Preparation method for elinzanetant intermediate and elinzanetant

Abstract

The present invention provides an elinzanetant intermediate compound, a preparation method therefor, and a process for preparing elinzanetant using same. Specifically, provided are elinzanetant intermediate compounds of formula IV, formula V, and formula VI, and a process for preparing elinzanetant using same. The elinzanetant intermediates and the preparation method of the present invention have a high yield, the raw materials are simple and readily available, and the raw materials and reagents have significant economic advantages, thereby reducing costs. In addition, the reaction conditions are mild and safe, making the preparation method suitable for industrial scale-up production.

Description

Ilinatetan intermediates and preparation methods of ilenetan Technical Field

[0001] This invention belongs to the field of organic synthesis and the preparation technology of active pharmaceutical ingredients and intermediates, specifically relating to linnetan intermediate and the preparation method of linnetan. Background Technology

[0002] Elinzanetant is a non-hormonal, once-daily oral dual neurokinin-1,3 (NK1 x NK3) receptor antagonist. On August 1, 2024, Bayer submitted a New Drug Application (NDA) for elinzanetant to the U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe vasomotor symptoms (VMS, also known as hot flashes) associated with menopause. Vasomotor symptoms severely disrupt the lives and work of perimenopausal women, but traditional treatments such as deprivation hormone therapy have limitations. Elinzanetant addresses vasomotor symptoms by modulating a group of estrogen-sensitive neurons (KNDy neurons) in the hypothalamus of the brain. In menopausal women, KNDy neurons become overactive due to estrogen deficiency, thereby disrupting the thermoregulatory mechanisms that can reduce hot flashes caused by vasomotor symptoms.

[0003] The chemical name of elinnetan is 2-(3,5-bis(trifluoromethyl)phenyl)-N-(4-(4-fluoro-2-methylphenyl)-6-((7S,9aS)-7-(hydroxymethyl)hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1H)-yl)pyridin-3-yl)-nitro,2-dimethylpropionamide, and its structural formula is:

[0004] Patent WO2007028654A reports a synthetic route for elinnetan. The key intermediate 2-(3,5-bis(trifluoromethyl)phenyl)-nitro-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-nitro,2-dimethylpropionamide and (7S,9aS)-7-((tert-butyldimethylsilyl)oxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine under alkaline conditions via a palladium catalyst and Buchwald coupling reaction yields the oxazine-8(1-hydro)-yl)-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-nitro,2-dimethylpropionamide. The tert-butyldimethylsilyl protecting group is then removed under acidic conditions to obtain the elenetan compound. The specific synthetic route is as follows:

[0005] In the above-mentioned synthesis of linnetanetan, the Buchwald coupling reaction for the synthesis of aromatic amines requires palladium as a catalyst and can only be carried out in an anhydrous and oxygen-free environment. Therefore, this route has disadvantages such as harsh reaction conditions, expensive palladium metal catalyst, and low yields of the key intermediates 2-(3,5-bis(trifluoromethyl)phenyl)-nitro-(6-((7S,9aS)-7-((tert-butyldimethylsilyl)oxy)methyl)hexahydropyrazinyl[2,1-c][1,4]oxazin-8(1-hydro)-yl)-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-nitro- and linnetanetan.

[0006] Patent WO2021094247A discloses a method for preparing an intermediate of elinnetan. The method involves a Suzuki coupling reaction of 4-chloro-5-nitropyridin-2(1-hydro)-one and (4-fluoro-2-methylphenyl)boronic acid under alkaline conditions, catalyzed by a palladium catalyst, to yield 4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2(1-hydro)-one. The hydroxyl group is then chlorinated with phosphorus oxychloride to give 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridin. Further hydrogenation reduction of the nitro group under platinum-carbon catalysis yields 6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-amine. Amide condensation with an acyl chloride under alkaline conditions yields 2-(3,5-bis(trifluoromethyl)phenyl)-azo-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-methylpropionamide. Methylation with iodomethane under alkaline conditions yields 2-(3,5-bis(trifluoromethyl)phenyl)-azo-(6-chloro-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-azo,2-dimethylpropionamide. This, combined with (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine under alkaline conditions with a palladium catalyst, yields azo-(6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1-hydro)-yl)-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-(3,5-bis(trifluoromethyl)phenyl)-azo,2-dimethylpropionamide. Hydrogenation under acidic conditions with a palladium catalyst removes the benzyl protecting group, yielding elenetan. The specific synthetic route is as follows:

[0007] In the above-described synthesis of linnetane, the nitro reduction reaction requires platinum catalysis, and this reduction step alone takes 7 days. Furthermore, the methylation reaction requires the use of cesium carbonate and iodomethane, a genotoxic reagent. Therefore, this route suffers from disadvantages such as expensive metal catalysts and other reagents, the risk of toxicity from iodomethane, and long reaction times, making it unsuitable for the industrial production of linnetane. Summary of the Invention

[0008] To address the shortcomings of existing processes, the present invention aims to provide a simple, efficient, safe, mild, low-cost, and high-yield method for preparing linnetan and its intermediates.

[0009] A first aspect of the present invention provides an intermediate compound for the preparation of linnetan, characterized in that the compound has the structure shown in formulas IV, V, and VI:

[0010] A second aspect of the invention provides a method for preparing compound IV, the method comprising reacting a compound of formula III with (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine in the presence of a first basic reagent via a nucleophilic substitution reaction to obtain compound IV.

[0011] In another preferred embodiment, the molar ratio of the compound of formula III to (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazine[2,1-c][1,4]oxazine is selected from 1:1 to 1:2.

[0012] In another preferred embodiment, the first alkaline reagent is selected from one or more of diisopropylethylamine, triethylamine, trimethylamine, tri-n-butylamine, 4-dimethylaminopyridine (DMAP), pyridine, imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, N-methylmorpholine (NMM), tetramethylethylenediamine, tetramethylguanidine (TMG), potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, potassium bis(trimethylsilyl)amino (KHMDS), sodium bis(trimethylsilyl)amino (NaHMDS), lithium bis(trimethylsilyl)amino (LiHMDS), lithium diisopropylamino (LDA), cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0013] In another preferred embodiment, the molar ratio of the compound of formula III to the first basic reagent is selected from 1:1 to 1:10.

[0014] In another preferred embodiment, the solvent for the nucleophilic substitution reaction is selected from one or more of the following: n-butanol, methanol, ethanol, isopropanol, tert-butanol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, acetone, methyl isobutyl ketone, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), water, toluene, ethyl acetate, acetonitrile, dichloromethane, and isopropyl acetate.

[0015] In another preferred embodiment, the nucleophilic substitution reaction temperature is selected from 50°C to 130°C.

[0016] In another preferred embodiment, the nucleophilic substitution reaction temperature is selected from 80°C to 110°C.

[0017] In another preferred embodiment, the nucleophilic substitution reaction time is selected from 2h to 24h.

[0018] In another preferred embodiment, the nucleophilic substitution reaction time is selected from 4 h to 16 h.

[0019] A third aspect of the present invention provides a method for preparing a compound of formula III, the method comprising reacting a compound of formula I with a compound of formula II in the presence of a catalyst and a second basic reagent via a Suzuki coupling reaction to obtain a compound of formula III.

[0020] In this compound, the R group is selected from...

[0021] In another preferred embodiment, the catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, tetratriphenylphosphine palladium, palladium acetate, bistriphenylphosphine palladium dichloride, and tridibenzylacetone dipalladium.

[0022] In another preferred embodiment, the molar ratio of the compound of formula I to the compound of formula II is selected from 1:0.3 to 1:3.

[0023] In another preferred embodiment, the molar ratio of the compound of formula I to the catalyst is selected from 1:1 to 1:10.

[0024] In another preferred embodiment, the second alkaline reagent is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, lithium carbonate, potassium phosphate, potassium hydrogen phosphate, sodium bicarbonate, and potassium bicarbonate.

[0025] In another preferred embodiment, the molar ratio of the compound of formula I to the second basic reagent is selected from 1:1 to 1:10.

[0026] In another preferred embodiment, the molar ratio of the compound of formula I to the second basic reagent is selected from 1:1 to 1:8.

[0027] In another preferred embodiment, the solvent for the Suzuki coupling reaction is selected from one or more of 1,4-dioxane, ethylene glycol dimethyl ether, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), toluene, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide (DMSO), methanol, ethanol, isopropanol, acetonitrile, and water.

[0028] In another preferred embodiment, the Suzuki coupling reaction temperature is selected from 30°C to 120°C.

[0029] In another preferred embodiment, the Suzuki coupling reaction temperature is selected from 50°C to 90°C.

[0030] In another preferred embodiment, the Suzuki coupling reaction time is selected from 1 h to 24 h.

[0031] In another preferred embodiment, the Suzuki coupling reaction time is selected from 4h to 12h.

[0032] A fourth aspect of the present invention provides a method for preparing compound V, the method comprising obtaining compound V by a first reduction reaction in the presence of a first reducing agent and a first acidic reagent.

[0033] In another preferred embodiment, the reducing agent for the first reduction reaction is selected from one or more of the following: iron powder, zinc powder, palladium on carbon, barium hydroxide on carbon, platinum on carbon, platinum oxide, Raney nickel, sodium sulfide, sodium dithionite, hydrazine hydrate, stannous chloride, titanium trichloride, lithium aluminum hydride, borane, sodium borohydride, and ferric chloride.

[0034] In another preferred embodiment, the first acidic reagent is selected from ammonium chloride, hydrochloric acid, acetic acid, or trifluoroacetic acid.

[0035] In another preferred embodiment, the molar ratio of the compound of formula IV and the first reducing agent is selected from 1:0.1 to 1:10.

[0036] In another preferred embodiment, the solvent for the first reduction reaction is selected from one or more of ethanol, methanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, methyl isobutyl ketone, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 1,4-dioxane, water, ethyl acetate, and isopropyl acetate.

[0037] In another preferred embodiment, the temperature of the first reduction reaction is selected from 20°C to 130°C.

[0038] In another preferred embodiment, the temperature of the first reduction reaction is selected from 40 to 80°C.

[0039] In another preferred embodiment, the duration of the first reduction reaction is selected from 1 h to 24 h.

[0040] In another preferred embodiment, the duration of the first reduction reaction is selected from 2 hours to 8 hours.

[0041] In a fifth aspect, the present invention provides a method for preparing elenetan.

[0042] In a preferred embodiment, the method for preparing elenetan includes the steps of:

[0043] (a1) Compound V of formula V undergoes a condensation reaction with an aldehyde reagent to generate an imine, and the imine undergoes a second reduction reaction in the presence of a second reducing agent to give compound VIII of formula VIII.

[0044] (a2) The compound of formula VIII undergoes a first condensation reaction with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid in the presence of a third basic reagent to give the compound of formula VII;

[0045] (a3) The compound of formula VII is debenzylated by catalytic hydrogenation in the presence of a second acidic reagent to give the compound of formula IX.

[0046] In another preferred embodiment, the aldehyde reagent is selected from one or more of paraformaldehyde, trioxymethylene, and formaldehyde.

[0047] In another preferred embodiment, the second reducing agent is selected from one or more of paraformaldehyde, trioxyformaldehyde, formaldehyde, sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride, sodium dihydrobis(dimethoxyethoxy)aluminate, sodium borohydride-Lewis acid (NaBH4-Lewis acid) system, and lithium tritert-butoxyaluminum hydride.

[0048] In another preferred embodiment, the solvent for the second reduction reaction is selected from one or more of ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, acetone, sodium methoxide, methyl isobutyl ketone, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 1,4-dioxane, water, ethyl acetate, and isopropyl acetate.

[0049] In another preferred embodiment, the third basic reagent is selected from one or more of triethylamine, pyridine, diisopropylethylamine, tri-n-butylamine, 4-dimethylaminopyridine (DMAP), imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, N-methylmorpholine (NMM), tetramethylethylenediamine, tetramethylguanidine (TMG), sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate.

[0050] In another preferred embodiment, the condensing agent for the first condensation reaction is selected from oxalyl chloride, thionyl chloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI); 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridine-3-oxide hexafluorophosphate (HATU); 1-hydroxybenzotriazole (HOBt); 1-hydroxy-7-azobenzotriazole (HOAt); N,N-carbodiimidazole (CDI); 1,3-dicyclohexylcarbodiimide (DCC). The following are some of the following: N,N'-dicyclohexylcarboimide (DIC); 1-propyl cyclophosphine (T3P); 1-butyl phosphine (T4P); O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU); Carter's condensing agent (BOP); 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate (pyBOP); diphenylphosphine chloride (DPPCl); bis(2-oxo-3-oxazolyl)phosphine chloride (BOP-Cl) and diphenyl azidophosphate (DPPA).

[0051] In another preferred embodiment, the molar ratio of the compound of formula VIII to 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid is selected from 1:1 to 1:3.

[0052] In another preferred embodiment, the temperature of the second reduction reaction is selected from -20°C to 80°C.

[0053] In another preferred embodiment, the temperature of the second reduction reaction is selected from 0 to 40°C.

[0054] In another preferred embodiment, the duration of the second reduction reaction is selected from 1 h to 24 h.

[0055] In another preferred embodiment, the duration of the second reduction reaction is selected from 2 h to 8 h.

[0056] In another preferred embodiment, the solvent for the first condensation reaction is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, and acetonitrile.

[0057] In another preferred embodiment, the temperature of the first condensation reaction is selected from 20°C to 130°C.

[0058] In another preferred embodiment, the temperature of the first condensation reaction is selected from 30°C to 50°C.

[0059] In another preferred embodiment, the first condensation reaction time is selected from 1 h to 24 h.

[0060] In another preferred embodiment, the first condensation reaction time is selected from 2h to 16h.

[0061] In another preferred embodiment, the second acidic reagent is selected from hydrochloric acid, acetic acid, or trifluoroacetic acid.

[0062] In another preferred embodiment, the method for preparing elenetan includes the steps of:

[0063] (b1) Compound V of formula V reacts with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid in the presence of a fourth basic reagent via a second condensation reaction to give compound VI of formula V;

[0064] (b2) The amide group of the compound of formula VI is methylated in the presence of a fifth basic reagent and a methylating agent to obtain the compound of formula VII;

[0065] (b3) In an organic solvent, compound VII is debenzylated by catalytic hydrogenation in the presence of a third acidic reagent to give compound IX.

[0066] In another preferred embodiment, the molar ratio of the compound of formula V to 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid is selected from 1:1 to 1:2.

[0067] In another preferred embodiment, the fourth basic reagent is selected from one or more of triethylamine, pyridine, diisopropylethylamine, tri-n-butylamine, 4-dimethylaminopyridine (DMAP), imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, N-methylmorpholine (NMM), tetramethylethylenediamine, tetramethylguanidine (TMG), sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate.

[0068] In another preferred embodiment, the solvent for the second condensation reaction is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, dichloroethane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), tetrahydrofuran, methyltetrahydrofuran, and acetonitrile.

[0069] In another preferred embodiment, the condensing agent for the second condensation reaction is selected from oxalyl chloride, thionyl chloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI); 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridine-3-oxide hexafluorophosphate (HATU); 1-hydroxybenzotriazole (HOBt); 1-hydroxy-7-azobenzotriazole (HOAt); N,N-carbodiimidazole (CDI); 1,3-dicyclohexylcarbodiimide (DCC). The following are some of the following: N,N'-dicyclohexylcarboimide (DIC); 1-propyl cyclophosphine (T3P); 1-butyl phosphine (T4P); O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU); Carter's condensing agent (BOP); 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate (pyBOP); diphenylphosphine chloride (DPPCl); bis(2-oxo-3-oxazolyl)phosphine chloride (BOP-Cl) and diphenyl azidophosphate (DPPA).

[0070] In another preferred embodiment, the temperature of the second condensation reaction is selected from 20°C to 130°C.

[0071] In another preferred embodiment, the temperature of the second condensation reaction is selected from 30°C to 50°C.

[0072] In another preferred embodiment, the time for the second condensation reaction is selected from 1 h to 24 h.

[0073] In another preferred embodiment, the time for the second condensation reaction is selected from 2h to 16h.

[0074] In another preferred embodiment, the fifth basic reagent is selected from one or more of cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, diisopropylethylamine, triethylamine, trimethylamine, tri-n-butylamine, 4-dimethylaminopyridine (DMAP), pyridine, imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylenediamine (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, N-methylmorpholine (NMM), tetramethylethylenediamine, tetramethylguanidine (TMG), potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, potassium bis(trimethylsilyl)amino (KHMDS), sodium bis(trimethylsilyl)amino (NaHMDS), lithium bis(trimethylsilyl)amino (LiHMDS), and lithium diisopropylamino (LDA).

[0075] In another preferred embodiment, the molar ratio of the compound of formula VI to the fifth basic reagent is selected from 1:1 to 1:3.

[0076] In another preferred embodiment, the methylating agent is selected from one of iodomethane, bromomethane, chloromethane, dimethyl sulfate, dimethyl carbonate, methyl methanesulfonate, trimethyl phosphate, tetramethylammonium fluoride, trimethyl orthoformate, triethyl orthoformate, methanol, formaldehyde, paraformaldehyde, and trioxymethane.

[0077] In another preferred embodiment, the molar ratio of the compound of formula VI to the methylating agent is selected from 1:1 to 1:5.

[0078] In another preferred embodiment, the solvent for the methylation reaction is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, dichloroethane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), tetrahydrofuran, methyltetrahydrofuran, and acetonitrile.

[0079] In another preferred embodiment, the third acidic reagent is selected from hydrochloric acid, acetic acid, or trifluoroacetic acid.

[0080] In another preferred embodiment, the temperature of the methylation reaction is selected from 20°C to 120°C.

[0081] In another preferred embodiment, the temperature of the methylation reaction is selected from 20°C to 70°C.

[0082] In another preferred embodiment, the methylation reaction time is selected from 1 h to 24 h.

[0083] In another preferred embodiment, the methylation reaction time is selected from 2h to 8h.

[0084] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0085] This invention, through extensive and in-depth research and numerous screenings, has for the first time developed intermediate compounds of formulas IV, V, and VI, along with their processes for preparing linnetane. The preparation process of linnetane and its intermediates in this invention features high yield, safety, significant economic benefits, and ease of industrial production.

[0086] the term

[0087] Unless otherwise specified herein, all terms and abbreviations shall have their conventional meanings as are known to those skilled in the art.

[0088] The term “room temperature” or “normal temperature” refers to a temperature of 4-40°C, preferably 25±5°C.

[0089] As used in this article, the term “about” when referring to measurable values, such as mass, time, temperature, etc., means that there is a certain range of fluctuation around a specific value, which can be ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0090] The abbreviations used in this invention are explained as follows:

[0091] EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0092] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridine-3-oxide hexafluorophosphate

[0093] HOBt: 1-Hydroxybenzotriazole

[0094] HOAt: 1-Hydroxy-7-azobenzotriazole

[0095] CDI: N,N-Carbodiimidazole

[0096] DCC: 1,3-Dicyclohexylcarbodiimide

[0097] DIC: N,N'-Dicyclohexylcarboimide

[0098] T3P: 1-Propylphosphocyclic anhydride

[0099] T4P: 1-Butylphosphine

[0100] HBTU: O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate

[0101] BOP: Carter's condensing agent

[0102] pyBOP: 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate

[0103] DPPCl: Diphenylphosphine chloride

[0104] BOP-Cl: Bis(2-oxo-3-oxazolyl)phosphine chloride

[0105] DPPA: Diphenyl azidophosphate

[0106] Boc2O: Di-tert-butyl carbonate anhydride

[0107] CbzCl: Benzyloxycarbonyl chloride

[0108] DMAP: 4-Dimethylaminopyridine

[0109] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0110] DABCO: Triethylenediamine

[0111] DBN: 1,5-diazabicyclo[4.3.0]non-5-ene

[0112] NMM: N-methylmorpholine

[0113] TMG: Tetramethylguanidine

[0114] KHMDS: Bis(trimethylsilyl)aminopotassium

[0115] NaHMDS: Sodium bis(trimethylsilyl)amino

[0116] LiHMDS: Lithium bis(trimethylsilyl)amino

[0117] LDA: Lithium diisopropylamino

[0118] DMA: N,N-dimethylacetamide

[0119] DMF: N,N-dimethylformamide

[0120] DMSO: Dimethyl sulfoxide

[0121] Compared with the prior art, the main advantages of the present invention include:

[0122] The elinnetan intermediate and its preparation method of the present invention have high yields, simple and readily available raw materials, and significant economic advantages in terms of raw materials and reagents, which can reduce costs. The reaction conditions are mild and safe, making them suitable for industrial-scale production.

[0123] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0124] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0125] Example 1 Preparation of 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (Compound III)

[0126] 2,4-Dichloro-5-nitropyridine (12.5 g, 65.0 mmol) and 4-fluoro-2-methylphenylboronic acid (10.0 g, 65.0 mmol) were purged with nitrogen, followed by the addition of 1,4-dioxane (100 mL), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (2.63 g, 3.25 mmol), and then potassium carbonate (26.9 g, 19.5 mmol). The mixture was stirred and heated to 80 °C under nitrogen protection. The mixture was cooled to room temperature over 18 hours, and ethyl acetate (200 mL) was added. The mixture was filtered, and the filtrate was concentrated. Recrystallization from ethanol and water yielded 15.6 g of solid, compound III, with a molar yield of 90.1%. 1 H-NMR (δ, ppm, Chloroform-d): 9.05 (s, 1H), 7.33 (s, 1H), 7.14-6.92 (m, 3H), 2.13 (s, 3H).

[0127] Example 2 Preparation of 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (compound III)

[0128] 2,4-Dichloro-5-nitropyridine (10.7 g, 65.0 mmol) and pinacol ester of 4-fluoro-2-methylphenylboronic acid (15.3 g, 65.0 mmol) were added under nitrogen atmosphere, followed by the addition of 1,4-dioxane (100 mL), Pd(dppf)Cl2*CH2Cl2 (2.63 g, 3.25 mmol), and then potassium carbonate (26.9 g, 19.5 mmol). The mixture was stirred and heated to 80 °C under nitrogen protection. The mixture was cooled to room temperature over 18 hours, and ethyl acetate (200 mL) was added. The mixture was filtered, and the filtrate was concentrated. Recrystallization from ethanol and water yielded 16.0 g of solid, compound III, with a molar yield of 92.2%. 1 H-NMR (δ, ppm, Chloroform-d): 9.05 (s, 1H), 7.33 (s, 1H), 7.14-6.92 (m, 3H), 2.13 (s, 3H).

[0129] The yield of compound III prepared according to the method disclosed in prior art WO2021094247 is 78%. The yield of compound III prepared by the method of this invention is approximately 18% higher than that of compound III prepared by prior art WO2021094247A. Furthermore, the raw material 2,4-dichloro-5-nitropyridine of this invention is more readily available and has a significant price advantage compared to 4-chloro-5-nitropyridine-2(1-hydro)-one in prior art WO2021094247A. Moreover, this invention eliminates the need for chlorination reagents (such as phosphorus oxychloride), thus avoiding the adverse effects of chlorination reagents on production equipment and safety in large-scale industrial production.

[0130] Example 3 Preparation of (7S,9aS)-7-((benzyloxy)methyl)-8-(4-(4-fluoro-2-methylphenyl)-5-nitropyridin-2-yl)octahydropyrazino[2,1-c][1,4]oxazine (compound IV)

[0131] (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine dioxazine dioxazine (10.8 g, 24.4 mmol) was added to ethyl acetate (100 mL) and sodium hydroxide solution (10 mL, 2 mol / L), and stirred at 35 °C for 30 min. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed with water (30 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to give crude (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine. (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine was dissolved in n-butanol (80 mL), compound III (5.00 g, 18.6 mmol) and diisopropylethylamine (9.30 mL, 56.3 mmol) were added, nitrogen was purged, and the mixture was heated to 100 °C with stirring. After 16 hours, the mixture was cooled to room temperature, and the solvent was removed by evaporation under reduced pressure. Silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) gave 8.50 g of solid, compound IV, with a molar yield of 92%. ESI-MS m / z: 493.4 [M+H] + . 1H-NMR(δ,ppm,Chloroform-d):δ9.02(s,1H),7.32-7.26(m,2H),7.26-7.22(m,1H) ),7.22-7.10(m,2H),7.04-6.67(m,3H),6.34(s,1H),5.00-4.56(m,1H),4.50(br s,2H),4.59-4.38(m,2H),3.92–3.62(m,6H),3.34–3.23(m,1H),2.96(d,J=11.7Hz,1H) ,2.79-2.54(m,2H),2.42(dd,J=11.7,4.0Hz,1H),2.36-2.21(m,2H),2.14-1.80(m,3H).

[0132] The existing technology WO2007028654A, which synthesizes aromatic amines via the Buchwald coupling reaction, requires harsh conditions such as palladium catalysis and anhydrous and oxygen-free environments. In contrast, the synthesis of aromatic amines in this invention does not require expensive metal catalysts or anhydrous and oxygen-free conditions; moreover, reagents such as n-butanol and diisopropylethylamine are readily available and have a significant cost advantage.

[0133] Example 4 Preparation of 6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1-hydro)-yl)-4-(4-fluoro-2-methylphenyl)pyridine-3-amine (compound V)

[0134] Compound IV (3.00 g, 6.09 mmol) was dissolved in anhydrous ethanol (50 mL), and reduced iron powder (6.80 g, 120 mmol) was added. The mixture was stirred and heated to 80 °C, and then saturated ammonium chloride aqueous solution (6.80 mL) was added. After 1 hour, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to give 2.50 g of solid, namely compound V, with a molar yield of 89%. ESI-MS m / z: 463.4 [M+H] + . 1H-NMR(δ,ppm,Chloroform-d):δ7.81(s,1H),7.33-7.27(m,1H),7.26-7.17(m,4H),7.15-6 .89(m,3H),6.36(d,J=7.7Hz,1H),4.59-4.44(m,2H),4.27(d,J=21.0Hz,1H),3.92(t,J=8. 7Hz,1H),3.88-3.62(m,4H),3.60-3.49(m,1H),3.29(t,J=10.5Hz,1H),3.03(d,J=13.2Hz, 1H),2.69-2.52(m,2H),2.43(dd,J=11.8,3.5Hz,1H),2.39-2.25(m,2H),2.10,2.16(m,3H).

[0135] Example 5 Preparation of 6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1-hydro)-yl)-4-(4-fluoro-2-methylphenyl)-aza-methylpyridin-3-amine (compound VIII)

[0136] Compound V (2.00 g, 4.32 mmol) and methanol (25 mL) were added to a flask and stirred until clear. The mixture was then cooled to 0 °C. Under nitrogen protection, sodium methoxide (467 mg, 8.64 mmol) was added to the reaction mixture and stirred for 15 minutes. Paraformaldehyde (130 mg, 4.32 mmol) was added and stirred until the solution was clear. Sodium borohydride (163 mg, 4.32 mmol) was added in portions, and the reaction was stirred for 1 hour. The reaction was quenched dropwise with 1 mol / L dilute hydrochloric acid solution until the pH reached 7. The mixture was extracted three times with ethyl acetate (30 mL), and the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 1.82 g of solid, compound VIII, with a molar yield of 88%. ESI-MS m / z: 477.38 [M+H] + , 1H NMR(400MHz,Chloroform-d)δ7.84-7.63(m,1H),7.32-7.20(m,5H),7.16-6.90(m,3H),6.56-6.35(m,1H),4.68-4.41(m,2H),4.39-4.20(m,1H),3.9 2-3.63(m,6H),3.41-3.23(m,1H),3.05-3.00(m,1H),2.89-2.72(m,3H),2 .71-2.56(m,2H),2.52-2.41(m,1H),2.41-2.27(m,2H),2.11-2.02(m,3H).

[0137] Example 6 Preparation of N-(6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1-hydro)-yl)-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropionamide dihydrochloride (compound VII)

[0138] Add 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid (1.51 g, 5.04 mmol) and dichloromethane (30 mL) to a flask, purge with nitrogen, add oxaloyl chloride (692 mg, 5.46 mmol), and add N,N-dimethylformamide (31 mg, 0.42 mmol) dropwise. Stir at 30 °C for 3 hours. Concentrate under reduced pressure, dissolve the residue in dichloromethane (10 mL) to obtain a dichloromethane solution of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid. Dissolve compound VIII (2.00 g, 4.20 mmol) in dichloromethane (20 mL), add N,N-diisopropylethylamine (1.63 g, 12.6 mmol), and add the dichloromethane solution of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid dropwise under ice bath conditions. Stir and heat to 40 °C. Three hours later, 20 mL of saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (30 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then subjected to silica gel column chromatography (dichloromethane:methanol = 80:1). The solid obtained from the column chromatography was dissolved in 20 mL of dichloromethane, and 4 mol / L dioxane hydrochloride solution was added dropwise under ice bath. The solvent was removed under reduced pressure to obtain 3.07 g of solid, compound VII, with a molar yield of 93%. 477.38 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.35(bd,1H),8.03(s,1H),7.94(s,1H),7.75(bd,2H), 7.27-6.91(m,8H),6.81(s,1H),4.97(bd,1H),4.61(m,1H),4.50(d,J=11.9Hz,1 H),4.48-3.94(m,7H),3.94-3.87(m,3H),3.61(d,J=12.7Hz,1H),3.46(d,J=12. 4Hz,1H),3.31(m,1H),3.20(m,1H),3.05(m,1H),2.12(m,4H),1.41-1.32(m,6H).

[0139] According to the method disclosed in prior art WO2021094247, the yield of compound VII is 88%. In comparison, the yield of compound VII prepared by the method of the present invention is 5% higher than that of compound VII prepared by WO2021094247A.

[0140] Example 7 Preparation of N-(6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1-hydro)-yl)-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionamide (compound VI)

[0141] Add 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid (1.51 g, 5.04 mmol) and dichloromethane (30 mL) to a flask, replace with nitrogen, add oxaloyl chloride (692 mg, 5.46 mmol), add DMF (31 mg, 0.42 mmol) dropwise, stir at 30 °C for 3 hours; concentrate under reduced pressure, dissolve the residue in dichloromethane (10 mL) to obtain a dichloromethane solution of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid. 6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1-hydro)-yl)-4-(4-fluoro-2-methylphenyl)pyridine-3-amine (2.00 g, 4.32 mmol) was dissolved in dichloromethane (20 mL), and pyridine (1.71 g, 21.6 mmol) was added. The prepared solution of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionyl chloride in dichloromethane was added dropwise under ice bath conditions, with stirring and the temperature raised to 40 °C. After 3 hours, saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (30 mL). The organic phases were combined, washed with water, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then subjected to silica gel column chromatography (dichloromethane:methanol = 80:1). The solid obtained from the column chromatography was dissolved in dichloromethane (20 mL), and 4 mol / L dioxane hydrochloride solution was added dropwise under ice bath. The solvent was removed under reduced pressure to obtain 3.13 g of solid, namely compound VI, with a molar yield of 89%. 1 H NMR(400MHz,Chloroform-d)δ8.96(s,1H),7.75(s,1H),7.62(s,2H),7.26–7.15(m,5H),6. 84–6.61(m,3H),6.30(d,J=4.3Hz,1H),4.54–4.40(m,2H),4.40–4.25(m,1H),3.96(t,J=14 .5Hz,1H),3.91–3.81(m,2H),3.80–3.64(m,2H),3.62–3.52(m,1H),3.33–3.22(m,1H),3.0 1(d,J=11.4Hz,1H),2.67–2.57(m,2H),2.44–2.25(m,3H),1.78(m,3H),1.60–1.48(m,6H).

[0142] Example 8 Preparation of N-(6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1-hydro)-yl)-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropionamide dihydrochloride (compound VII)

[0143] Add acetonitrile (30 mL), N-(6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1-hydro)-yl)-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionamide (2.00 g, 2.69 mmol), and cesium carbonate (3.51 g, 10.8 mmol) to a flask, stir for 10 minutes, and cool to 0 °C. Under nitrogen protection, add iodomethane (213 mg, 4.04 mmol) dropwise to the reaction mixture, stir, and heat to 30 °C. Sixteen hours later, the reaction mixture was poured into water (80 mL), extracted twice with ethyl acetate (60 mL), and the organic phases were combined. The mixture was washed with water (20 mL), then with saturated brine (10 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (10 mL), and a 4 mol / L solution of dioxane hydrochloride (1 mL) was added dropwise at 0 °C. The solvent was removed under reduced pressure to give 1.93 g of solid, compound VII, with a molar yield of 88%. ESI-MS m / z: 477.38 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.84-7.63(m,1H),7.32-7.20(m,5H),7.16-6.90 (m,3H),6.56-6.35(m,1H),4.68-4.41(m,2H),4.39-4.20(m,1H),3.92-3 .63(m,5H),3.41-3.23(m,1H),3.05-3.00(m,1H),2.89-2.72(m,3H),2.7 1-2.56(m,2H),2.52-2.41(m,1H),2.41-2.27(m,2H),2.11-2.02(m,3H).

[0144] According to the method disclosed in prior art WO2021094247, the yield of compound VII is 67%. In comparison, the yield of compound VII prepared by the method of the present invention is 21% higher than that prepared by WO2021094247.

[0145] Example 9 Preparation of 2-(3,5-bis(trifluoromethyl)phenyl)-aza-(4-(4-fluoro-2-methylphenyl)-6-((7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1-hydro)-yl)pyridin-3-yl)-aza,2-dimethylpropionamide (compound IX)

[0146] Nitrogen-(6-((7S,9aS)-7-((benzyloxy)methyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1-hydro)-yl)-4-(4-fluoro-2-methylphenyl)pyridin-3-yl)-2-(3,5-bis(trifluoromethyl)phenyl)-nitro,2-dimethylpropionamide dihydrochloride (1.00 g, 1.20 mmol) was dissolved in isopropanol (20 mL), followed by the addition of deionized water (2 mL) and concentrated hydrochloric acid (0.44 mL) to displace nitrogen gas. Then, 5% palladium on carbon (400 mg) was added to displace hydrogen gas. The mixture was stirred and heated to 50 °C. After 16 hours, the reaction mixture was filtered under vacuum, and the filtrate was concentrated under reduced pressure. Add ethyl acetate (30 mL) and 1 mol / L sodium hydroxide (30 mL), stir for 5 minutes, separate the organic phase, extract the aqueous phase twice with ethyl acetate (30 mL), combine the organic phases, wash with water, wash with saturated brine, dry to anhydrous sodium sulfate, and remove the solvent by vacuum distillation. Perform silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give 676 mg of solid, i.e., elinnetan, with a molar yield of 84%. ESI-MS m / z: 669.6 [M+H] + , 1 H NMR(400MHz,Chloroform-d)δ7.96(s,1H),7.77(s,1H),7.65(s,2H),6.95(m,3H),6.42(s,1H),4.54(d,J=25.2Hz,1H),4.02(s,2H), 3.96-3.56(m,4H),3.44-3.25(m,1H),3.17-2.98(m,2H),2.88-2.71(m,1H),2.71-2.50(m,2H),2.49-2.07(m,7H),1.76-1.46(m,6H).

[0147] The total yield of elenetan (compound of formula IX) prepared according to the method disclosed in prior art WO2021094247 is 24%. In comparison, the yield of elenetan prepared by the process of the present invention is significantly improved to 49%.

[0148] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing a compound of formula IV, characterized in that, The preparation method comprises a nucleophilic substitution reaction between compound III and (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazine[2,1-c][1,4]oxazine in the presence of a first basic reagent to obtain compound IV.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the compound of formula III to (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazine[2,1-c][1,4]oxazine is selected from 1:1 to 1:2; And / or, the first alkaline reagent is selected from one or more of diisopropylethylamine, triethylamine, trimethylamine, tri-n-butylamine, 4-dimethylaminopyridine, pyridine, imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, N-methylmorpholine, tetramethylethylenediamine, tetramethylguanidine, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, potassium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, lithium bis(trimethylsilyl)amino, lithium diisopropylamino, cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide; And / or, the molar ratio of the compound of formula III to the first basic reagent is selected from 1:1 to 1:10; And / or, the solvent for the nucleophilic substitution reaction is selected from one or more of the following: n-butanol, methanol, ethanol, isopropanol, tert-butanol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, acetone, methyl isobutyl ketone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, water, toluene, ethyl acetate, acetonitrile, dichloromethane, and isopropyl acetate.

3. A method for preparing a compound of formula III, characterized in that, The preparation method includes a Suzuki coupling reaction between compound I and compound II in the presence of a catalyst and a second basic reagent to obtain compound III. In this compound, the R group is selected from... And / or, the catalyst is selected from the group consisting of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, tetratriphenylphosphine palladium, palladium acetate, bistriphenylphosphine palladium dichloride, and tridibenzylacetone dipalladium.

4. The preparation method according to claim 3, characterized in that, The molar ratio of the compound of formula I to the compound of formula II is selected from 1:0.3 to 1:3; And / or, the molar ratio of the compound of formula I to the catalyst is selected from 1:1 to 1:10; And / or, the second alkaline reagent is selected from one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, lithium carbonate, potassium phosphate, potassium hydrogen phosphate, sodium bicarbonate, and potassium bicarbonate; And / or, the solvent for the Suzuki coupling reaction is selected from one or more of 1,4-dioxane, ethylene glycol dimethyl ether, N,N-dimethylacetamide, N,N-dimethylformamide, toluene, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and water. And / or, the Suzuki coupling reaction temperature is selected from 30°C to 120°C.

5. A method for preparing a compound of formula V, characterized in that, The method includes obtaining compound V from compound IV by a first reduction reaction in the presence of a first reducing agent and a first acidic reagent; 6. The preparation method according to claim 5, characterized in that, The first reducing agent is selected from one or more of the following: iron powder, zinc powder, palladium on carbon, barium hydroxide on carbon, platinum on carbon, platinum oxide, Raney nickel, sodium sulfide, sodium dithionite, hydrazine hydrate, stannous chloride, titanium trichloride, lithium aluminum hydride, borane, sodium borohydride, and ferric chloride. And / or, the first acidic reagent is selected from ammonium chloride, hydrochloric acid, acetic acid, or trifluoroacetic acid; And / or, the molar ratio of the compound of formula IV to the first reducing agent is selected from 1:0.1 to 1:10; And / or, the solvent for the first reduction reaction is selected from one or more of ethanol, methanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, methyl isobutyl ketone, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, water, ethyl acetate, and isopropyl acetate; And / or, the temperature of the first reduction reaction is selected from 20℃ to 130℃.

7. A method for preparing a compound of formula IX, characterized in that, The method includes the following steps: (a1) Compound V of formula V undergoes a condensation reaction with an aldehyde reagent to generate an imine, and the imine undergoes a second reduction reaction in the presence of a second reducing agent to give compound VIII of formula VIII. (a2) The compound of formula VIII undergoes a first condensation reaction with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid in the presence of a third basic reagent to give the compound of formula VII; (a3) The compound of formula VII is debenzylated by catalytic hydrogenation in the presence of a second acidic reagent to obtain the compound of formula IX; 8. A method for preparing the compound of formula IX as described in claim 7, characterized in that, The aldehyde reagent is selected from paraformaldehyde, trioxyformaldehyde, or formaldehyde; the second reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride, sodium dihydrobis(dimethoxyethoxy)aluminate, sodium borohydride-Lewis acid system, and lithium tritert-butoxyaluminum hydride. And / or, the solvent for the second reduction reaction is selected from one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, acetone, sodium methoxide, methyl isobutyl ketone, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, water, ethyl acetate, and isopropyl acetate; And / or, the third basic reagent is selected from one or more of triethylamine, pyridine, diisopropylethylamine, tri-n-butylamine, 4-dimethylaminopyridine, imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, N-methylmorpholine, tetramethylethylenediamine, tetramethylguanidine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate; And / or, the condensing agent in the first condensation reaction is selected from oxalyl chloride, thionyl chloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridine-3-oxide hexafluorophosphate; 1-hydroxybenzotriazole; 1-hydroxy-7-azobenzotriazole; N,N-carbodiimidazole; 1,3-dicyclohexylcarbodiimide; N,N'-dicyclohexylcarbodiimide; 1-propyl phosphate cyclic anhydride; 1-butyl phosphate anhydride; O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate; Carter's condensing agent; 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate; diphenylphosphine chloride; bis(2-oxo-3-oxazolyl)phosphine chloride and diphenyl azidophosphate; And / or, the solvent for the first condensation reaction is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, and acetonitrile; And / or, the molar ratio of the compound of formula VIII to 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid is selected from 1:1 to 1:3; And / or, the second acidic reagent is selected from hydrochloric acid, acetic acid, or trifluoroacetic acid.

9. A method for preparing linnetane, characterized in that, The method includes the following steps: (b1) Compound V of formula V reacts with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid in the presence of a fourth basic reagent via a second condensation reaction to give compound VI of formula V; (b2) The amide group of the compound of formula VI is methylated in the presence of a fifth basic reagent and a methylating agent to obtain the compound of formula VII; (b3) In an organic solvent, compound VII is debenzylated by catalytic hydrogenation in the presence of a third acidic reagent to give compound IX. The molar ratio of compound V to 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid is selected from 1:1 to 1:2; And / or, the fourth basic reagent is selected from one or more of triethylamine, pyridine, diisopropylethylamine, tri-n-butylamine, 4-dimethylaminopyridine, imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, N-methylmorpholine, tetramethylethylenediamine, tetramethylguanidine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate; And / or, the solvent for the second condensation reaction is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, and acetonitrile; And / or, the condensing agent in the second condensation reaction is selected from oxalyl chloride, thionyl chloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridine-3-oxide hexafluorophosphate; 1-hydroxybenzotriazole; 1-hydroxy-7-azobenzotriazole; N,N-carbodiimidazole; 1,3-dicyclohexylcarbodiimide; N,N'-dicyclohexylcarbodiimide; 1-propyl cyclic anhydride; 1-butyl phosphate anhydride; O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate; Carter's condensing agent; 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate; diphenylphosphine chloride; bis(2-oxo-3-oxazolyl)phosphine chloride and diphenyl azidophosphate; And / or, the fifth basic reagent is selected from one or more of cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, diisopropylethylamine, triethylamine, trimethylamine, tri-n-butylamine, 4-dimethylaminopyridine, pyridine, imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, N-methylmorpholine, tetramethylethylenediamine, tetramethylguanidine, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, potassium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, lithium bis(trimethylsilyl)amino, and lithium diisopropylamino. And / or, the molar ratio of the compound of formula VI to the fifth basic reagent is selected from 1:1 to 1:3; And / or, the methylating agent is selected from one of iodomethane, bromomethane, chloromethane, dimethyl sulfate, dimethyl carbonate, methyl methanesulfonate, trimethyl phosphate, tetramethylammonium fluoride, trimethyl orthoformate, triethyl orthoformate, methanol, formaldehyde, paraformaldehyde, and trioxymethane. And / or, the molar ratio of the compound of formula VI to the methylating agent is selected from 1:1 to 1:5; And / or, the solvent for the methylation reaction is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, and acetonitrile; And / or, the third acidic reagent is selected from hydrochloric acid, acetic acid, or trifluoroacetic acid.

10. An intermediate compound for the preparation of linnetan, characterized in that, Selected from compounds of formula IV, formula V, and formula VI:

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