Method for preparing elinzanetant and intermediate thereof

Abstract

Provided in the present invention is a method for preparing elinzanetant and an intermediate compound thereof. Specifically, provided are an elinzanetant intermediate compound of formula X and an elinzanetant intermediate compound of formula VIII, which are used in the preparation process of elinzanetant. The elinzanetant intermediate and the preparation method of the present invention feature high yield, simple and readily available starting materials, reduced cost attributed to significant economic advantages in starting materials and reagents, as well as mild and safe reaction conditions, rendering them suitable for industrial scale-up production.

Description

Preparation method of linnetan and its intermediates 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 a method for preparing linnetane and its intermediates. 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 WO2007028654 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 synthesis route is as follows:

[0005] In the synthesis of elinnetan via the Buchwald coupling reaction, palladium is required as a catalyst, and the reaction can only proceed in an anhydrous and oxygen-free environment. Therefore, this route is characterized by harsh reaction conditions, expensive palladium catalysts, and low yields of both the key intermediate 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)-nitrogen and the elinnetan compound.

[0006] Patent WO2021094247 reports another synthetic route for elinnetan. 4-(4-fluoro-2-methylphenyl)-2(1-hydro)-one and (4-fluoro-2-methylphenyl)boronic acid are coupled via a Suzuki coupling reaction under alkaline conditions using 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. The nitro group is then reduced by hydrogenation under platinum-carbon catalysis to give 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] The above-described route for synthesizing elinnetan requires platinum catalysis for the nitro reduction reaction, which alone takes 7 days. Furthermore, the methylation reaction requires the participation of cesium carbonate and iodomethane, with iodomethane being genotoxic. Therefore, this route suffers from drawbacks such as expensive and toxic reagents, high cost of platinum catalysts, genotoxicity of iodomethane, and long reaction time, making it unsuitable for the industrial production of elinnetan. Summary of the Invention

[0008] To address the shortcomings of existing processes, the present invention aims to provide a safe, mild, simple, efficient, low-cost, and high-yield process for preparing elinnetan 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 X and VIII:

[0010] In this case, compound R of formula X is selected from hydrogen, oxyalkyl, or oxybenzyl.

[0011] A second aspect of the present invention provides a method for preparing elenetan, comprising the steps of:

[0012] (a1) Compound VIII of formula undergoes a condensation reaction with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid in the presence of a first basic reagent to give compound VII;

[0013] (a2) The compound of formula VII is debenzylated by catalytic hydrogenation in the presence of a first acidic reagent to give the compound of formula IX.

[0014] In another preferred embodiment, the molar ratio of the compound of formula VIII to 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid is 1:1 to 1:3.

[0015] In another preferred embodiment, the first alkaline 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.

[0016] In another preferred embodiment, the condensing agent used in the 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); and 1,3-dicyclohexylcarbodiimide (DCC). The following are one or more 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).

[0017] In another preferred embodiment, the solvent for the condensation reaction is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, water, oxaloyl chloride, and dichloromethane.

[0018] In another preferred embodiment, the first acidic reagent is selected from hydrochloric acid, acetic acid, or trifluoroacetic acid.

[0019] In another preferred embodiment, the temperature of the condensation reaction is selected from 20°C to 130°C.

[0020] In another preferred embodiment, the temperature of the condensation reaction is selected from 30°C to 50°C.

[0021] In another preferred embodiment, the condensation reaction time is selected from 1 h to 24 h.

[0022] In another preferred embodiment, the condensation reaction time is selected from 2h to 16h.

[0023] A third aspect of the present invention provides a method for preparing a compound of formula VIII, the method comprising a first reduction reaction of a compound of formula X in the presence of a first reducing agent to obtain a compound of formula VIII.

[0024] In compound X, 'R is selected from hydrogen, oxyalkyl, or oxybenzyl.

[0025] In another preferred embodiment, the first reducing agent is selected from one or more of the following: iron powder, zinc powder, sodium borohydride, potassium borohydride, lithium borohydride, borane, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum oxide, Raney nickel, NaBH4-Lewis acid system, lithium aluminum hydride, lithium tritert-butoxyaluminum hydride, sodium sulfide, sodium dithionite, hydrazine hydrate, stannous chloride, titanium trichloride, and ferric chloride.

[0026] In another preferred embodiment, the solvent for the first reduction reaction is selected from water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, xylene, ethyl acetate, methyl acetate, isopropyl acetate, acetone, cyclohexanone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, chlorobenzene, pyridine, or one or more.

[0027] In another preferred embodiment, the molar ratio of the compound of formula X to the first reducing agent is 1:1 to 1:5.

[0028] In another preferred embodiment, the temperature of the first reduction reaction is selected from 0°C to 80°C.

[0029] In another preferred embodiment, the temperature of the first reduction reaction is selected from 0°C to 40°C.

[0030] In another preferred embodiment, the duration of the first reduction reaction is selected from 1 h to 24 h.

[0031] In another preferred embodiment, the duration of the first reduction reaction is selected from 2 hours to 8 hours.

[0032] In a fourth aspect, the present invention provides a method for preparing a compound of formula X, the method comprising a formylation reaction of a compound of formula V in the presence of an acylation reagent to generate a compound of formula X;

[0033] In compound X, 'R is selected from hydrogen, oxyalkyl, or oxybenzyl.

[0034] In another preferred embodiment, 'R' is selected from hydrogen, C1-6 oxoalkyl, or oxobenzyl.

[0035] In another preferred embodiment, the acylation agent is selected from one or more of methyl acetic anhydride, trimethyl orthoformate, triethyl orthoformate, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, di-tert-butyl carbonate (Boc2O), benzyloxycarbonyl chloride (Cb2Cl), formic acid, and acetic anhydride.

[0036] In another preferred embodiment, the solvent for the acylation reaction is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, xylene, ethyl acetate, methyl acetate, isopropyl acetate, acetone, cyclohexanone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, chlorobenzene, and pyridine.

[0037] In another preferred embodiment, the molar ratio of the compound of formula V to the acylation reagent is 1:1 to 1:10.

[0038] In another preferred embodiment, the acylation reaction temperature is selected from 20°C to 120°C.

[0039] In another preferred embodiment, the acylation reaction temperature is selected from 20°C to 70°C.

[0040] In another preferred embodiment, the acylation reaction time is selected from 1 h to 24 h.

[0041] In another preferred embodiment, the acylation reaction time is selected from 2h to 8h.

[0042] In a fifth aspect, the present invention provides a method for preparing a compound of formula VIII, the method comprising: a condensation reaction of the compound of formula V and an aldehyde reagent to generate an imine, wherein the imine undergoes a second reduction reaction in the presence of a second reducing agent to obtain the compound of formula VIII.

[0043] In another preferred embodiment, the aldehyde reagent is selected from paraformaldehyde, trioxyformaldehyde, or formaldehyde.

[0044] In another preferred embodiment, the second reducing agent is selected from sodium borohydride, iron powder, zinc powder, sodium borohydride, potassium borohydride, lithium borohydride, borane, sodium cyanoborohydride, sodium triacetoxyborohydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum oxide, Raney nickel, NaBH4-Lewis acid system, lithium aluminum hydride, lithium tritert-butoxyaluminum hydride, sodium sulfide, sodium dithionite, hydrazine hydrate, stannous chloride, titanium trichloride, and ferric chloride.

[0045] In another preferred embodiment, 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.

[0046] In another preferred embodiment, the temperature of the second reduction reaction is selected from -20°C to 80°C.

[0047] In another preferred embodiment, the temperature of the second reduction reaction is selected from 0°C to 40°C.

[0048] In another preferred embodiment, the duration of the second reduction reaction is selected from 1 h to 24 h.

[0049] In another preferred embodiment, the duration of the second reduction reaction is selected from 2 h to 8 h.

[0050] In another preferred embodiment, the molar ratio of the compound of formula V to the second reducing agent is 1:1 to 1:3.

[0051] In a sixth aspect, the present invention provides a method for preparing a compound of formula V, specifically comprising the following steps:

[0052] (b1) Compound I undergoes a Suzuki coupling reaction with compound II in the presence of a catalyst and a second basic reagent to give compound III;

[0053] (b2) Compound III undergoes a nucleophilic substitution reaction with (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazine[2,1-c][1,4]oxazine in the presence of a third basic reagent to give compound IV;

[0054] (b3) Compound IV of formula IV is reduced to compound V of formula IV in the presence of a third reducing agent and a second acidic reagent via a third reduction reaction.

[0055] Wherein, compound R of formula II is selected from

[0056] 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.

[0057] 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.

[0058] In another preferred embodiment, the molar ratio of the compound of formula I to the catalyst is selected from 1:1 to 1:10.

[0059] 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.

[0060] In another preferred embodiment, the molar ratio of the compound of formula II and the second basic reagent is selected from 1:1 to 1:10.

[0061] In another preferred embodiment, the molar ratio of the compound of formula II and the second basic reagent is selected from 1:1 to 1:8.

[0062] 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.

[0063] In another preferred embodiment, the Suzuki coupling reaction temperature is selected from 30°C to 120°C.

[0064] In another preferred embodiment, the Suzuki coupling reaction temperature is selected from 50°C to 90°C.

[0065] In another preferred embodiment, the Suzuki coupling reaction time is selected from 1 h to 24 h.

[0066] In another preferred embodiment, the Suzuki coupling reaction time is selected from 4h to 12h.

[0067] 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, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, water, toluene, ethyl acetate, acetonitrile, dichloromethane, and isopropyl acetate.

[0068] In another preferred embodiment, the nucleophilic substitution reaction temperature is selected from 50°C to 130°C.

[0069] In another preferred embodiment, the nucleophilic substitution reaction temperature is selected from 80°C to 110°C.

[0070] In another preferred embodiment, the nucleophilic substitution reaction time is selected from 2h to 24h.

[0071] In another preferred embodiment, the nucleophilic substitution reaction time is selected from 4 h to 16 h.

[0072] In another preferred embodiment, the third basic 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), sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0073] In another preferred embodiment, the molar ratio of the compound of formula III and the third basic reagent is selected from 1:1 to 1:10.

[0074] In another preferred embodiment, the molar ratio of the compound of formula III and the third basic reagent is selected from 1:1 to 1:3.

[0075] In another preferred embodiment, the second acidic reagent is selected from ammonium chloride, hydrochloric acid, acetic acid, or trifluoroacetic acid.

[0076] In another preferred embodiment, the third reducing agent is selected from one of the following: iron powder, zinc powder, sodium borohydride, potassium borohydride, lithium borohydride, borane, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum oxide, Raney nickel, NaBH4-Lewis acid system, lithium aluminum hydride, lithium tritert-butoxyaluminum hydride, sodium sulfide, sodium dithionite, hydrazine hydrate, stannous chloride, titanium trichloride, and ferric chloride.

[0077] In another preferred embodiment, the solvent for the third reduction reaction is selected from one or more of the following: 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.

[0078] In another preferred embodiment, the molar ratio of the compound of formula IV to the third reducing agent is selected from 1:0.1 to 1:10.

[0079] In another preferred embodiment, the temperature of the third reduction reaction is selected from 20°C to 130°C.

[0080] In another preferred embodiment, the temperature of the third reduction reaction is selected from 40°C to 80°C.

[0081] In another preferred embodiment, the third reduction reaction time is selected from 1 h to 24 h.

[0082] In another preferred embodiment, the third reduction reaction time is selected from 2h to 8h.

[0083] 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

[0084] This invention, through extensive and in-depth research and numerous screenings, has for the first time developed intermediates of formulas X and VIII with novel structures, along with their process for preparing linnetan. The method for preparing linnetan and its intermediates according to this invention is simple, efficient, safe, mild, low-cost, high-yield, and easy for industrial production.

[0085] the term

[0086] Unless otherwise specified herein, all terms and abbreviations shall have their conventional meanings as are known to those skilled in the art.

[0087] The term “room temperature” or “normal temperature” refers to a temperature of 4-40°C, preferably 25±5°C.

[0088] The abbreviations used in this article are as follows:

[0089] EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0090] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridine-3-oxide hexafluorophosphate

[0091] HOBt: 1-Hydroxybenzotriazole

[0092] HOAt: 1-Hydroxy-7-azobenzotriazole

[0093] CDI: N,N-Carbodiimidazole

[0094] DCC: 1,3-Dicyclohexylcarbodiimide

[0095] DIC: N,N'-Dicyclohexylcarboimide

[0096] T3P: 1-Propylphosphocyclic anhydride

[0097] T4P: 1-Butylphosphine

[0098] HBTU: O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate

[0099] BOP: Carter's condensing agent

[0100] pyBOP: 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate

[0101] DPPCl: Diphenylphosphine chloride

[0102] BOP-Cl: Bis(2-oxo-3-oxazolyl)phosphine chloride

[0103] DPPA: Diphenyl azidophosphate

[0104] Boc2O: Di-tert-butyl carbonate anhydride

[0105] CbzCl: Benzyloxycarbonyl chloride

[0106] DMAP: 4-Dimethylaminopyridine

[0107] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0108] DABCO: Triethylenediamine

[0109] DBN: 1,5-diazabicyclo[4.3.0]non-5-ene

[0110] NMM: N-methylmorpholine

[0111] TMG: Tetramethylguanidine

[0112] KHMDS: Bis(trimethylsilyl)aminopotassium

[0113] NaHMDS: Sodium bis(trimethylsilyl)amino

[0114] LiHMDS: Lithium bis(trimethylsilyl)amino

[0115] LDA: Lithium diisopropylamino

[0116] DMA: N,N-dimethylacetamide

[0117] DMF: N,N-dimethylformamide

[0118] DMSO: Dimethyl sulfoxide

[0119] The preparation methods of the compounds of the present invention are described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0120] Typically, the preparation process of the compounds of the present invention is as shown in the embodiments of the present invention, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

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

[0122] (1) The preparation method of linnetane intermediate and linnetane of the present invention has high yield and simple and readily available raw materials.

[0123] (2) The raw materials and reagents have obvious economic advantages, which can reduce costs. The reaction conditions are mild and safe, and suitable for industrial scale-up production.

[0124] 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.

[0125] 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.

[0126] Example 1 Preparation of 2-chloro-4-(4-fluoro-2-methylphenyl)-5-nitropyridine (Compound III)

[0127] 2,4-Dichloro-5-nitropyridine (12.5 g, 65.0 mmol) and (4-fluoro-2-methylphenyl)boronic acid (10.0 g, 65.0 mmol) were added to a flask, and nitrogen was introduced. 1,4-Dioxane (100 mL) and Pd(dppf)Cl2*CH2Cl2 (2.63 g, 3.25 mmol) were added, and nitrogen was introduced again. Potassium carbonate (26.9 g, 19.5 mmol) was added. 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%. 1H-NMR (δ, ppm, Chloroform-d): 9.05 (s, 1H), 7.33 (s, 1H), 7.14-6.92 (m, 3H), 2.13 (s, 3H).

[0128] 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.

[0129] Example 2 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)

[0130] (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 under reduced pressure to obtain crude (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazino[2,1-c][1,4]oxazine. The crude product 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 stirred and heated to 100 °C. Sixteen hours later, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. Silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) yielded 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).

[0131] 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.

[0132] Example 3 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)

[0133] 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, followed by the addition of saturated ammonium chloride aqueous solution (6.80 mL). 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).

[0134] 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)-aza-methylpyridin-3-amine (compound X)

[0135] Under ice bath conditions, formic acid (2.04 mL, 54.1 mmol) and acetic anhydride (2.04 mL, 21.6 mmol) were added to a flask, and the mixture was stirred and heated to 30 °C. After 1 h, a tetrahydrofuran solution (30 mL) of compound V (2.00 g, 4.32 mmol) was added to the reaction mixture, and the temperature was raised to 70 °C. The reaction was stirred for 16 h. The mixture was cooled to room temperature, concentrated under reduced pressure, and then ice water (25 mL) was added. The mixture was stirred for 15 min, filtered, and dried to give compound X. ESI-MS m / z: 491.2 [M+H]+. 1H NMR(400MHz,Chloroform-d)δ8.94(s,0.5H),8.26(d,J=11.5Hz,0.5H),8.11(d,J=28.7Hz,1H),7 .36–7.13(m,5H),7.12–6.79(m,3.5H),6.60(s,0.5H),6.45(s,0.5H),6.40(d,J=2.8Hz,0.5H),4 .61–4.44(m,2H),4.44–4.29(m,1H),4.08–3.94(m,1H),3.94–3.80(m,2H),3.80–3.51(m,3H),3. 28(t,J=10.5Hz,1H),3.10–2.94(m,1H),2.72–2.53(m,2H),2.45–2.21(m,3H),2.16–1.94(m,3H).

[0136] 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)

[0137] Compound X was dissolved in tetrahydrofuran (30 mL), and the mixture was heated to 35 °C under nitrogen protection and stirring. A 1 mol / L solution of borane-tetrahydrofuran (13.0 mL, 13.0 mmol) was added dropwise. The reaction was stirred for 1 hour. The reaction was quenched with water (15 mL), stirred for 15 minutes, and the solvent was removed under reduced pressure. Ethyl acetate (50 mL) and 1 mol / L NaOH (30 mL) were added, and the mixture was stirred for 15 minutes. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL). The organic phases were combined, washed with water (10 mL), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was dissolved in dichloromethane (10 mL), and a 4 mol / L solution of dioxane hydrochloride (2 mL) was added dropwise at 0 °C, followed by concentration under reduced pressure. The crude product was suspended in ethyl acetate (30 mL), and 10 mL of 1 mol / L NaOH was added. The mixture was stirred for 15 minutes, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed with water (10 mL), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.85 g of solid, namely compound VIII, with a molar yield of 90%. ESI-MS m / z: 477.38 [M+H] + . 1 H 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),3.92-3.63(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).

[0138] Example 6 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 of formula VIII)

[0139] 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 the mixture was stirred for 15 minutes. Paraformaldehyde (130 mg, 4.32 mmol) was added, and the mixture was stirred until clear. Sodium borohydride (163 mg, 4.32 mmol) was added in portions, and the mixture 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] + , 1 H 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).

[0140] Compared with the preparation method disclosed in the prior art WO2021094247, the present invention provides a method for preparing elinnetan intermediate VIII. Methylation is performed using conventional reagents such as formic acid, acetic anhydride, and boranetetrahydrofuran solution, or by direct reduction, to obtain the methylated intermediate VIII. This avoids the use of genotoxic iodomethane methylating agents. Furthermore, compared with the 69% yield of the methylated product 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 in the prior art WO2021094247, the yield of the methylated product VIII in the present invention is increased by 19%.

[0141] 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)-N,2-dimethylpropionamide dihydrochloride (compound of formula VII)

[0142] 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), and add N,N-dimethylformamide (31 mg, 0.42 mmol) dropwise. Stir the reaction at 30 °C for 3 hours. Concentrate under reduced pressure, and dissolve the residue in dichloromethane (10 mL) to obtain a dichloromethane solution. 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 (2.00 g, 4.20 mmol) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (1.63 g, 12.6 mmol) was added. The dichloromethane solution was added dropwise under ice bath conditions, and the mixture was stirred and heated 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 3.07 g of solid, namely compound VII, with a molar yield of 93%. 1 H 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),2.25(s,1H),2.12(m,3H),1.41-1.32(m,6H).

[0143] The total yield of compounds of formula VII prepared according to the method disclosed in prior art WO2021094247 is 29%. In comparison, the total yield of compounds of formula VII prepared by the method of the present invention is 61%, which is 32% higher than the total yield of compounds of formula VII in prior art WO2021094247.

[0144] Example 8 Preparation of 2-(3,5-bis(trifluoromethyl)phenyl)-azo-(4-(4-fluoro-2-methylphenyl)-6-((7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1-hydro)-yl)pyridin-3-yl)-azo,2-dimethylpropionamide (compound of formula IX, elenetan)

[0145] 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), deionized water (2 mL) and concentrated hydrochloric acid (0.44 mL) were added to displace nitrogen gas, and 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 (compound IX), 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).

[0146] API was prepared according to the experimental method described in the examples of WO2021094247, with an overall yield of 24%. The preparation method of the present invention yielded an overall yield of elinnetan of 51%. Therefore, the overall yield of API prepared by the method of the present invention is 27% higher than that of the API compound in WO2021094247.

[0147] 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 IX, characterized in that, The method includes the following steps: (a1) Compound VIII of formula undergoes a condensation reaction with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid in the presence of a first basic reagent to give compound VII; (a2) The compound of formula VII is debenzylated by catalytic hydrogenation in the presence of a first acidic reagent to give the compound of formula IX.

2. A method for preparing the compound of formula IX as described in claim 1, characterized in that, The molar ratio of the compound of formula VIII to 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionic acid is 1:1 to 1:3; And / or, the first 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 used in the condensation reaction is selected from one or more of the following: oxaloyl 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 solvent for the condensation reaction is selected from one or more of dichloromethane, ethyl acetate, isopropyl acetate, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, water, oxaloyl chloride, and dichloromethane; And / or, the first acidic reagent is selected from hydrochloric acid, acetic acid, or trifluoroacetic acid.

3. A method for preparing a compound of formula VIII, characterized in that, The method includes a first reduction reaction of compound X in the presence of a first reducing agent to obtain compound VIII; In compound X, 'R is selected from hydrogen, oxyalkyl, or oxybenzyl.

4. The preparation method according to claim 3, characterized in that, The first reducing agent is selected from one or more of the following: iron powder, zinc powder, sodium borohydride, potassium borohydride, lithium borohydride, borane, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum oxide, Raney nickel, sodium borohydride-Lewis acid system, lithium aluminum hydride, lithium tritert-butoxyaluminum hydride, sodium sulfide, sodium dithionite, hydrazine hydrate, stannous chloride, titanium trichloride, and ferric chloride. And / or, the solvent for the first reduction reaction is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, xylene, ethyl acetate, methyl acetate, isopropyl acetate, acetone, cyclohexanone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, chlorobenzene, and pyridine; And / or, the molar ratio of the compound of formula X to the first reducing agent is 1:1 to 1:

5.

5. A method for preparing a compound of formula X, characterized in that, The method includes acylation of compound V in the presence of an acylation reagent to generate compound X; In compound X, 'R is selected from hydrogen, oxyalkyl, or oxybenzyl.

6. The preparation method according to claim 5, characterized in that, The acylation reagent is selected from one or more of methyl acetic anhydride, trimethyl orthoformate, triethyl orthoformate, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, di-tert-butyl carbonate, benzyloxycarbonyl chloride, formic acid, and acetic anhydride. And / or, the solvent for the acylation reaction is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, xylene, ethyl acetate, methyl acetate, isopropyl acetate, acetone, cyclohexanone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane, 1,2-dichloroethane, chlorobenzene, and pyridine; And / or, the molar ratio of the compound of formula V to the acylation reagent is 1:1 to 1:

10.

7. A method for preparing a compound of formula VIII, characterized in that, The method involves a condensation reaction between a compound of formula V and an aldehyde reagent to generate an imine, followed by a second reduction reaction of the imine in the presence of a second reducing agent to obtain a compound of formula VIII.

8. The preparation method according to claim 7, wherein the aldehyde reagent is selected from paraformaldehyde, trioxyformaldehyde, or formaldehyde; the second reducing agent is selected from sodium borohydride, iron powder, zinc powder, sodium borohydride, potassium borohydride, lithium borohydride, borane, sodium cyanoborohydride, sodium triacetoxyborohydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum oxide, Raney nickel, NaBH4-Lewis acid system, lithium aluminum hydride, lithium tritert-butoxyaluminum hydride, sodium sulfide, sodium dithionite, hydrazine hydrate, stannous chloride, titanium trichloride, and ferric chloride; 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 (DMA), N,N-dimethylformamide (DMF), 1,4-dioxane, water, ethyl acetate, and isopropyl acetate; And / or, the molar ratio of the compound of formula V to the second reducing agent is 1:1 to 1:

3.

9. A method for preparing a compound of formula V, characterized in that, Includes the following steps: (b1) Compound I undergoes a Suzuki coupling reaction with compound II in the presence of a catalyst and a second basic reagent to give compound III; (b2) Compound III undergoes a nucleophilic substitution reaction with (7S,9aS)-7-((benzyloxy)methyl)octahydropyrazine[2,1-c][1,4]oxazine in the presence of a third basic reagent to give compound IV; (b3) Compound IV of formula IV is reduced to compound V of formula IV in the presence of a third reducing agent and a second acidic reagent via a third reduction reaction. Wherein, compound R of formula II is selected from The catalyst is selected from one of the following: [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. And / or, 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; And / or, the third basic 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, sodium hydroxide, potassium hydroxide, and lithium hydroxide; And / or, the molar ratio of the compound of formula III to the third 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; And / or, the second acidic reagent is selected from ammonium chloride, hydrochloric acid, acetic acid, or trifluoroacetic acid; And / or, the third reducing agent is selected from one of the following: iron powder, zinc powder, sodium borohydride, potassium borohydride, lithium borohydride, borane, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum oxide, Raney nickel, sodium borohydride-Lewis acid system, lithium aluminum hydride, lithium tritert-butoxyaluminum hydride, sodium sulfide, sodium dithionite, hydrazine hydrate, stannous chloride, titanium trichloride, and ferric chloride; And / or, the molar ratio of the compound of formula IV and the third reducing agent is selected from 1:0.1 to 1:10; And / or, the solvent for the third 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.

10. An intermediate compound for the preparation of linnetan, characterized in that, Selected from compounds of formula X and formula VIII: In compound X, 'R is selected from hydrogen, oxyalkyl, or oxybenzyl.

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