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, a 3-methylpyrazine compound is used as a raw material, a compound 3 is obtained through an amine alkylation reaction or a condensation reaction, the compound 3 reacts with orthoester to obtain a compound 4, the compound 4 is subjected to a hydrogenation reduction reaction to obtain a compound 5, and the compound 5 is subjected to chiral resolution or chiral separation to obtain a compound 6. And carrying out condensation reaction on the compound 6 and p-fluorobenzoyl halide to obtain the non-azonepan. The raw materials are simple and easy to obtain, low in cost and more suitable for large-scale industrial production; according to the present invention, the route reaction is simple, the preparation efficiency is high, the yield of each reaction step can achieve about 90%, the ee value of the final product can achieve more than 99.0%, the chiral purity is high, no harsh reaction condition exists, and the method is suitable for large-scale production, and has 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] Fezolinetant is an NK3 receptor antagonist developed by Astellas for menopausal VMS. It was approved for marketing by the FDA in May 2023 for the treatment of menopausal polycystic ovary syndrome (PCOS) and vasomotor symptoms (hot flashes) caused by uterine leiomyoma and other diseases. It is the world's first non-hormonal treatment for VMS. Compared with traditional HRT, fezolinetant works more quickly and can last for several weeks. There are a large number of patients suffering from VMS in the world, and the market potential for such drugs is huge. The approval of fezolinetant tablets fills a long-standing gap in the market and is a major breakthrough in the care of menopausal women. Therefore, an economical and efficient synthesis route for fezolinetant is needed. Fezolinetant, whose structural formula is shown in Formula A:

[0003]

[0004] The synthesis route of fezonetam in the prior art is reported as follows:

[0005]

[0006] 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.

[0007] CN117510506 A discloses a method for preparing fezonetam, and its synthesis route is shown in the following formula:

[0008]

[0009] Although this route is shorter, it requires the use of chiral raw materials with relatively complex structures. Currently, there is no reported synthesis route for this raw material and it is not commercially available, making it difficult to obtain and unable to meet commercial requirements.

[0010] 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

[0011] 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 environmental protection.

[0012] 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:

[0013] The following steps are involved:

[0014] 1) Compound 3, in Under the action of orthoester, the reaction yields compound 4;

[0015] 2) Compound 4 is subjected to hydrogenation reduction reaction to obtain compound 5;

[0016] 3) Compound 5 is subjected to chiral resolution or chiral separation to obtain compound 6;

[0017] 4) Compound 6 and p-fluorobenzoyl halide are reacted to obtain the compound of formula A, fezonetam, by condensation reaction;

[0018] R1 and R2 are the same or different and are independently selected from H, C1-C6 alkyl or C6-C 20 Aryl.

[0019] wherein the orthoester in step 1 is selected from the group consisting of trimethyl orthoformate, trimethyl orthoacetate, trimethyl orthopropionate, trimethyl orthoisopropionate, trimethyl orthobutyrate, trimethyl orthobenzoate, triethyl orthoformate, triethyl orthoacetate, triethyl orthopropionate, triethyl orthoisopropionate, triethyl orthobutyrate, triethyl orthobenzoate, tripropyl orthoformate, tripropyl orthoacetate, tripropyl orthopropionate, tripropyl orthoisopropionate, tripropyl orthobutyrate, tripropyl orthobenzoate, triisopropyl orthoformate, triisopropyl orthoacetate, triisopropyl orthopropionate, triisopropyl orthoisopropyl orthobenzoate, triisopropyl orthoacetate, triisopropyl orthopropionate, triisopropyl orthopropionate, triisopropyl orthobenzoate, triisopropyl orthoform ... orthobutyl orthoformate, triisopropyl orthobutyrate, triisopropyl orthobenzoate, tributyl orthoformate, tributyl orthoacetate, tributyl orthopropionate, tributyl orthoisopropionate, tributyl orthobutyrate, tributyl orthobenzoate, triisobutyl orthoformate, triisobutyl orthoacetate, triisobutyl orthopropionate, triisobutyl orthoisopropionate, triisobutyl orthobutyrate, triisobutyl orthobenzoate, tri-tert-butyl orthoformate, tri-tert-butyl orthoacetate, tri-tert-butyl orthopropionate, tri-tert-butyl orthoisopropionate, tri-tert-butyl orthobutyrate, or tri-tert-butyl orthobenzoate.

[0020] In some embodiments, the reaction temperature in step 1 is 80-130°C, preferably 80-100°C.

[0021] In some embodiments, the reaction time in step 1 is 2 to 5 hours, preferably 2.5 to 3.5 hours.

[0022] In some embodiments, step 2 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 acetate, preferably palladium carbon; the mass amount (g) of the catalyst is 0.1% to 12% of the mass amount (g) of compound 4, preferably 1 to 10%.

[0023] In some embodiments, the reaction temperature in step 2 is 35-60°C, preferably 50°C.

[0024] In some embodiments, the reaction time in step 2 is 2 to 5 hours, preferably 3.5 hours.

[0025] In some embodiments, the hydrogen pressure used in the hydrogenation reduction reaction in step 2 is 0.5 to 10 MPa, preferably 0.5 to 1 MPa, and more preferably 0.8 to 1 MPa.

[0026] In some embodiments, the solvent used in the hydrogenation reduction reaction in step 2 is selected from one or any combination of alcohol, amide, and ether solvents; the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol or butanol, the amide solvent is selected from N,N-dimethylformamide, and the ether solvent is selected from tetrahydrofuran or dioxane; the solvent is preferably ethanol.

[0027] In some embodiments, the chiral resolution or chiral separation of step 3 can be achieved by conventional methods in the art, such as resolution by a chiral resolution agent or SFC chiral chromatography, wherein the chiral resolution agent 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.

[0028] In some embodiments, the p-fluorobenzoyl halide in step 4 is selected from p-fluorobenzoyl chloride, p-fluorobenzoyl bromide, and p-fluorobenzoyl iodide, preferably p-fluorobenzoyl chloride.

[0029] In some embodiments, the condensation reaction in step 4 is carried out in a solvent, and the solvent 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 dichloroethane; the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol or butanol; the amide solvent is selected from N,N-dimethylformamide; the ether solvent is selected from tetrahydrofuran or dioxane; the solvent used is preferably a mixed solvent of water and dichloromethane.

[0030] In some embodiments, the condensation reaction in step 4 further comprises an acid binding agent, and the acid binding agent is selected from one or any combination of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, N-methylmorpholine, triethylamine or DIPEA, preferably sodium bicarbonate.

[0031] In some embodiments, the reaction temperature in step 4 is 10-40°C, preferably 25-30°C.

[0032] In another aspect, the present invention provides a method for preparing a nonazonaitant intermediate of a compound of formula 3, comprising the following method:

[0033] Method (1): Compound 1 is reacted with compound 2 to obtain compound 3 by amine alkylation reaction. The reaction formula is as follows:

[0034]

[0035] In some embodiments, X is selected from a leaving group, further selected from a halogen, preferably bromine;

[0036] "Leaving group" refers to the reactant attacked by the nucleophile in a nucleophilic substitution reaction, which is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Common leaving groups include, but are not limited to, halogens, -OTs, -OMs, or -OH.

[0037] In some embodiments, a base is added in the reaction of method (1), and the base can be selected from sodium carbonate, potassium carbonate, sodium bicarbonate or triethylamine or any combination thereof, preferably triethylamine;

[0038] In some embodiments, the reaction solvent in the method (1) is selected from one or any combination of aromatic hydrocarbons, halogenated hydrocarbons, alcohols, amides or ether solvents; the aromatic hydrocarbon solvent is selected from toluene or xylene, the halogenated hydrocarbon solvent is selected from dichloromethane, carbon tetrachloride or ethylene dichloride, 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 reaction solvent is preferably tetrahydrofuran;

[0039] In some embodiments, the reaction temperature in the method (1) is 50 to 70° C., preferably 60° C.;

[0040] In some embodiments, the reaction time of method (1) is selected from 1 to 18 hours, preferably 12 to 18 hours.

[0041] Method (2): Compound 1' and compound 2' undergo condensation reaction to obtain compound 3, and the reaction formula is as follows:

[0042]

[0043] In some embodiments, R is hydroxy, benzyloxy, or C1-C6 alkoxy;

[0044] In some embodiments, the reaction solvent in the 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 or dichloroethane, the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol or butanol, the amide solvent is selected from N,N-dimethylformamide, and the ether solvent is selected from tetrahydrofuran or dioxane; the solvent used is preferably dichloromethane.

[0045] In some embodiments, the condensation reaction of method (2) comprises adding an acid-binding agent, wherein the acid-binding agent is selected from one or any combination of sodium carbonate, sodium bicarbonate, N-methylmorpholine, triethylamine or DIPEA, preferably DIPEA.

[0046] In some embodiments, the condensation reaction of method (2) includes adding a condensation agent, and the condensation agent is selected from 1-hydroxybenzotriazole (HOBT), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), preferably TBTU.

[0047] Beneficial technical effects of the present invention:

[0048] 1) The route of the present invention uses 3-methylpyrazine compounds as raw materials, providing a new preparation process. Compared with the expensive and difficult-to-obtain chiral raw materials in the prior art, the raw materials are simple and easy to obtain, low in cost, and more suitable for large-scale industrial production.

[0049] 2) The route of the present invention has simple reaction, high preparation efficiency, each step of the reaction can achieve a yield of about 90%, no harsh reaction conditions, is suitable for large-scale production, and has good market value and far-reaching practical significance.

[0050] 3) The route of the present invention can obtain high chiral products, and the ee value of the final product is as high as 99.0% or more, for example, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or higher, and the chiral purity is high, which provides quality assurance for the subsequent preparation production and can make the patient's medication safer and more controllable.

[0051] 4) Compared with the prior art, the advantages of the present invention also lie in that the method of the present invention is safe to operate, avoids expensive raw materials and reagents, has low cost, simple post-processing, and less environmental pollution. DETAILED DESCRIPTION

[0052] 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.

[0053] 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.

[0054] Example 1

[0055]

[0056] (1) Dissolve 2-chloro-3-methylpyrazine (50.0 g, 0.4 mol) in 500 mL THF, add 3-methyl-1,2,4-thiadiazole-2(3H)-carbohydrazide (69.6 g, 0.44 mol), cool to 10 degrees, and dropwise add triethylamine (60.6 g, 1.5 eq.). Heat to 60°C and stir for 16 hours. After the reaction is complete, concentrate to dryness under reduced pressure to obtain the concentrate, compound 3, which can be used directly in the next step. MS (ESI): 251 [M+H] + .

[0057] Example 2

[0058]

[0059] Dissolve 2-hydrazine-3-methylpyrazine (10.0 g, 0.08 mol) in 200 mL DCM, add 3-methyl-[1,2,4]thiadiazole-5-carboxylic acid (11.8 g, 0.08 mol), TBTU (31.0 g, 0.1 mol). Cool to 5 °C, add DIPEA (20.7 g, 0.16 mol) dropwise, heat to 30 °C, and react for 6 h. After the reaction is complete, the reaction solution is washed with 0.1 N hydrochloric acid, water, saturated sodium bicarbonate, and water in sequence. The organic phase is dried over sodium sulfate and concentrated under reduced pressure to obtain 38.1 g of oily liquid compound 3, which can be used directly in the next step. MS (ESI): 251 [M+H]+ .

[0060] Example 3

[0061]

[0062] Trimethyl orthoformate (180.4 g, 1.7 mol) was added to the compound 3 obtained in Example 1, the temperature was raised to 100°C, and the reaction was stirred for 3.5 hours. The reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, and methanol was evaporated to dryness to obtain 82.7 g of oily liquid compound 4. The calculated yield was 89.0%. MS (ESI): 233 [M+H] + .

[0063] Example 4

[0064]

[0065] 82.7g of oily liquid compound 4 obtained in Example 4 and 10V of ethanol were added to a reactor, stirring was started, palladium carbon (8.2g, 10%) was added, and the reaction was kept at 50°C, and the hydrogen pressure was maintained at 0.8-1Mpa. The filtrate was filtered under reduced pressure on diatomaceous earth, and the filtrate was concentrated under reduced pressure. Rapid column chromatography obtained 75.5g of off-white solid with a yield of 89.7%. SFC chiral preparation obtained 52.1g of off-white solid compound 6, ee 99.2%. 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] + .

[0066] Example 5

[0067]

[0068] 52.1 g of off-white solid compound 6 obtained in Example 4, 5V of dichloromethane and 5V of water were added to a reaction kettle and stirred. Sodium bicarbonate (37.0 g, 2 eq.) was added dropwise, and p-fluorobenzoyl chloride (35.0 g, 1 eq.) was added and the mixture was kept at 25°C for reaction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from petroleum ether and ethyl acetate to obtain 74.7 g of white solid compound A. The yield was 94.5%, and the ee was 99.2%. 1H 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] + .

[0069] 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, characterized in that: The specific steps include: 1) Compound 3, in Under the action of orthoester, the reaction yields compound 4; 2) Compound 4 is subjected to a hydrogenation reduction reaction in the presence of a catalyst to obtain compound 5; 3) Compound 5 is subjected to chiral resolution or chiral separation to obtain compound 6; 4) Compound 6 reacts with p-fluorobenzoyl halide in the presence of an acid-binding agent to obtain the compound of formula A, fezonetam, through a condensation reaction; R1 and R2 are the same or different and are independently selected from H, C1-C6 alkyl or C6-C 20 Aryl; Wherein, the compound 3 is obtained by the following two methods: Method (1): Compound 1 and compound 2 are subjected to an amine alkylation reaction in the presence of a base to obtain compound 3, as shown in the following reaction formula: wherein X is selected from a leaving group, further selected from a halogen, preferably bromine; Method (2): Compound 1' and compound 2' undergo condensation reaction in the presence of an acid-binding agent and a condensing agent to obtain compound 3. The reaction formula is as follows: Wherein, R is hydroxyl, benzyloxy or C1-C6 alkoxy.

2. The preparation method according to claim 1, characterized in that: In the step 1, the orthoester is selected from trimethyl orthoformate, trimethyl orthoacetate, trimethyl orthopropionate, trimethyl orthoisopropionate, trimethyl orthobutyrate, trimethyl orthobenzoate, triethyl orthoformate, triethyl orthoacetate, triethyl orthopropionate, triethyl orthoisopropionate, triethyl orthobutyrate, triethyl orthobenzoate, tripropyl orthoformate, tripropyl orthoacetate, tripropyl orthopropionate, tripropyl orthoisopropionate, tripropyl orthobutyrate, tripropyl orthobenzoate, triisopropyl orthoformate, triisopropyl orthoacetate, triisopropyl orthopropionate, triisopropyl orthoisopropionate, triisopropyl orthobenzo ... One or more of triisopropyl butyrate, triisopropyl orthobenzoate, tributyl orthoformate, tributyl orthoacetate, tributyl orthopropionate, tributyl orthoisopropionate, tributyl orthobutyrate, tributyl orthobenzoate, triisobutyl orthoformate, triisobutyl orthoacetate, triisobutyl orthopropionate, triisobutyl orthoisopropionate, triisobutyl orthobutyrate, triisobutyl orthobenzoate, tri-tert-butyl orthoformate, tri-tert-butyl orthoacetate, tri-tert-butyl orthopropionate, tri-tert-butyl orthoisopropionate, tri-tert-butyl orthobutyrate, and tri-tert-butyl orthobenzoate, and further selected from trimethyl orthoformate.

3. The preparation method according to claim 1, characterized in that: In step 1, the reaction temperature is 80-130° C., preferably 80-100° C.; the reaction time is 2-5 h, preferably 2.5-3.5 h.

4. The preparation method according to claim 1, characterized in that: In the step 2, the catalyst is selected from any one of palladium, palladium carbon, palladium trifluoroacetate, and palladium acetate, preferably palladium carbon; the mass amount g of the catalyst is 0.1% to 12% of the mass amount g of compound 4, preferably 1 to 10%; the reaction temperature is 35 to 60°C, preferably 50°C; the reaction time is 2 to 5h, preferably 3.5h; the solvent used in the reaction is selected from one or any combination of alcohol, amide, and ether solvents; the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol or butanol, the amide solvent is selected from N,N-dimethylformamide, and the ether solvent is selected from tetrahydrofuran or dioxane; the solvent is preferably ethanol.

5. The preparation method according to claim 1, characterized in that: The condensation reaction in step 4 satisfies 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; the reaction solvent 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 dichloroethane; the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, or butanol; the amide solvent is selected from N,N-dimethylformamide; the ether solvent is selected from tetrahydrofuran or dioxane; the solvent used is preferably a mixed solvent of water and dichloromethane; and / or, the acid binding agent is selected from one or any combination of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, N-methylmorpholine, triethylamine or DIPEA, preferably sodium bicarbonate; And / or, the reaction temperature is 10 to 40°C, preferably 25 to 30°C.

6. The preparation method according to claim 1, characterized in that: The method (1) satisfies at least one of the following conditions: the base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or triethylamine or any combination thereof, preferably triethylamine; And / or, the reaction solvent is selected from one or any combination of aromatic hydrocarbons, halogenated hydrocarbons, alcohols, amides or ether solvents; the aromatic hydrocarbon solvent is selected from toluene or xylene, the halogenated hydrocarbon solvent is selected from dichloromethane, carbon tetrachloride or ethylene dichloride, 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 reaction solvent is preferably tetrahydrofuran; and / or, the reaction temperature is 50 to 70°C, preferably 60°C; And / or, the reaction time is selected from 1 to 18 hours, preferably 12 to 18 hours.

7. The preparation method according to claim 1, characterized in that: The method (2) satisfies at least one of the following conditions: the reaction solvent in the 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 or dichloroethane; the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol or butanol; the amide solvent is selected from N,N-dimethylformamide; the ether solvent is selected from tetrahydrofuran or dioxane; the solvent used is preferably dichloromethane; and / or, the acid binding agent is selected from sodium carbonate, sodium bicarbonate, N-methylmorpholine, triethylamine or DIPEA or any combination thereof, preferably DIPEA; And / or, the condensing agent is selected from HOBT, HBTU, TBTU, preferably TBTU.

8. A method for preparing the compound of formula A, fezonetam, characterized in that: The specific steps include: Trimethyl orthoformate was added to compound 3, the temperature was raised to 100°C, and the reaction was stirred for 3.5 hours. The reaction solution was cooled, concentrated under reduced pressure, and evaporated to obtain compound 4; compound 4 and ethanol were added to a reactor, stirred, palladium carbon was added, and the reaction was kept at 50°C, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. An off-white solid was obtained by column chromatography, and compound 6 was obtained by SFC chiral preparation; compound 6, dichloromethane, and water were added to a reactor, stirred, sodium bicarbonate and p-fluorobenzoyl chloride were added, and the reaction was carried out at 25°C. The liquids were separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from petroleum ether and ethyl acetate to obtain compound A fezonetant.

9. The preparation method according to claim 8, characterized in that: Wherein compound 3 is obtained by the following method: Dissolve 2-chloro-3-methylpyrazine in THF, add 3-methyl-1,2,4-thiadiazole-2(3H)-carbohydrazide, cool to 10°C, and add triethylamine dropwise; heat to 60°C, stir for 16 hours, and after the reaction is complete, concentrate to dryness under reduced pressure to obtain compound 3.

10. The preparation method according to claim 8, characterized in that: Wherein compound 3 is obtained by the following method: Dissolve 2-hydrazine-3-methylpyrazine in DCM, add 3-methyl-[1,2,4]thiadiazole-5-carboxylic acid, TBTU; cool to 5°C, add DIPEA dropwise, heat to 30°C, and react for 6 hours; after the reaction is complete, wash the reaction solution with hydrochloric acid, water, saturated sodium bicarbonate, and water, dry the organic phase with sodium sulfate, and concentrate under reduced pressure to obtain compound 3.

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