A process for the preparation of a non-zanidatamab

Abstract

The application discloses a preparation method of fezolinetant, and belongs to the technical field of medicinal chemistry. The cheap and easily obtained 2-halogenated-3-methyl pyrazine is used as a raw material in the route, and is sequentially reacted with hydrazine hydrate and ortho ester, and then is subjected to a hydrogenation reduction reaction to generate compound 4; the compound 4 is subjected to chiral resolution or chiral separation and condensation reaction with p-fluorobenzoyl halide to obtain intermediate compounds 5 or 5' and new intermediate compound 6. The compound 6 is reacted with a halogenating reagent to obtain compound 7; the compound 7 is subjected to Suzuki coupling reaction with compound 8 to obtain the compound fezolinetant of formula A; the route is simple in reaction, high in preparation efficiency, and the reaction yield of each step can be higher than 90%; the reaction condition is not harsh, the operation is safe, the post-treatment is simple, and the environmental pollution is small. The route is suitable for large-scale production, can obtain high-chiral products, and the chiral purity of the final product is as high as 99.5%, and has good market value and far-reaching practical significance.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical drugs, and particularly relates to a preparation method of fezolinetant. BACKGROUND

[0002] Menopausal vasomotor symptoms (VMS) are mainly caused by the decrease or fluctuation of estrogen levels after menopause, leading to unstable vascular contraction function and thus characteristic symptoms, mainly including hot flashes and / or sweating. In the menopausal period of women, the gradual decrease of estrogen and progesterone in the female body caused by menopause can cause moderate to severe vasomotor symptoms in women, and about 80% of menopausal women will have hot flashes, including sweating, flushing and cold for several minutes, which is particularly severe at night and can interfere with sleep and affect mental state. Previously, the main treatment for menopausal VMS in the world was hormone replacement therapy (HRT), which can significantly improve the symptoms of patients, but 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 can increase the risk of cardiovascular disease, venous thromboembolism (VTE), breast cancer and endometrial cancer in patients.

[0003] Fezolinetant, the Chinese name of which 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]pyrazin-7-(8H)-yl]methanone, and its structural formula is shown as formula A:

[0004]

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

[0006]

[0007] This method needs to be protected by 2,4-dimethoxybenzyl (DMB), ethylated, cyclized, deprotected by DMB and acylated to obtain the product, and the reaction is complicated, the atomic utilization degree is low, and it does not meet the concept of green and clean. In addition, the starting material and 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 fezolinetant with easy-to-obtain raw materials, convenient operation, simple route and green and clean, so as to improve the efficiency and promote industrial production. SUMMARY

[0009] To solve the problems in the prior art, the present application provides a novel preparation method of fezolinetant, which is simple in process, high in yield, high in applicability, low in cost and green and environmentally friendly.

[0010] In one aspect, the present application provides a method for preparing a compound of Formula A, namely, fezolinetant, as shown in the following reaction scheme:

[0011]

[0012] comprising the following steps:

[0013] 1. reacting compound 6 with a halogenating reagent to obtain compound 7;

[0014] 2. reacting compound 7 with compound 8 via Suzuki coupling reaction to obtain a compound of Formula A;

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

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

[0017] wherein a base is added in step 1, 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 or any combination of amides, halogenated hydrocarbons, nitriles, alcohols, or ethers, 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; and the ether solvent is selected from tetrahydrofuran or dioxane; preferably, the solvent used is chloroform or dichloromethane.

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

[0020] wherein a catalyst is used in step 2, and the catalyst is selected from Pd(dppf)Cl2, Pd(PPh3)4, PdCl2, Pd(OAc)2, or Pd(PPh3)2Cl2, preferably Pd(dppf)Cl2; the molar amount of the catalyst is 5-10% 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, or dioxane, preferably dioxane.

[0022] wherein the base is selected from the group consisting of 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 application provides a new intermediate compound 5' and a new intermediate compound 6 of non-azamianan:

[0025]

[0026] In another aspect, the present application also provides a preparation method of non-azamianan intermediate compound of formula 6, comprising the following method:

[0027] Method (1) reaction formula is as follows:

[0028]

[0029] comprising the following steps: compound 4 is obtained by chiral resolution or SFC chiral separation to obtain compound 5; compound 5 is condensed with p-fluorobenzoyl halide to obtain compound 6.

[0030] Method (2) reaction formula is as follows:

[0031]

[0032] comprising the following steps: compound 4 is reacted with p-fluorobenzoyl halide to obtain compound 5' by condensation reaction, and compound 5' is obtained by chiral resolution or asymmetric synthesis to obtain compound 6.

[0033] The chiral resolution or chiral separation in the method (1) and method (2) can be achieved by a method conventional in the art, for example, by SFC resolution or chiral resolution reagent, which 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'-binaphthyl phosphate, (S)-(-)-binaphthyl phosphate, D(+)-10-camphorsulfonic acid, D(+)-camphoric acid, L(-)-camphorsulfonic acid, (+)-diacetyl-L-tartaric acid anhydride, (-)-di-p-toluoyl-L-tartaric acid, L-glutamic acid, D(+)-malic acid, L(-)-malic acid, (S)-(-)-a-methylbenzyl isocyanate D-glucuronic acid, L-(-)-acetyl glutamic acid, (-)-acetyl mandelic acid, L-(-)-dibenzoyl tartaric acid, preferably L-(+)-tartaric acid, D-(-)-quinic acid, (-)-di-p-toluoyl-L-tartaric acid, L-(-)-dibenzoyl tartaric acid.

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

[0035] Further, the reaction solvent for the condensation reaction in the method (1) and method (2) is selected from any one or a mixture of more than one of halogenated hydrocarbon, alcohol, amide, ether solvent or water; the halogenated hydrocarbon solvent is selected from dichloromethane, carbon tetrachloride, dichloroethane, the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, the amide solvent is selected from dimethylformamide, the ether solvent is selected from tetrahydrofuran, dioxane; preferably a mixture of water and dichloromethane;

[0036] Further, the base added in the condensation reaction in the method (1) and method (2) is selected from sodium carbonate, sodium bicarbonate, N-methylmorpholine, triethylamine or DIPEA, or any combination thereof, preferably sodium bicarbonate.

[0037] Further, the reaction temperature for the condensation reaction in the method (1) and method (2) is 20-40°C, preferably 25°C.

[0038] In another aspect, the present application provides a method for preparing a compound of formula 4:

[0039]

[0040] comprising the following steps:

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

[0042] II. Compound 2 reacts with ortho ester to form compound 3 through cyclization reaction;

[0043] III. Compound 3 is reduced to form compound 4 through hydrogenation reaction;

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

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

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

[0047] In step I, the reaction time is 12-18h, preferably 16h.

[0048] In step II, the ortho ester is selected from trimethyl orthoformate, triethyl orthoformate, preferably trimethyl orthoformate.

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

[0050] In step II, the reaction time is 2-5h, preferably 3.5h.

[0051] In step III, the reaction is carried out in the presence of a catalyst selected from any one of palladium, palladium on carbon, palladium trifluoroacetate, palladium diacetate, preferably palladium on carbon; the mass amount of catalyst (g) is 0.1%-12% of the mass amount of compound 2 (g), preferably 5-10%.

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

[0053] In step III, the hydrogen pressure is 0.5-10Mpa, preferably 0.8-1Mpa.

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

[0055] The beneficial technical effects of the present application are as follows:

[0056] 1. Compared with the chiral raw materials in the prior art which are expensive and difficult to obtain, the route of the present application uses 2-halo-3-methylpyrazine as a raw material, and there is no report on the preparation of fezolinetant using this compound as a raw material, and the raw material is simple and low in cost, and is more suitable for large-scale industrial production.

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

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

[0059] 4. The new intermediate compound 5' and the new intermediate compound 6 in the present application are stable in property and good in reactivity. The intermediate compounds in the present application are judged according to the method of producing subsequent API products or the obtained products. The new intermediate compounds in the present application make great contribution to the creative method of producing subsequent API products, and the preparation method of the new intermediate compounds in the present application is simple in operation, high in yield and good in product quality. DETAILED DESCRIPTION

[0060] The beneficial effects of the present application will be further described through the following examples, and it should be understood that these examples are only for illustrative purposes, and do not limit the scope of the present application, and the changes and modifications made by those skilled in the art according to the present application are also included in the scope of the present application.

[0061] The new synthesis method of fezolinetant and the advantages of the method will be further described below in combination with the examples of the present application.

[0062] Example 1

[0063]

[0064] (1) 2-chloro-3-methylpyrazine (200.0 g, 1.6 mol) was dissolved in 20 mL of ethanol, and hydrazine hydrate solution (500 g, 8 mol) was added. The temperature was raised to 90°C, and stirred for 16 h. After the reaction was completed, it was concentrated to dryness under reduced pressure, and filtered by slurry with a small amount of dichloromethane. After vacuum drying, 180.2 g of yellow solid was obtained, which was directly used in the next step reaction, and the yield was 94.3%. 1H NMR: (400 MHz, CD3OD) δ 7.99-7.96 (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 above yellow solid (180.2 g, 1.45 mol) and trimethyl orthoformate (667.0 g, 6.3 mol) were added to a reaction kettle, warmed to 100 °C, stirred for 3.5 h, the reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, and methanol was distilled to dryness to obtain 186.6 g of an oily liquid, with a yield of 95.8%. It was directly used for the next step. 1 H NMR: (400 MHz, CD3OD) δ 7.99-7.96 (d, 1H), 7.68-7.67 (d, 1H), 4.90 (s, 3H), 2.36 (s, 3H), ms (ESI): 125 [M+H] + .

[0068] Example 3

[0069]

[0070] The above 186.6 g of oily liquid and 10 V of ethanol were added to a reaction kettle, stirring was started, palladium on carbon (18.6 g, 10%) was added, and the reaction was carried out at 50 °C, with the hydrogen pressure maintained at 0.5-1 Mpa. Filtration under reduced pressure, and the filtrate was concentrated to a small volume under reduced pressure, and then filtered with toluene to dryness to obtain 190.4 g of a viscous liquid, with a yield of 98.9%. SFC chiral preparation obtained 124.3 g of a colorless viscous liquid, with a chiral purity of 99.5% and a yield of 65.3%. SFC conditions: chiral column: Chiralpak AS (250 mm x 30 mm, 5 um); mobile phase: supercritical CO2 / ethanol (0.05% DEA) = 70 / 30; flow rate: 60 mL / min; detection wavelength: 220 nm. 1 H NMR (CDCI3): δ 4.66 (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) δ 8.42 (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] The above 124.3 g of colorless viscous liquid, dichloromethane 5V, water 5V were added to the reaction kettle, and stirring was started. Sodium bicarbonate (151.2 g, 2 eq.) was added, and p-fluorobenzoyl chloride (142.7 g, 1 eq.) was added dropwise, and the reaction was incubated at 25°C. The liquid was separated, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed to obtain 213.0 g of white solid. The yield was 91.0%. 1 H NMR: (400MHz, CDCl3) δ 8.10 (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] The above 213.0 g of white solid, chloroform 3.2 L, sodium bicarbonate (137.5 g, 2 eq.) were added to the reaction kettle, and stirring was started. NBS (145.6 g, 1 eq.) was added in portions, and the reaction was incubated at 60°C. The temperature was lowered to room temperature, and 10V water was added. The liquid was stirred and allowed to stand, and the liquid was separated, the organic phase was washed twice with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed to obtain 259.2 g of white solid, and the yield was 93.4%. 1 H NMR: (400MHz, CDCl3) δ 7.49-7.46 (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] Into a reaction kettle were placed the above 259.2 g of white solid, 2.5 L of 1,4-dioxane, Pd(dppf)Cl2(27.9 g, 5% mol), potassium acetate (112.5 g, 1.5 eq.), and 3-methyl-5-boronic acid ester-1,2,4-thiadiazole (176.2 g, 1.02 eq.), and stirring was started under nitrogen protection. The reaction was carried out at 90°C. After cooling, filtration was performed under reduced pressure, and the filtrate was concentrated under reduced pressure. Column chromatography was performed to obtain 244.3 g of white solid with a purity of 98.9% and a chiral purity of 99.5%. The yield was 89.2%. 1 H NMR: (400 MHz, CDCl3) δ 7.50-7.47 (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] Into a reaction kettle were placed the oil obtained in Example 2 (10 g, 0.075 mol) and 10 V of ethanol, and stirring was started. Palladium-carbon (1.0 g, 10%) was added, and the reaction was carried out at 50°C under hydrogen pressure of 0.5-1 mpa. Filtration was performed under reduced pressure, and the filtrate was concentrated under reduced pressure to a small volume. Toluene was added to the filtrate, and evaporation was performed to obtain 9.9 g of viscous liquid. The yield was 96.7%. 1 H NMR: (400 MHz, CD3OD) δ 8.42 (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] Into a reaction flask was added the above 9.9 g (0.071 mol, 1.0 eq.) colorless viscous liquid, dichloromethane 5 V, water 5 V, and stirring was started. Sodium bicarbonate (12.0 g, 0.14 mol, 2.0 eq.) was added, and p-fluorobenzoyl chloride (11.4 g, 1 eq.) was added dropwise, and the reaction was allowed to proceed at 25 °C. The mixture was separated, and the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give 16.5 g of a white solid. Yield 88.6%. 1 H NMR: (400 MHz, CDC13) δ 8.10 (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] Into a reaction flask was added the above 9.9 g (0.071 mol, 1.0 eq.) colorless viscous liquid, dichloromethane 5 V, water 5 V, and stirring was started. Sodium bicarbonate (12.0 g, 0.14 mol, 2.0 eq.) was added, and p-fluorobenzoyl chloride (11.4 g, 1 eq.) was added dropwise, and the reaction was allowed to proceed at 25 °C. The mixture was separated, and the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give 16.5 g of a white solid. Yield 88.6%. 1 H NMR: (400 MHz, CDC13) δ 8.10 (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 only is the preferred embodiment of the present application, and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing a compound of Formula A, fezolinetant, comprising the steps of: comprising the steps of:

1. reacting compound 6 with a halogenating reagent in the presence of a base to obtain compound 7; 2. reacting compound 7 with compound 8 via Suzuki coupling reaction to obtain a compound of Formula A; wherein X is halogen.

2. The production method according to claim 1, characterized by, halogen is selected from Cl, Br, I.

3. The preparation method according to claim 1, characterized in that, In step 1, at least one of the following conditions is satisfied: 1) the halogenating reagent is selected from NCS, NBS, bromine, benzyltrimethylammonium tribromide, NIS, iodoiodide, dibromo hydantoin; 2) the base is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, or potassium hydroxide; 3) the solvent for the reaction is selected from one or any combination of amides, halogenated hydrocarbons, nitriles, alcohols, ethers; 4) the reaction temperature is 25-60 °C.

4. The production method according to claim 3, characterized by, In step 1, at least one of the following conditions is satisfied: 1) the halogenating reagent is dibromo hydantoin; 2) the base is sodium bicarbonate; 3) the amide solvent is 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; 4) the reaction temperature is 60 °C.

5. The preparation method according to claim 4, characterized in that, The halogenated hydrocarbon solvent is selected from chloroform or dichloromethane.

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

7. The production method according to claim 6, characterized by, In step 2, at least one of the following conditions is satisfied: 1) the catalyst is Pd(dppf)Cl2; 2) the molar amount of the catalyst is 5% of the molar amount of compound 7; 3) the solvent in step 2 is dioxane; 4) the base in step 2 is potassium acetate; 5) the reaction temperature in step 2 is 90 °C.

8. The method of claim 1, wherein, The compound of Formula 6, an intermediate of fezolinetant, is obtained by the following preparation method: Method (1): comprising the steps of: compound 4 is obtained by chiral resolution or SFC chiral separation to obtain compound 5; compound 5 is condensed with p-fluorobenzoyl halide in the presence of a base to obtain compound 6; or Method (2): comprising the steps of: compound 4 is reacted with p-fluorobenzoyl halide in the presence of a base to obtain compound 5' by condensation reaction, and compound 5' is obtained by chiral resolution or asymmetric synthesis to obtain compound 6.

9. The preparation method according to claim 8, characterized in that, In method (1) and method (2), at least one of the following conditions is satisfied: 1) the p-fluorobenzoyl halide is selected from p-fluorobenzoyl chloride, p-fluorobenzoyl bromide, p-fluorobenzoyl iodide; 2) the reaction solvent of the condensation reaction is selected from any one or a mixture of more than one of halogenated hydrocarbon, alcohol, amide, ether solvent or water; 3) the base is selected from sodium carbonate, sodium bicarbonate, N-methyl morpholine, triethylamine or DIPEA or any combination thereof; 4) the reaction temperature of the condensation reaction is 20-40℃.

10. The method of claim 9, wherein, In the method (1) and the method (2), at least one of the following conditions is met: 1) the p-fluorobenzoyl halide is p-fluorobenzoyl chloride; 2) the halogenated hydrocarbon solvent is selected from dichloromethane, carbon tetrachloride, dichloroethane, the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, the amide solvent is selected from dimethylformamide, and the ether solvent is selected from tetrahydrofuran, dioxane; 3) the base is sodium bicarbonate; 4) the reaction temperature of the condensation reaction is 25℃.

11. The preparation method according to claim 9, characterized in that, The solvent of the condensation reaction is a mixed solvent of water and dichloromethane.

12. The preparation method according to claim 8, characterized in that, The compound of formula 4 is prepared by the following method: comprising the following steps: I, compound 1 reacts with hydrazine hydrate to generate compound 2; II, compound 2 reacts with ortho ester to generate compound 3 through cyclization reaction; III, compound 3 is reduced by hydrogenation under the action of a catalyst to generate compound 4; In the step I, X is a leaving group, and the leaving group is halogen; The ortho ester in the step II is selected from trimethyl orthoformate and triethyl orthoformate.

13. The method of claim 12, wherein, In the step I, the leaving group is bromine, and the ortho ester in the step II is trimethyl orthoformate.

14. The method of claim 12, wherein, In the step I, at least one of the following conditions is met: 1) the reaction solvent in the step I is selected from one or any combination of aromatic hydrocarbon, halogenated hydrocarbon, alcohol, amide solvent; 2) the reaction temperature is 80-120℃; 3) the reaction time is 12-18h.

15. The preparation method according to claim 14, characterized in that, In the step I, at least one of the following conditions is met: 1) 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; 2) the reaction temperature is 90℃; 3) the reaction time is 16h.

16. The method of claim 15, wherein, The alcohol solvent used is ethanol.

17. The method of claim 12, wherein, In the step II, at least one of the following conditions is met: 1) the reaction temperature is 80-130℃; 2) the reaction time is 2-5h.

18. The method of claim 13, wherein, In the step II, at least one of the following conditions is met: 1) the reaction temperature is 100℃; 2) the reaction time is 3.5h.

19. The method of claim 12, wherein, In the step III, at least one of the following conditions is met: 1) the catalyst is selected from any one of palladium, palladium on carbon, palladium trifluoroacetate and palladium diacetate; 2) the mass amount of the catalyst g is 0.1%-12% of the mass amount of compound 2 g; 3) the reaction temperature is 35-60℃; 4) the reaction solvent is selected from one or any combination of alcohol, amide or ether solvent.

20. The method of claim 19, wherein, In the step III, at least one of the following conditions is met: 1) the catalyst is palladium on carbon; 2) the mass amount of the catalyst g is 5-10% of the mass amount of compound 2 g; 3) the reaction temperature is 50℃; 4) the alcoholic solvent is selected from methanol, ethanol, propanol, isopropanol or butanol, the amide solvent is selected from dimethylformamide, the ether solvent is selected from tetrahydrofuran or dioxane.

21. The method of claim 20, wherein, The alcoholic solvent used is ethanol.

22. An intermediate compound 5' and compound 6: 。

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