride (11.4g, 1eq.) and keep the reaction at 25℃. Separate the liquids, wash the organic phase twice with saturated brine, dry it with anhydrous sodium sulfate, concentrate it under reduced pressure, and perform rapid column chromatography to obtain 16.5g of off-white solid. The yield is 88.6%. 1 H NMR: (400MHz, CDCl3) δ8.10 (s, 1H), 7.45-7.41 (m, 2H), 7.15-7.10 (m, 2H), 5.60 (s, 1H), 4 .51(s, 1H), 4.19-4.04(m, 2H), 3.51-3.42(t, 1H), 1.66-1.64(d, 3H), ms(ESI): 261[M+H] + .

[0086] Example 9

[0087]

[0088] Take D-(-)-quinic acid (3.69g, 0.02mol), add 10V ethanol, stir at 70℃ until dissolved, add the above off-white solid (5.0g, 0.02mol) in batches, stir at 70℃ for 1h after addition, slowly cool to 5-10℃, and filter. Add 10V ethanol to the obtained salt, stir at 70℃ until dissolved, and slowly cool to 20-25℃. Filter and rinse. Disperse the obtained salt with 5V DCM, adjust the pH of the aqueous phase to 8-8.5 with NaOH, stand and separate, concentrate the organic phase to a small volume, add 10V n-heptane, cool to 5-10℃, precipitate solid, keep warm for 5h, filter and dry to obtain 1.3g white solid. Yield 26%. ee value 98.2%. 1 H NMR: (400MHz, CDCl3) δ8.10 (s, 1H), 7.45-7.41 (m, 2H), 7.15-7.10 (m, 2H), 5.60 (s, 1H), 4 .51(s, 1H), 4.19-4.04(m, 2H), 3.51-3.42(t, 1H), 1.66-1.64(d, 3H), ms(ESI): 261[M+H] + .

[0089] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing the compound of formula A, fezonetam, comprising the following steps: The following steps are involved:

1. Compound 6 reacts with a halogenating agent in the presence of a base to obtain compound 7; 2. Compound 7 and compound 8 are subjected to Suzuki coupling reaction to obtain a compound of formula A; Wherein, X is a halogen, such as Cl, Br, I.

2. The preparation method according to claim 1, characterized in that: In step 1, at least one of the following conditions is met: The halogenating agent is selected from NCS, NBS, bromine, benzyltrimethylammonium tribromide, NIS, iodine chloride, dibromohydantoin, preferably dibromohydantoin; and / or, the base is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate or potassium hydroxide, preferably sodium bicarbonate; and / or, the reaction solvent is selected from one of amides, halogenated hydrocarbons, nitriles, alcohols, and ether solvents or any combination thereof, preferably, the amide solvent is selected from dimethylformamide; the halogenated hydrocarbon solvent is selected from dichloromethane, carbon tetrachloride, dichloroethane or chloroform; the nitrile solvent is selected from acetonitrile or propionitrile; the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol or butanol; the ether solvent is selected from tetrahydrofuran or dioxane; the solvent used is preferably chloroform or dichloromethane; And / or, the reaction temperature is 25 to 60°C, preferably 60°C.

3. The preparation method according to claim 1, characterized in that: In step 2, at least one of the following conditions is met: The catalyst is selected from Pd(dppf)Cl2, Pd(PPh3)4, PdCl2, Pd(OAc)2, Pd(PPh3)2Cl2, preferably Pd(dppf)Cl2; the molar amount of the catalyst is 5% to 10% of the molar amount of compound 7, preferably 5%; And / or, in step 2, the solvent is selected from any one of methanol, ethanol, dichloromethane, dichloroethane, chloroform, DMF, THF, acetonitrile and dioxane, preferably dioxane; And / or, a base is added during the reaction in step 2, wherein the base is selected from potassium acetate, potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, preferably potassium acetate; And / or, the reaction temperature in step 2 is 70-120°C, preferably 90°C.

4. The preparation method according to claim 1, characterized in that: The fenazolinitan intermediate compound of formula 6 is obtained by the following preparation method: Method (1): The method comprises the following steps: compound 4 is subjected to chiral resolution or SFC chiral separation to obtain compound 5; compound 5 is subjected to condensation reaction with p-fluorobenzoyl halide in the presence of a base to obtain compound 6; or Method (2): The method comprises the following steps: compound 4 reacts with p-fluorobenzoyl halide in the presence of a base to obtain compound 5' through a condensation reaction, and compound 5' is subjected to chiral resolution or asymmetric synthesis to obtain compound 6.

5. The preparation method according to claim 4, characterized in that: Method (1) and method (2) satisfy at least one of the following conditions: The p-fluorobenzoyl halide is selected from p-fluorobenzoyl chloride, p-fluorobenzoyl bromide, and p-fluorobenzoyl iodide, preferably p-fluorobenzoyl chloride; And / or, the reaction solvent of the condensation reaction is selected from any one or more mixtures of halogenated hydrocarbons, alcohols, amides, ether solvents or water; the halogenated hydrocarbon solvent is selected from dichloromethane, carbon tetrachloride, and ethylene dichloride; the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, and butanol; the amide solvent is selected from dimethylformamide; the ether solvent is selected from tetrahydrofuran and dioxane; preferably, it is a mixed solvent of water and dichloromethane; and / or, the base in the condensation reaction is selected from one or any combination of sodium carbonate, sodium bicarbonate, N-methylmorpholine, triethylamine or DIPEA, preferably sodium bicarbonate; And / or, the reaction temperature of the condensation reaction is 20-40°C, preferably 25°C.

6. The preparation method according to claim 4, characterized in that: The compound of formula 4 is prepared by the following method: The steps include: I. Compound 1 reacts with hydrazine hydrate to generate compound 2; II. Compound 2 and orthoester undergo cyclization reaction to obtain compound 3; III. Compound 3 undergoes a hydrogenation reduction reaction in the presence of a catalyst to generate compound 4; Wherein, in step I, X is a leaving group selected from halogen, preferably bromine.

7. The preparation method according to claim 5, characterized in that: The step I satisfies at least one of the following conditions: The reaction solvent of step I is selected from one or any combination of aromatic hydrocarbons, halogenated hydrocarbons, alcohols, and amide solvents; the aromatic hydrocarbon solvent is selected from toluene and xylene, the halogenated hydrocarbon solvent is selected from dichloromethane, carbon tetrachloride, and ethylene dichloride, the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, and butanol, and the amide solvent is selected from dimethylformamide; the solvent used is preferably ethanol; and / or, the reaction temperature is 80 to 120° C., preferably 90° C.; And / or, the reaction time is 12 to 18 hours, preferably 16 hours.

8. The preparation method according to claim 5, characterized in that: The step II satisfies at least one of the following conditions: The orthoester is selected from trimethyl orthoformate and triethyl orthoformate, preferably trimethyl orthoformate; and / or, the reaction temperature is 80 to 130° C., preferably 100° C.; And / or, the reaction time is 2 to 5 hours, preferably 3.5 hours.

9. The preparation method according to claim 5, characterized in that: The step III satisfies at least one of the following conditions: The catalyst is selected from any one of palladium, palladium carbon, palladium trifluoroacetate, and palladium diacetate, preferably palladium carbon; the mass amount g of the catalyst is 0.1% to 12% of the mass amount g of compound 2, preferably 5 to 10%; and / or, the reaction temperature is 35 to 60°C, preferably 50°C; And / or, the reaction solvent is selected from one or any combination of alcohol, amide or ether solvents; the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol or butanol, the amide solvent is selected from dimethylformamide, and the ether solvent is selected from tetrahydrofuran or dioxane; the solvent used is preferably ethanol.

10. An intermediate compound 5' and compound 6:

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