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WO2024092420A1 - Preparation method for ((2r,7as)-2-fluorohexahydro-1h-pyrrolizin-7a-yl)methanol - Google Patents

Preparation method for ((2r,7as)-2-fluorohexahydro-1h-pyrrolizin-7a-yl)methanol Download PDF

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Publication number
WO2024092420A1
WO2024092420A1 PCT/CN2022/128678 CN2022128678W WO2024092420A1 WO 2024092420 A1 WO2024092420 A1 WO 2024092420A1 CN 2022128678 W CN2022128678 W CN 2022128678W WO 2024092420 A1 WO2024092420 A1 WO 2024092420A1
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Prior art keywords
compound
tert
substituted
aryl
alkyl
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French (fr)
Chinese (zh)
Inventor
王诚
何辉青
胡益平
杨成武
陈永刚
李硕梁
高强
郑保富
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Shanghai Haoyuan Chemexpress Co Ltd
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Shanghai Haoyuan Chemexpress Co Ltd
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Priority to PCT/CN2022/128678 priority Critical patent/WO2024092420A1/en
Priority to CN202280101239.0A priority patent/CN120166992A/en
Publication of WO2024092420A1 publication Critical patent/WO2024092420A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/02—Monohydroxylic acyclic alcohols
    • C07C31/04—Methanol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present application belongs to the field of pharmaceutical chemistry, and in particular relates to a method for preparing ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol.
  • KRAS gene mutation is the most common activating mutation in human cancer, present in 90% of pancreatic cancer, 40% of colon cancer, and 20% of lung cancer. Due to the spherical and smooth spatial structure of the KARS protein and its extremely strong affinity for GTP at the picomolar level, it has become an extremely difficult target for drug development.
  • KARS G12D mutation is a substitution of the glycine (G) at the 12th codon with aspartic acid (D) at the end of a carboxylic acid.
  • the new compounds disclosed so far all contain the compound ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol (hereinafter referred to as Compound VI) shown in the following formula.
  • the currently disclosed preparation methods of compound VI have a low overall yield (for example, only 3.5%), and involve steps such as ozonation and chiral chromatographic separation that are difficult to implement in scale-up production, which is difficult to industrialize; or, starting from the chiral fluorinated raw material, the target product is obtained through multiple steps (for example, nine steps), and involves multiple reductions and Dess-Martin periodate oxidation with different reducing agents, which has the problem of complex preparation process and high production cost. Therefore, it is urgent to develop a preparation method of compound VI with simple preparation and high yield, which is conducive to the realization of industrial production.
  • the present application provides a method for preparing ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol to simplify the preparation method and improve the product yield.
  • the first aspect of the present application provides a method for preparing compound VI, the preparation method being method 1 or method 2;
  • Method 1 includes the following steps:
  • Step 1 Compound III undergoes fluorination reaction to obtain compound V;
  • Step 2 Compound V undergoes reduction reaction to obtain compound VI.
  • Method 2 includes the following steps:
  • Step 1' Compound IV undergoes fluorination reaction to obtain compound V;
  • Step 2 Compound V undergoes reduction reaction to obtain compound VI.
  • (R) in each compound indicates that the corresponding chiral carbon atom is in R configuration
  • (S) indicates that the corresponding chiral carbon atom is in S configuration
  • R1 is selected from hydrogen, allyl, C1-C8 alkyl, C3-C7 cycloalkyl, C1-C8 alkyl substituted by aryl, C6-C20 aryl unsubstituted or substituted by Ra, C4-C8 heteroaryl, the aryl in the C1-C8 alkyl substituted by aryl is C6-C25 aryl unsubstituted or substituted by Ra, Ra is selected from methyl, ethyl, methoxy, nitro or halogen (e.g. F, Cl, Br, I).
  • halogen e.g. F, Cl, Br, I
  • the C1-C8 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl; the C3-C7 cycloalkyl group is selected from cyclopropyl, cyclopentyl, and cyclohexyl; the C1-C8 alkyl group substituted with an aryl group is selected from benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, and p-methoxybenzyl; the C6-C20 aryl group which is unsubstituted or substituted with Ra is selected from phenyl, methoxyphenyl, and p-nitrophenyl; the C4-C8 heteroaryl group is selected from furanyl, thienyl, and indolyl.
  • the above groups when R1 is not hydrogen are all carboxyl protecting groups.
  • R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, p-nitrobenzyl; preferably, R 1 is selected from methyl, isopropyl, tert-butyl, benzyl, p-nitrobenzyl.
  • R2 is a hydroxyl protecting group selected from C1-C25 sulfonyl, C1-C6 alkyl, C7-C25 alkyl substituted by Rb, C1-C25 silyl, C6-C25 aryl unsubstituted or arbitrarily substituted by Rc, C3-C25 heteroaryl
  • Rb is selected from phenyl or phenyl arbitrarily substituted by halogen, alkoxy, cyano, nitro
  • Rc is selected from C1-C6 alkyl, trityl, halogen, alkoxy, cyano, nitro.
  • R 2 is selected from trimethylsilyl, methanesulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl, perfluorobutylsulfonyl.
  • step 1 in method 1 comprises the following steps: compound III undergoes a fluorination reaction with a fluorinating agent in an aprotic solvent to separate compound V; the molar ratio of compound III to the fluorinating agent is 1:(1-5).
  • step 1-2 in method 2 comprises the following steps: compound IV undergoes a fluorination reaction with a fluorinating agent in an aprotic solvent to separate compound V; the molar ratio of compound IV to the fluorinating agent is 1:(1-5).
  • the temperature of the fluorination reaction in the method 1 and the method 2 is -80°C to 40°C, preferably -40°C to 30°C; the time of the fluorination reaction is 1h to 48h, preferably 1h to 24h.
  • the fluorination agent is selected from at least one of triethylamine trihydrofluoride, [bis(2-methoxyethyl)amine] sulfur trifluoride, (diethylamino)difluorosulfonium tetrafluoroborate, difluoro(morpholino)sulfonium tetrafluoroborate, 4-tert-butyl-2,6-dimethylphenyl sulfur trifluoride, potassium fluoride, copper fluoride, cesium fluoride, tetrabutylammonium fluoride, 4-chloro-N-[(4-methylphenyl)sulfonyl]benzenesulfonylimide fluoride, p-
  • the aprotic solvent is selected from at least one of acetonitrile, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, and benzene, preferably at least one of acetonitrile, tetrahydrofuran, methyltetrahydrofuran, and dichloromethane.
  • the above fluorination reaction does not need to be carried out under high temperature and high pressure, the reaction conditions are mild, the yield is high, and the above fluorination reagent is stable and does not produce explosive substances.
  • the present application has no particular restrictions on the amount of aprotic solvent added in step 1 of method 1 and step 1-2 of method 2, as long as the normal fluorination reaction can be ensured.
  • the mass ratio of compound III to the volume of the aprotic solvent is 1: (2 to 20), preferably 1: (2 to 10);
  • the mass ratio of compound IV to the volume of the aprotic solvent is 1: (2 to 20), preferably 1: (2 to 10), wherein the mass of compound III and compound IV is in g, and the volume of the aprotic solvent is in mL.
  • an alkali agent may be added to the fluorination reaction in the above step 1 and step 1-2, and the molar ratio of compound III to the alkali agent is 1:(1-20), preferably 1:(5-15); the molar ratio of compound IV to the alkali agent is 1:(1-20), preferably 1:(5-15); the alkali agent is selected from at least one of triethylamine, diethylamine, N,N-diisopropylethylamine, and 1,4-diazabicyclo[2.2.2]octane.
  • the alkali agent may be added after the fluorination agent is added, or may be mixed with the fluorination agent according to the above-mentioned molar ratio before being added.
  • step 2 in method 1 and method 2 comprises the following steps: compound V undergoes a reduction reaction with a reducing agent in an organic solvent, and compound VI is separated; preferably, the temperature of the reduction reaction is less than or equal to 0°C, for example, -10°C to 0°C; preferably, the reaction time of the reduction reaction is 0.5h to 5h, and the molar ratio of compound V to the reducing agent is 1:(1 to 5).
  • the reducing agent is selected from at least one of lithium aluminum hydride and borane.
  • the organic solvent is selected from at least one of toluene, tetrahydrofuran, methyltetrahydrofuran, ether, and dioxane (also known as 1,4-dioxane).
  • the above reduction reaction has simple reaction conditions, high safety, good selectivity, and the reaction reagents are all conventional reagents with low cost.
  • the present application has no particular restriction on the amount of organic solvent added in step 2 of method 1 and method 2, as long as the reduction reaction can proceed normally.
  • the mass ratio of compound V to the volume of the organic solvent is 1:(5-20), preferably 1:(5-15), wherein the unit of the mass of compound III is g, and the unit of the volume of the organic solvent is mL.
  • the second aspect of the present application provides a compound having a structure shown in the following formula IV:
  • R 1 is the same as the substituent R 1 in the first aspect
  • R2 is the same as defined for the substituent R2 in the first aspect.
  • compound IV is selected from the following compounds:
  • Me in the compound refers to methyl
  • Ts refers to methanesulfonyl
  • TMS refers to trimethylsilyl
  • tBu refers to tert-butyl
  • the third aspect of the present application provides a method for preparing compound IV in any of the aforementioned embodiments, which comprises the following steps:
  • Step 1-1a Compound III undergoes a substitution reaction to obtain compound IV; the substitution reaction uses cheap raw materials to obtain new compound IV, and is also beneficial to improving the purity and yield of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol.
  • step 1-1a comprises the following steps: Compound III and an alkali agent undergo a substitution reaction in an aprotic solvent to separate and obtain Compound IV; the temperature of the substitution reaction is -78°C to 40°C, and the time of the substitution reaction is 1h to 36h, preferably 24h to 36h; the molar ratio of Compound III to the alkali agent is 1:(1 to 50), preferably 1:(1 to 20), and more preferably 1:(1 to 15).
  • the alkali agent is selected from at least one of triethylamine, pyridine, diisopropylethylamine, and N,N-dimethylaniline, preferably triethylamine.
  • a hydroxyl protecting agent is further added to the substitution reaction in step 1-1a, and the hydroxyl protecting agent, the alkali agent and the compound III undergo substitution reaction in an aprotic solvent to generate compound IV.
  • the C1-C25 halogenated silane is selected from trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, triethylchlorosilane, tri-n-butylchlorosilane, dimethylisopropylchlorosilane, diethylisopropylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosilane, tert-butyldiphenylchlorosilane, triisopropylchlorosilyloxymethyl, [2-(trimethylchlorosilane)ethoxy]methyl, tetraisopropyldichlorosilane, di-tert-butyldimethylchlorosilane or diphenyldimethoxychlorosilane.
  • the hydroxyl protecting agent is selected from trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl chloride, tert-butyldimethylsilyl chloride, triisopropylsilyl chloride, tert-butyldiphenylsilyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or perfluorobutylsulfonyl chloride; preferably trimethylsilyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or perfluorobutylsulfonyl chloride; the selected hydroxyl protecting agent can effectively protect the hydroxyl group in compound III and play an activation role, the subsequent reaction steps have high
  • the present application has no particular restriction on the amount of aprotic solvent added in step 1-1a, as long as the substitution reaction can proceed normally.
  • the mass ratio of compound III to the volume of the aprotic solvent is 1:(15-30), wherein the mass of compound III is in g and the volume of the aprotic solvent is in mL.
  • the fourth aspect of the present application provides a method for preparing compound IV in any of the aforementioned embodiments, comprising the following steps:
  • Step 1-1b Compound II undergoes a ring-closing reaction to obtain compound IV.
  • step 1-1b comprises the following steps: Compound II and a strong base agent undergo a ring-closing reaction in an organic solvent to obtain Compound IV; the temperature of the ring-closing reaction is -100°C to 30°C, and the time is 10h to 24h; the molar ratio of Compound II to the strong base agent is 1:(1-5), preferably 1:(2-3); the mass ratio of Compound II to the volume of the organic solvent is 1:(1-30), preferably 1:(2-15), wherein the unit of the mass of Compound II is g, and the unit of the volume of the organic solvent is mL.
  • the strong base agent is selected from at least one of lithium hexamethyldisilazide, sodium hexamethyldisilazide, 2,2,6,6-tetramethylpiperidinium lithium, potassium hexamethyldisilazide, and lithium isopropylamide, preferably lithium hexamethyldisilazide.
  • the organic solvent is selected from at least one of methanol, ethanol, isopropanol, tert-butyl alcohol, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, acetone, and benzene, preferably at least one of methyltetrahydrofuran and tetrahydrofuran.
  • the compound IV can be obtained by adding acid and filtering for the next reaction. There is no complicated separation step, which makes the preparation process more concise, and the "one-pot method" reaction has few by-products and high atomic utilization.
  • the above-mentioned acid is selected from at least one of formic acid, acetic acid, and Lewis acid, and the Lewis acid is selected from at least one of zinc chloride, tin chloride, titanium tetrachloride, etc.
  • the molar ratio of acid to compound II is 1: (1 to 10), preferably 1: (1 to 4).
  • the above-mentioned ring-closing reaction has high safety and good selectivity, and the reaction reagents are all conventional reagents with low cost.
  • the fifth aspect of the present application provides a compound having a structure shown in the following formula III:
  • substituent R1 is the same as defined in the first aspect.
  • compound III is selected from the following compounds:
  • the present application provides a method for preparing compound III in any of the aforementioned embodiments, comprising the following steps:
  • Compound II undergoes a ring-closing reaction to obtain compound III, wherein X is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy, preferably Cl, Br, I.
  • X is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy, preferably Cl, Br, I.
  • the ring-closing reaction cleverly uses new compound II to obtain new compound III, has few reaction by-products, high atomic utilization, good selectivity (for example, compound II with SR or RR configuration can obtain new compound III with SS configuration), the obtained isomer has high purity, and the reaction yield is also good.
  • the ring-closing reaction comprises the following steps: Compound II and a strong base agent undergo a ring-closing reaction in an organic solvent to separate and obtain Compound III; the temperature of the ring-closing reaction is -100°C to 30°C, and the time is 10h to 24h; the molar ratio of Compound II to the strong base agent is 1:(1-10), preferably 1:(1-6), and more preferably 1:(1-3); the mass of Compound II to the volume of the organic solvent is 1:(1-30), wherein the unit of the mass of Compound II is g, and the unit of the volume of the organic solvent is mL.
  • the strong base agent is selected from at least one of sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, 2,2,6,6-tetramethylpiperidinium lithium, potassium hexamethyldisilazide, and lithium diisopropylamide, preferably lithium hexamethyldisilazide.
  • the organic solvent is selected from at least one of methanol, ethanol, isopropanol, tert-butyl alcohol, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, methyl tert-butyl ether, and benzene, preferably at least one of methyltetrahydrofuran and tetrahydrofuran.
  • the above ring-closing reaction has simple reaction conditions, high safety, good selectivity, and the reaction reagents are all conventional reagents with low cost.
  • the seventh aspect of the present application provides a compound having a structure shown in the following formula II:
  • R1 is the same as the definition of the substituent R1 in the first aspect;
  • X is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy, preferably Cl, Br, I.
  • compound II is selected from the following compounds:
  • Me in the compound refers to methyl
  • Bn refers to benzyl
  • tBu refers to tert-butyl
  • the eighth aspect of the present application provides a method for preparing compound II in any of the aforementioned embodiments, comprising the following steps:
  • Compound I or its salt undergoes a ring-opening reaction with compound VII to separate compound II.
  • the ring-opening reaction does not undergo an isomerization reaction, is suitable for large-scale production, and has a high reaction yield.
  • the above-mentioned compound I or its salt refers to compound I or a salt of compound I, and the salt of compound I may include but is not limited to a salt formed by combining NH in compound I with HCl, hydrobromic acid, tartaric acid, mandelic acid, sulfuric acid, methanesulfonic acid or oxalic acid.
  • the above-mentioned ring-opening reaction comprises the following steps: under the condition of an alkaline agent, compound I or its salt and compound VII undergo a ring-opening reaction in an organic solvent to separate compound II; the temperature of the ring-opening reaction is from room temperature to the reflux temperature of the organic solvent, preferably 40°C to 100°C, and the time is 1h to 72h; the molar ratio of compound I to the alkaline agent is 1:(1-10), preferably 1:(1-4); the molar ratio of compound I to compound VII is 1:(1-10), preferably 1:(1-2), and further preferably 1:(1-1.5); the ratio of the mass of compound I to the volume of the organic solvent is 1:(1-20), preferably 1:(5-15), wherein the unit of the mass of compound I is g, and the unit of the volume of the organic solvent is mL.
  • the alkali agent is selected from an inorganic base or an organic base, the inorganic base is selected from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate, and the organic base is selected from at least one of triethylamine, pyridine, diisopropylethylamine, and N,N-dimethylaniline; the alkali agent is preferably at least one of triethylamine, pyridine, diisopropylethylamine, and N,N-dimethylaniline, and further selected as triethylamine.
  • the organic solvent is selected from at least one of alcohol solvents, chlorinated alkanes, ether solvents, and liquid alkane solvents
  • the alcohol solvent is selected from at least one of methanol, ethanol, isopropanol, n-butanol, and tert-butanol
  • the chlorinated alkane solvent is selected from at least one of dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and chloroform
  • the ether solvent is selected from at least one of tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, and methyl tert-butyl ether
  • the liquid alkane solvent is selected from at least one of n-hexane, n-heptane, cyclohexane, and toluene.
  • the present application does not specifically limit the separation steps in the above steps, and separation steps known in the art can be used, as long as the purpose of the present application can be achieved.
  • the separation steps may include, but are not limited to: quenching the reaction with water, salt solution or other organic solvents, extraction, washing with water or other solvents, activated carbon treatment, filtration, concentration, recrystallization, etc.
  • the above-mentioned salt solution and other organic solvents can be conventional salt solutions and organic solvents used for separation known in the art, and the present application does not limit this, as long as the purpose of the present application can be achieved.
  • the preparation method of compound VI provided in the present application can be any of the following synthetic routes: compound III ⁇ compound V ⁇ compound VI, compound IV ⁇ compound V ⁇ compound VI, compound III ⁇ compound IV ⁇ compound V ⁇ compound VI, compound II ⁇ compound IV ⁇ compound V ⁇ compound VI, compound II ⁇ compound III ⁇ compound IV ⁇ compound V ⁇ compound VI, compound I ⁇ compound II ⁇ compound IV ⁇ compound V ⁇ compound VI, compound I ⁇ compound II ⁇ compound III ⁇ compound IV ⁇ compound V ⁇ compound VI.
  • Compound VI has a fluorine-containing tertiary carbon chiral center and a nitrogen-containing quaternary carbon chiral center, and is difficult to synthesize.
  • the preparation method provided in the present application is not only simple to operate, has mild reaction conditions, and a short reaction time, but also has a high yield and high chiral purity.
  • the obtained compound VI is of high quality.
  • the total reaction yield can reach 36%
  • the chiral purity of the chiral carbon atom can reach more than 99.0%.
  • compound II-1 (2 g, 9 mmol, 1 equiv) was dissolved in tetrahydrofuran (THF, 45 mL), cooled to -70°C, and then lithium hexamethyldisilazide (LiHMDS, 14.4 mL, 14.4 mmol, 1.6 equiv) was added dropwise, and then kept warm for 12 h. A 10% NH4Cl aqueous solution was added to quench the reaction, and DCM was extracted.
  • THF tetrahydrofuran
  • reaction solution was added dropwise to a 10% NaHCO 3 aqueous solution, stirred for 0.5 hours, separated, the organic phase was washed with water once, separated again, the organic phase was concentrated under reduced pressure, and purified by column chromatography to obtain 0.4 g of compound V-4 with a yield of 53%.

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Abstract

A preparation method for a compound VI, the compound VI having a fluorotertiary carbon chiral center and an azaquaternary carbon chiral center, making the compound difficult to synthesize. The preparation method provided by the present application not only has simple operation, mild reaction conditions and a short reaction time, but also has high yield and high chiral purity. The obtained compound VI has relatively high quality.

Description

一种((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲醇的制备方法A preparation method of ((2R, 7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol 技术领域Technical Field

本申请属于药物化学领域，特别是涉及一种((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲醇的制备方法。The present application belongs to the field of pharmaceutical chemistry, and in particular relates to a method for preparing ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol.

背景技术Background technique

KRAS基因突变是人类癌症中最常见的一种激活突变，90％的胰腺癌、40％的结肠癌、20％的肺癌中都存在这种基因突变。由于KARS蛋白球形平滑的空间结构和GTP皮摩尔级的极强亲和力，使其成为极难成药的靶点。KARS G12D突变为12位密码子的甘氨酸(G)被末端为羧酸的天冬氨酸(D)取代，目前公开的该靶点新化合物均含有下式所示化合物((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲醇(以下记为化合物VI)。KRAS gene mutation is the most common activating mutation in human cancer, present in 90% of pancreatic cancer, 40% of colon cancer, and 20% of lung cancer. Due to the spherical and smooth spatial structure of the KARS protein and its extremely strong affinity for GTP at the picomolar level, it has become an extremely difficult target for drug development. KARS G12D mutation is a substitution of the glycine (G) at the 12th codon with aspartic acid (D) at the end of a carboxylic acid. The new compounds disclosed so far all contain the compound ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol (hereinafter referred to as Compound VI) shown in the following formula.

Figure PCTCN2022128678-appb-000001
Figure PCTCN2022128678-appb-000001

但是，目前公开的化合物VI的制备方法存在总体收率较低(例如仅为3.5％)，且涉及臭氧化和手性色谱拆分等难以在放大生产中实施的步骤，存在难以工业化的问题；或者，从手性氟代原料出发经过多步(例如九步)得到目标产物，且涉及不同还原剂进行多次还原和Dess-Martin过碘酸酯氧化，存在制备过程复杂且生产成本高的问题。因此，亟待开发一种制备简单且收率高的化合物VI的制备方法，进而有利于实现工业化生产。However, the currently disclosed preparation methods of compound VI have a low overall yield (for example, only 3.5%), and involve steps such as ozonation and chiral chromatographic separation that are difficult to implement in scale-up production, which is difficult to industrialize; or, starting from the chiral fluorinated raw material, the target product is obtained through multiple steps (for example, nine steps), and involves multiple reductions and Dess-Martin periodate oxidation with different reducing agents, which has the problem of complex preparation process and high production cost. Therefore, it is urgent to develop a preparation method of compound VI with simple preparation and high yield, which is conducive to the realization of industrial production.

发明内容Summary of the invention

本申请提供了((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲醇的制备方法，以简化制备方法、提高产物收率。The present application provides a method for preparing ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol to simplify the preparation method and improve the product yield.

本申请第一方面提供了一种化合物VI的制备方法，制备方法为方法一或方法二；The first aspect of the present application provides a method for preparing compound VI, the preparation method being method 1 or method 2;

方法一包括以下步骤：Method 1 includes the following steps:

Figure PCTCN2022128678-appb-000002
Figure PCTCN2022128678-appb-000002

步骤1：化合物III发生氟化反应得到化合物V；Step 1: Compound III undergoes fluorination reaction to obtain compound V;

步骤2：化合物V发生还原反应得到化合物VI。Step 2: Compound V undergoes reduction reaction to obtain compound VI.

方法二包括以下步骤：Method 2 includes the following steps:

Figure PCTCN2022128678-appb-000003
Figure PCTCN2022128678-appb-000003

步骤1’：化合物IV发生氟化反应得到化合物V；Step 1': Compound IV undergoes fluorination reaction to obtain compound V;

步骤2：化合物V发生还原反应得到化合物VI。Step 2: Compound V undergoes reduction reaction to obtain compound VI.

在本申请中，各个化合物中的(R)表示对应的手性碳原子为R构型，(S)表示对应的手性碳原子为S构型。In the present application, (R) in each compound indicates that the corresponding chiral carbon atom is in R configuration, and (S) indicates that the corresponding chiral carbon atom is in S configuration.

其中，in,

R 1选自氢、烯丙基、C1～C8的烷基、C3～C7的环烷基、被芳基取代的C1～C8的烷基、未取代或被Ra取代的C6～C20的芳基、C4～C8的杂芳基，被芳基取代的C1～C8的烷基中的芳基为未取代或被Ra取代的C6～C25的芳基，Ra选自甲基、乙基、甲氧基、硝基或卤素(例如：F、Cl、Br、I)。优选地，C1～C8的烷基选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基；C3～C7的环烷基选自环丙基、环戊基、环己基；被芳基取代的C1～C8的烷基选自苄基、二苯甲基、三苯甲基、对硝基苄基、对甲氧基苄基；未取代或被Ra取代的C6～C20的芳基选自苯基、甲氧基苯基、对硝基苯基；C4-C8的杂芳基选自呋喃基、噻吩基、吲哚基。上述R 1不为氢时的基团均为羧基保护基。 R1 is selected from hydrogen, allyl, C1-C8 alkyl, C3-C7 cycloalkyl, C1-C8 alkyl substituted by aryl, C6-C20 aryl unsubstituted or substituted by Ra, C4-C8 heteroaryl, the aryl in the C1-C8 alkyl substituted by aryl is C6-C25 aryl unsubstituted or substituted by Ra, Ra is selected from methyl, ethyl, methoxy, nitro or halogen (e.g. F, Cl, Br, I). Preferably, the C1-C8 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl; the C3-C7 cycloalkyl group is selected from cyclopropyl, cyclopentyl, and cyclohexyl; the C1-C8 alkyl group substituted with an aryl group is selected from benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, and p-methoxybenzyl; the C6-C20 aryl group which is unsubstituted or substituted with Ra is selected from phenyl, methoxyphenyl, and p-nitrophenyl; the C4-C8 heteroaryl group is selected from furanyl, thienyl, and indolyl. The above groups when R1 is not hydrogen are all carboxyl protecting groups.

优选地，R 1选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环戊基、环己基、苯基、苄基、对硝基苄基；优选地，R 1选自甲基、异丙基、叔丁基、苄基、对硝基苄基。 Preferably, R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, p-nitrobenzyl; preferably, R 1 is selected from methyl, isopropyl, tert-butyl, benzyl, p-nitrobenzyl.

R 2为羟基保护基团，选自C1～C25的磺酰基、C1～C6的烷基、被Rb取代的C7～C25的烷基、C1～C25的硅烷基、未取代或被Rc任意取代的C6～C25的芳基、C3～C25的杂芳基，Rb选自苯基或被卤素、烷氧基、氰基、硝基任意取代的苯基，Rc选自C1～C6的烷基、三苯甲基、卤素、烷氧基、氰基、硝基。优选地，C1～C25的磺酰基为-S(＝O) 2-R 3，R 3选自未取代或被氟取代的C1～C12的烷基、未取代或被氟取代的C6～C10的芳基，优选地，C1～C25的磺酰基优选选自甲磺酰基、乙磺酰基、丙磺酰基、对甲基苯磺酰基、三氟甲磺酰基、全氟丁基磺酰基；C1～C6的烷基选自甲基、乙基、丙基、异丙基、正丁基、叔丁基或戊基；被Rb取代的C7～C25的烷基选自苄基、对硝基苄基或对甲氧基苄基；C1～C25的 硅烷基选自三甲基甲硅烷基、三乙基甲硅烷基、三正丁基硅烷基、二甲基异丙基甲硅烷基、二乙基异丙基甲硅烷基、叔丁基二甲基甲硅烷基、三异丙基甲硅烷基、叔丁基二苯基甲硅烷基、三异丙基甲硅烷氧基甲基、[2-(三甲基甲硅烷基)乙氧基]甲基、四异丙基二亚甲硅烷基、二叔丁基二甲基亚甲硅烷基、二苯基二甲氧基硅烷基(DPS)，优选为三甲基甲硅烷基、三乙基硅烷基、叔丁基二甲基甲硅烷基、三异丙基甲硅烷基、叔丁基二苯基甲硅烷基；未取代或被Rc取代的C6～C25的芳基选自苯基、3-叔丁基苯基、3-正丙基苯基、3-异丙基苯基、3-甲基苯基、4-叔丁基苯基、4-三氟甲基苯基、4-正丙基苯基、4-异丙基苯基、4-甲基苯基、3,5-二甲基苯基、对硝基苯基、对甲氧基苯基、蒽基或萘基；C3～C25的杂芳基选自2-噻吩基、吡啶基、哒嗪基、吡嗪基、三嗪基、吖啶基。 R2 is a hydroxyl protecting group selected from C1-C25 sulfonyl, C1-C6 alkyl, C7-C25 alkyl substituted by Rb, C1-C25 silyl, C6-C25 aryl unsubstituted or arbitrarily substituted by Rc, C3-C25 heteroaryl, Rb is selected from phenyl or phenyl arbitrarily substituted by halogen, alkoxy, cyano, nitro, Rc is selected from C1-C6 alkyl, trityl, halogen, alkoxy, cyano, nitro. Preferably, C1-C25 sulfonyl is -S(=O) 2 - R3 , R 3 is selected from unsubstituted or fluorine-substituted C1-C12 alkyl, unsubstituted or fluorine-substituted C6-C10 aryl, preferably, C1-C25 sulfonyl is selected from methylsulfonyl, ethylsulfonyl, propylsulfonyl, p-methylbenzenesulfonyl, trifluoromethylsulfonyl, perfluorobutylsulfonyl; C1-C6 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or pentyl; C7-C25 alkyl substituted by Rb is selected from benzyl, p-nitrobenzyl or p-methoxybenzyl; C1-C25 silyl is selected from trimethylsilyl, triethylsilyl, tri-n-butylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, triisopropylsiloxymethyl, [2 -(trimethylsilyl)ethoxy]methyl, tetraisopropyldisilyl, di-tert-butyldimethylsilyl, diphenyldimethoxysilyl (DPS), preferably trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl; the C6~C25 aryl group which is unsubstituted or substituted by Rc is selected from phenyl, 3-tert-butylphenyl, 3-n-propylphenyl, 3-isopropylphenyl, 3-methylphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-n-propylphenyl, 4-isopropylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, p-nitrophenyl, p-methoxyphenyl, anthracenyl or naphthyl; the C3~C25 heteroaryl group is selected from 2-thienyl, pyridyl, pyridazinyl, pyrazinyl, triazinyl and acridinyl.

优选地，R 2选自三甲基甲硅烷基、甲磺酰基、对甲基苯磺酰基、三氟甲磺酰基、全氟丁基磺酰基。 Preferably, R 2 is selected from trimethylsilyl, methanesulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl, perfluorobutylsulfonyl.

优选地，方法一中的步骤1包括以下步骤：化合物III与氟化试剂在非质子溶剂中发生氟化反应，分离得到化合物V；化合物III与氟化试剂的摩尔比为1:(1～5)。Preferably, step 1 in method 1 comprises the following steps: compound III undergoes a fluorination reaction with a fluorinating agent in an aprotic solvent to separate compound V; the molar ratio of compound III to the fluorinating agent is 1:(1-5).

优选地，方法二中的步骤1-2包括以下步骤：化合物Ⅳ与氟化试剂在非质子溶剂中发生氟化反应，分离得到化合物V；化合物Ⅳ与氟化试剂的摩尔比为1:(1～5)。Preferably, step 1-2 in method 2 comprises the following steps: compound IV undergoes a fluorination reaction with a fluorinating agent in an aprotic solvent to separate compound V; the molar ratio of compound IV to the fluorinating agent is 1:(1-5).

所述方法一和方法二的氟化反应的温度为-80℃～40℃，优选为-40℃～30℃；氟化反应的时间为1h～48h，优选为1h～24h。其中，氟化试剂选自三乙胺三氢氟酸盐、[双(2-甲氧基乙基)胺]三氟化硫、(二乙氨基)二氟锍鎓四氟硼酸盐、二氟(吗啉代)锍四氟硼酸盐、4-叔丁基-2,6-二甲基苯基三氟化硫、氟化钾、氟化铜、氟化铯、四丁基氟化铵、4-氯-N-[(4-甲基苯基)磺酰基]苯磺酰亚胺基氟、对硝基苯磺酰氟、吡啶-2-磺酰氟、硫酰氟、三氟化硫吗啉、二乙胺基三氟化硫、或全氟丁基磺酰氟中的至少一种，优选为全氟丁基磺酰氟、二乙胺基三氟化硫、三乙胺三氢氟酸盐中的至少一种。非质子溶剂选自乙腈、甲苯、二甲苯、三甲苯、二氯甲烷、1,2-二氯乙烷、1,1,2,2-四氯乙烷、氯仿、二甲基亚砜、N,N-二甲基甲酰胺、四氢呋喃、甲基四氢呋喃，1,4-二氧六环、乙醚、苯中的至少一种，优选为乙腈、四氢呋喃、甲基四氢呋喃、二氯甲烷中的至少一种。上述氟化反应无需在高温高压下进行，反应条件温和、收率高，且上述氟化试剂稳定不会产生爆炸性物质。The temperature of the fluorination reaction in the method 1 and the method 2 is -80°C to 40°C, preferably -40°C to 30°C; the time of the fluorination reaction is 1h to 48h, preferably 1h to 24h. Among them, the fluorination agent is selected from at least one of triethylamine trihydrofluoride, [bis(2-methoxyethyl)amine] sulfur trifluoride, (diethylamino)difluorosulfonium tetrafluoroborate, difluoro(morpholino)sulfonium tetrafluoroborate, 4-tert-butyl-2,6-dimethylphenyl sulfur trifluoride, potassium fluoride, copper fluoride, cesium fluoride, tetrabutylammonium fluoride, 4-chloro-N-[(4-methylphenyl)sulfonyl]benzenesulfonylimide fluoride, p-nitrobenzenesulfonyl fluoride, pyridine-2-sulfonyl fluoride, sulfuryl fluoride, sulfur trifluoride morpholine, diethylamino sulfur trifluoride, or perfluorobutylsulfonyl fluoride, preferably at least one of perfluorobutylsulfonyl fluoride, diethylamino sulfur trifluoride, and triethylamine trihydrofluoride. The aprotic solvent is selected from at least one of acetonitrile, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, and benzene, preferably at least one of acetonitrile, tetrahydrofuran, methyltetrahydrofuran, and dichloromethane. The above fluorination reaction does not need to be carried out under high temperature and high pressure, the reaction conditions are mild, the yield is high, and the above fluorination reagent is stable and does not produce explosive substances.

本申请对方法一的步骤1和方法二的步骤1-2中的非质子溶剂的加入量没有特别限制，只要能保证氟化反应的正常进行即可。示例性地，化合物III的质量与非质子溶剂的体积比值为1:(2～20)，优选为1:(2～10)；化合物Ⅳ的质量与非质子溶剂的体积比值为1: (2～20)，优选为1:(2～10)，其中，化合物III和化合物Ⅳ的质量的单位为g，非质子溶剂的体积的单位为mL。The present application has no particular restrictions on the amount of aprotic solvent added in step 1 of method 1 and step 1-2 of method 2, as long as the normal fluorination reaction can be ensured. Exemplarily, the mass ratio of compound III to the volume of the aprotic solvent is 1: (2 to 20), preferably 1: (2 to 10); the mass ratio of compound IV to the volume of the aprotic solvent is 1: (2 to 20), preferably 1: (2 to 10), wherein the mass of compound III and compound IV is in g, and the volume of the aprotic solvent is in mL.

在本申请的一些实施方案中，上述步骤1和步骤1-2中的氟化反应中还可以加入碱剂，化合物III与碱剂的摩尔比为1:(1～20)，优选为1:(5～15)；化合物Ⅳ与碱剂的摩尔比为1:(1～20)，优选为1:(5～15)；碱剂选自三乙胺、二乙胺、N,N-二异丙基乙胺、1,4-二氮杂二环[2.2.2]辛烷中的至少一种。碱剂可以在加入氟化试剂后再加入，也可以先与氟化试剂按照上述投料摩尔比混合再加入。In some embodiments of the present application, an alkali agent may be added to the fluorination reaction in the above step 1 and step 1-2, and the molar ratio of compound III to the alkali agent is 1:(1-20), preferably 1:(5-15); the molar ratio of compound IV to the alkali agent is 1:(1-20), preferably 1:(5-15); the alkali agent is selected from at least one of triethylamine, diethylamine, N,N-diisopropylethylamine, and 1,4-diazabicyclo[2.2.2]octane. The alkali agent may be added after the fluorination agent is added, or may be mixed with the fluorination agent according to the above-mentioned molar ratio before being added.

优选地，方法一和方法二中的步骤2包括以下步骤：化合物V与还原剂在有机溶剂中发生还原反应，分离得到化合物VI；优选还原反应的温度小于或等于0℃，例如-10℃～0℃；优选还原反应的的反应时间为0.5h～5h，化合物V与还原剂的摩尔比为1:(1～5)。其中，还原剂选自氢化铝锂、甲硼烷中的至少一种。有机溶剂选自甲苯、四氢呋喃、甲基四氢呋喃、乙醚、二噁烷(也称1,4-二氧六环)中的至少一种。上述还原反应的反应条件简单、安全性高、选择性好，而且反应试剂均为常规试剂、成本低。Preferably, step 2 in method 1 and method 2 comprises the following steps: compound V undergoes a reduction reaction with a reducing agent in an organic solvent, and compound VI is separated; preferably, the temperature of the reduction reaction is less than or equal to 0°C, for example, -10°C to 0°C; preferably, the reaction time of the reduction reaction is 0.5h to 5h, and the molar ratio of compound V to the reducing agent is 1:(1 to 5). Among them, the reducing agent is selected from at least one of lithium aluminum hydride and borane. The organic solvent is selected from at least one of toluene, tetrahydrofuran, methyltetrahydrofuran, ether, and dioxane (also known as 1,4-dioxane). The above reduction reaction has simple reaction conditions, high safety, good selectivity, and the reaction reagents are all conventional reagents with low cost.

本申请对方法一和方法二的步骤2中有机溶剂的加入量没有特别限制，只要能保证还原反应的正常进行即可。示例性地，化合物V的质量与有机溶剂的体积比值为1:(5～20)，优选为1:(5～15)，其中，化合物III的质量的单位为g，有机溶剂的体积的单位为mL。The present application has no particular restriction on the amount of organic solvent added in step 2 of method 1 and method 2, as long as the reduction reaction can proceed normally. Exemplarily, the mass ratio of compound V to the volume of the organic solvent is 1:(5-20), preferably 1:(5-15), wherein the unit of the mass of compound III is g, and the unit of the volume of the organic solvent is mL.

本申请第二方面提供了一种化合物，其具有下式IV所示结构：The second aspect of the present application provides a compound having a structure shown in the following formula IV:

Figure PCTCN2022128678-appb-000004
Figure PCTCN2022128678-appb-000004

其中，R 1同第一方面的取代基R 1定义； Wherein, R 1 is the same as the substituent R 1 in the first aspect;

R 2同第一方面的取代基R 2定义。 R2 is the same as defined for the substituent R2 in the first aspect.

例如，化合物IV选自以下化合物：For example, compound IV is selected from the following compounds:

Figure PCTCN2022128678-appb-000005
Figure PCTCN2022128678-appb-000005

在本申请中，化合物中的Me是指甲基，Ts是指甲磺酰基，TMS是指三甲基硅烷基， tBu是指叔丁基。In the present application, Me in the compound refers to methyl, Ts refers to methanesulfonyl, TMS refers to trimethylsilyl, and tBu refers to tert-butyl.

本申请第三方面提供了一种前述任一实施方案中的化合物IV的制备方法，其包括以下步骤：The third aspect of the present application provides a method for preparing compound IV in any of the aforementioned embodiments, which comprises the following steps:

Figure PCTCN2022128678-appb-000006
Figure PCTCN2022128678-appb-000006

步骤1-1a：化合物III发生取代反应得到化合物IV；该取代反应使用廉价的原料得到新化合物Ⅳ，同时有利于提高((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲醇的纯度和收率。Step 1-1a: Compound III undergoes a substitution reaction to obtain compound IV; the substitution reaction uses cheap raw materials to obtain new compound IV, and is also beneficial to improving the purity and yield of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol.

优选地，步骤1-1a包括以下步骤：化合物III与碱剂在非质子溶剂中发生取代反应，分离得到化合物IV；取代反应的温度为-78℃～40℃，取代反应的时间为1h～36h，优选为24h～36h；化合物III与碱剂的摩尔比为1:(1～50)，优选为1:(1～20)，进一步优选为1:(1～15)。其中，碱剂选自三乙胺、吡啶、二异丙基乙基胺、N,N-二甲基苯胺中的至少一种，优选为三乙胺。非质子溶剂选自乙腈、甲苯、二甲苯、三甲苯、二氯甲烷、1,2-二氯乙烷、1,1,2,2-四氯乙烷、氯仿、二甲基亚砜、N,N-二甲基甲酰胺、四氢呋喃、甲基四氢呋喃，1,4-二氧六环、乙醚、苯中的至少一种，优选为二氯甲烷。上述取代反应的反应条件简单、安全性高、选择性好，而且反应试剂均为常规试剂、成本低。Preferably, step 1-1a comprises the following steps: Compound III and an alkali agent undergo a substitution reaction in an aprotic solvent to separate and obtain Compound IV; the temperature of the substitution reaction is -78°C to 40°C, and the time of the substitution reaction is 1h to 36h, preferably 24h to 36h; the molar ratio of Compound III to the alkali agent is 1:(1 to 50), preferably 1:(1 to 20), and more preferably 1:(1 to 15). Wherein, the alkali agent is selected from at least one of triethylamine, pyridine, diisopropylethylamine, and N,N-dimethylaniline, preferably triethylamine. The aprotic solvent is selected from at least one of acetonitrile, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, and benzene, preferably dichloromethane. The reaction conditions of the above substitution reaction are simple, safe, and selective, and the reaction reagents are all conventional reagents with low cost.

在本申请的一些实施方案中，步骤1-1a中的取代反应中还加入羟基保护剂，羟基保护剂、碱剂与化合物III在非质子溶剂中发生取代反应生成化合物IV，化合物III与羟基保护剂的摩尔比为1:(1～20)，优选为1:(1～3)，羟基保护剂优选为C1～C25的磺酰卤X-S(＝O) 2-R 3或C1～C25的卤代硅烷；其中，X为卤素，卤素优选Cl或Br，更优选Cl；R 3选自未取代或被氟取代的C1～C12的烷基、未取代或被氟取代的C6～C10的芳基；-S(＝O) 2-R 3优选选自甲磺酰基、乙磺酰基、丙磺酰基、对甲基苯磺酰基、三氟甲磺酰基、全氟丁基磺酰基，C1～C25的卤代硅烷中的卤素优选Cl、I或Br，更优选Cl。 In some embodiments of the present application, a hydroxyl protecting agent is further added to the substitution reaction in step 1-1a, and the hydroxyl protecting agent, the alkali agent and the compound III undergo substitution reaction in an aprotic solvent to generate compound IV. The molar ratio of compound III to the hydroxyl protecting agent is 1:(1-20), preferably 1:(1-3), and the hydroxyl protecting agent is preferably a C1-C25 sulfonyl halide XS(=O) 2 -R 3 or a C1-C25 halogenated silane; wherein X is a halogen, and the halogen is preferably Cl or Br, more preferably Cl; R 3 is selected from unsubstituted or fluorinated C1-C12 alkyl, unsubstituted or fluorinated C6-C10 aryl; -S(=O) 2 -R 3 is preferably selected from methanesulfonyl, ethanesulfonyl, propylsulfonyl, p-methylbenzenesulfonyl, trifluoromethanesulfonyl, and perfluorobutylsulfonyl; the halogen in the C1-C25 halogenated silane is preferably Cl, I or Br, more preferably Cl.

C1～C25的卤代硅烷选自三甲基氯硅烷、三甲基溴硅烷、三甲基碘硅烷、三乙基氯硅烷、三正丁基氯硅烷、二甲基异丙基氯硅烷、二乙基异丙基氯硅烷、叔丁基二甲基氯硅烷、三异丙基氯硅烷、叔丁基二苯基氯硅烷、三异丙基氯硅烷氧基甲基、[2-(三甲基氯硅烷)乙氧基]甲基、四异丙基二亚氯硅烷、二叔丁基二甲基亚氯硅烷或二苯基二甲氧基氯硅烷。The C1-C25 halogenated silane is selected from trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, triethylchlorosilane, tri-n-butylchlorosilane, dimethylisopropylchlorosilane, diethylisopropylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosilane, tert-butyldiphenylchlorosilane, triisopropylchlorosilyloxymethyl, [2-(trimethylchlorosilane)ethoxy]methyl, tetraisopropyldichlorosilane, di-tert-butyldimethylchlorosilane or diphenyldimethoxychlorosilane.

羟基保护剂选自三甲基氯硅烷、三甲基溴硅烷、三甲基碘硅烷、三乙基氯硅烷、叔丁 基二甲基氯硅烷、三异丙基氯硅烷、叔丁基二苯基氯硅烷、甲磺酰氯、对甲基苯磺酰氯、三氟甲磺酰氯或全氟丁基磺酰氯；优选三甲基氯硅烷、甲磺酰氯、对甲基苯磺酰氯、三氟甲磺酰氯或全氟丁基磺酰氯；所选的羟基保护剂可以有效的对化合物III中的羟基进行保护，并起到活化作用，后续反应步骤活性高、副产物少，纯度高，且反应条件简便易控制。The hydroxyl protecting agent is selected from trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl chloride, tert-butyldimethylsilyl chloride, triisopropylsilyl chloride, tert-butyldiphenylsilyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or perfluorobutylsulfonyl chloride; preferably trimethylsilyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or perfluorobutylsulfonyl chloride; the selected hydroxyl protecting agent can effectively protect the hydroxyl group in compound III and play an activation role, the subsequent reaction steps have high activity, few by-products, high purity, and the reaction conditions are simple and easy to control.

在本申请的一些实施方案中，步骤1-1a中的取代反应中还加入催化剂，化合物III与催化剂的摩尔比为1:(0.01～1)，优选为1:(0.05～0.2)，催化剂选自4-二甲氨基吡啶(DMAP)。In some embodiments of the present application, a catalyst is also added to the substitution reaction in step 1-1a, and the molar ratio of compound III to the catalyst is 1:(0.01-1), preferably 1:(0.05-0.2), and the catalyst is selected from 4-dimethylaminopyridine (DMAP).

本申请对步骤1-1a中非质子溶剂的加入量没有特别限制，只要能保证取代反应的正常进行即可。示例性地，化合物III的质量与非质子溶剂的体积比值为1:(15～30)，其中，化合物III的质量的单位为g，非质子溶剂的体积的单位为mL。The present application has no particular restriction on the amount of aprotic solvent added in step 1-1a, as long as the substitution reaction can proceed normally. Exemplarily, the mass ratio of compound III to the volume of the aprotic solvent is 1:(15-30), wherein the mass of compound III is in g and the volume of the aprotic solvent is in mL.

本申请第四方面提供了一种前述任一实施方案中的化合物IV的制备方法，其包括以下步骤：The fourth aspect of the present application provides a method for preparing compound IV in any of the aforementioned embodiments, comprising the following steps:

Figure PCTCN2022128678-appb-000007
Figure PCTCN2022128678-appb-000007

步骤1-1b：化合物II发生闭环反应得到化合物IV。Step 1-1b: Compound II undergoes a ring-closing reaction to obtain compound IV.

在本申请中，各个化合物中的*表示对应的碳原子具有手性。In the present application, * in each compound indicates that the corresponding carbon atom has chirality.

优选地，步骤1-1b包括以下步骤：化合物II与强碱剂在有机溶剂中发生闭环反应得到化合物IV；闭环反应的温度为-100℃～30℃、时间为10h～24h；化合物II与强碱剂的摩尔比为1:(1～5)，优选1:(2～3)；化合物II的质量与有机溶剂的体积比值为1:(1～30)，优选为1:(2～15)，其中，化合物II的质量的单位为g，有机溶剂的体积的单位为mL。其中，强碱剂选自六甲基二硅基胺基锂、六甲基二硅基胺基钠、2,2,6,6-四甲基哌啶锂，六甲基二硅基胺基钾、异丙基胺基锂中的至少一种，优选为六甲基二硅基胺基锂。有机溶剂选自甲醇、乙醇、异丙醇、叔丁醇、甲苯、二甲苯、三甲苯、二氯甲烷、1,2-二氯乙烷、1,1,2,2-四氯乙烷、氯仿、二甲基亚砜、N,N-二甲基甲酰胺、四氢呋喃、甲基四氢呋喃，1,4-二氧六环、乙醚、丙酮、苯中的至少一种，优选为甲基四氢呋喃、四氢呋喃中的至少一种。上述闭环反应在反应完成后，加入酸过滤后即可得到化合物IV进行下一步反应，没有复 杂的分离步骤，使得制备过程更为简洁，且“一锅法”反应副产物少，原子利用率高。上述酸选自甲酸、醋酸、路易斯酸中的至少一种，路易斯酸选自氯化锌、氯化锡、四氯化钛等中的至少一种。酸与化合物II的摩尔比为1:(1～10)，优选为1:(1～4)。另外，上述闭环反应的安全性高、选择性好，而且反应试剂均为常规试剂、成本低。Preferably, step 1-1b comprises the following steps: Compound II and a strong base agent undergo a ring-closing reaction in an organic solvent to obtain Compound IV; the temperature of the ring-closing reaction is -100°C to 30°C, and the time is 10h to 24h; the molar ratio of Compound II to the strong base agent is 1:(1-5), preferably 1:(2-3); the mass ratio of Compound II to the volume of the organic solvent is 1:(1-30), preferably 1:(2-15), wherein the unit of the mass of Compound II is g, and the unit of the volume of the organic solvent is mL. Wherein, the strong base agent is selected from at least one of lithium hexamethyldisilazide, sodium hexamethyldisilazide, 2,2,6,6-tetramethylpiperidinium lithium, potassium hexamethyldisilazide, and lithium isopropylamide, preferably lithium hexamethyldisilazide. The organic solvent is selected from at least one of methanol, ethanol, isopropanol, tert-butyl alcohol, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, acetone, and benzene, preferably at least one of methyltetrahydrofuran and tetrahydrofuran. After the above-mentioned ring-closing reaction is completed, the compound IV can be obtained by adding acid and filtering for the next reaction. There is no complicated separation step, which makes the preparation process more concise, and the "one-pot method" reaction has few by-products and high atomic utilization. The above-mentioned acid is selected from at least one of formic acid, acetic acid, and Lewis acid, and the Lewis acid is selected from at least one of zinc chloride, tin chloride, titanium tetrachloride, etc. The molar ratio of acid to compound II is 1: (1 to 10), preferably 1: (1 to 4). In addition, the above-mentioned ring-closing reaction has high safety and good selectivity, and the reaction reagents are all conventional reagents with low cost.

本申请第五方面提供了一种化合物，其具有下式III所示结构：The fifth aspect of the present application provides a compound having a structure shown in the following formula III:

Figure PCTCN2022128678-appb-000008
Figure PCTCN2022128678-appb-000008

其中，同第一方面的取代基R 1定义。 Wherein, the substituent R1 is the same as defined in the first aspect.

例如，化合物III选自以下化合物：For example, compound III is selected from the following compounds:

Figure PCTCN2022128678-appb-000009
Figure PCTCN2022128678-appb-000009

在本申请中，化合物中的Me是指甲基，Bn是苄基，tBu是指叔丁基。In the present application, Me in the compound refers to methyl, Bn refers to benzyl, and tBu refers to tert-butyl.

本申请第六方面提供了一种前述任一实施方案中的化合物III的制备方法，其包括如下步骤：In a sixth aspect, the present application provides a method for preparing compound III in any of the aforementioned embodiments, comprising the following steps:

Figure PCTCN2022128678-appb-000010
Figure PCTCN2022128678-appb-000010

化合物II发生关环反应，得到化合物III；其中，X选自卤素、甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基、苯磺酰氧基，优选为Cl、Br、I。该关环反应巧妙地使用新化合物Ⅱ得到新化合Ⅲ，反应副产物少，原子利用率高，选择性好(例如：化合物Ⅱ的构型为SR或RR均可得到SS构型的新化合Ⅲ)，得到的异构体纯度高，反应收率也较好。Compound II undergoes a ring-closing reaction to obtain compound III, wherein X is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy, preferably Cl, Br, I. The ring-closing reaction cleverly uses new compound II to obtain new compound III, has few reaction by-products, high atomic utilization, good selectivity (for example, compound II with SR or RR configuration can obtain new compound III with SS configuration), the obtained isomer has high purity, and the reaction yield is also good.

优选地，关环反应包括以下步骤：化合物II与强碱剂在有机溶剂中发生关环反应，分离得到化合物III；关环反应的温度为-100℃～30℃、时间为10h～24h；化合物II与强碱剂的摩尔比为1:(1～10)，优选为1:(1～6)，进一步优选为1:(1～3)；化合物II的质量与有机溶剂的体积比值为1:(1～30)，其中，化合物II的质量的单位为g，有机溶剂的体积的单位为mL。强碱剂选自氢化钠、叔丁醇钾、甲醇钠、乙醇钠、叔丁醇锂、六甲基二硅基胺基锂、六甲基二硅基胺基钠、2,2,6,6-四甲基哌啶锂、六甲基二硅基胺基钾、二异丙基胺基锂中的至少一种，优选为六甲基二硅基胺基锂。有机溶剂选自甲醇、乙醇、异丙醇、叔丁醇、甲苯、二甲苯、三甲苯、二氯甲烷、1,2-二氯乙烷、1,1,2,2-四氯乙烷、氯仿、二甲基亚砜、N,N-二甲基甲酰胺、四氢呋喃、甲基四氢呋喃，1,4-二氧六环、乙醚、甲基叔丁基醚、苯中的至少一种，优选为甲基四氢呋喃、四氢呋喃中的至少一种。上述关环反应的反应条件简单、安全性高、选择性好，而且反应试剂均为常规试剂、成本低。Preferably, the ring-closing reaction comprises the following steps: Compound II and a strong base agent undergo a ring-closing reaction in an organic solvent to separate and obtain Compound III; the temperature of the ring-closing reaction is -100°C to 30°C, and the time is 10h to 24h; the molar ratio of Compound II to the strong base agent is 1:(1-10), preferably 1:(1-6), and more preferably 1:(1-3); the mass of Compound II to the volume of the organic solvent is 1:(1-30), wherein the unit of the mass of Compound II is g, and the unit of the volume of the organic solvent is mL. The strong base agent is selected from at least one of sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, 2,2,6,6-tetramethylpiperidinium lithium, potassium hexamethyldisilazide, and lithium diisopropylamide, preferably lithium hexamethyldisilazide. The organic solvent is selected from at least one of methanol, ethanol, isopropanol, tert-butyl alcohol, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, methyl tert-butyl ether, and benzene, preferably at least one of methyltetrahydrofuran and tetrahydrofuran. The above ring-closing reaction has simple reaction conditions, high safety, good selectivity, and the reaction reagents are all conventional reagents with low cost.

本申请第七方面提供了一种化合物，其具有下式II所示结构：The seventh aspect of the present application provides a compound having a structure shown in the following formula II:

Figure PCTCN2022128678-appb-000011
Figure PCTCN2022128678-appb-000011

其中，R 1同第一方面的取代基R 1定义；X选自卤素、甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基、苯磺酰氧基，优选为Cl、Br、I。 Wherein, R1 is the same as the definition of the substituent R1 in the first aspect; X is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy, preferably Cl, Br, I.

例如，化合物II选自以下化合物：For example, compound II is selected from the following compounds:

Figure PCTCN2022128678-appb-000012
Figure PCTCN2022128678-appb-000012

在本申请中，化合物中的Me是指甲基，Bn是苄基，tBu是指叔丁基。In the present application, Me in the compound refers to methyl, Bn refers to benzyl, and tBu refers to tert-butyl.

本申请第八方面提供了一种前述任一实施方案中的化合物II的制备方法，其包括以下 步骤：The eighth aspect of the present application provides a method for preparing compound II in any of the aforementioned embodiments, comprising the following steps:

Figure PCTCN2022128678-appb-000013
Figure PCTCN2022128678-appb-000013

化合物I或其盐与化合物VII发生开环反应，分离得到化合物II。该开环反应未进行异构化反应，适合规模化生产，且反应收率高。上述化合物I或其盐是指化合物I或者化合物I的盐，化合物I的盐可以包括但不限于化合物I中的NH与HCl、氢溴酸、酒石酸、扁桃酸、硫酸、甲磺酸或草酸结合形成的盐。Compound I or its salt undergoes a ring-opening reaction with compound VII to separate compound II. The ring-opening reaction does not undergo an isomerization reaction, is suitable for large-scale production, and has a high reaction yield. The above-mentioned compound I or its salt refers to compound I or a salt of compound I, and the salt of compound I may include but is not limited to a salt formed by combining NH in compound I with HCl, hydrobromic acid, tartaric acid, mandelic acid, sulfuric acid, methanesulfonic acid or oxalic acid.

优选地，上述开环反应包括以下步骤：在碱剂的条件下，化合物I或其盐与化合物VII在有机溶剂中发生开环反应，分离得到化合物II；开环反应的温度为室温到有机溶剂的回流温度，优选为40℃～100℃、时间为1h～72h；化合物I与碱剂的摩尔比为1:(1～10)，优选为1:(1～4)；化合物I与化合物VII的摩尔比为1:(1～10)，优选为1:(1～2)，进一步优选为1:(1～1.5)；化合物I的质量与有机溶剂的体积比值为1:(1～20)，优选为1:(5～15)，其中，化合物I的质量的单位为g，有机溶剂的体积的单位为mL。碱剂选自无机碱或有机碱，无机碱选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸铯、碳酸锂中的至少一种，有机碱选自三乙胺、吡啶、二异丙基乙基胺或N,N-二甲基苯胺中的至少一种；碱剂优选为三乙胺、吡啶、二异丙基乙基胺、N,N-二甲基苯胺中的至少一种，进一步选为三乙胺。有机溶剂选自醇类溶剂、氯代烷烃、醚类溶剂、液态烷烃类溶剂中的至少一种，醇类溶剂选自甲醇、乙醇、异丙醇、正丁醇、叔丁醇中的至少一种；氯代烷烃溶剂选自二氯甲烷、1,2-二氯乙烷、1,1,2,2-四氯乙烷、氯仿中的至少一种；醚类溶剂选自四氢呋喃、甲基四氢呋喃，1,4-二氧六环、乙醚、甲基叔丁基醚中的至少一种；液态烷烃类溶剂选自正己烷、正庚烷、环己烷、甲苯中的至少一种。上述开环反应的反应条件简单、安全性高、选择性好，而且反应试剂均为常规试剂、成本低。Preferably, the above-mentioned ring-opening reaction comprises the following steps: under the condition of an alkaline agent, compound I or its salt and compound VII undergo a ring-opening reaction in an organic solvent to separate compound II; the temperature of the ring-opening reaction is from room temperature to the reflux temperature of the organic solvent, preferably 40°C to 100°C, and the time is 1h to 72h; the molar ratio of compound I to the alkaline agent is 1:(1-10), preferably 1:(1-4); the molar ratio of compound I to compound VII is 1:(1-10), preferably 1:(1-2), and further preferably 1:(1-1.5); the ratio of the mass of compound I to the volume of the organic solvent is 1:(1-20), preferably 1:(5-15), wherein the unit of the mass of compound I is g, and the unit of the volume of the organic solvent is mL. The alkali agent is selected from an inorganic base or an organic base, the inorganic base is selected from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate, and the organic base is selected from at least one of triethylamine, pyridine, diisopropylethylamine, and N,N-dimethylaniline; the alkali agent is preferably at least one of triethylamine, pyridine, diisopropylethylamine, and N,N-dimethylaniline, and further selected as triethylamine. The organic solvent is selected from at least one of alcohol solvents, chlorinated alkanes, ether solvents, and liquid alkane solvents, the alcohol solvent is selected from at least one of methanol, ethanol, isopropanol, n-butanol, and tert-butanol; the chlorinated alkane solvent is selected from at least one of dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and chloroform; the ether solvent is selected from at least one of tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, and methyl tert-butyl ether; the liquid alkane solvent is selected from at least one of n-hexane, n-heptane, cyclohexane, and toluene. The above ring-opening reaction has simple reaction conditions, high safety, good selectivity, and the reaction reagents are all conventional reagents with low cost.

本申请对上述各步骤中的分离步骤没有特别限定，可以采用本领域已知的分离步骤，只要能实现本申请的目的即可。例如，分离步骤可以包括但不限于：采用水、盐溶液或其他有机溶剂淬灭反应、萃取、水洗或其他溶剂洗涤、活性炭处理、过滤、浓缩、重结晶等。上述盐溶液、其他有机溶剂可以采用本领域已知的分离时所用的常规盐溶液、有机溶剂， 本申请对此不作限定，只要能实现本申请的目的即可。The present application does not specifically limit the separation steps in the above steps, and separation steps known in the art can be used, as long as the purpose of the present application can be achieved. For example, the separation steps may include, but are not limited to: quenching the reaction with water, salt solution or other organic solvents, extraction, washing with water or other solvents, activated carbon treatment, filtration, concentration, recrystallization, etc. The above-mentioned salt solution and other organic solvents can be conventional salt solutions and organic solvents used for separation known in the art, and the present application does not limit this, as long as the purpose of the present application can be achieved.

本申请的有益效果：Beneficial effects of this application:

本申请提供的化合物VI的制备方法，可以为以下任一合成路线：化合物III→化合物V→化合物VI、化合物IV→化合物V→化合物VI、化合物III→化合物IV→化合物V→化合物VI、化合物II→化合物IV→化合物V→化合物VI、化合物II→化合物III→化合物IV→化合物V→化合物VI、化合物I→化合物II→化合物IV→化合物V→化合物VI、化合物I→化合物II→化合物III→化合物IV→化合物V→化合物VI。化合物VI具有一个氟杂叔碳的手性中心和一个氮杂季碳手性中心，合成难度较高，本申请提供的制备方法，不仅操作简单、反应条件温和、反应时间短，而且收率高、手性纯度高，得到的化合物VI质量较高，例如，反应总收率可达36％，手性碳原子的手性纯度可达99.0％以上。The preparation method of compound VI provided in the present application can be any of the following synthetic routes: compound III→compound V→compound VI, compound IV→compound V→compound VI, compound III→compound IV→compound V→compound VI, compound II→compound IV→compound V→compound VI, compound II→compound III→compound IV→compound V→compound VI, compound I→compound II→compound IV→compound V→compound VI, compound I→compound II→compound III→compound IV→compound V→compound VI. Compound VI has a fluorine-containing tertiary carbon chiral center and a nitrogen-containing quaternary carbon chiral center, and is difficult to synthesize. The preparation method provided in the present application is not only simple to operate, has mild reaction conditions, and a short reaction time, but also has a high yield and high chiral purity. The obtained compound VI is of high quality. For example, the total reaction yield can reach 36%, and the chiral purity of the chiral carbon atom can reach more than 99.0%.

当然，实施本申请的任一产品或方法并不一定需要同时达到以上所述的所有优点。Of course, implementing any product or method of the present application does not necessarily require achieving all of the advantages described above at the same time.

具体实施方式Detailed ways

为使本申请的目的、技术方案、及优点更加清楚明白，以下参照实施例，对本申请进一步详细说明。显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员所获得的所有其他实施例，都属于本申请保护的范围。In order to make the purpose, technical scheme, and advantages of the present application more clearly understood, the present application is further described in detail with reference to the embodiments below. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field belong to the scope of protection of the present application.

实施例1：化合物II-1的制备Example 1: Preparation of Compound II-1

Figure PCTCN2022128678-appb-000014
Figure PCTCN2022128678-appb-000014

将化合物I-1(50g，303mmol，1.0当量(equiv))加入甲醇(500mL)中，然后加入(R)-环氧氯丙烷(化合物VII-1，33.5g，362.1mmol，1.2equiv)，三乙胺(TEA，36.7g，362.7mmol，1.2equiv)，加热到80℃回流3小时。将体系浓缩至不出流，加入二氯甲烷(DCM)溶解，再加入KHCO 3(30g)水(250ml)溶液洗涤，分液，浓缩至基本无馏出，将体系于DCM：MeOH(体积比40:1)过柱子后缩干得到57g化合物II-1，淡黄色油状物，收率85％。 Compound I-1 (50 g, 303 mmol, 1.0 equiv) was added to methanol (500 mL), and then (R)-epichlorohydrin (Compound VII-1, 33.5 g, 362.1 mmol, 1.2 equiv) and triethylamine (TEA, 36.7 g, 362.7 mmol, 1.2 equiv) were added, and the mixture was heated to 80°C and refluxed for 3 hours. The system was concentrated until no outflow occurred, and dichloromethane (DCM) was added to dissolve it, and then KHCO 3 (30 g) and water (250 ml) were added to wash, and the mixture was separated and concentrated until almost no distillation occurred. The system was passed through a column in DCM:MeOH (volume ratio 40:1) and then dried to obtain 57 g of compound II-1 as a light yellow oil with a yield of 85%.

1H NMR(400MHz,CDCl 3)δ3.73(dt,J＝12.3,5.5Hz,1H),3.69(s,3H),3.67(d,J＝5.3Hz,1H),3.60–3.49(m,2H),3.36–3.28(m,1H),3.13(ddd,J＝11.2,7.3,4.0Hz,1H),2.83– 2.70(m,2H),2.63(dd,J＝16.4,7.7Hz,1H),2.19–2.08(m,1H),1.97–1.74(m,3H). 13C NMR(100MHz,DMSO-d 6)δ174.0,69.2,65.4,57.4,53.6,51.4,48.5,28.6,23.3.m/z calcd for C 9H 17ClNO 3 +,[M+H] +:222.1,found:222.1. 1 H NMR (400 MHz, CDCl 3 ) δ 3.73 (dt, J = 12.3, 5.5 Hz, 1H), 3.69 (s, 3H), 3.67 (d, J = 5.3 Hz, 1H), 3.60–3.49 (m, 2H), 3.36–3.28 (m, 1H), 3.13 (ddd, J = 11.2, 7.3, 4.0 Hz, 1H), 2.83– 2.70 (m, 2H), 2.63 (dd, J = 16.4, 7.7 Hz, 1H), 2.19–2.08 (m, 1H), 1.97–1.74 (m, 3H). 13 C NMR (100 MHz, DMSO-d 6 )δ174.0,69.2,65.4,57.4,53.6,51.4,48.5,28.6,23.3.m/z calcd for C 9 H 17 ClNO 3 + ,[M+H] + :222.1,found:222.1.

实施例2：化合物II-2的制备Example 2: Preparation of Compound II-2

Figure PCTCN2022128678-appb-000015
Figure PCTCN2022128678-appb-000015

将化合物I-2(58.5g，353.2mmol，1.0equiv)加入甲醇(585mL)中，搅拌溶清，然后滴加(R)-环氧氯丙烷(39.2g，423.7mmol，1.2equiv)，TEA(35.7g，352.8mmol，1.0equiv)，滴毕，加热到80℃回流反应3小时。浓缩至基本无馏出，加入DCM溶解，用8％碳酸氢钾(585mL)洗两次，水洗一次，浓缩至基本无馏出，过柱纯化得到55.5g产物化合物II-2，淡黄色油状物，收率71％。Compound I-2 (58.5 g, 353.2 mmol, 1.0 equiv) was added to methanol (585 mL), stirred to dissolve, and then (R)-epichlorohydrin (39.2 g, 423.7 mmol, 1.2 equiv) and TEA (35.7 g, 352.8 mmol, 1.0 equiv) were added dropwise. After the addition was completed, the mixture was heated to 80° C. and refluxed for 3 hours. The mixture was concentrated until almost no distillate was produced, DCM was added to dissolve the mixture, the mixture was washed twice with 8% potassium bicarbonate (585 mL), washed once with water, concentrated until almost no distillate was produced, and purified by column to obtain 55.5 g of the product compound II-2 as a light yellow oil with a yield of 71%.

1H NMR(400MHz,DMSO-d 6)δ3.67-3.61(m,1H),3.60(s,3H),3.52(dd,J＝10.9,5.5Hz,1H),3.37-3.24(m,2H),3.09-2.96(m,1H),2.62(dd,J＝5.7,3.8Hz,2H),2.50(dd,J＝5.5,3.8Hz,1H),2.12-1.97(m,1H),1.87-1.58(m,4H). 13C NMR(100MHz,DMSO-d 6)δ174.3,69.1,65.3,57.3,53.9,51.4,48.3,29.0,23.3.m/z calcd for C 9H 17ClNO 3 +,[M+H] +:222.1,found:222.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.67-3.61 (m, 1H), 3.60 (s, 3H), 3.52 (dd, J = 10.9, 5.5 Hz, 1H), 3.37-3.24 (m, 2H), 3.09-2.96 (m, 1H), 2.62 (dd, J = 5.7, 3.8 Hz, 2H), 2.50 (dd, J = 5.5, 3.8 Hz, 1H), 2.12-1.97 (m, 1H), 1.87-1.58 (m, 4H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 174.3, 69.1, 65.3, 57.3, 53.9, 51.4, 48.3, 29.0, 23.3. m/z calcd for C 9 H 17 ClNO 3 + ,[M+H] + :222.1,found:222.1.

实施例3：化合物III-1的制备Example 3: Preparation of Compound III-1

Figure PCTCN2022128678-appb-000016
Figure PCTCN2022128678-appb-000016

N 2保护下，将化合物II-1(2g，9mmol，1equiv)溶于四氢呋喃(THF，45mL)，降温至-70℃，然后滴入六甲基二硅基胺基锂(LiHMDS，14.4mL,14.4mmol，1.6equiv)，然后保温反应12h。加入10％NH 4Cl水溶液淬灭反应，DCM萃取，合并有机相，饱和氯化钠水溶液洗一次，无水硫酸钠干燥，过滤浓缩后柱层析纯化，得698mg产物化合物III-1，收率42％。 Under N2 protection, compound II-1 (2 g, 9 mmol, 1 equiv) was dissolved in tetrahydrofuran (THF, 45 mL), cooled to -70°C, and then lithium hexamethyldisilazide (LiHMDS, 14.4 mL, 14.4 mmol, 1.6 equiv) was added dropwise, and then kept warm for 12 h. A 10% NH4Cl aqueous solution was added to quench the reaction, and DCM was extracted. The organic phases were combined, washed once with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography to obtain 698 mg of the product compound III-1, with a yield of 42%.

1H NMR(400MHz,CDCl 3)δ4.41(t,J＝4.4Hz,1H),3.74(s,3H),3.27(d,J＝10.7Hz,1H), 3.13(dt,J＝10.7,6.4Hz,1H),2.76(dd,J＝10.7,4.1Hz,1H),2.64(dt,J＝10.7,6.3Hz,1H),2.45(d,J＝14.0Hz,1H),2.33(dt,J＝13.0,6.7Hz,1H),1.95-1.79(m,3H),1.74-1.62(m,1H).m/z calcd for C 9H 16NO 3 +,[M+H] +:186.1,found:186.3. 1 H NMR (400 MHz, CDCl 3 ) δ 4.41 (t, J = 4.4 Hz, 1H), 3.74 (s, 3H), 3.27 (d, J = 10.7 Hz, 1H), 3.13 (dt, J = 10.7, 6.4 Hz, 1H), 2.76 (dd, J = 10.7, 4.1 Hz, 1H), 2.64 (dt, J = 10.7, 6.3 Hz, 1H), 2.45 (d, J = 14.0 Hz, 1H), 2.33 (dt, J = 13.0, 6.7 Hz, 1H), 1.95-1.79 (m, 3H), 1.74-1.62 (m, 1H). m/z calcd for C 9 H 16 NO 3 + , [M+H] + : 186.1, found: 186.3.

实施例4：化合物III-1的制备Example 4: Preparation of Compound III-1

Figure PCTCN2022128678-appb-000017
Figure PCTCN2022128678-appb-000017

将化合物II-2(20g，90.2mmol，1equiv)溶于THF(450mL)，然后降温至-70℃，滴加LiHMDS(144.3mL，144.3mmol，1.6equiv)，滴毕后保温反应24h。加入10％氯化铵(500mL)，搅拌20min，DCM(200mL)萃取，有机相浓缩至无馏出，柱层析纯化得到7.1g产物化合物III-1，棕色固体，收率42.5％。Compound II-2 (20 g, 90.2 mmol, 1 equiv) was dissolved in THF (450 mL), then cooled to -70°C, and LiHMDS (144.3 mL, 144.3 mmol, 1.6 equiv) was added dropwise, and the mixture was kept warm for 24 h. 10% ammonium chloride (500 mL) was added, stirred for 20 min, extracted with DCM (200 mL), the organic phase was concentrated until no distillate was produced, and purified by column chromatography to obtain 7.1 g of the product compound III-1 as a brown solid with a yield of 42.5%.

实施例5：化合物IV-1的制备Example 5: Preparation of Compound IV-1

Figure PCTCN2022128678-appb-000018
Figure PCTCN2022128678-appb-000018

将化合物III-1(1g，5.4mmol，1equiv)溶于DCM(27mL)中，加入TEA(1.5mL，10.8mmol，2.0equiv)，降温至0℃，将对甲基苯磺酰氯(TsCl，1.5g，8.1mmol，1.5equiv)和4-二甲氨基吡啶(DMAP，66mg，0.54mmol，0.1eq)加入，然后恢复至室温(25±5℃)反应。28h后，加入10％NH 4Cl水溶液淬灭反应，乙酸乙酯(EA)稀释，分液，饱和氯化钠水溶液洗三次，无水硫酸钠干燥。过滤浓缩后柱层析纯化，得1g产物化合物IV-1，收率55％。 Compound III-1 (1 g, 5.4 mmol, 1 equiv) was dissolved in DCM (27 mL), TEA (1.5 mL, 10.8 mmol, 2.0 equiv) was added, the temperature was lowered to 0°C, p-toluenesulfonyl chloride (TsCl, 1.5 g, 8.1 mmol, 1.5 equiv) and 4-dimethylaminopyridine (DMAP, 66 mg, 0.54 mmol, 0.1 eq) were added, and then the temperature was restored to room temperature (25±5°C) for reaction. After 28 h, 10% NH 4 Cl aqueous solution was added to quench the reaction, and the mixture was diluted with ethyl acetate (EA), separated, washed three times with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After filtration and concentration, the mixture was purified by column chromatography to obtain 1 g of the product compound IV-1 with a yield of 55%.

1H NMR(400MHz,CDCl 3)δ7.76(d,J＝8.3Hz,2H),7.33(d,J＝8.3Hz,2H),5.14-5.07(m,1H),3.69(s,3H),3.32(dd,J＝12.2,2.8Hz,1H),3.27-3.18(m,1H),2.89(dd,J＝12.2,5.0Hz,1H),2.75-2.66(m,1H),2.60(ddd,J＝10.5,7.0,2.4Hz,1H),2.44(s,3H),2.23-2.14(m,1H),1.96(dd,J＝14.3,5.6Hz,1H),1.92-1.72(m,3H).m/z calcd for C 16H 22NO 5S +,[M+H] +:340.1,found:340.1. 1 H NMR (400 MHz, CDCl 3 ) δ 7.76 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 5.14-5.07 (m, 1H), 3.69 (s, 3H), 3.32 (dd, J = 12.2, 2.8 Hz, 1H), 3.27-3.18 (m, 1H), 2.89 (dd, J = 12.2, 5.0 Hz, 1H), 2.75-2.66 (m, 1H), 2.60 (ddd, J = 10.5, 7.0, 2.4 Hz, 1H), 2.44 (s, 3H), 2.23-2.14 (m, 1H), 1.96 (dd, J = 14.3, 5.6 Hz, 1H), 1.92-1.72 (m, 3H). m/z calcd for C 16 H 22 NO 5 S + ,[M+H] + :340.1,found:340.1.

实施例6：化合物V-1的制备Example 6: Preparation of Compound V-1

Figure PCTCN2022128678-appb-000019
Figure PCTCN2022128678-appb-000019

将化合物III-1(500mg，2.7mmol，1equiv)溶于乙腈(2mL)中，加入TEA(2.3mL，16.2mmol，6.0equiv)，降温至0℃，然后滴入将三乙胺三氢氟酸盐(1.3mL，8.1mmol，3equiv)，冰浴下反应两小时。滴入全氟丁基磺酰氟(0.5mL，2.8mmol，1.05equiv)，然后升至室温反应14小时。缓慢滴加饱和碳酸氢钠水溶液淬灭反应，DCM萃取，饱和氯化钠水溶液洗一次，无水硫酸钠干燥。过滤浓缩后柱层析纯化，得291mg产物化合物V-1，收率57.6％。Compound III-1 (500 mg, 2.7 mmol, 1 equiv) was dissolved in acetonitrile (2 mL), TEA (2.3 mL, 16.2 mmol, 6.0 equiv) was added, the temperature was lowered to 0 ° C, and triethylamine trihydrofluoride (1.3 mL, 8.1 mmol, 3 equiv) was then added dropwise, and the mixture was reacted for two hours under an ice bath. Perfluorobutylsulfonyl fluoride (0.5 mL, 2.8 mmol, 1.05 equiv) was added dropwise, and the mixture was heated to room temperature and reacted for 14 hours. Saturated sodium bicarbonate aqueous solution was slowly added dropwise to quench the reaction, extracted with DCM, washed once with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After filtration and concentration, the mixture was purified by column chromatography to obtain 291 mg of the product compound V-1 with a yield of 57.6%.

1H NMR(400MHz,CDCl 3)δ5.33-5.26(m,0.5H),5.19-5.12(m,0.5H),3.71(s,3H),3.39-3.31(m,1H),3.29-3.20(m,1H),3.20-3.15(m,1H),2.99-2.86(m,1H),2.55-2.37(m,2H),2.33-2.16(m,1H),2.00-1.80(m,3H).m/z calcd for C 9H 15FNO 2 +,[M+H] +:188.1,found:188.2. 1 H NMR (400 MHz, CDCl 3 ) δ 5.33-5.26 (m, 0.5H), 5.19-5.12 (m, 0.5H), 3.71 (s, 3H), 3.39-3.31 (m, 1H), 3.29-3.20 (m, 1H), 3.20-3.15 (m, 1H), 2.99-2.86 (m, 1H), 2.55-2.37 (m, 2H), 2.33-2.16 (m, 1H), 2.00-1.80 (m, 3H). m/z calcd for C 9 H 15 FNO 2 + , [M+H] + : 188.1, found: 188.2.

实施例7：化合物VI的制备Example 7: Preparation of Compound VI

Figure PCTCN2022128678-appb-000020
Figure PCTCN2022128678-appb-000020

将化合物V-1(196mg，1.05mmol，1equiv)溶于THF(2.6mL)中，降温至0℃，将氢化铝锂(LiAlH4，119mg，3.1mmol，3.0equiv)加入，保持0℃反应30分钟。依次加入水(0.12mL)，15％NaOH水溶液(0.24mL)和水(0.36mL)淬灭反应，硅藻土过滤，乙酸乙酯冲洗，滤液浓缩后柱层析纯化，得到164mg产物化合物VI，收率52.5％，淡黄色固体，产品手性纯度(ee)为99.5％。Compound V-1 (196 mg, 1.05 mmol, 1 equiv) was dissolved in THF (2.6 mL), cooled to 0°C, and lithium aluminum hydride (LiAlH4, 119 mg, 3.1 mmol, 3.0 equiv) was added, and the reaction was maintained at 0°C for 30 minutes. Water (0.12 mL), 15% NaOH aqueous solution (0.24 mL) and water (0.36 mL) were added in sequence to quench the reaction, filtered through diatomaceous earth, rinsed with ethyl acetate, and the filtrate was concentrated and purified by column chromatography to obtain 164 mg of product compound VI, with a yield of 52.5%, a light yellow solid, and a product chiral purity (ee) of 99.5%.

1H NMR(400MHz,CDCl 3)δ5.25(m,0.5H),5.11(m,0.5H),3.35(brs,1H),3.25(s,2H),3.21-3.14(m,1H),3.14-3.09(m,1H),3.07(s,0.5H),3.00(dd,J＝13.9,3.1Hz,0.5H),2.90(dd,J＝15.0,8.7Hz,1H),2.13(dd,J＝14.7,4.5Hz,0.5H),2.06(s,0.5H),2.01(dd,J＝7.1,2.9Hz,1H),1.96-1.82(m,2H),1.82-1.66(m,2H). 13C NMR(100MHz,CDCl 3)δ97.9(d,J＝175.2Hz),74.6,68.0,61.2(d,J＝19.5Hz),57.1,41.4(d,J＝20.0Hz),35.5,25.7. 19F NMR (376MHz,CDCl 3)δ-172.2.m/z calcd for C 8H 15FNO +,[M+H] +:160.1,found:160.3. 1 H NMR (400 MHz, CDCl 3 ) δ 5.25 (m, 0.5 H), 5.11 (m, 0.5 H), 3.35 (brs, 1 H), 3.25 (s, 2 H), 3.21-3.14 (m, 1 H), 3.14-3.09 (m, 1 H), 3.07 (s, 0.5 H), 3.00 (dd, J = 13.9, 3.1 Hz, 0.5 H), 2.90 (dd, J = 15.0, 8.7 Hz, 1 H), 2.13 (dd, J = 14.7, 4.5 Hz, 0.5 H), 2.06 (s, 0.5 H), 2.01 (dd, J = 7.1, 2.9 Hz, 1 H), 1.96-1.82 (m, 2 H), 1.82-1.66 (m, 2 H). 13 C NMR (100 MHz, CDCl 3 ) δ97.9 (d, J＝175.2 Hz), 74.6, 68.0, 61.2 (d, J＝19.5 Hz), 57.1, 41.4 (d, J＝20.0 Hz), 35.5, 25.7. 19 F NMR (376 MHz, CDCl 3 ) δ-172.2. m/z calcd for C 8 H 15 FNO + , [M+H] + : 160.1, found: 160.3.

实施例8：化合物II-3的制备Example 8: Preparation of Compound II-3

Figure PCTCN2022128678-appb-000021
Figure PCTCN2022128678-appb-000021

烧瓶中加入化合物I-3(52.10g，215.5mmol，1.0equiv)，异丙醇(260mL)，(R)-环氧氯丙烷(30.5g，329.7mmol，1.5equiv)，TEA(30mL，215.5mmol，1.0equiv)，升温至70℃，反应3小时。然后降至室温，浓缩至基本无馏出，加入DCM溶解，用8％碳酸氢钾(521mL)洗，水洗一次，浓缩至基本无馏出，柱层析纯化得到58g产物化合物II-3，淡黄色油状物，收率90％。Compound I-3 (52.10 g, 215.5 mmol, 1.0 equiv), isopropanol (260 mL), (R)-epichlorohydrin (30.5 g, 329.7 mmol, 1.5 equiv), TEA (30 mL, 215.5 mmol, 1.0 equiv) were added to a flask, and the temperature was raised to 70°C for 3 hours. Then the mixture was cooled to room temperature, concentrated until almost no distillate was produced, dissolved in DCM, washed with 8% potassium bicarbonate (521 mL), washed once with water, concentrated until almost no distillate was produced, and purified by column chromatography to obtain 58 g of the product compound II-3 as a light yellow oil with a yield of 90%.

1H NMR(400MHz,CDCl 3)δ7.42-7.28(m,5H),5.23-5.06(m,2H),3.87(dt,J＝13.6,4.9Hz,1H),3.51(qd,J＝11.2,5.2Hz,2H),3.41(dd,J＝9.1,5.8Hz,1H),3.28-3.20(m,1H),2.76-2.68(m,2H),2.44(dd,J＝16.5,8.1Hz,1H),2.22-2.08(m,1H),2.00-1.77(m,3H).m/z calcd for C 15H 21ClNO 3 +,[M+H] +:298.1,found:298.1. 1 H NMR (400 MHz, CDCl 3 ) δ 7.42-7.28 (m, 5H), 5.23-5.06 (m, 2H), 3.87 (dt, J=13.6, 4.9 Hz, 1H), 3.51 (qd, J=11.2, 5.2 Hz, 2H), 3.41 (dd, J=9.1, 5.8 Hz, 1H), 3.28-3.20 (m, 1H), 2.76-2.68 (m, 2H), 2.44 (dd, J=16.5, 8.1 Hz, 1H), 2.22-2.08 (m, 1H), 2.00-1.77 (m, 3H). m/z calcd for C 15 H 21 ClNO 3 + , [M+H] + : 298.1, found: 298.1.

实施例9：化合物III-2的制备Example 9: Preparation of Compound III-2

Figure PCTCN2022128678-appb-000022
Figure PCTCN2022128678-appb-000022

将化合物II-3(40.0g，134.3mmol，1equiv)加入THF(1.1L)中，N 2置换三次，降温-70℃，滴加LiHMDS(221.5mL，214.9mmol，1.6equiv)，保温反应12小时。加入10％氯化铵淬灭，DCM萃取，有机相饱和食盐水洗一次，有机相干燥，柱层析纯化得到26g产物化合物III-2，白色固体，收率74％。 Compound II-3 (40.0 g, 134.3 mmol, 1 equiv) was added to THF (1.1 L), replaced with N 2 three times, cooled to -70 ° C, and LiHMDS (221.5 mL, 214.9 mmol, 1.6 equiv) was added dropwise, and the reaction was kept warm for 12 hours. 10% ammonium chloride was added to quench, DCM was extracted, the organic phase was washed once with saturated brine, the organic phase was dried, and column chromatography was used to purify to obtain 26 g of the product compound III-2 as a white solid with a yield of 74%.

1H NMR(400MHz,CDCl 3)δ7.40-7.28(m,5H),5.18(q,J＝12.4Hz,2H),4.41(t,J＝4.4Hz,1H),3.29(dt,J＝10.6,1.3Hz,1H),3.14(dt,J＝10.6,6.4Hz,1H),2.76(dd,J＝10.6,4.0Hz,1H),2.64(dt,J＝10.7,6.3Hz,1H),2.46(dt,J＝14.0,1.4Hz,1H),2.35(dt,J＝13.0,6.6Hz,1H),1.93-1.76(m,3H),1.73-1.60(m,1H).m/z calcd for C 15H 20NO 3 +,[M+H] +:262.3,found:262.1. 1 H NMR (400 MHz, CDCl 3 ) δ 7.40-7.28 (m, 5H), 5.18 (q, J = 12.4 Hz, 2H), 4.41 (t, J = 4.4 Hz, 1H), 3.29 (dt, J = 10.6, 1.3 Hz, 1H), 3.14 (dt, J = 10.6, 6.4 Hz, 1H), 2.76 (dd, J = 10.6, 4.0 Hz, 1H), 2.64 (dt, J = 10.7, 6.3 Hz, 1H), 2.46 (dt, J = 14.0, 1.4 Hz, 1H), 2.35 (dt, J = 13.0, 6.6 Hz, 1H), 1.93-1.76 (m, 3H), 1.73-1.60 (m, 1H). m/z calcd for C 15 H 20 NO 3 + ,[M+H] + :262.3,found:262.1.

实施例10：化合物V-2的制备Example 10: Preparation of Compound V-2

Figure PCTCN2022128678-appb-000023
Figure PCTCN2022128678-appb-000023

将化合物III-2(10g，38mmol，1equiv)溶于THF(38mL)中，加入TEA(32mL，228mmol，6.0equiv)，降温至0℃，滴入三乙胺三氢氟酸盐(19mL，114mmol，3equiv)，然后冰浴下反应两小时。滴入全氟丁基磺酰氟(7mL，39.9mmol，1.05equiv)，然后升至室温反应12小时。缓慢滴加饱和碳酸氢钠水溶液淬灭反应，DCM萃取两次，饱和氯化钠水溶液洗一次，无水硫酸钠干燥，过滤浓缩后柱层析纯化，得57g产物化合物V-2 6.，收率66％。Compound III-2 (10 g, 38 mmol, 1 equiv) was dissolved in THF (38 mL), TEA (32 mL, 228 mmol, 6.0 equiv) was added, the temperature was lowered to 0 °C, triethylamine trihydrofluoride (19 mL, 114 mmol, 3 equiv) was added dropwise, and then the mixture was reacted under ice bath for two hours. Perfluorobutylsulfonyl fluoride (7 mL, 39.9 mmol, 1.05 equiv) was added dropwise, and then the mixture was heated to room temperature for 12 hours. Saturated sodium bicarbonate aqueous solution was slowly added dropwise to quench the reaction, the mixture was extracted twice with DCM, washed once with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography to obtain 57 g of product compound V-2 6., with a yield of 66%.

1H NMR(400MHz,CDCl 3)δ7.39-7.27(m,5H),5.30-5.24(m,0.5H),5.15(s,2H),5.17-5.11(m,0.5H),3.33(ddd,J＝8.4,3.2,1.6Hz,1H),3.29-3.21(m,1H),3.18(dd,J＝15.1,2.4Hz,1H),2.93(ddd,J＝9.0,7.7,4.5Hz,1H),2.57-2.34(m,2H),2.28-2.14(m,1H),1.97-1.78(m,3H).m/z calcd for C 15H 19FNO 2 +,[M+H] +:264.1,found:264.2. 1 H NMR (400 MHz, CDCl 3 ) δ 7.39-7.27 (m, 5H), 5.30-5.24 (m, 0.5H), 5.15 (s, 2H), 5.17-5.11 (m, 0.5H), 3.33 (ddd, J = 8.4, 3.2, 1.6 Hz, 1H), 3.29-3.21 (m, 1H), 3.18 (dd, J = 15.1, 2.4 Hz, 1H), 2.93 (ddd, J = 9.0, 7.7, 4.5 Hz, 1H), 2.57-2.34 (m, 2H), 2.28-2.14 (m, 1H), 1.97-1.78 (m, 3H). m/z calcd for C 15 H 19 FNO 2 + , [M+H] + :264.1,found:264.2.

实施例11：化合物VI的制备Example 11: Preparation of Compound VI

Figure PCTCN2022128678-appb-000024
Figure PCTCN2022128678-appb-000024

将化合物V-2(5.6g，21.2mmol，1equiv)溶于THF(60mL)中，降温至0℃，将LiAlH 4(2.4g，63.8mmol，3.0equiv)加入，保持0℃反应1小时。依次加入水(2.4mL)，15％NaOH水溶液(.4.8mL)和水(7.2mL)淬灭反应，硅藻土过滤，乙酸乙酯冲洗，滤液浓缩后柱层析纯化，得2.8g产物化合物VI，淡黄色固体，收率82％，产品ee为99.8％。 Compound V-2 (5.6 g, 21.2 mmol, 1 equiv) was dissolved in THF (60 mL), cooled to 0°C, and LiAlH 4 (2.4 g, 63.8 mmol, 3.0 equiv) was added, and the reaction was maintained at 0°C for 1 hour. Water (2.4 mL), 15% NaOH aqueous solution (.4.8 mL) and water (7.2 mL) were added in sequence to quench the reaction, filtered with diatomaceous earth, rinsed with ethyl acetate, and the filtrate was concentrated and purified by column chromatography to obtain 2.8 g of product compound VI as a light yellow solid, with a yield of 82% and a product ee of 99.8%.

实施例12：化合物II-4的制备Example 12: Preparation of Compound II-4

Figure PCTCN2022128678-appb-000025
Figure PCTCN2022128678-appb-000025

将化合物I-4(10g，48.1mmol，1equiv)加入异丙醇(50mL)中，然后加入(R)-环氧氯丙烷(6.68g，72.2mmol，1.5equiv)，降温-5℃，滴加TEA(4.8g，47.4mmol，1.0equiv)，滴毕加热到95℃回流反应72小时。然后降至室温，浓缩至基本无馏出，加入DCM溶解，用8％碳酸氢钾(521mL)洗，水洗一次，浓缩至基本无馏出，柱层析纯化得到9.2g产物化合物II-4，淡黄色油状物，收率73％。Compound I-4 (10 g, 48.1 mmol, 1 equiv) was added to isopropanol (50 mL), and then (R)-epichlorohydrin (6.68 g, 72.2 mmol, 1.5 equiv) was added, the temperature was lowered to -5°C, TEA (4.8 g, 47.4 mmol, 1.0 equiv) was added dropwise, and the mixture was heated to 95°C for reflux reaction for 72 hours. The mixture was then cooled to room temperature, concentrated until almost no distillate was produced, dissolved in DCM, washed with 8% potassium bicarbonate (521 mL), washed once with water, concentrated until almost no distillate was produced, and purified by column chromatography to obtain 9.2 g of product compound II-4 as a light yellow oil with a yield of 73%.

1H NMR(400MHz,CDCl 3)δ3.88(dt,J＝11.8,5.9Hz,1H),3.69(d,J＝5.3Hz,1H),3.59-3.46(m,2H),3.27-3.19(m,2H),2.72(d,J＝6.8Hz,2H),2.46-2.34(m,1H),2.20-2.04(m,1H),1.98-1.74(m,3H),1.46(s,9H).m/z calcd for C 12H 23ClNO 3 +,[M+H] +:264.1,found:264.1. 1 H NMR (400 MHz, CDCl 3 ) δ 3.88 (dt, J = 11.8, 5.9 Hz, 1H), 3.69 (d, J = 5.3 Hz, 1H), 3.59-3.46 (m, 2H), 3.27-3.19 (m, 2H), 2.72 (d, J = 6.8 Hz, 2H), 2.46-2.34 (m, 1H), 2.20-2.04 (m, 1H), 1.98-1.74 (m, 3H), 1.46 (s, 9H). m/z calcd for C 12 H 23 ClNO 3 + , [M+H] + : 264.1, found: 264.1.

实施例13：化合物IV-2的制备Example 13: Preparation of Compound IV-2

Figure PCTCN2022128678-appb-000026
Figure PCTCN2022128678-appb-000026

将化合物II-4(20g，75.8mmol，1equiv)加入THF(60mL)中，氮气置换三次，降温-70℃，滴加LiHMDS(121mL，121mol，1.6equiv)，滴毕，保温反应16小时。滴加醋酸(6.5mL，113.7mmol，1.5equiv)，氮气保护下，垫硅藻土，过滤。滤液浓缩后减压蒸馏得17.7g化合物IV-2，淡黄色液体，收率78％。Compound II-4 (20 g, 75.8 mmol, 1 equiv) was added to THF (60 mL), replaced with nitrogen three times, cooled to -70 ° C, and LiHMDS (121 mL, 121 mol, 1.6 equiv) was added dropwise. After the addition was completed, the reaction was kept warm for 16 hours. Acetic acid (6.5 mL, 113.7 mmol, 1.5 equiv) was added dropwise, and diatomaceous earth was padded under nitrogen protection and filtered. The filtrate was concentrated and distilled under reduced pressure to obtain 17.7 g of compound IV-2, a light yellow liquid, with a yield of 78%.

1H NMR(400MHz,CDCl 3)δ4.30(p,J＝5.1Hz,1H),3.26-3.16(m,1H),3.05(dd,J＝10.9,4.9Hz,1H),2.80-2.67(m,1H),2.62-2.51(m,1H),2.31(dd,J＝12.9,4.9Hz,1H),2.18-2.06(m,1H),1.88-1.81(m,1H),1.81-1.59(m,3H),1.44(s,9H),0.08(s,9H).m/z calcd for C 15H 30NO 3Si +,[M+H] +:300.2,found:300.2. 1 H NMR (400 MHz, CDCl 3 ) δ 4.30 (p, J = 5.1 Hz, 1H), 3.26-3.16 (m, 1H), 3.05 (dd, J = 10.9, 4.9 Hz, 1H), 2.80-2.67 (m, 1H), 2.62-2.51 (m, 1H), 2.31 (dd, J = 12.9, 4.9 Hz, 1H), 2.18-2.06 (m, 1H), 1.88-1.81 (m, 1H), 1.81-1.59 (m, 3H), 1.44 (s, 9H), 0.08 (s, 9H). m/z calcd for C 15 H 30 NO 3 Si + , [M+H] + : 300.2, found: 300.2.

实施例14：化合物V-3的制备Example 14: Preparation of Compound V-3

Figure PCTCN2022128678-appb-000027
Figure PCTCN2022128678-appb-000027

将化合物IV-2(5g，16.7mmol，1equiv)加入THF(25mL)中，N 2置换3次，降至5℃，滴加三乙胺三氢氟酸盐(TEA-3HF，8g，49.6mmol，3.0equiv)，TEA(20.2g， 199.6mmol，12equiv)，然后滴加全氟丁基磺酰氟(5.3g，17.5mmol，1.05equiv)，保温反应5小时后，升至室温反应16小时。滴入10％碳酸钾调节pH至9-10，搅拌，分液，上层有机相，分层，干燥，旋干，柱层析纯化后得2.5g产物化合物V-3，收率：65％。 Compound IV-2 (5 g, 16.7 mmol, 1 equiv) was added to THF (25 mL), replaced with N 2 for 3 times, cooled to 5°C, triethylamine trihydrofluoride (TEA-3HF, 8 g, 49.6 mmol, 3.0 equiv), TEA (20.2 g, 199.6 mmol, 12 equiv) were added dropwise, and then perfluorobutylsulfonyl fluoride (5.3 g, 17.5 mmol, 1.05 equiv) was added dropwise. After keeping the temperature for 5 hours, the temperature was raised to room temperature for 16 hours. 10% potassium carbonate was added dropwise to adjust the pH to 9-10, stirred, separated, the upper organic phase was separated, dried, and spin-dried. After column chromatography purification, 2.5 g of product compound V-3 was obtained, with a yield of 65%.

1H NMR(400MHz,CDCl 3)δ5.28-5.23(m,0.5H),5.14-5.09(m,0.5H),3.33-3.25(m,1H),3.25-3.16(m,1H),3.14(ddd,J＝5.8,2.8,1.5Hz,1H),2.89(td,J＝8.9,5.7Hz,1H),2.44(dd,J＝15.0,4.8Hz,0.5H),2.38-2.29(m,1.5H),2.17(ddd,J＝23.5,12.5,8.3Hz,1H),1.92-1.74(m,3H),1.44(s,9H).m/z calcd for C 12H 21FNO 2 +,[M+H] +:230.2,found:230.2. 1 H NMR (400 MHz, CDCl 3 ) δ 5.28-5.23 (m, 0.5H), 5.14-5.09 (m, 0.5H), 3.33-3.25 (m, 1H), 3.25-3.16 (m, 1H), 3.14 (ddd, J = 5.8, 2.8, 1.5 Hz, 1H), 2.89 (td, J = 8.9, 5.7 Hz, 1H), 2.44 (dd, J = 15.0, 4.8 Hz, 0.5H), 2.38-2.29 (m, 1.5H), 2.17 (ddd, J = 23.5, 12.5, 8.3 Hz, 1H), 1.92-1.74 (m, 3H), 1.44 (s, 9H). m/z calcd for C 12 H 21 FNO 2 + ,[M+H] + :230.2,found:230.2.

实施例15：化合物VI的制备Example 15: Preparation of Compound VI

Figure PCTCN2022128678-appb-000028
Figure PCTCN2022128678-appb-000028

将化合物V-3(1g，4.4mmol，1equiv)加入THF(10mL)中，氮气置换三次，降温至0℃，加入四氢铝锂(0.50g，13.2mmol，3equiv)。冰浴下反应1h后依次滴加水(0.5mL)，15％氢氧化钠(1mL)和水(1.5mL)淬灭反应。将反应液用硅藻土过滤，乙酸乙酯冲洗，滤液浓缩后柱层析纯化，得0.43g化合物VI，收率61％，淡黄色固体，产品ee为99.4％。Compound V-3 (1 g, 4.4 mmol, 1 equiv) was added to THF (10 mL), replaced with nitrogen three times, cooled to 0°C, and lithium aluminum tetrahydride (0.50 g, 13.2 mmol, 3 equiv) was added. After reacting for 1 h under ice bath, water (0.5 mL), 15% sodium hydroxide (1 mL) and water (1.5 mL) were added dropwise in sequence to quench the reaction. The reaction solution was filtered through diatomaceous earth and rinsed with ethyl acetate. The filtrate was concentrated and purified by column chromatography to obtain 0.43 g of compound VI, with a yield of 61%, a light yellow solid, and a product ee of 99.4%.

实施例16：化合物II-5的制备Example 16: Preparation of Compound II-5

Figure PCTCN2022128678-appb-000029
Figure PCTCN2022128678-appb-000029

将化合物I-6(9.8g，50.7mmol，1.0equiv)溶于异丙醇(49mL)中，加入(R)-环氧氯丙烷(7.0g，75.7mmol，1.5equiv)，降温至-5℃，滴加TEA(5.1g，50.6mmol，1.0equiv)。滴完后升温至70℃搅拌12h。然后降至室温，浓缩至基本无馏出，加入DCM溶解，用8％碳酸氢钾(521mL)洗，水洗一次，浓缩至基本无馏出，柱层析纯化得到8.1g产物化合物II-5，淡黄色油状物，收率64％。Compound I-6 (9.8 g, 50.7 mmol, 1.0 equiv) was dissolved in isopropanol (49 mL), (R)-epichlorohydrin (7.0 g, 75.7 mmol, 1.5 equiv) was added, the temperature was lowered to -5 °C, and TEA (5.1 g, 50.6 mmol, 1.0 equiv) was added dropwise. After the addition was completed, the temperature was raised to 70 °C and stirred for 12 h. Then the temperature was lowered to room temperature, concentrated until almost no distillate was produced, DCM was added to dissolve, washed with 8% potassium bicarbonate (521 mL), washed once with water, concentrated until almost no distillate was produced, and purified by column chromatography to obtain 8.1 g of product compound II-5 as a light yellow oil with a yield of 64%.

1H NMR(400MHz,CDCl 3)δ5.10-4.94(m,1H),4.17-3.99(m,1H),3.95-3.80(m,1H), 3.57-3.45(m,2H),3.35-3.26(m,1H),3.26-3.19(m,1H),2.69(t,J＝4.2Hz,1H),2.41(dt,J＝17.3,6.5Hz,1H),2.22-2.07(m,1H),1.99-1.72(m,3H),1.24(d,J＝3.2Hz,3H),1.23(d,J＝3.2Hz,3H).m/z calcd for C 11H 21ClNO 3 +,[M+H] +:250.1,found:250.1. 1 H NMR (400 MHz, CDCl 3 ) δ 5.10-4.94 (m, 1H), 4.17-3.99 (m, 1H), 3.95-3.80 (m, 1H), 3.57-3.45 (m, 2H), 3.35-3.26 (m, 1H), 3.26-3.19 (m, 1H), 2.69 (t, J = 4.2 Hz, 1H), 2.41 (dt, J = 17.3, 6.5 Hz, 1H), 2.22-2.07 (m, 1H), 1.99-1.72 (m, 3H), 1.24 (d, J = 3.2 Hz, 3H), 1.23 (d, J = 3.2 Hz, 3H). m/z calcd for C 11 H 21 ClNO 3 + , [M+H] + :250.1,found:250.1.

实施例17：化合物IV-3的制备Example 17: Preparation of Compound IV-3

Figure PCTCN2022128678-appb-000030
Figure PCTCN2022128678-appb-000030

将化合物II-5(4.0g，16.0mmol，1.0equiv)溶于THF(45mL)中，开启搅拌，氮气置换三次，降温至-70℃，滴加LiHMDS(25.6mL，25.6mmol，1.6equiv)，保温反应搅拌12h。向反应液中滴加醋酸(1.4g，24mmol，1.5equiv)，滴毕，升温至20～30℃，搅拌0.5小时，过滤，滤液浓缩至无溶剂滴出，得到2.8g产物化合物IV-3，黄色油状液体，收率61.2％。Compound II-5 (4.0 g, 16.0 mmol, 1.0 equiv) was dissolved in THF (45 mL), stirred, replaced with nitrogen three times, cooled to -70 ° C, and LiHMDS (25.6 mL, 25.6 mmol, 1.6 equiv) was added dropwise, and the reaction was stirred for 12 h. Acetic acid (1.4 g, 24 mmol, 1.5 equiv) was added dropwise to the reaction solution, and after the addition, the temperature was raised to 20-30 ° C, stirred for 0.5 hours, filtered, and the filtrate was concentrated until no solvent was dropped to obtain 2.8 g of the product compound IV-3, a yellow oily liquid, with a yield of 61.2%.

1H NMR(400MHz,CDCl 3)δ5.10-4.84(m,1H),4.31(p,J＝4.8Hz,1H),3.27-3.15(m,1H),3.07(dd,J＝10.9,4.4Hz,1H),2.74(dd,J＝10.9,4.8Hz,1H),2.65-2.49(m,1H),2.34(dd,J＝13.0,4.7Hz,1H),2.18-2.06(m,1H),1.91-1.81(m,1H),1.81-1.63(m,3H),1.22(d,J＝6.2Hz,6H),0.06(s,9H).m/z calcd for C 14H 28NO 3Si +,[M+H] +:286.2,found:286.2. 1 H NMR (400 MHz, CDCl 3 ) δ 5.10-4.84 (m, 1H), 4.31 (p, J = 4.8 Hz, 1H), 3.27-3.15 (m, 1H), 3.07 (dd, J = 10.9, 4.4 Hz, 1H), 2.74 (dd, J = 10.9, 4.8 Hz, 1H), 2.65-2.49 (m, 1H), 2.34 (dd, J = 13.0, 4.7 Hz, 1H), 2.18-2.06 (m, 1H), 1.91-1.81 (m, 1H), 1.81-1.63 (m, 3H), 1.22 (d, J = 6.2 Hz, 6H), 0.06 (s, 9H). m/z calcd for C 14 H 28 NO 3 Si + , [M+H] + :286.2,found:286.2.

实施例18：化合物V-4的制备Example 18: Preparation of Compound V-4

Figure PCTCN2022128678-appb-000031
Figure PCTCN2022128678-appb-000031

将化合物IV-3(1.0g，3.5mmol，1.0equiv)溶于THF(5mL)，开启搅拌，氮气置换三次。然后降温至-5℃，滴加TEA-3HF(1.4g，8.7mmol，2.5equiv)，TEA(2.48g，24.5mmol，7.0equiv)，全氟丁基磺酰氟(1.1g，3.7mmol，1.05equiv)，滴毕，恢复室温，搅拌12h。将反应液滴加至10％NaHCO 3水溶液中，搅拌0.5小时，分液，有机相水洗一次，再分液，有机相减压浓缩，柱层析纯化得0.4g化合物V-4，收率53％。 Compound IV-3 (1.0 g, 3.5 mmol, 1.0 equiv) was dissolved in THF (5 mL), stirred, and replaced with nitrogen three times. Then the temperature was lowered to -5 ° C, TEA-3HF (1.4 g, 8.7 mmol, 2.5 equiv), TEA (2.48 g, 24.5 mmol, 7.0 equiv), and perfluorobutylsulfonyl fluoride (1.1 g, 3.7 mmol, 1.05 equiv) were added dropwise, and the mixture was returned to room temperature and stirred for 12 h. The reaction solution was added dropwise to a 10% NaHCO 3 aqueous solution, stirred for 0.5 hours, separated, the organic phase was washed with water once, separated again, the organic phase was concentrated under reduced pressure, and purified by column chromatography to obtain 0.4 g of compound V-4 with a yield of 53%.

1H NMR(400MHz,CDCl 3)δ5.29-5.24(m,0.5H),5.15-5.10(m,0.5H),4.97(hept,J＝6.3 Hz,1H),3.34-3.25(m,1H),3.21(dd,J＝17.1,8.6Hz,1H),3.14(s,1H),2.90(tt,J＝13.6,6.7Hz,1H),2.45(dt,J＝8.4,4.2Hz,0.5H),2.38(ddd,J＝15.0,11.0,3.9Hz,1.5H),2.27-2.12(m,1H),1.95-1.75(m,3H),1.23(d,J＝6.3Hz,6H).m/z calcd for C 11H 19FNO 2 +,[M+H] +:216.1,found:216.1. 1 H NMR (400 MHz, CDCl 3 ) δ 5.29-5.24 (m, 0.5H), 5.15-5.10 (m, 0.5H), 4.97 (hept, J = 6.3 Hz, 1H), 3.34-3.25 (m, 1H), 3.21 (dd, J = 17.1, 8.6 Hz, 1H), 3.14 (s, 1H), 2.90 (tt, J = 13.6, 6.7 Hz, 1H), 2.45 (dt, J = 8.4, 4.2 Hz, 0.5H), 2.38 (ddd, J = 15.0, 11.0, 3.9 Hz, 1.5H), 2.27-2.12 (m, 1H), 1.95-1.75 (m, 3H), 1.23 (d, J = 6.3 Hz, 6H). m/z calcd for C 11 H 19 FNO 2 + ,[M+H] + :216.1,found:216.1.

实施例19：化合物VI的制备Example 19: Preparation of Compound VI

Figure PCTCN2022128678-appb-000032
Figure PCTCN2022128678-appb-000032

将化合物V-4(0.3g，1.3mmol，1.0equiv)溶于THF(2mL)，开启搅拌，氮气置换三次，降温至0℃，分批加LiAlH 4(63mg，1.6mmol，1.2equiv)，保温0℃反应半小时。然后控温-5℃，依次加入水(63μL)，15％NaOH水溶液(120μL)和水(240μL)淬灭反应，搅拌30min，硅藻土垫滤，滤液浓缩至无溶剂滴出，柱层析纯化，减压浓缩得180mg化合物VI，淡黄色固体，收率82％，产品ee为99.2％。 Compound V-4 (0.3 g, 1.3 mmol, 1.0 equiv) was dissolved in THF (2 mL), stirred, replaced with nitrogen three times, cooled to 0°C, and LiAlH 4 (63 mg, 1.6 mmol, 1.2 equiv) was added in batches, and kept at 0°C for half an hour. Then the temperature was controlled at -5°C, and water (63 μL), 15% NaOH aqueous solution (120 μL) and water (240 μL) were added in sequence to quench the reaction, stirred for 30 min, filtered through a celite pad, and the filtrate was concentrated until no solvent was dripped out, purified by column chromatography, and concentrated under reduced pressure to obtain 180 mg of compound VI as a light yellow solid with a yield of 82% and a product ee of 99.2%.

上述实施例中的收率为摩尔收率，手性纯度采用测试步骤如下：采用手性气相色谱(Chiral GC)测试，Chiral GC(Agilent_CYCLOSIL-B_30mx0.25mm_0.25μm,N 2 3mL/min,Rate:80℃,1min，10℃/min,140℃,3min,FID检测器(FID detector))RT＝10.14min(minor),RT＝10.32min(major),ee＝99.2％。 The yield in the above embodiment is the molar yield, and the chiral purity is tested by the following steps: Chiral GC (Agilent_CYCLOSIL-B_30mx0.25mm_0.25μm, N2 3mL/min, Rate: 80℃, 1min, 10℃/min, 140℃, 3min, FID detector (FID detector)) RT=10.14min(minor), RT=10.32min(major), ee=99.2%.

以上所述仅为本申请的较佳实施例，并不用以限制本申请，凡在本申请的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本申请保护的范围之内。The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present application shall be included in the scope of protection of the present application.

Claims (13)

一种化合物VI的制备方法，其为方法一或方法二；A method for preparing compound VI, which is method 1 or method 2; 所述方法一包括以下步骤：The method 1 comprises the following steps:
Figure PCTCN2022128678-appb-100001
Figure PCTCN2022128678-appb-100001
 步骤1：化合物III发生氟化反应得到化合物V；Step 1: Compound III undergoes fluorination reaction to obtain compound V; 步骤2：化合物V发生还原反应得到化合物VI；Step 2: Compound V undergoes reduction reaction to obtain compound VI; 所述方法二包括以下步骤：The second method comprises the following steps:
Figure PCTCN2022128678-appb-100002
Figure PCTCN2022128678-appb-100002
 步骤1’：化合物IV发生氟化反应得到化合物V；Step 1': Compound IV undergoes fluorination reaction to obtain compound V; 步骤2：化合物V发生还原反应得到化合物VI；Step 2: Compound V undergoes reduction reaction to obtain compound VI; 其中，in, R 1选自氢、烯丙基、C1～C8的烷基、C3～C7的环烷基、被芳基取代的C1～C8的烷基、未取代或被Ra取代的C6～C20的芳基、C4～C8的杂芳基，所述被芳基取代的C1～C8的烷基中的芳基为未取代或被Ra取代的C6～C25的芳基，所述Ra选自甲基、乙基、甲氧基、硝基或卤素； R1 is selected from hydrogen, allyl, C1-C8 alkyl, C3-C7 cycloalkyl, C1-C8 alkyl substituted by aryl, C6-C20 aryl unsubstituted or substituted by Ra, C4-C8 heteroaryl, the aryl in the C1-C8 alkyl substituted by aryl is C6-C25 aryl unsubstituted or substituted by Ra, and Ra is selected from methyl, ethyl, methoxy, nitro or halogen; 优选地，所述C1～C8的烷基选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基；所述C3～C7的环烷基选自环丙基、环戊基、环己基；所述被芳基取代的C1～C8的烷基选自苄基、二苯甲基、三苯甲基、对硝基苄基、对甲氧基苄基；所述未取代或被Ra取代的C6～C20的芳基选自苯基、甲氧基苯基、对硝基苯基；所述C4-C8的杂芳基选自呋喃基、噻吩基、吲哚基；Preferably, the C1-C8 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl; the C3-C7 cycloalkyl group is selected from cyclopropyl, cyclopentyl, and cyclohexyl; the C1-C8 alkyl group substituted by an aryl group is selected from benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, and p-methoxybenzyl; the C6-C20 aryl group which is unsubstituted or substituted by Ra is selected from phenyl, methoxyphenyl, and p-nitrophenyl; the C4-C8 heteroaryl group is selected from furyl, thienyl, and indolyl; 进一步优选地，R 1选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环戊基、环己基、苯基、苄基、对硝基苄基；更进一步优选地，R 1选自甲基、异丙基、叔丁基、苄基、对硝基苄基； Further preferably, R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, p-nitrobenzyl; further preferably, R 1 is selected from methyl, isopropyl, tert-butyl, benzyl, p-nitrobenzyl; R 2选自C1～C25的磺酰基、C1～C6的烷基、被Rb取代的C7～C25的烷基、C1～C25的 硅烷基、未取代或被Rc取代的C6～C25的芳基、C3～C25的杂芳基，Rb选自苯基或被卤素、烷氧基、氰基、硝基任意取代的苯基，Rc选自C1～C6的烷基、三苯甲基、卤素、烷氧基、氰基、硝基； R2 is selected from C1-C25 sulfonyl, C1-C6 alkyl, C7-C25 alkyl substituted by Rb, C1-C25 silyl, C6-C25 aryl unsubstituted or substituted by Rc, C3-C25 heteroaryl, Rb is selected from phenyl or phenyl arbitrarily substituted by halogen, alkoxy, cyano, nitro, Rc is selected from C1-C6 alkyl, trityl, halogen, alkoxy, cyano, nitro; 优选地，C1～C25的磺酰基为-S(＝O) 2-R 3，R 3选自未取代或被氟取代的C1～C12的烷基、未取代或被氟取代的C6～C10的芳基，优选地，所述C1～C25的磺酰基优选选自甲磺酰基、乙磺酰基、丙磺酰基、对甲基苯磺酰基、三氟甲磺酰基、全氟丁基磺酰基；所述C1～C6的烷基选自甲基、乙基、丙基、异丙基、正丁基、叔丁基或戊基；所述被Rb取代的C7～C25的烷基选自苄基、对硝基苄基或对甲氧基苄基；所述C1～C25的硅烷基选自三甲基甲硅烷基、三乙基甲硅烷基、三正丁基硅烷基、二甲基异丙基甲硅烷基、二乙基异丙基甲硅烷基、叔丁基二甲基甲硅烷基、三异丙基甲硅烷基、叔丁基二苯基甲硅烷基、三异丙基甲硅烷氧基甲基、[2-(三甲基甲硅烷基)乙氧基]甲基、四异丙基二亚甲硅烷基、二叔丁基二甲基亚甲硅烷基、二苯基二甲氧基硅烷基(DPS)，优选为三甲基甲硅烷基、三乙基硅烷基、叔丁基二甲基甲硅烷基、三异丙基甲硅烷基、叔丁基二苯基甲硅烷基；所述未取代或被Rc取代的C6～C25的芳基选自苯基、3-叔丁基苯基、3-正丙基苯基、3-异丙基苯基、3-甲基苯基、4-叔丁基苯基、4-三氟甲基苯基、4-正丙基苯基、4-异丙基苯基、4-甲基苯基、3,5-二甲基苯基、对硝基苯基、对甲氧基苯基、蒽基或萘基；C3～C25的杂芳基选自2-噻吩基、吡啶基、哒嗪基、吡嗪基、三嗪基、吖啶基； Preferably, the C1-C25 sulfonyl group is -S(=O) 2 -R 3 , R 3 is selected from unsubstituted or fluorine-substituted C1-C12 alkyl, unsubstituted or fluorine-substituted C6-C10 aryl, preferably, the C1-C25 sulfonyl is preferably selected from methylsulfonyl, ethylsulfonyl, propylsulfonyl, p-methylbenzenesulfonyl, trifluoromethylsulfonyl, perfluorobutylsulfonyl; the C1-C6 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or pentyl; the C7-C25 alkyl substituted by Rb is selected from benzyl, p-nitrobenzyl or p-methoxybenzyl; the C1-C25 silyl is selected from trimethylsilyl, triethylsilyl, tri-n-butylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, triisopropylsiloxymethyl , [2-(trimethylsilyl)ethoxy]methyl, tetraisopropyldisilyl, di-tert-butyldimethylsilyl, diphenyldimethoxysilyl (DPS), preferably trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl; the unsubstituted or Rc-substituted C6-C25 aryl is selected from phenyl, 3-tert-butylphenyl, 3-n-propylphenyl, 3-isopropylphenyl, 3-methylphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-n-propylphenyl, 4-isopropylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, p-nitrophenyl, p-methoxyphenyl, anthracenyl or naphthyl; the C3-C25 heteroaryl is selected from 2-thienyl, pyridyl, pyridazinyl, pyrazinyl, triazinyl, acridinyl; 进一步优选地，R 2选自三甲基硅烷基、甲磺酰基、对甲基苯磺酰基、三氟甲磺酰基、全氟丁基磺酰基。 More preferably, R 2 is selected from trimethylsilyl, methanesulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl, and perfluorobutylsulfonyl. 根据权利要求1所述的制备方法，其中，The preparation method according to claim 1, wherein 所述步骤1包括以下步骤：所述化合物III与氟化试剂在非质子溶剂中发生氟化反应，分离得到所述化合物V；所述化合物III与所述氟化试剂的摩尔比为1:(1～5)；The step 1 comprises the following steps: the compound III reacts with a fluorination agent in an aprotic solvent to undergo a fluorination reaction, and the compound V is separated; the molar ratio of the compound III to the fluorination agent is 1:(1-5); 所述步骤1’包括以下步骤：所述化合物IV与氟化试剂在非质子溶剂中发生氟化反应，分离得到所述化合物V；所述化合物IV与所述氟化试剂的摩尔比为1:(1～5)；The step 1' comprises the following steps: the compound IV reacts with a fluorination agent in an aprotic solvent to undergo a fluorination reaction, and the compound V is separated; the molar ratio of the compound IV to the fluorination agent is 1:(1-5); 所述氟化反应的温度为-80℃～40℃，优选为-40℃～30℃；所述氟化反应的时间为1h～48h，优选为1h～24h；The temperature of the fluorination reaction is -80°C to 40°C, preferably -40°C to 30°C; the time of the fluorination reaction is 1h to 48h, preferably 1h to 24h; 所述氟化试剂选自三乙胺三氢氟酸盐、[双(2-甲氧基乙基)胺]三氟化硫、(二乙氨基)二氟锍鎓四氟硼酸盐、二氟(吗啉代)锍四氟硼酸盐、4-叔丁基-2,6-二甲基苯基三氟化硫、氟化钾、氟化铜、氟化铯、四丁基氟化铵、4-氯-N-[(4-甲基苯基)磺酰基]苯磺酰亚胺基氟、对硝 基苯磺酰氟、吡啶-2-磺酰氟、硫酰氟、三氟化硫吗啉、二乙胺基三氟化硫、或全氟丁基磺酰氟中的至少一种，优选为全氟丁基磺酰氟、二乙胺基三氟化硫、三乙胺三氢氟酸盐中的至少一种；The fluorination agent is selected from at least one of triethylamine trihydrofluoride, [bis(2-methoxyethyl)amine] sulfur trifluoride, (diethylamino)difluorosulfonium tetrafluoroborate, difluoro(morpholino)sulfonium tetrafluoroborate, 4-tert-butyl-2,6-dimethylphenyl sulfur trifluoride, potassium fluoride, copper fluoride, cesium fluoride, tetrabutylammonium fluoride, 4-chloro-N-[(4-methylphenyl)sulfonyl]benzenesulfonylimide fluoride, p-nitrobenzenesulfonyl fluoride, pyridine-2-sulfonyl fluoride, sulfuryl fluoride, sulfur trifluoride morpholine, diethylamino sulfur trifluoride, or perfluorobutylsulfonyl fluoride, preferably at least one of perfluorobutylsulfonyl fluoride, diethylamino sulfur trifluoride, and triethylamine trihydrofluoride; 所述非质子溶剂选自乙腈、甲苯、二甲苯、三甲苯、二氯甲烷、1,2-二氯乙烷、1,1,2,2-四氯乙烷、氯仿、二甲基亚砜、N,N-二甲基甲酰胺、四氢呋喃、甲基四氢呋喃，1,4-二氧六环、乙醚、苯中的至少一种，优选为乙腈、四氢呋喃、甲基四氢呋喃、二氯甲烷中的至少一种；The aprotic solvent is selected from at least one of acetonitrile, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, and benzene, preferably at least one of acetonitrile, tetrahydrofuran, methyltetrahydrofuran, and dichloromethane; 优选地，所述氟化反应中还加入碱剂，所述化合物III与所述碱剂的摩尔比为1:(1～20)，优选为1:(5～15)；所述碱剂选自三乙胺、二乙胺、N,N-二异丙基乙胺、1,4-二氮杂二环[2.2.2]辛烷中的至少一种。Preferably, an alkali is also added to the fluorination reaction, and the molar ratio of the compound III to the alkali is 1:(1-20), preferably 1:(5-15); the alkali is selected from at least one of triethylamine, diethylamine, N,N-diisopropylethylamine, and 1,4-diazabicyclo[2.2.2]octane. 根据权利要求1～2中任一项所述的制备方法，其中，所述步骤2包括以下步骤：The preparation method according to any one of claims 1 to 2, wherein the step 2 comprises the following steps: 所述化合物V与还原剂在有机溶剂中发生还原反应，分离得到所述化合物VI；所述还原反应的温度小于或等于0℃，优选为-10℃～0℃；所述还原反应的时间为0.5h～5h，所述化合物IV与所述还原剂的摩尔比为1:(1～5)；The compound V reacts with a reducing agent in an organic solvent to separate the compound VI; the temperature of the reduction reaction is less than or equal to 0°C, preferably -10°C to 0°C; the time of the reduction reaction is 0.5h to 5h, and the molar ratio of the compound IV to the reducing agent is 1:(1 to 5); 所述还原剂选自氢化铝锂、甲硼烷中的至少一种；The reducing agent is selected from at least one of lithium aluminum hydride and borane; 所述有机溶剂选自甲苯、四氢呋喃、甲基四氢呋喃、乙醚、二噁烷中的至少一种。The organic solvent is selected from at least one of toluene, tetrahydrofuran, methyltetrahydrofuran, diethyl ether and dioxane. 一种化合物，其具有下式IV所示结构：A compound having a structure shown in the following formula IV:
Figure PCTCN2022128678-appb-100003
Figure PCTCN2022128678-appb-100003
 其中，in, R 1选自氢、烯丙基、C1～C8的烷基、C3～C7的环烷基、被芳基取代的C1～C8的烷基、未取代或被Ra取代的C6～C20的芳基、C4～C8的杂芳基，所述被芳基取代的C1～C8的烷基中的芳基为未取代或被Ra取代的C6～C25的芳基，所述Ra选自甲基、乙基、甲氧基、硝基或卤素； R1 is selected from hydrogen, allyl, C1-C8 alkyl, C3-C7 cycloalkyl, C1-C8 alkyl substituted by aryl, C6-C20 aryl unsubstituted or substituted by Ra, C4-C8 heteroaryl, the aryl in the C1-C8 alkyl substituted by aryl is C6-C25 aryl unsubstituted or substituted by Ra, and Ra is selected from methyl, ethyl, methoxy, nitro or halogen; 优选地，所述C1～C8的烷基选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基；所述C3～C7的环烷基选自环丙基、环戊基、环己基；所述被芳基取代的C1～C8的烷基选自苄基、二苯甲基、三苯甲基、对硝基苄基、对甲氧基苄基；所述未取代或被Ra取代的C6～C20 的芳基选自苯基、甲氧基苯基、对硝基苯基；所述C4-C8的杂芳基选自呋喃基、噻吩基、吲哚基；Preferably, the C1-C8 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and tert-butyl; the C3-C7 cycloalkyl group is selected from cyclopropyl, cyclopentyl, and cyclohexyl; the C1-C8 alkyl group substituted by an aryl group is selected from benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, and p-methoxybenzyl; the C6-C20 aryl group which is unsubstituted or substituted by Ra is selected from phenyl, methoxyphenyl, and p-nitrophenyl; the C4-C8 heteroaryl group is selected from furyl, thienyl, and indolyl; 进一步优选地，R 1选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环戊基、环己基、苯基、苄基、对硝基苄基；更进一步优选地，R 1选自甲基、异丙基、叔丁基、苄基、对硝基苄基； Further preferably, R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, p-nitrobenzyl; further preferably, R 1 is selected from methyl, isopropyl, tert-butyl, benzyl, p-nitrobenzyl; R 2选自C1～C25的磺酰基、C1～C6的烷基、被Rb取代的C7～C25的烷基、C1～C25的硅烷基、未取代或被Rc取代的C6～C25的芳基、C3～C25的杂芳基，Rb选自苯基或被卤素、烷氧基、氰基、硝基任意取代的苯基，Rc选自C1～C6的烷基、三苯甲基、卤素、烷氧基、氰基、硝基； R2 is selected from C1-C25 sulfonyl, C1-C6 alkyl, C7-C25 alkyl substituted by Rb, C1-C25 silyl, C6-C25 aryl unsubstituted or substituted by Rc, C3-C25 heteroaryl, Rb is selected from phenyl or phenyl arbitrarily substituted by halogen, alkoxy, cyano, nitro, Rc is selected from C1-C6 alkyl, trityl, halogen, alkoxy, cyano, nitro; 优选地，C1～C25的磺酰基为-S(＝O) 2-R 3，R 3选自未取代或被氟取代的C1～C12的烷基、未取代或被氟取代的C6～C10的芳基，优选地，所述C1～C25的磺酰基优选选自甲磺酰基、乙磺酰基、丙磺酰基、对甲基苯磺酰基、三氟甲磺酰基、全氟丁基磺酰基；所述C1～C6的烷基选自甲基、乙基、丙基、异丙基、正丁基、叔丁基或戊基；所述被Rb取代的C7～C25的烷基选自苄基、对硝基苄基或对甲氧基苄基；所述C1～C25的硅烷基选自三甲基甲硅烷基、三乙基甲硅烷基、三正丁基硅烷基、二甲基异丙基甲硅烷基、二乙基异丙基甲硅烷基、叔丁基二甲基甲硅烷基、三异丙基甲硅烷基、叔丁基二苯基甲硅烷基、三异丙基甲硅烷氧基甲基、[2-(三甲基甲硅烷基)乙氧基]甲基、四异丙基二亚甲硅烷基、二叔丁基二甲基亚甲硅烷基、二苯基二甲氧基硅烷基(DPS)，优选为三甲基甲硅烷基、三乙基硅烷基、叔丁基二甲基甲硅烷基、三异丙基甲硅烷基、叔丁基二苯基甲硅烷基；所述未取代或被Rc取代的C6～C25的芳基选自苯基、3-叔丁基苯基、3-正丙基苯基、3-异丙基苯基、3-甲基苯基、4-叔丁基苯基、4-三氟甲基苯基、4-正丙基苯基、4-异丙基苯基、4-甲基苯基、3,5-二甲基苯基、对硝基苯基、对甲氧基苯基、蒽基或萘基；C3～C25的杂芳基选自2-噻吩基、吡啶基、哒嗪基、吡嗪基、三嗪基、吖啶基； Preferably, the C1-C25 sulfonyl group is -S(=O) 2 -R 3 , R 3 is selected from unsubstituted or fluorine-substituted C1-C12 alkyl, unsubstituted or fluorine-substituted C6-C10 aryl, preferably, the C1-C25 sulfonyl is preferably selected from methylsulfonyl, ethylsulfonyl, propylsulfonyl, p-methylbenzenesulfonyl, trifluoromethylsulfonyl, perfluorobutylsulfonyl; the C1-C6 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or pentyl; the C7-C25 alkyl substituted by Rb is selected from benzyl, p-nitrobenzyl or p-methoxybenzyl; the C1-C25 silyl is selected from trimethylsilyl, triethylsilyl, tri-n-butylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, triisopropylsiloxymethyl , [2-(trimethylsilyl)ethoxy]methyl, tetraisopropyldisilyl, di-tert-butyldimethylsilyl, diphenyldimethoxysilyl (DPS), preferably trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl; the unsubstituted or Rc-substituted C6-C25 aryl is selected from phenyl, 3-tert-butylphenyl, 3-n-propylphenyl, 3-isopropylphenyl, 3-methylphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-n-propylphenyl, 4-isopropylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, p-nitrophenyl, p-methoxyphenyl, anthracenyl or naphthyl; the C3-C25 heteroaryl is selected from 2-thienyl, pyridyl, pyridazinyl, pyrazinyl, triazinyl, acridinyl; 进一步优选地，R 2选自三甲基硅烷基、甲磺酰基、对甲基苯磺酰基、三氟甲磺酰基、全氟丁基磺酰基。 More preferably, R 2 is selected from trimethylsilyl, methanesulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl, and perfluorobutylsulfonyl. 根据权利要求4所述的化合物，其选自以下化合物：The compound according to claim 4, which is selected from the following compounds:
Figure PCTCN2022128678-appb-100004
Figure PCTCN2022128678-appb-100004
 一种权利要求4～5中任一项所述的化合物的制备方法，其包括以下步骤：A method for preparing the compound according to any one of claims 4 to 5, comprising the following steps:
Figure PCTCN2022128678-appb-100005
Figure PCTCN2022128678-appb-100005
 步骤1-1a：化合物III发生取代反应得到化合物IV；Step 1-1a: Compound III undergoes substitution reaction to obtain compound IV; 所述步骤1-1a包括以下步骤：所述化合物III与碱剂在非质子溶剂中发生取代反应，分离得所述到化合物IV；所述取代反应的温度为-78℃～40℃、时间为1h～36h；所述化合物III与碱剂的摩尔比为1:(1～50)，优选为1:(1～20)，进一步优选为1:(1～15)；The step 1-1a comprises the following steps: the compound III undergoes a substitution reaction with an alkali agent in an aprotic solvent to separate the compound IV; the temperature of the substitution reaction is -78°C to 40°C and the time is 1h to 36h; the molar ratio of the compound III to the alkali agent is 1:(1-50), preferably 1:(1-20), and more preferably 1:(1-15); 所述碱剂选自三乙胺、吡啶、二异丙基乙基胺、N,N-二甲基苯胺中的至少一种，优选为三乙胺；The alkaline agent is selected from at least one of triethylamine, pyridine, diisopropylethylamine, and N,N-dimethylaniline, preferably triethylamine; 所述非质子溶剂选自乙腈、甲苯、二甲苯、三甲苯、二氯甲烷、1,2-二氯乙烷、1,1,2,2-四氯乙烷、氯仿、二甲基亚砜、N,N-二甲基甲酰胺、四氢呋喃、甲基四氢呋喃，1,4-二氧六环、乙醚、苯中的至少一种，优选为二氯甲烷；The aprotic solvent is selected from at least one of acetonitrile, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether and benzene, preferably dichloromethane; 进一步优选地，所述取代反应中还加入催化剂，所述化合物III与所述催化剂的摩尔比为1:(0.01～1)，优选为1:(0.05～0.2)，所述催化剂选自4-二甲氨基吡啶。Further preferably, a catalyst is added to the substitution reaction, and the molar ratio of the compound III to the catalyst is 1:(0.01-1), preferably 1:(0.05-0.2), and the catalyst is selected from 4-dimethylaminopyridine. 一种权利要求4～5中任一项所述的化合物的制备方法，其包括以下步骤：A method for preparing the compound according to any one of claims 4 to 5, comprising the following steps:
Figure PCTCN2022128678-appb-100006
Figure PCTCN2022128678-appb-100006
 步骤1-1b：化合物II发生闭环反应得到化合物IV；Step 1-1b: Compound II undergoes a ring-closing reaction to obtain compound IV; 优选地，所述步骤1-1b包括以下步骤：所述化合物II与强碱剂在有机溶剂中发生闭环 反应，分离得到所述化合物IV；所述闭环反应的温度为-100℃～30℃、时间为10h～24h；所述化合物II与强碱剂的摩尔比为1:(1～5)，优选1:(2～3)；所述化合物II的质量与所述有机溶剂的体积比值为1:(1～30)，优选为1:(2～15)，其中，所述化合物II的质量的单位为g，所述有机溶剂的体积的单位为mL；Preferably, the step 1-1b comprises the following steps: the compound II undergoes a ring-closing reaction with a strong base in an organic solvent to separate the compound IV; the temperature of the ring-closing reaction is -100°C to 30°C and the time is 10h to 24h; the molar ratio of the compound II to the strong base is 1:(1-5), preferably 1:(2-3); the ratio of the mass of the compound II to the volume of the organic solvent is 1:(1-30), preferably 1:(2-15), wherein the unit of the mass of the compound II is g and the unit of the volume of the organic solvent is mL; 所述强碱剂选自六甲基二硅基胺基锂、六甲基二硅基胺基钠、2,2,6,6-四甲基哌啶锂，六甲基二硅基胺基钾、异丙基胺基锂中的至少一种，优选为六甲基二硅基胺基锂；The strong alkali agent is at least one selected from lithium hexamethyldisilazide, sodium hexamethyldisilazide, 2,2,6,6-tetramethylpiperidinium lithium, potassium hexamethyldisilazide, and lithium isopropylamide, preferably lithium hexamethyldisilazide; 所述有机溶剂选自甲醇、乙醇、异丙醇、叔丁醇、甲苯、二甲苯、三甲苯、二氯甲烷、1,2-二氯乙烷、1,1,2,2-四氯乙烷、氯仿、二甲基亚砜、N,N-二甲基甲酰胺、四氢呋喃、甲基四氢呋喃，1,4-二氧六环、乙醚、丙酮、苯中的至少一种，优选为甲基四氢呋喃、四氢呋喃中的至少一种。The organic solvent is selected from at least one of methanol, ethanol, isopropanol, tert-butanol, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, acetone, and benzene, and is preferably at least one of methyltetrahydrofuran and tetrahydrofuran. 一种化合物，其具有下式III所示结构：A compound having a structure shown in the following formula III:
Figure PCTCN2022128678-appb-100007
Figure PCTCN2022128678-appb-100007
 其中，in, R 1选自氢、的烯丙基、C1～C8的烷基、C3～C7的环烷基、被芳基取代的C1～C8的烷基、未取代或被Ra取代的C6～C20的芳基、C4～C8的杂芳基，所述被芳基取代的C1～C8的烷基中的芳基为未取代或被Ra取代的C6～C25的芳基，所述Ra选自甲基、乙基、甲氧基、硝基或卤素； R1 is selected from hydrogen, allyl, C1-C8 alkyl, C3-C7 cycloalkyl, C1-C8 alkyl substituted by aryl, C6-C20 aryl unsubstituted or substituted by Ra, C4-C8 heteroaryl, the aryl in the C1-C8 alkyl substituted by aryl is C6-C25 aryl unsubstituted or substituted by Ra, and Ra is selected from methyl, ethyl, methoxy, nitro or halogen; 优选地，所述C1～C8的烷基选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基；所述C3～C7的环烷基选自环丙基、环戊基、环己基；所述被芳基取代的C1～C8的烷基选自苄基、二苯甲基、三苯甲基、对硝基苄基、对甲氧基苄基；所述未取代或被Ra取代的C6～C20的芳基选自苯基、甲氧基苯基、对硝基苯基；所述C4-C8的杂芳基选自呋喃基、噻吩基、吲哚基。Preferably, the C1-C8 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl; the C3-C7 cycloalkyl group is selected from cyclopropyl, cyclopentyl and cyclohexyl; the C1-C8 alkyl group substituted by aryl is selected from benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl and p-methoxybenzyl; the unsubstituted or Ra-substituted C6-C20 aryl group is selected from phenyl, methoxyphenyl and p-nitrophenyl; the C4-C8 heteroaryl group is selected from furyl, thienyl and indolyl. 根据权利要求8所述的化合物，其选自以下化合物：The compound according to claim 8, which is selected from the following compounds:
Figure PCTCN2022128678-appb-100008
Figure PCTCN2022128678-appb-100008
 一种根据权利要求8～9中任一项所述的化合物的制备方法，其包括如下步骤：A method for preparing the compound according to any one of claims 8 to 9, comprising the following steps:
Figure PCTCN2022128678-appb-100009
Figure PCTCN2022128678-appb-100009
 化合物II发生关环反应，得到所述化合物III；Compound II undergoes a ring-closing reaction to obtain the compound III; 其中，X选自卤素、甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基、苯磺酰氧基，优选为Cl、Br、I；Wherein, X is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy, preferably Cl, Br, I; 优选地，所述关环反应包括以下步骤：将所述化合物II与强碱剂在有机溶剂中发生关环反应，分离得到所述化合物III；所述关环反应的温度为-100℃～30℃、时间为10h～24h；所述化合物II与强碱剂的摩尔比为1:(1～10)，优选为1:(1～6)，进一步优选为1:(1～3)；所述化合物II的质量与所述有机溶剂的体积比值为1:(1～30)，其中，所述化合物II的质量的单位为g，所述有机溶剂的体积的单位为mL；Preferably, the ring-closing reaction comprises the following steps: reacting the compound II with a strong base in an organic solvent to obtain the compound III by ring-closing reaction, wherein the temperature of the ring-closing reaction is -100°C to 30°C and the time is 10h to 24h; the molar ratio of the compound II to the strong base is 1:(1-10), preferably 1:(1-6), and more preferably 1:(1-3); the ratio of the mass of the compound II to the volume of the organic solvent is 1:(1-30), wherein the unit of the mass of the compound II is g and the unit of the volume of the organic solvent is mL; 所述强碱剂选自氢化钠、叔丁醇钾、甲醇钠、乙醇钠、叔丁醇锂、六甲基二硅基胺基锂、六甲基二硅基胺基钠、2,2,6,6-四甲基哌啶锂、六甲基二硅基胺基钾、二异丙基胺基锂中的至少一种，优选为六甲基二硅基胺基锂；The strong alkaline agent is selected from at least one of sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, 2,2,6,6-tetramethylpiperidinium lithium, potassium hexamethyldisilazide, and lithium diisopropylamide, preferably lithium hexamethyldisilazide; 所述有机溶剂选自甲醇、乙醇、异丙醇、叔丁醇、甲苯、二甲苯、三甲苯、二氯甲烷、1,2-二氯乙烷、1,1,2,2-四氯乙烷、氯仿、二甲基亚砜、N,N-二甲基甲酰胺、四氢呋喃、甲基四氢呋喃，1,4-二氧六环、乙醚、甲基叔丁基醚、苯中的至少一种，优选为甲基四氢呋喃、四氢呋喃中的至少一种。The organic solvent is selected from at least one of methanol, ethanol, isopropanol, tert-butyl alcohol, toluene, xylene, trimethylbenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, methyl tert-butyl ether, and benzene, and is preferably at least one of methyltetrahydrofuran and tetrahydrofuran. 一种化合物，其具有下式II所示结构：A compound having the structure shown in the following formula II:
Figure PCTCN2022128678-appb-100010
Figure PCTCN2022128678-appb-100010
 其中，in, R 1选自氢、烯丙基、C1～C8的烷基、C3～C7的环烷基、被芳基取代的C1～C8的烷基、未取代或被Ra取代的C6～C20的芳基、C4～C8的杂芳基，所述被芳基取代的C1～C8的烷基中的芳基为未取代或被Ra取代的C6～C25的芳基，所述Ra选自甲基、乙基、甲氧基、硝基或卤素；优选地，所述C1～C8的烷基选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基；所述C3～C7的环烷基选自环丙基、环戊基、环己基；所述被芳基取代的C1～C8的烷基选自苄基、二苯甲基、三苯甲基、对硝基苄基、对甲氧基苄基；所述未取代或被Ra取代的C6～C20的芳基选自苯基、甲氧基苯基、对硝基苯基；所述C4-C8的杂芳基选自呋喃基、噻吩基、吲哚基； R1 is selected from hydrogen, allyl, C1-C8 alkyl, C3-C7 cycloalkyl, C1-C8 alkyl substituted by aryl, C6-C20 aryl unsubstituted or substituted by Ra, C4-C8 heteroaryl, the aryl in the C1-C8 alkyl substituted by aryl is C6-C25 aryl unsubstituted or substituted by Ra, wherein Ra is selected from methyl, ethyl, methoxy, nitro or halogen; preferably, the C1-C8 alkyl is selected from methyl The C3-C7 cycloalkyl is selected from cyclopropyl, cyclopentyl and cyclohexyl; the C1-C8 alkyl substituted by aryl is selected from benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl and p-methoxybenzyl; the C6-C20 aryl which is unsubstituted or substituted by Ra is selected from phenyl, methoxyphenyl and p-nitrophenyl; the C4-C8 heteroaryl is selected from furyl, thienyl and indolyl; X选自卤素、甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基、苯磺酰氧基；优选地X选自Cl、Br、I。X is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy; preferably X is selected from Cl, Br, I. 根据权利要求11所述的化合物，其选自以下化合物：The compound according to claim 11, which is selected from the following compounds:
Figure PCTCN2022128678-appb-100011
Figure PCTCN2022128678-appb-100011
 一种根据权利要求11～12中任一项所述的化合物的制备方法，其包括以下步骤：A method for preparing the compound according to any one of claims 11 to 12, comprising the following steps:
Figure PCTCN2022128678-appb-100012
Figure PCTCN2022128678-appb-100012
 化合物I或其盐与化合物VII发生开环反应，分离得到化合物II；Compound I or its salt undergoes a ring-opening reaction with compound VII to separate compound II; 优选地，所述开环反应包括以下步骤：在碱剂的条件下，所述化合物I或其盐与化合物VII在有机溶剂中发生开环反应，分离得到所述化合物III；所述开环反应的温度为40℃～100℃、时间为1h～72h；所述化合物I与碱剂的摩尔比为1:(1～10)，优选为1:(1～4)；所述化合物I与化合物VII的摩尔比为1:(1～10)，优选为1:(1～2)，进一步优选为1:(1～1.5)；所述化合物I的质量与所述有机溶剂的体积比值为1:(1～20)，优选为1:(5～15)，其中，所述化合物I的质量的单位为g，所述有机溶剂的体积的单位为mL；Preferably, the ring-opening reaction comprises the following steps: under the condition of an alkali agent, the compound I or its salt and the compound VII undergo a ring-opening reaction in an organic solvent to separate the compound III; the temperature of the ring-opening reaction is 40°C to 100°C and the time is 1h to 72h; the molar ratio of the compound I to the alkali agent is 1:(1-10), preferably 1:(1-4); the molar ratio of the compound I to the compound VII is 1:(1-10), preferably 1:(1-2), and further preferably 1:(1-1.5); the mass ratio of the compound I to the volume of the organic solvent is 1:(1-20), preferably 1:(5-15), wherein the unit of the mass of the compound I is g, and the unit of the volume of the organic solvent is mL; 所述碱剂选自无机碱或有机碱，所述无机碱选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸铯、碳酸锂中的至少一种，所述有机碱选自三乙胺、吡啶、二异丙基乙基胺或N,N-二甲基苯胺中的至少一种；所述碱剂优选为三乙胺、吡啶、二异丙基乙基胺、N,N-二甲基苯胺中的至少一种，进一步选为三乙胺；The alkaline agent is selected from an inorganic base or an organic base, the inorganic base is selected from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate, and the organic base is selected from at least one of triethylamine, pyridine, diisopropylethylamine, and N,N-dimethylaniline; the alkaline agent is preferably at least one of triethylamine, pyridine, diisopropylethylamine, and N,N-dimethylaniline, and is further selected as triethylamine; 所述有机溶剂选自醇类溶剂、氯代烷烃、醚类溶剂、液态烷烃类溶剂中的至少一种，醇类溶剂选自甲醇、乙醇、异丙醇、正丁醇、叔丁醇中的至少一种；氯代烷烃溶剂选自二氯甲烷、1,2-二氯乙烷、1,1,2,2-四氯乙烷、氯仿中的至少一种；醚类溶剂选自四氢呋喃、甲基四氢呋喃，1,4-二氧六环、乙醚、甲基叔丁基醚中的至少一种；液态烷烃类溶剂选自正己烷、正庚烷、环己烷、甲苯中的至少一种。The organic solvent is selected from at least one of alcohol solvents, chlorinated alkanes, ether solvents, and liquid alkane solvents; the alcohol solvent is selected from at least one of methanol, ethanol, isopropanol, n-butanol, and tert-butanol; the chlorinated alkane solvent is selected from at least one of dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and chloroform; the ether solvent is selected from at least one of tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, ether, and methyl tert-butyl ether; and the liquid alkane solvent is selected from at least one of n-hexane, n-heptane, cyclohexane, and toluene.
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