Preparation method of ((2R, 7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl) methanol

Abstract

According to the preparation method of the compound VI, the compound VI has a chiral center of fluoro-tertiary carbon and a chiral center of aza-quaternary carbon, the synthesis difficulty is high, the preparation method provided by the invention is simple to operate, mild in reaction condition, short in reaction time, high in yield and high in chiral purity, and the obtained compound VI is high in quality.

Description

A preparation method of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol Technical Field

[0001] The present application belongs to the field of medicinal chemistry, and in particular relates to a method for preparing ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol. Background Art

[0002] KRAS gene mutations are the most common activating mutations in human cancers, occurring in 90% of pancreatic cancers, 40% of colon cancers, and 20% of lung cancers. The KARS protein's smooth, spherical structure and extremely strong GTP affinity, at picomolar levels, make it an extremely difficult target for drug development. The KARS G12D mutation replaces the glycine (G) at codon 12 with aspartic acid (D), which has a carboxylic acid terminal. Currently disclosed novel compounds targeting this target all contain the compound ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (hereinafter referred to as Compound VI) shown below.

[0003]

[0004] However, currently disclosed methods for preparing Compound VI suffer from low overall yields (e.g., only 3.5%) and involve steps such as ozonation and chiral chromatography, which are difficult to implement in scale-up production and pose difficulties in industrialization. Alternatively, the target product is obtained through multiple steps (e.g., nine) from the chiral fluorinated starting material, involving multiple reductions with different reducing agents and Dess-Martin periodate oxidation, resulting in a complex preparation process and high production costs. Therefore, there is an urgent need to develop a simple and high-yield method for preparing Compound VI that would facilitate industrial production.

[0005] Summary of the Invention

[0006] 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.

[0007] The first aspect of the present application provides a method for preparing compound VI, which is method 1 or method 2;

[0008] Method 1 includes the following steps:

[0009]

[0010] Step 1: Compound III undergoes fluorination reaction to obtain compound V;

[0011] Step 2: Compound V undergoes reduction reaction to obtain compound VI.

[0012] Method 2 includes the following steps:

[0013]

[0014] Step 1': Compound IV undergoes fluorination reaction to obtain compound V;

[0015] Step 2: Compound V undergoes reduction reaction to obtain compound VI.

[0016] 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.

[0017] in,

[0018] 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 (for example: 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, unsubstituted or substituted with Ra, is selected from phenyl, methoxyphenyl, and p-nitrophenyl; and the C4-C8 heteroaryl group is selected from furyl, thienyl, and indolyl. The above groups where R1 is not hydrogen are all carboxyl protecting groups.

[0019] Preferably, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, p-nitrobenzyl; preferably, R1 is selected from methyl, isopropyl, tert-butyl, benzyl, p-nitrobenzyl.

[0020] R2 is a hydroxy protecting group selected from C1-C25 sulfonyl, C1-C6 alkyl, C7-C25 alkyl substituted by Rb, C1-C25 silyl, C6-C25 aryl which is unsubstituted or arbitrarily substituted by Rc, C3-C25 heteroaryl, Rb is selected from phenyl or phenyl arbitrarily substituted by halogen, alkoxy, cyano or nitro, and Rc is selected from C1-C6 alkyl, trityl, halogen, alkoxy, cyano or nitro. Preferably, the sulfonyl group of C1 to C25 is -S(=O)2-R3, R3 is selected from unsubstituted or fluorinated C1 to C12 alkyl, unsubstituted or fluorinated C6 to C10 aryl, preferably, the sulfonyl group of C1 to C25 is selected from methylsulfonyl, ethylsulfonyl, propylsulfonyl, p-methylphenylsulfonyl, trifluoromethylsulfonyl, perfluorobutylsulfonyl; the alkyl group of C1 to C6 is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or pentyl; the alkyl group of C7 to C25 substituted by Rb is selected from benzyl, p-nitrobenzyl or p-methoxybenzyl; the silyl group of C1 to C25 is selected from trimethylsilyl, triethylsilyl, tri-n-butylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tri- Isopropylsilyloxymethyl, [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.

[0021] Preferably, R2 is selected from trimethylsilyl, methylsulfonyl, p-methylphenylsulfonyl, trifluoromethylsulfonyl, and perfluorobutylsulfonyl.

[0022] 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).

[0023] 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).

[0024] 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 reagent 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, diethyl ether, and benzene, preferably at least one of acetonitrile, tetrahydrofuran, methyltetrahydrofuran, and dichloromethane. The fluorination reaction does not require high temperature or high pressure, and the reaction conditions are mild, the yield is high, and the fluorination reagent is stable and does not produce explosive substances.

[0025] The present application does not particularly limit the amount of aprotic solvent added in step 1 of method 1 and steps 1-2 of method 2, as long as the normal progress of the fluorination reaction is guaranteed. For example, 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 unit of the mass of compound III and compound IV is g, and the unit of the volume of the aprotic solvent is mL.

[0026] In some embodiments of the present application, an alkali agent may be added to the fluorination reaction in Step 1 and Step 1-2. 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 it may be mixed with the fluorination agent according to the above-mentioned molar ratio before addition.

[0027] 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 to separate compound VI; the reduction reaction temperature is preferably less than or equal to 0°C, for example, -10°C to 0°C; the reduction reaction time is preferably 0.5h to 5h, and the molar ratio of compound V to the reducing agent is 1:(1-5). 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, diethyl 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 and low cost.

[0028] The present application does not particularly limit the amount of organic solvent added in step 2 of method 1 and method 2, as long as the normal progress of the reduction reaction is guaranteed. Exemplarily, the ratio of the mass 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.

[0029] The second aspect of the present application provides a compound having the structure shown in the following formula IV:

[0030]

[0031] Wherein, R1 is the same as the substituent R1 defined in the first aspect;

[0032] R2 is the same as the substituent R2 defined in the first aspect.

[0033] For example, compound IV is selected from the following compounds:

[0034]

[0035] 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.

[0036] The third aspect of the present application provides a method for preparing compound IV in any of the aforementioned embodiments, comprising the following steps:

[0037]

[0038] Step 1-1a: Compound III undergoes a substitution reaction to obtain compound IV. This substitution reaction uses inexpensive raw materials to obtain new compound IV and is also beneficial for improving the purity and yield of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine-7a-yl)methanol.

[0039] Preferably, step 1-1a comprises the following steps: Compound III undergoes a substitution reaction with an alkaline agent in an aprotic solvent to separate Compound IV; the substitution reaction temperature is -78°C to 40°C, and the substitution reaction time is 1 hour to 36 hours, preferably 24 hours to 36 hours; the molar ratio of Compound III to the alkaline agent is 1:(1 to 50), preferably 1:(1 to 20), and more preferably 1:(1 to 15). The alkaline 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, diethyl ether, and benzene, preferably dichloromethane. The reaction conditions of the substitution reaction are simple, safe, and selective, and the reaction reagents are all conventional reagents with low cost.

[0040] 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 base agent and the compound III undergo a 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-R3 or a C1-C25 halogenated silane; wherein X is a halogen, and the halogen is preferably Cl or Br, more preferably Cl; R3 is selected from unsubstituted or fluorinated C1-C12 alkyl, unsubstituted or fluorinated C6-C10 aryl; -S(=O)2-R3 is preferably selected from methylsulfonyl, ethylsulfonyl, propylsulfonyl, p-methylphenylsulfonyl, trifluoromethylsulfonyl, and perfluorobutylsulfonyl. The halogen in the C1-C25 halogenated silane is preferably Cl, I or Br, more preferably Cl.

[0041] The C1-C25 halosilane 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.

[0042] 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-methylbenzenesulfonyl chloride, trifluoromethanesulfonyl chloride or perfluorobutylsulfonyl chloride; preferably trimethylsilyl chloride, methanesulfonyl chloride, p-methylbenzenesulfonyl 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.

[0043] In some embodiments of the present application, a catalyst is further 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).

[0044] The present application does not particularly limit the amount of aprotic solvent added in step 1-1a, as long as the substitution reaction can proceed normally. Exemplarily, the ratio of the mass of compound III to the volume of the aprotic solvent is 1:(15-30), wherein the unit of the mass of compound III is g and the unit of the volume of the aprotic solvent is mL.

[0045] In a fourth aspect, the present application provides a method for preparing compound IV in any of the aforementioned embodiments, comprising the following steps:

[0046]

[0047] Step 1-1b: Compound II undergoes a ring-closing reaction to obtain compound IV.

[0048] In the present application, * in each compound indicates that the corresponding carbon atom has chirality.

[0049] Preferably, step 1-1b comprises the following steps: compound II and a strong base agent undergo a ring-closure reaction in an organic solvent to obtain compound IV; the ring-closure reaction temperature 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, diethyl ether, acetone, and benzene, preferably at least one of methyltetrahydrofuran and tetrahydrofuran. After the ring-closure reaction is complete, acid is added and filtered to obtain Compound IV for the next reaction. This eliminates the need for complex separation steps, making the preparation process more streamlined. The "one-pot" reaction produces fewer byproducts and achieves high atomic efficiency. The acid is selected from at least one of formic acid, acetic acid, and a Lewis acid, and the Lewis acid is selected from at least one of zinc chloride, tin chloride, and titanium tetrachloride. The molar ratio of the acid to Compound II is 1:(1-10), preferably 1:(1-4). Furthermore, the ring-closure reaction is highly safe and selective, and the reaction reagents are all conventional and low-cost.

[0050] The fifth aspect of the present application provides a compound having the structure shown in the following formula III:

[0051]

[0052] wherein, the substituent R1 is defined the same as in the first aspect.

[0053] For example, compound III is selected from the following compounds:

[0054]

[0055] In the present application, Me in the compound refers to methyl, Bn refers to benzyl, and tBu refers to tert-butyl.

[0056] In a sixth aspect, the present application provides a method for preparing Compound III in any of the aforementioned embodiments, comprising the following steps:

[0057]

[0058] Compound II undergoes a ring-closure reaction to produce compound III; wherein X is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, and benzenesulfonyloxy, and is preferably Cl, Br, or I. This ring-closure reaction cleverly utilizes new compound II to produce new compound III, resulting in few byproducts, high atom utilization, and good selectivity (for example, compound II with either SR or RR configuration can yield new compound III with SS configuration). The resulting isomers are of high purity and offer good reaction yields.

[0059] Preferably, the ring-closure reaction comprises the following steps: Compound II and a strong base react in an organic solvent to undergo a ring-closure reaction, and Compound III is separated; the ring-closure reaction temperature is -100°C to 30°C, and the time is 10 hours to 24 hours; the molar ratio of Compound II to the strong base 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 is selected from at least one of sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium tert-butoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, lithium 2,2,6,6-tetramethylpiperidinium, 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, diethyl ether, methyl tert-butyl ether, and benzene, preferably at least one of methyltetrahydrofuran and tetrahydrofuran. The ring-closure reaction has simple reaction conditions, high safety, and good selectivity, and the reaction reagents are all conventional reagents and low cost.

[0060] In a seventh aspect, the present application provides a compound having the structure shown in the following formula II:

[0061]

[0062] Wherein, R1 is the same as the substituent R1 defined in the first aspect; X is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy, preferably Cl, Br, I.

[0063] For example, compound II is selected from the following compounds:

[0064]

[0065] In the present application, Me in the compound refers to methyl, Bn refers to benzyl, and tBu refers to tert-butyl.

[0066] In an eighth aspect, the present application provides a method for preparing Compound II in any of the aforementioned embodiments, comprising the following steps:

[0067]

[0068] Compound I or its salt undergoes a ring-opening reaction with Compound VII to separate Compound II. This 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. The salt of Compound I may include, but is not limited to, a salt formed by the combination of NH in Compound I with HCl, hydrobromic acid, tartaric acid, mandelic acid, sulfuric acid, methanesulfonic acid, or oxalic acid.

[0069] Preferably, the 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 and obtain 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 to 10), preferably 1:(1 to 4); the molar ratio of compound I to compound VII is 1:(1 to 10), preferably 1:(1 to 2), and further preferably 1:(1 to 1.5); the mass ratio of compound I to the volume of the organic solvent is 1:(1 to 20), preferably 1:(5 to 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. 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 is further selected from triethylamine. The organic solvent is selected from at least one of an alcohol solvent, a chlorinated alkane, an ether solvent, and a liquid alkane solvent. 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, diethyl 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 ring-opening reaction has simple reaction conditions, high safety, good selectivity, and the reaction reagents are all conventional reagents with low cost.

[0070] This application does not specifically limit the separation steps in the above steps. Separation steps known in the art may be used, as long as the objectives of this application are achieved. For example, the separation steps may include, but are not limited to, quenching the reaction with water, a salt solution, or other organic solvent, extraction, washing with water or other solvents, treatment with activated carbon, filtration, concentration, recrystallization, etc. The salt solution and other organic solvents mentioned above can be conventional salt solutions and organic solvents used in separations known in the art. This application does not limit these steps, as long as the objectives of this application are achieved.

[0071] Beneficial effects of this application:

[0072] The preparation method of Compound VI provided herein 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 IV → Compound V → Compound VI, Compound I → Compound II → Compound III → Compound IV → Compound V → Compound VI. Compound VI has a fluorinated tertiary carbon chiral center and a nitrogen-containing quaternary carbon chiral center, making its synthesis relatively difficult. The preparation method provided herein 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 resulting Compound VI is of high quality. For example, the overall reaction yield can reach 36%, and the chiral purity of the chiral carbon atoms can reach over 99.0%.

[0073] Of course, it is not necessary to achieve all the advantages described above at the same time when implementing any product or method of the present application. DETAILED DESCRIPTION

[0074] To make the purpose, technical solutions, and advantages of this application more clearly understood, the present application is further described in detail below with reference to the embodiments. It is apparent that the embodiments described are only a portion of the embodiments of this application, rather than all of them. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments in this application are intended to fall within the scope of protection of this application.

[0075] Example 1: Preparation of Compound II-1

[0076]

[0077] Compound I-1 (50 g, 303 mmol, 1.0 equivalent (equiv)) was added to methanol (500 mL), followed by (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). The mixture was heated to 80°C and refluxed for 3 hours. The mixture was concentrated until no effluent was generated, dissolved in dichloromethane (DCM), and then washed with a solution of KHCO3 (30 g) in water (250 mL). The mixture was separated and concentrated until almost no effluent was generated. The mixture was then passed through a column with DCM:MeOH (40:1 volume ratio) and dried to dryness to obtain 57 g of compound II-1 as a light yellow oil in an 85% yield.

[0078] 1 H NMR(400MHz, CDCl3) δ3.73(dt,J=12.3,5.5Hz,1H),3.69(s,3H),3.67(d,J=5.3Hz,1 H),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). 13 C NMR(100MHz,DMSO-d6)δ174.0,69.2,65.4,57.4,53.6,51.4,48.5,28.6,23.3.m / z calcd for C9H 17 ClNO3 + ,[M+H] + :222.1,found:222.1.

[0079] Example 2: Preparation of Compound II-2

[0080]

[0081] Compound I-2 (58.5 g, 353.2 mmol, 1.0 equiv) was added to methanol (585 mL) and stirred to dissolve. (R)-epichlorohydrin (39.2 g, 423.7 mmol, 1.2 equiv) and TEA (35.7 g, 352.8 mmol, 1.0 equiv) were then added dropwise. The mixture was heated to 80°C and refluxed for 3 hours. The mixture was concentrated until almost no residue was distilled off, dissolved in DCM, washed twice with 8% potassium bicarbonate (585 mL), washed once with water, concentrated until almost no residue was distilled off, and purified by column chromatography to obtain 55.5 g of the product, compound II-2, as a light yellow oil in a 71% yield.

[0082] 1 H NMR (400MHz, DMSO-d6) 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). 13 C NMR(100MHz,DMSO-d6)δ174.3,69.1,65.3,57.3,53.9,51.4,48.3,29.0,23.3.m / z calcd for C9H 17 ClNO3 + ,[M+H] + :222.1,found:222.1.

[0083] Example 3: Preparation of Compound III-1

[0084]

[0085] Under nitrogen protection, compound II-1 (2 g, 9 mmol, 1 equiv) was dissolved in tetrahydrofuran (THF, 45 mL) and cooled to -70°C. Lithium hexamethyldisilazide (LiHMDS, 14.4 mL, 14.4 mmol, 1.6 equiv) was then added dropwise and allowed to react for 12 h. The reaction was quenched by the addition of 10% aqueous NH4Cl solution, extracted with DCM, and the combined organic phases were washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to yield 698 mg of compound III-1 (42% yield).

[0086] 1 H NMR (400MHz, CDCl3) 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 C9H 16 NO3 +,[M+H] + :186.1,found:186.3.

[0087] Example 4: Preparation of Compound III-1

[0088]

[0089] Compound II-2 (20 g, 90.2 mmol, 1 equiv) was dissolved in THF (450 mL) and then cooled to -70°C. LiHMDS (144.3 mL, 144.3 mmol, 1.6 equiv) was added dropwise and allowed to react for 24 h. 10% ammonium chloride (500 mL) was added, stirred for 20 min, and extracted with DCM (200 mL). The organic phase was concentrated to a minimum and purified by column chromatography to afford 7.1 g of compound III-1 as a brown solid in a 42.5% yield.

[0090] Example 5: Preparation of Compound IV-1

[0091]

[0092] Compound III-1 (1 g, 5.4 mmol, 1 equiv) was dissolved in DCM (27 mL), and TEA (1.5 mL, 10.8 mmol, 2.0 equiv) was added. The temperature was lowered to 0°C, and p-toluenesulfonyl chloride (TsCl, 1.5 g, 8.1 mmol, 1.5 equiv) and 4-dimethylaminopyridine (DMAP, 66 mg, 0.54 mmol, 0.1 equiv) were added. The reaction was then allowed to return to room temperature (25±5°C) and allowed to react. After 28 h, the reaction was quenched by the addition of 10% aqueous NH4Cl solution, diluted with ethyl acetate (EA), separated, washed three times with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration, concentration, and column chromatography were then performed to obtain 1 g of the product, compound IV-1, in a 55% yield.

[0093] 1H NMR(400MHz, CDCl3) 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 16 H 22 NO5S + ,[M+H] + :340.1,found:340.1.

[0094] Example 6: Preparation of Compound V-1

[0095]

[0096] Compound III-1 (500 mg, 2.7 mmol, 1 equiv) was dissolved in acetonitrile (2 mL), and TEA (2.3 mL, 16.2 mmol, 6.0 equiv) was added. The mixture was cooled to 0°C, and triethylamine trihydrofluoride (1.3 mL, 8.1 mmol, 3 equiv) was then added dropwise. The mixture was allowed to react on ice for two hours. Perfluorobutylsulfonyl fluoride (0.5 mL, 2.8 mmol, 1.05 equiv) was then added dropwise, and the mixture was allowed to warm to room temperature and react for 14 hours. The reaction was quenched by the slow addition of saturated aqueous sodium bicarbonate solution, extracted with DCM, washed once with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The product was filtered, concentrated, and purified by column chromatography to obtain 291 mg of the product, compound V-1, in a 57.6% yield.

[0097] 1 H NMR(400MHz, CDCl3)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 C9H 15 FNO2 + ,[M+H] +:188.1,found:188.2.

[0098] Example 7: Preparation of Compound VI

[0099]

[0100] 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. The reaction was maintained at 0°C for 30 minutes. Water (0.12 mL), 15% aqueous NaOH (0.24 mL), and water (0.36 mL) were added to quench the reaction. The mixture was filtered through celite and rinsed with ethyl acetate. The filtrate was concentrated and purified by column chromatography to obtain 164 mg of the product, compound VI, in a yield of 52.5%, as a light yellow solid with an enantiomeric purity (ee) of 99.5%.

[0101] 1 H NMR(400MHz, CDCl3)δ5.25(m,0.5H),5.11(m,0.5H),3.35(brs,1H),3.25(s,2 H),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),2.0 6(s,0.5H),2.01(dd,J=7.1,2.9Hz,1H),1.96-1.82(m,2H),1.82-1.66(m,2H). 13 C NMR (100MHz, CDCl3) 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. 19 F NMR (376MHz, CDCl3)δ-172.2.m / z calcd for C8H 15 FNO + ,[M+H] + :160.1,found:160.3.

[0102] Example 8: Preparation of Compound II-3

[0103]

[0104] A flask was charged with compound I-3 (52.10 g, 215.5 mmol, 1.0 equiv), isopropyl alcohol (260 mL), (R)-epichlorohydrin (30.5 g, 329.7 mmol, 1.5 equiv), and TEA (30 mL, 215.5 mmol, 1.0 equiv). The temperature was raised to 70°C and the reaction was allowed to proceed for 3 hours. The mixture was then cooled to room temperature and concentrated until almost no distillate was generated. DCM was added for dissolution, and the mixture was washed with 8% potassium bicarbonate (521 mL), washed once with water, and concentrated until almost no distillate was generated. The product, compound II-3, was purified by column chromatography to obtain 58 g of the product, compound II-3, as a light yellow oil in a 90% yield.

[0105] 1 H NMR (400MHz, CDCl3) 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 15 H 21 ClNO3 + ,[M+H] + :298.1,found:298.1.

[0106] Example 9: Preparation of Compound III-2

[0107]

[0108] Compound II-3 (40.0 g, 134.3 mmol, 1 equiv) was added to THF (1.1 L), and the atmosphere was replaced with N2 three times. The temperature was lowered to -70°C, and LiHMDS (221.5 mL, 214.9 mmol, 1.6 equiv) was added dropwise. The reaction was incubated for 12 hours. 10% ammonium chloride was added to quench the reaction, and the mixture was extracted with DCM. The organic phase was washed once with saturated brine, dried, and purified by column chromatography to obtain 26 g of the product, compound III-2, as a white solid in a 74% yield.

[0109] 1H NMR (400MHz, CDCl3) 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(d d,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 15 H 20 NO3 + ,[M+H] + :262.3,found:262.1.

[0110] Example 10: Preparation of Compound V-2

[0111]

[0112] Compound III-2 (10 g, 38 mmol, 1 equiv) was dissolved in THF (38 mL), and TEA (32 mL, 228 mmol, 6.0 equiv) was added. The mixture was cooled to 0°C, and triethylamine trihydrofluoride (19 mL, 114 mmol, 3 equiv) was added dropwise. The mixture was then reacted on ice for two hours. Perfluorobutylsulfonyl fluoride (7 mL, 39.9 mmol, 1.05 equiv) was added dropwise, and the mixture was warmed to room temperature and reacted for 12 hours. The reaction was quenched by the slow addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted twice with DCM, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 57 g of the product, compound V-2 6., with a yield of 66%.

[0113] 1 H NMR (400MHz, CDCl3) 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 19 FNO2 + ,[M+H] + :264.1,found:264.2.

[0114] Example 11: Preparation of Compound VI

[0115]

[0116] Compound V-2 (5.6 g, 21.2 mmol, 1 equiv) was dissolved in THF (60 mL), cooled to 0°C, and LiAlH4 (2.4 g, 63.8 mmol, 3.0 equiv) was added. The reaction was maintained at 0°C for 1 hour. Water (2.4 mL), 15% aqueous NaOH (4.8 mL), and water (7.2 mL) were added sequentially to quench the reaction. The mixture was filtered through celite and rinsed with ethyl acetate. The filtrate was concentrated and purified by column chromatography to obtain 2.8 g of the product, compound VI, as a light yellow solid. The yield was 82% and the product ee was 99.8%.

[0117] Example 12: Preparation of Compound II-4

[0118]

[0119] Compound I-4 (10 g, 48.1 mmol, 1 equiv) was added to isopropanol (50 mL), followed by the addition of (R)-epichlorohydrin (6.68 g, 72.2 mmol, 1.5 equiv). The temperature was lowered to -5°C, and TEA (4.8 g, 47.4 mmol, 1.0 equiv) was added dropwise. After completion of the addition, the mixture was heated to 95°C and refluxed for 72 hours. The mixture was then cooled to room temperature and concentrated until almost no residue was distilled off. DCM was added for dissolution, and the mixture was washed with 8% potassium bicarbonate (521 mL), washed once with water, and concentrated until almost no residue was distilled off. The mixture was purified by column chromatography to obtain 9.2 g of the product, compound II-4, as a light yellow oil in a 73% yield.

[0120] 1 H NMR (400MHz, CDCl3) 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 12 H 23 ClNO3 + ,[M+H] +:264.1,found:264.1.

[0121] Example 13: Preparation of Compound IV-2

[0122]

[0123] Compound II-4 (20 g, 75.8 mmol, 1 equiv) was added to THF (60 mL), the atmosphere was replaced with nitrogen three times, the temperature was lowered to -70°C, and LiHMDS (121 mL, 121 mol, 1.6 equiv) was added dropwise. The reaction was incubated for 16 hours. Acetic acid (6.5 mL, 113.7 mmol, 1.5 equiv) was added dropwise. Under nitrogen, the mixture was padded with celite and filtered. The filtrate was concentrated and distilled under reduced pressure to obtain 17.7 g of compound IV-2 as a light yellow liquid, with a yield of 78%.

[0124] 1 H NMR (400MHz, CDCl3) 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 15 H 30 NO3Si + ,[M+H] + :300.2,found:300.2.

[0125] Example 14: Preparation of Compound V-3

[0126]

[0127] Compound IV-2 (5 g, 16.7 mmol, 1 equiv) was added to THF (25 mL), and the atmosphere was replaced with N2 three times. The temperature was then lowered to 5°C, and triethylamine trihydrofluoride (TEA-3HF, 8 g, 49.6 mmol, 3.0 equiv) and TEA (20.2 g, 199.6 mmol, 12 equiv) were added dropwise. Then, perfluorobutylsulfonyl fluoride (5.3 g, 17.5 mmol, 1.05 equiv) was added dropwise. The reaction was incubated for 5 hours, then the temperature was raised to room temperature and the reaction was continued for 16 hours. 10% potassium carbonate was added dropwise to adjust the pH to 9-10. The mixture was stirred and separated. The upper organic phase was separated, dried, and then purified by column chromatography to obtain 2.5 g of the product, compound V-3, in a yield of 65%.

[0128] 1 H NMR (400MHz, CDCl3) 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 12 H 21 FNO2 + ,[M+H] + :230.2,found:230.2.

[0129] Example 15: Preparation of Compound VI

[0130]

[0131] Compound V-3 (1 g, 4.4 mmol, 1 equiv) was added to THF (10 mL), the atmosphere was replaced with nitrogen three times, the temperature was lowered to 0°C, and lithium aluminum tetrahydride (0.50 g, 13.2 mmol, 3 equiv) was added. After reacting for 1 h on an ice bath, the reaction was quenched by the dropwise addition of water (0.5 mL), 15% sodium hydroxide (1 mL), and water (1.5 mL). The reaction solution was filtered through celite and rinsed with ethyl acetate. The filtrate was concentrated and purified by column chromatography to afford 0.43 g of compound VI in a 61% yield as a light yellow solid with an ee of 99.4%.

[0132] Example 16: Preparation of Compound II-5

[0133]

[0134] Compound I-6 (9.8 g, 50.7 mmol, 1.0 equiv) was dissolved in isopropanol (49 mL), and (R)-epichlorohydrin (7.0 g, 75.7 mmol, 1.5 equiv) was added. The temperature was cooled to -5°C, and TEA (5.1 g, 50.6 mmol, 1.0 equiv) was added dropwise. After completion of the addition, the temperature was raised to 70°C and stirred for 12 h. The mixture was then cooled to room temperature and concentrated until almost no distillate was generated. DCM was added for dissolution, and the mixture was washed with 8% potassium bicarbonate (521 mL), washed once with water, and concentrated until almost no distillate was generated. Purification by column chromatography afforded 8.1 g of the product, compound II-5, as a light yellow oil in a 64% yield.

[0135] 1 H NMR (400MHz, CDCl3) 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 11 H 21 ClNO3 + ,[M+H] + :250.1,found:250.1.

[0136] Example 17: Preparation of Compound IV-3

[0137]

[0138] Compound II-5 (4.0 g, 16.0 mmol, 1.0 equiv) was dissolved in THF (45 mL) with stirring. The mixture was purged with nitrogen three times and cooled to -70°C. 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. After addition, the temperature was raised to 20-30°C, stirred for 0.5 h, filtered, and the filtrate was concentrated until no solvent was present to obtain 2.8 g of compound IV-3 as a yellow oily liquid in a 61.2% yield.

[0139] 1H NMR (400MHz, CDCl3) 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 14 H 28 NO3Si + ,[M+H] + :286.2,found:286.2.

[0140] Example 18: Preparation of Compound V-4

[0141]

[0142] Compound IV-3 (1.0 g, 3.5 mmol, 1.0 equiv) was dissolved in THF (5 mL) with stirring and nitrogen purging three times. The temperature was then lowered to -5°C, and 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. The mixture was returned to room temperature and stirred for 12 h. The reaction solution was added dropwise to a 10% aqueous solution of NaHCO₃ and stirred for 0.5 h. The layers were separated, and the organic phase was washed once with water, separated again, and concentrated under reduced pressure. The organic phase was purified by column chromatography to afford 0.4 g of compound V-4 in a 53% yield.

[0143] 1H NMR (400MHz, CDCl3) 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 11 H 19 FNO2 + ,[M+H] + :216.1,found:216.1.

[0144] Example 19: Preparation of Compound VI

[0145]

[0146] Compound V-4 (0.3 g, 1.3 mmol, 1.0 equiv) was dissolved in THF (2 mL) and stirred. The mixture was purged with nitrogen three times and cooled to 0°C. LiAlH4 (63 mg, 1.6 mmol, 1.2 equiv) was added portionwise and maintained at 0°C for half an hour. The reaction was then quenched by adding water (63 μL), 15% aqueous NaOH solution (120 μL), and water (240 μL) in sequence at -5°C. The reaction was stirred for 30 min, filtered through a celite pad, and the filtrate was concentrated until no solvent was present. The mixture was purified by column chromatography and concentrated under reduced pressure to afford 180 mg of compound VI as a light yellow solid in an 82% yield with an ee of 99.2%.

[0147] The yields in the above examples are molar yields, and the chiral purity is tested using the following procedure: chiral gas chromatography (Chiral GC) (Agilent CYCLOSIL-B 30 mx0.25 mm 0.25 μm, N 2 3 mL / min, Rate: 80°C, 1 min, 10°C / min, 140°C, 3 min, FID detector) RT = 10.14 min (minor), RT = 10.32 min (major), ee = 99.2%.

[0148] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent replacements, 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

1. A method for preparing compound VI, which is method 1 or method 2; The method 1 comprises 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; The second method comprises 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; in, 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; 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 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; Further preferably, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, p-nitrobenzyl; further preferably, R1 is selected from methyl, isopropyl, tert-butyl, benzyl, p-nitrobenzyl; 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 optionally substituted by halogen, alkoxy, cyano, or nitro, and Rc is selected from C1-C6 alkyl, trityl, halogen, alkoxy, cyano, or nitro; Preferably, the C1-C25 sulfonyl group is -S(=O)2-R3, R3 is selected from unsubstituted or fluorinated C1-C12 alkyl, unsubstituted or fluorinated C6-C10 aryl, preferably, the C1-C25 sulfonyl group is selected from methylsulfonyl, ethylsulfonyl, propylsulfonyl, p-methylphenylsulfonyl, trifluoromethylsulfonyl, perfluorobutylsulfonyl; the C1-C6 alkyl group 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-butyldiphenylsilane alkyl, 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; More preferably, R2 is selected from trimethylsilyl, methylsulfonyl, p-methylphenylsulfonyl, trifluoromethylsulfonyl, and perfluorobutylsulfonyl.

2. The preparation method according to claim 1, wherein The step 1 comprises the following steps: the compound III undergoes a fluorination reaction with a fluorination agent in an aprotic solvent to separate and obtain the compound V; the molar ratio of the compound III to the fluorination agent is 1:(1-5); The step 1' comprises the following steps: the compound IV undergoes a fluorination reaction with a fluorination agent in an aprotic solvent to separate and obtain the compound V; the molar ratio of the compound IV to the fluorination agent is 1:(1-5); 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; 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 morpholine trifluoride, diethylaminosulfur trifluoride, or perfluorobutylsulfonyl fluoride, preferably at least one of perfluorobutylsulfonyl fluoride, diethylaminosulfur 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, diethyl ether, and benzene, preferably at least one of acetonitrile, tetrahydrofuran, methyltetrahydrofuran, and dichloromethane; Preferably, an alkali is further 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.

3. The preparation method according to any one of claims 1 to 2, wherein The step 2 comprises the following steps: The compound V reacts with a reducing agent in an organic solvent to undergo a reduction reaction to obtain the compound VI; the reduction reaction temperature is less than or equal to 0°C, preferably -10°C to 0°C; the reduction reaction time is 0.5h to 5h, and the molar ratio of the compound IV to the reducing agent is 1:(1-5); 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, diethyl ether and dioxane.

4. A compound having the structure shown in the following formula IV: in, 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; 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 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; Further preferably, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, p-nitrobenzyl; further preferably, R1 is selected from methyl, isopropyl, tert-butyl, benzyl, p-nitrobenzyl; 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 optionally substituted by halogen, alkoxy, cyano, or nitro, and Rc is selected from C1-C6 alkyl, trityl, halogen, alkoxy, cyano, or nitro; Preferably, the C1-C25 sulfonyl group is -S(=O)2-R3, R3 is selected from unsubstituted or fluorinated C1-C12 alkyl, unsubstituted or fluorinated C6-C10 aryl, preferably, the C1-C25 sulfonyl group is selected from methylsulfonyl, ethylsulfonyl, propylsulfonyl, p-methylphenylsulfonyl, trifluoromethylsulfonyl, perfluorobutylsulfonyl; the C1-C6 alkyl group 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-butyldiphenylsilane alkyl, 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; More preferably, R2 is selected from trimethylsilyl, methylsulfonyl, p-methylphenylsulfonyl, trifluoromethylsulfonyl, and perfluorobutylsulfonyl.

5. The compound according to claim 4, which is selected from the following compounds:

6. A method for preparing the compound according to any one of claims 4 to 5, comprising the following steps: Step 1-1a: Compound III undergoes substitution reaction to obtain compound IV; The step 1-1a comprises the following steps: the compound III undergoes a substitution reaction with an alkaline agent in an aprotic solvent to separate the compound IV; the substitution reaction temperature is -78°C to 40°C, and the time is 1 hour to 36 hours; the molar ratio of the compound III to the alkaline agent is 1:(1 to 50), preferably 1:(1 to 20), and more preferably 1:(1 to 15); The alkaline 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, diethyl ether, and benzene, preferably dichloromethane; 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.

7. A method for preparing the compound according to any one of claims 4 to 5, comprising the following steps: Step 1-1b: Compound II undergoes a ring-closing reaction to obtain compound IV; Preferably, step 1-1b comprises the following steps: compound II undergoes a ring-closing reaction with a strong base in an organic solvent to separate and 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 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 alkaline 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; 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.

8. A compound having the structure shown in the following formula III: in, 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; 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 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.

9. The compound according to claim 8, which is selected from the following compounds:

10. A method for preparing the compound according to any one of claims 8 to 9, comprising the steps of: Compound II undergoes a ring-closure reaction to obtain compound III; in, X is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy, preferably Cl, Br, I; Preferably, the ring-closure reaction comprises the following steps: reacting the compound II with a strong base in an organic solvent to undergo a ring-closure reaction, and isolating the compound III; the temperature of the ring-closure 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; 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; 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, diethyl ether, methyl tert-butyl ether, and benzene, and is preferably at least one of methyltetrahydrofuran and tetrahydrofuran.

11. A compound having the structure shown in the following formula II: in, 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, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl; the C3-C7 cycloalkyl is selected from cyclopropyl, cyclopentyl, and cyclohexyl; the C1-C8 alkyl substituted by an aryl is selected from benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, and p-methoxybenzyl; the unsubstituted or Ra-substituted C6-C20 aryl is selected from phenyl, methoxyphenyl, and p-nitrophenyl; the C4-C8 heteroaryl is selected from furyl, thienyl, and indolyl; X is selected from halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, benzenesulfonyloxy; preferably, X is selected from Cl, Br, I.

12. The compound according to claim 11, which is selected from the following compounds:

13. A method for preparing the compound according to any one of claims 11 to 12, comprising the following steps: Compound I or its salt undergoes a ring-opening reaction with compound VII to separate compound II; Preferably, the ring-opening reaction comprises the following steps: in the presence of an alkaline 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 alkaline 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 more 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; 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 from 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, diethyl 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.