Preparation method for various opioids and intermediates thereof

Abstract

Disclosed in the present invention are a preparation method for various opioids and intermediates thereof. Provided in the present invention is a preparation method for various opioids. Specifically, provided are a preparation method for a compound represented by formula A7 and a series of compounds, such as a compound represented by formula A6-2. The preparation method comprises the following step: S10: subjecting a compound represented by formula A6-2 to a cyclization reaction represented by the following formula in an organic solvent under the action of a cyclization reagent, so as to obtain a compound represented by formula A7. A series of intermediates provided by the present invention enables the divergent synthesis of various opioids, including naltrexone, nalmefene, nalbuphine, buprenorphine, etc. The preparation method provided by the present invention has one or more of the following advantages: cheap and readily available raw materials, short synthetic steps, simple operation, easy scale-up of the process, and a high product yield.

Description

Preparation methods of various opioid drugs and their intermediates

[0001] This application claims priority to Chinese patent application 2024115313869, filed on October 30, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of chemical synthesis and relates to various methods for preparing opioid drugs and their intermediates. Background Technology

[0003] Opioids are a class of compounds that exert their effects by binding to opioid receptors in the body (mainly μ-, δ-, and κ-opioid receptors), and are among the most potent analgesics. The earliest total synthesis of opioid compounds can be traced back to the 1950s, when chemist Gates completed the total synthesis of morphine (Gates, M.; Tschudi, G. J. A.M. Chem. Soc. 1952, 75, 1109). Since then, over the past seventy years, chemists have successively published methods for the total synthesis of other opioid compounds such as dihydrocodeine, codeine, and hydromorphone.

[0004] However, long-term use of such opioids can lead to tolerance and dependence, resulting in drug addiction. To address this, medicinal chemists have developed various effective opioid derivatives such as naltrexone, nalmefene, buprenorphine, and nalbuphine (as shown in the formula below) for medical use. Naltrexone is a pure opioid receptor antagonist that blocks μ-, δ-, and κ-opioid receptors. It was approved by the FDA in 1984 as an oral medication to block dependence on opioids and alcohol. Nalmefene is a specific morphine receptor blocker that competitively antagonizes various opioid receptors and has become an alternative to naloxone. Buprenorphine is a partial opioid receptor agonist that provides analgesia for postoperative pain, cancer pain, burns, angina, or limb pain caused by overexertion. It can also be used for maintenance therapy in addiction treatment, helping to break down tension. Nalbuphine is a sedative-type psychotropic drug with opioid receptors. Its sedative effect is similar to morphine, with some respiratory depression but no cardiovascular side effects. Clinically, it is generally used for postoperative analgesia.

[0005] Although significant progress has been made in the total synthesis of opioid compounds, the market supply of opioids still relies on semi-synthetic routes based on extracts from poppies, such as morphine, codeine, papaverine, and thebaine. These routes are subject to several uncertainties: 1) poppy cultivation is heavily influenced by climate; 2) the extraction costs of raw materials are high; and 3) poppy cultivation leads to soil degradation. Given the substantial global market demand for opioids (approximately 900 tons), developing efficient, economical, and divergent chemical synthesis routes to stably supply a range of opioids to meet market demand is both challenging and urgent. Summary of the Invention

[0006] The technical problem this invention aims to solve is the limited variety of existing methods for synthesizing opioid derivatives. To address this, this invention provides multiple methods for preparing opioid drugs and their intermediates. The intermediates provided by this invention enable the dispersive synthesis of several opioid drugs, including naltrexone, nalmefene, nalbuphine, and buprenorphine. The preparation methods provided by this invention have one or more of the following advantages: inexpensive and readily available raw materials, short synthesis steps, simple operation, easy process scale-up, and high product yield.

[0007] This invention provides a method for preparing a compound as shown in Formula A7, comprising the following step S10:

[0008] S10: Under the action of a cyclizing agent, the compound shown in formula A6-2 undergoes a cyclization reaction in an organic solvent as shown in the following formula to give the compound shown in formula A7.

[0009] Wherein, "*" indicates that the carbon atom is a chiral carbon with a configuration of R, S or a mixture thereof;

[0010] R 1 For H, C 1-4 Alkyl or C 3-7 cycloalkyl;

[0011] R 2 For H or C 1-4 alkyl;

[0012] R 3 For H, C 1-4 Alkyl, C 3-7 cycloalkyl or C 6-14 Aryl;

[0013] R 5 and R 6 Independently for H and C 1-4 Alkyl, C 3-7 cycloalkyl, C 6-14 Aryl or -OC 1-4 alkyl;

[0014] L represents a single bond or C represents a single bond. 1-4 Alkylene;

[0015] R 7 For H, C 3-7 cycloalkyl or C 6-14 Aryl.

[0016] In one scheme, the C 1-4 Alkyl and -OC 1-4 C in alkyl 1-4 Each alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; for example, methyl.

[0017] In one scheme, the C 3-7 Each cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, such as cyclopropyl or cyclobutyl.

[0018] In one scheme, the C 6-14 Each aryl group can be anthracene, naphthyl, or phenyl.

[0019] In one scheme, the C 1-4 The alkylene group is methylene. For example, methylene.

[0020] In one of the schemes, R 1 R 2 R 3 R 5 and R 6 For H.

[0021] In one of the schemes, R 2 C 1-4 Alkyl; for example, methyl.

[0022] In one scheme, L is C 1-4 Alkylene; for example, methylene.

[0023] In one of the schemes, R 7 C 3-7 Cycloalkyl; for example, cyclopropyl or cyclobutyl.

[0024] In the preparation method of the compound shown in Formula A7 (hereinafter referred to as step S10), the reaction conditions, reagent types and amounts of the cyclization reaction can be the conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably includes the following.

[0025] In one embodiment, in step S10, the cyclization reaction is carried out under the protection of an inert gas and / or nitrogen. The inert gas is a conventional protective gas in the art, such as argon. Preferably, the cyclization reaction is carried out under nitrogen protection.

[0026] In one embodiment, in step S10, the organic solvent is a chloroalkane solvent and / or an ether solvent, such as an ether solvent. The chloroalkane solvent may be selected from one or more of dichloromethane, 1,2-dichloroethane, and chloroform, such as dichloromethane; the ether solvent may be selected from one or more of 1,4-dioxane, tetrahydrofuran, and methyltetrahydrofuran, such as 1,4-dioxane.

[0027] In step S10, the amount of organic solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, the molar volume ratio of the compound shown in formula A6-2 to the solvent is (0.05-5) mol:1L, for example, 0.1 mol:1L or 0.3 mol:1L.

[0028] In one embodiment, in step S10, the cyclizing agent is selected from one or more of N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide dinepentyl acetal, tert-butoxybis(dimethylamino)methane, N,N-dimethylformamide ditert-butyl acetal, N,N-dimethylformamide diethyl acetal, and 1,1-diisopropoxytrimethylamine, for example, N,N-dimethylformamide dimethyl acetal.

[0029] In one embodiment, in step S10, the molar ratio of the cyclizing agent to the compound shown in formula A6-2 is (1-20):1, for example (5-15):1, or even 10:1.

[0030] In one embodiment, in step S10, the temperature of the cyclization reaction is 40-80°C, for example, 50°C.

[0031] In step S10, the progress of the cyclization reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound shown in Formula A6-2. The cyclization reaction can take 8-40 hours, for example, 24 hours.

[0032] In step S10, after the cyclization reaction is completed, the following post-processing steps may be included. These post-processing steps are routine post-processing operations for this type of reaction, such as one or more of concentration and purification. The concentration may be vacuum distillation. The purification may be column chromatography, where the eluent is dichloromethane / methanol, for example, a volume ratio of (20-30):1.

[0033] In one embodiment, in step S10, the compound shown in formula A6-2 is... The compound shown in A7 is Alternatively, the compound shown in Formula A6-2 is The compound shown in A7 is

[0034] In one embodiment, the preparation method of the compound shown in Formula A7 further includes a preparation method of the compound shown in Formula A6-2, which includes the following step S9: under the action of a reducing agent and a Lewis acid, the compound shown in Formula A6-1 undergoes a reduction reaction in an organic solvent as shown in the following formula to obtain the compound shown in Formula A6-2.

[0035] *, L, R 1 R 2 R 3 R 5 R 6 and R 7 The definition is as described in any embodiment of this invention.

[0036] In the preparation method of the compound shown in Formula A6-2 (hereinafter referred to as step S9), the reaction conditions, reagent types and amounts of the reduction reaction can be the conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably includes the following.

[0037] In one embodiment, in step S9, the organic solvent is an alcohol solvent, for example, the organic solvent is selected from one or more of methanol, ethanol and isopropanol, such as ethanol.

[0038] The amount of organic solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, in step S9, the molar volume ratio of the compound shown in formula A6-1 to the organic solvent is (0.1-2) mol:1 L, for example, 0.3 mol:1 L.

[0039] In one embodiment, in step S9, the reducing agent is selected from one or more of alkali metal borohydrides, lithium aluminum hydride, diisobutylaluminum hydride, and sodium dihydrobis(dimethoxyethoxy)aluminate (red aluminum), for example, alkali metal borohydrides. The alkali metal borohydride may be selected from one or more of sodium borohydride, lithium borohydride, and potassium borohydride, for example, sodium borohydride.

[0040] In one embodiment, in step S9, the molar ratio of the reducing agent to the compound shown in formula A6-1 is (1-5):1, for example (1-3):1, or for example 2:1.

[0041] In one embodiment, in step S9, the Lewis acid is selected from one or more of indium trichloride, aluminum trichloride, boron trichloride, cerium trichloride, and boron trifluoride, such as cerium trichloride. The cerium trichloride may be anhydrous cerium trichloride and / or cerium trichloride hydrate, such as cerium trichloride hydrate, or cerium trichloride heptahydrate.

[0042] In one embodiment, in step S9, the molar ratio of the Lewis acid to the compound shown in formula A6-1 is (1-5):1, for example (1-3):1, or even 1:1.

[0043] In one embodiment, in step S9, the temperature of the reduction reaction is 10-30°C, for example, 25°C.

[0044] In step S9, the progress of the reduction reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and the reaction is generally considered to have ended when the compound shown in Formula A6-1 disappears or ceases to react. The duration of the reduction reaction can be 0.5-5 hours, for example, 1 hour.

[0045] In one embodiment, step S9 includes the following steps: dissolving the compound as shown in formula A6-1 in the organic solvent to form a mixture solution, adding (preferably at 25°C) the Lewis acid to the mixture solution and stirring, and then adding the reducing agent (preferably at 0°C) to carry out a reduction reaction.

[0046] In step S9, after the reduction reaction is completed, a post-processing step may be included. The post-processing step is a conventional post-processing operation for this type of reaction, such as one or more of quenching, extraction, drying and concentration. The solvent for quenching may be water; the solvent for extraction may be ethyl acetate; the drying agent may be anhydrous sodium sulfate; and the concentration may be vacuum distillation.

[0047] In one embodiment, the compound represented by formula A6-1 is...

[0048] In one embodiment, the method for preparing the compound shown in Formula A6-2 further includes a method for preparing the compound shown in Formula A6-1, comprising the following step S8: under the action of an acid, the compound shown in Formula A6 undergoes a hydrolysis reaction in a solvent as shown below to obtain the compound shown in Formula A6-1.

[0049] Among them, R 4 Each independently is C 1-4 Alkyl, C 6-14 aryl or aryl with one or more R 4a Replacement C 6-14 Aryl; R4a Each independently is C 1-4 Alkyl or -OC 1-4 alkyl;

[0050] L, R 1 R 2 R 3 R 5 R 6 and R 7 The definition is the same as that described in any embodiment of this invention.

[0051] In the preparation method of the compound shown in Formula A6-1 (hereinafter referred to as step S8), the reaction conditions, reagent types and amounts of the hydrolysis reaction can be the conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably includes the following.

[0052] In one embodiment, the solvent in step S8 is water and / or an alcohol solvent, such as water. The alcohol solvent may be methanol and / or ethanol.

[0053] The amount of solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, in step S8, the molar volume ratio of the compound represented by formula A6 to the solvent is (0.1-5) mol:1L, for example, 1.3 mol:1L, 1.7 mol:1L, or 1 mol:1L.

[0054] In one embodiment, in step S8, the acid is selected from one or more of trifluoroacetic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, and trifluoromethanesulfonic acid, such as hydrochloric acid and / or trifluoroacetic acid, or trifluoroacetic acid.

[0055] In one embodiment, in step S8, the molar ratio of the acid to the compound shown in formula A6 is (5-500):1, for example (10-100):1, or for example 24:1, 33:1 or 42:1.

[0056] In one embodiment, in step S8, the temperature of the hydrolysis reaction is -5 to 100°C.

[0057] In one solution, in step S8, R 4 Each independently is C 1-4 When alkyl groups are involved, the hydrolysis reaction is carried out at a temperature of 50-100°C. For example, 80°C; or, R 4 Each independently is C 6-14 When aryl is used, the hydrolysis reaction is carried out at a temperature of 10-30°C, for example, 25°C.

[0058] In step S8, the progress of the hydrolysis reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound represented by Formula A6. The hydrolysis reaction time can be 10-48 hours, for example, 24 hours or 30 hours.

[0059] In step S8, after the hydrolysis reaction is completed, the following post-processing steps may be included, which are routine post-processing operations for this type of reaction. In one embodiment, the post-processing steps include one or more of filtration, concentration, and purification. The concentration may be vacuum distillation. The purification may be crystallization, and the solvent for crystallization may be dichloromethane.

[0060] In one of the schemes, R 4 Each independently is C 1-4 Alkyl or C 6-14 Aryl, for example R 4 Each can be independently phenyl or methyl, for example R 4 Simultaneously, it is either phenyl or R 4 It is also methyl.

[0061] In one scheme, the compound represented by formula A6 is The compound shown in formula A6-1 is The compound represented by formula A6 is The compound shown in formula A6-1 is

[0062] In one embodiment, the method for preparing the compound shown in Formula A6-1 further includes a method for preparing the compound shown in Formula A6, comprising the following step S7: under alkaline conditions, the compound shown in Formula A5-1 and the compound shown in Formula T3 undergo a substitution reaction in a solvent as shown in the following formula to obtain the compound shown in Formula A6.

[0063] Where X is a halogen,

[0064] L and R 7 The definition satisfies any of the following conditions:

[0065] (1) L is C 1-4 Alkylene, R 7 For H, C 3-7 cycloalkyl or C 6-14 Aryl;

[0066] (2) L is a single bond, R 7 C 3-7 cycloalkyl or C 6-14 Aryl;

[0067] R 1 R 2 R 3 R 4 R 5 and R 6 The definition is the same as that described in any embodiment of this invention.

[0068] In one scheme, X is F, Cl, Br or I, for example Br.

[0069] In the preparation method of the compound shown in Formula A6 (hereinafter referred to as step S7), the reaction conditions, reagent types and amounts of the substitution reaction can be the conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably includes the following.

[0070] In one embodiment, in step S7, the substitution reaction is carried out under the protection of an inert gas and / or nitrogen. The inert gas is a conventional protective gas in the art, such as argon. Preferably, the substitution reaction is carried out under nitrogen protection.

[0071] In one embodiment, in step S7, the solvent is a benzene-based solvent, a nitrile solvent, a pyrrolidone, or an amide solvent, such as a benzene-based solvent or a nitrile solvent. The benzene-based solvent may be one or more of toluene, xylene, and mesitylene, for example, toluene. The nitrile solvent may be acetonitrile; the pyrrolidone solvent may be N-methylpyrrolidone; and the amide solvent may be N,N-dimethylacetamide and / or N,N-dimethylformamide.

[0072] In one embodiment, in step S7, the molar volume ratio of the compound as shown in formula A5-1 to the solvent is (0.01-0.5) mol:1L, for example, 0.25 mol:1L, 0.3 mol:1L or 0.4 mol:1L.

[0073] In one scheme, in step S7, L is C 1-4 Alkylene; R 7 For H or C 3-7 Cycloalkyl; for example, compounds of formula T3 are iodomethane, iodoethane, cyclopropylmethyl bromide, cyclobutylmethyl iodide, bromomethylcyclobutane, cyclopentylmethyl bromide or cyclohexylmethyl bromide, such as cyclopropylmethyl bromide or bromomethylcyclobutane.

[0074] In one embodiment, in step S7, the molar ratio of the compound shown in formula T3 to the compound shown in formula A5-1 is (1-5):1, for example, 2:1 or 4:1.

[0075] In one embodiment, in step S7, the base is an organic base and / or an inorganic base, such as an inorganic base. The organic base may be an organic amine, such as triethylamine. The inorganic base may be selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, or cesium carbonate, such as potassium bicarbonate or sodium bicarbonate.

[0076] In one embodiment, in step S7, the molar ratio of the base to the compound shown in formula A5-1 is (1-10):1, for example (2-5):1, or for example 2:1 or 3:1.

[0077] In one embodiment, in step S7, the temperature of the substitution reaction is 50-120°C, for example, 80°C or 100°C.

[0078] In step S7, the progress of the substitution reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound shown in Formula A5-1. The duration of the substitution reaction can be 8-48 hours, for example, 16 hours or 24 hours.

[0079] In step S7, after the substitution reaction is completed, the following post-processing steps may be included. These post-processing steps are routine post-processing operations for this type of reaction, such as one or more of extraction, drying, concentration, and purification. The solvent for extraction may be ethyl acetate. The drying agent may be anhydrous sodium sulfate. The concentration may be vacuum distillation. The purification may be column chromatography, for example, using dichloromethane and methanol (volume ratio 40:1) as the eluent.

[0080] In one embodiment, in step S7, the compound shown in formula A5-1 is... The compound shown in Formula T3 is cyclopropylmethyl bromide; or the compound shown in Formula A5-1 is... The compound shown in Formula T3 is bromomethylcyclobutane.

[0081] In one embodiment, the method for preparing the compound shown in Formula A6 further includes a method for preparing the compound shown in Formula A5-1, which includes the following step S6: under the action of a deprotecting agent, the compound shown in Formula A5 undergoes a deprotection reaction in a solvent as shown below to obtain the compound shown in Formula A5-1.

[0082] Where R is C 1-10 Alkyl, C 3-10 cycloalkyl, C 6-12 Aryl or -C 1-4 Alkylene-C 6-12 Aryl; R 1 R 2 R3 R 4 R 5 and R 6 The definition is the same as described above.

[0083] In the preparation method of the compound shown in Formula A5-1 (hereinafter referred to as step S6), the reaction conditions, reagent types and amounts of the deprotection reaction can be the conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably includes the following.

[0084] In one embodiment, in step S6, the solvent is an ester solvent and / or an alcohol solvent, for example, a mixture of ester and alcohol solvents. The ester solvent may be ethyl acetate; the alcohol solvent may be methanol or ethanol, for example, methanol.

[0085] The amount of solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, in step S6, the molar volume ratio of the compound shown in formula A5 to the solvent is (0.01-1) mol:1 L, for example, 0.2 mol:1 L or 0.3 mol:1 L.

[0086] In one embodiment, in step S6, the deprotection agent is an acid or a base; the acid can be selected from one or more of HCl, H2SO4, CH3COOH, H3PO4, trifluoroacetic acid, and methanesulfonic acid, for example, HCl; the base can be selected from one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide.

[0087] In one embodiment, in step S6, the molar ratio of the deprotecting agent to the compound shown in Formula A5 is (1-100):1, for example (3-10):1, or for example 5:1 or 6.5:1.

[0088] In one embodiment, in step S6, the solvent is a mixture of ester solvent and alcohol solvent, and the alcohol solvent and the deprotecting agent are added to the reaction system in the form of a deprotecting agent solution, such as a methanol solution of HCl.

[0089] In one embodiment, in step S6, the temperature of the deprotection reaction is -10 to 20°C, for example, 0°C.

[0090] In step S6, the progress of the deprotection reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound shown in Formula A5. The deprotection reaction time can be 0.5-8 hours, for example, 3 hours.

[0091] Step S6, after the deprotection reaction is completed, may further include the following post-processing steps. These post-processing steps are routine post-processing operations for this type of reaction, including one or more of quenching, extraction, drying, and concentration. The quenching reagent may be an aqueous solution of Na₂CO₃. The extraction solvent may be ethyl acetate. The drying agent may be anhydrous sodium sulfate. The concentration may be vacuum distillation.

[0092] In one scheme, R is C 1-4 Alkyl, C 3-6 cycloalkyl, C 6-12 Aryl or -C 1-4 Alkylene-C 6-12 Aryl; for example, R is C 1-4 Alkyl or -C 1-4 Alkylene-C 6-12 Aryl, such as tert-butyl or benzyl, and tert-butyl for example.

[0093] In one embodiment, in step S6, the compound shown in formula A5 is...

[0094] In one embodiment, the compound represented by formula A5-1 further includes a method for preparing the compound represented by formula A5, comprising the following step S5: In the presence of a palladium catalyst, a phosphine ligand represented by formula T2, and a base, the compound represented by formula A4 undergoes a dearomatization cyclization reaction in an organic solvent as shown below to obtain the compound represented by formula A5:

[0095] Where R 11 R 12 and R 13 Independently for C 1-10 Alkyl, C 1-10 cycloalkyl or with one or more C 1-4 Alkyl-substituted C 3-10 cycloalkyl; R, R 1 R 2 R 3 R 4 R 5 and R 6 The definition is as described in any embodiment of this invention.

[0096] In the preparation method of the compound shown in Formula A5 (hereinafter referred to as step S5), the reaction conditions, reagent types and amounts of the dearomatic cyclization reaction can be the conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably includes the following.

[0097] In one embodiment, in step S5, the dearomatization reaction is carried out under the protection of an inert gas and / or nitrogen. The inert gas is a conventional protective gas in the art, such as argon. Preferably, the dearomatization reaction is carried out under nitrogen protection.

[0098] In one embodiment, in step S5, the organic solvent is a sulfoxide solvent, an amide solvent, or a coal tar solvent, such as an amide solvent. The amide solvent may be selected from one or more of N-pyrrolidone, N,N-dimethylformamide, and N,N-dimethylacetamide, for example, N,N-dimethylacetamide. The coal tar solvent may be selected from one or more of toluene, xylene, trimethylbenzene, and nitrotoluene.

[0099] In step S5, the amount of organic solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, the molar volume ratio of the compound shown in Formula A4 to the organic solvent is (0.01-0.5) mol:1 L, for example, 0.2 mol:1 L.

[0100] In one embodiment, in step S5, the palladium catalyst is selected from one or more of 1,5-cyclooctadiene palladium chloride, tris(dibenzylacetone)palladium, bis(acetonitrile)palladium chloride, palladium chloride, palladium trifluoromethanesulfonate, and palladium acetate, such as palladium chloride.

[0101] In one embodiment, in step S5, the molar ratio of the palladium catalyst to the compound shown in Formula A4 is (0.01-0.5):1, for example, 0.02:1.

[0102] In one of the schemes, R 11 R 12 and R 13 Independently for C 1-10 Alkyl or C 1-10 Cycloalkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl, such as tert-butyl, n-butyl, cyclobutyl, or adamantyl.

[0103] In one embodiment, in step S5, the phosphine ligand represented by formula T2 is one or more of the following: di-tert-butylcyclobutylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, diadamantyl-n-butylphosphine, diadamantyl-isopropylphosphine, diadamantyl-propylphosphine, diadamantyl-cyclopropylphosphine, diadamantyl-cyclobutylphosphine, diadamantyl-cyclopentylphosphine, diadamantyl-cyclohexylphosphine, and diadamantyl-cycloheptylphosphine; for example, di-tert-butylcyclobutylphosphine.

[0104] In one embodiment, in step S5, the molar ratio of the phosphine ligand as shown in formula T2 to the compound as shown in formula A4 is (0.01-0.5):1, for example (0.01-0.1):1, or for example 0.03:1.

[0105] In one embodiment, in step S5, the base is an inorganic base; the inorganic base may be selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, and potassium phosphate, for example, potassium carbonate.

[0106] In one embodiment, in step S5, the molar ratio of the base to the compound shown in Formula A4 is (1-10):1, for example (1-3):1, or even 1.5:1.

[0107] In one embodiment, in step S5, the temperature of the dearomatic cyclization reaction is 80℃-180℃, for example 120℃-170℃, or for example 150℃.

[0108] In step S5, the progress of the dearomatic cyclization reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound shown in Formula A4. The reaction time can be 1-12 hours, for example, 2 hours.

[0109] In step S5, after the dearomatic cyclization reaction is completed, the following post-processing steps may be included. These post-processing steps can be routine post-processing operations for this type of reaction, such as one or more of extraction, drying, concentration, and purification. The solvent for extraction can be ethyl acetate. The drying agent can be anhydrous sodium sulfate. The concentration can be vacuum distillation. The purification can be column chromatography (eluent: dichloromethane / methanol = (60-50):1).

[0110] In one embodiment, the compound represented by formula A4 is...

[0111] In one embodiment, the method for preparing the compound shown in Formula A5 further includes a method for preparing the compound shown in Formula A4, which includes the following step S4: under the action of a base, the compound shown in Formula A3-2 and the compound shown in Formula T1 undergo a substitution reaction in a solvent as shown in the following formula to obtain the compound shown in Formula A4.

[0112] Where: R a Halogen or R, R 1 R 2 R 3 R 4 R 5 and R 6The definition is the same as that described in any embodiment of this invention.

[0113] In the preparation method of the compound shown in Formula A4 (hereinafter referred to as step S4), the reaction conditions, reagent types and amounts of the substitution reaction can be the conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably includes the following.

[0114] In one embodiment, in step S4, the solvent is an organic solvent or a mixture of an organic solvent and water, such as a mixture of an organic solvent and water. The organic solvent may be a chloroalkane solvent, a coal tar solvent, or an amide solvent, such as a chloroalkane solvent. The chloroalkane solvent may be selected from one or more of dichloromethane, 1,2-dichloroethane, and chloroform, for example, dichloromethane. The coal tar solvent may be selected from one or more of toluene, xylene, or mesitylene. The amide solvent is N-methylpyrrolidone and / or N,N-dimethylacetamide.

[0115] In one embodiment, in step S4, the solvent is a mixture of an organic solvent and water, wherein the volume ratio of the organic solvent to water is (1-10):1, for example (1-8):1, or for example 2.5:1 or 5:1. The water and the base are preferably added to the reaction system of the substitution reaction in the form of an aqueous solution of the base.

[0116] In step S4, the amount of solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, the molar volume ratio of the compound shown in formula A3-2 to the solvent is (0.01-1) mol:1 L, for example, 0.15 mol:1 L or 0.3 mol:1 L.

[0117] In one scheme, in step S4, R a It is chlorine.

[0118] In one embodiment, in step S4, the compound represented by formula T1 is benzyl chloroformate, phenyl chloroformate, methyl chloroformate, ethyl chloroformate, or di-tert-butyl dicarbonate, for example, di-tert-butyl dicarbonate.

[0119] In one embodiment, in step S4, the molar ratio of the compound shown in formula T1 to the compound shown in formula A3-2 is (1-3):1, for example, 1.2:1.

[0120] In one embodiment, in step S4, the base is an inorganic base; the inorganic base may be selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate, such as sodium bicarbonate.

[0121] In one embodiment, in step S4, the molar ratio of the base to the compound shown in formula A3-2 is (1-10):1, for example (1-5):1, or even 2:1.

[0122] In one embodiment, in step S4, the temperature of the substitution reaction is 20-35°C, for example, 25°C.

[0123] In step S4, the progress of the substitution reaction is monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound shown in formula A3-2. The duration of the substitution reaction can be 2-24 hours, for example, 8 hours.

[0124] In step S4, after the substitution reaction is completed, the following post-processing steps may be included. These post-processing steps are routine post-processing operations for this type of reaction, such as one or more of extraction, drying, concentration, and purification. The solvent for extraction may be ethyl acetate. The drying agent may be anhydrous sodium sulfate. The concentration may be vacuum distillation. The purification may be crystallization, for example, using isopropanol crystallization.

[0125] In one embodiment, in step S4, the compound shown in formula A3-2 is...

[0126] In one embodiment, the preparation method of the compound shown in Formula A4 further includes a preparation method of the compound shown in Formula A3-2, which includes the following step S3: the compound shown in Formula A3-1 undergoes a halogenation reaction with a halogenating reagent in an organic solvent, followed by an elimination reaction under the action of a base, and finally an asymmetric transfer hydrogenation catalytic reaction under the action of a hydrogen source and a catalyst to obtain the compound shown in Formula A3-2.

[0127] Where R 1 R 2 R 3 R 4 R 5 and R 6 The definition is the same as that described in any embodiment of this invention.

[0128] In the preparation method of the compound shown in Formula A4 (hereinafter referred to as step S3), the reaction conditions, reagent types and amounts can be the conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably includes the following.

[0129] In one embodiment, in step S3, the reduction reaction is carried out under the protection of an inert gas and / or nitrogen. The inert gas is a conventional protective gas in the art, such as argon. Preferably, the reduction reaction is carried out under nitrogen protection.

[0130] In one embodiment, in step S3, the organic solvent is an ether solvent and / or an alcohol solvent, such as an ether solvent. The ether solvent may be selected from one or more of tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, or anisole, such as tetrahydrofuran.

[0131] In step S3, the amount of organic solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, the molar volume ratio of the compound shown in formula A3-1 to the organic solvent is (0.01-1) mol:1 L, for example, 0.2 mol:1 L.

[0132] In one embodiment, in step S3, the halogenated reagent is N-chlorosuccinimide, N-bromosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, or trichloroisocyanuric acid, such as N-chlorosuccinimide (NCS).

[0133] In one embodiment, in step S3, the molar ratio of the halogenated reagent to the compound shown in formula A3-1 is (0.9-1.5):1, for example, 1:1.

[0134] In one embodiment, in step S3, the temperature of the halogenation reaction is -10 to 20°C, for example, 0°C.

[0135] In one embodiment, in step S3, the base is an inorganic base; for example, the inorganic base is selected from one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, and sodium methoxide, and potassium hydroxide is another example.

[0136] In one embodiment, in step S3, the molar ratio of the base to the compound shown in formula A3-1 is (1-10):1, for example (1-5):1, or even 2:1.

[0137] In one embodiment, in step S3, the temperature of the elimination reaction is 0-35°C, for example, 20°C.

[0138] In one embodiment, in step S3, the hydrogen source is a mixed solvent of formic acid and triethylamine; for example, the molar ratio of formic acid and triethylamine is (0.5-5):1, such as 2.5:1 or 1:1.

[0139] In step S3, the amount of hydrogen source used is the conventional amount used in this type of reaction in the art. In one embodiment, the hydrogen source is a mixed solvent of formic acid and triethylamine, and the molar volume ratio of the compound shown in Formula A3-1 to the hydrogen source is (0.5-10) mol:1L, for example (0.5-3) mol:1L, or for example 0.9:1 or 1.2:1.

[0140] In one embodiment, in step S3, the catalyst is a Noyori-type transfer hydrogenation catalyst, for example, the catalyst is selected from any of the following:

[0141] Another example is a catalyst as shown in formula ATH-01.

[0142] In one embodiment, in step S3, the molar ratio of the catalyst to the compound shown in formula A3-1 is (0.0001-0.5):1, for example (0.001-0.1):1, or even more specifically 0.01:1.

[0143] In one embodiment, in step S3, the temperature of the asymmetric transfer hydrogenation catalytic reaction is 0-35°C, for example, 25°C.

[0144] In one embodiment, in step S3, the progress of the (one-pot) chlorination / elimination / asymmetric reduction reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), generally with the disappearance or cessation of the reaction of the compound shown in Formula A3-1 as the endpoint. The chlorination reaction time can be 0.1–1 h, for example, 0.2 h. The elimination reaction time can be 1–3 h, for example, 1 h. The asymmetric transfer hydrogenation catalytic reaction time can be 3–24 h, for example, 16 h.

[0145] In one embodiment, step S3, after the asymmetric transfer hydrogenation catalytic reaction, includes a post-processing step. This post-processing step is a standard procedure for this type of reaction, including one or more of extraction, drying, concentration, and purification. The solvent for extraction can be ethyl acetate. The drying agent can be anhydrous sodium sulfate. The concentration can be vacuum distillation. The purification can be column chromatography or crystallization.

[0146] In one embodiment, the compound represented by formula A3-1 is

[0147] In one embodiment, the method for preparing the compound shown in formula A3-2 further includes a method for preparing the compound shown in formula A3-1, which includes the following step S2: under the action of a deprotecting agent, the compound shown in formula A3 undergoes a deprotection reaction in a solvent as shown in the following formula to obtain the compound shown in formula A3-1.

[0148] Among them, R, R 1 R 2 R 3 R 4 R 5 and R 6 The definition is as described in any embodiment of this invention.

[0149] In the preparation method of the compound shown in Formula A3-1 (hereinafter referred to as step S2), the reaction conditions, reagent types and amounts of the deprotection reaction can be the conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably includes the following.

[0150] In one embodiment, in step S2, the solvent is an ester solvent and / or an alcohol solvent, for example, a mixture of ester and alcohol solvents. The ester solvent may be ethyl acetate; the alcohol solvent may be methanol or ethanol, for example, methanol.

[0151] The amount of solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, in step S6, the molar volume ratio of the compound as shown in formula A3 to the solvent is (0.01-1) mol:1 L, for example, 0.2 mol:1 L or 0.3 mol:1 L.

[0152] In one embodiment, in step S2, the deprotection reagent is an acid or a base; the acid may be selected from one or more of HCl, H2SO4, CH3COOH, H3PO4, trifluoroacetic acid, and methanesulfonic acid, for example, HCl; the base may be selected from one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and sodium tert-butoxide.

[0153] In one embodiment, in step S2, the molar ratio of the deprotecting agent to the compound shown in formula A3 is (1-100):1, for example (3-10):1, or for example 5:1 or 6:1.

[0154] In one embodiment, in step S2, the solvent is a mixture of ester solvent and alcohol solvent, and the alcohol solvent and the deprotecting agent are added to the reaction system in the form of a deprotecting agent solution, such as a methanol solution of HCl.

[0155] In one embodiment, in step S2, the temperature of the deprotection reaction is -10 to 20°C, for example, 0°C.

[0156] In step S2, the progress of the deprotection reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound shown in Formula A3. The deprotection reaction time can be 0.5-8 hours, for example, 3 hours.

[0157] In step S2, after the deprotection reaction is completed, the following post-processing steps may be included. These post-processing steps are routine post-processing operations for this type of reaction, such as one or more of quenching, extraction, drying, concentration, and purification. The quenching reagent may be an aqueous solution of Na₂CO₃. The extraction solvent may be ethyl acetate. The drying agent may be anhydrous sodium sulfate. The concentration may be vacuum distillation. The purification may be crystallization, for example, using n-heptane crystallization.

[0158] In one embodiment, the compound represented by formula A3 is...

[0159] In one embodiment, the preparation method of the compound shown in formula A3-1 further includes a preparation method of the compound shown in formula A3, which includes the following step S1: under the action of acid, the compound shown in formula A1 and the compound shown in formula A2 undergo a condensation cyclization reaction as shown in the following formula in an organic solvent to obtain the compound shown in formula A3.

[0160] Among them, R, R 1 R 2 R 3 R 4 R 5 and R 6 The definition is as described in any embodiment of this invention.

[0161] In the preparation method of the compound shown in Formula A3 (hereinafter referred to as step S1), the reaction conditions, reagent types and amounts of the condensation cyclization reaction can be the conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably includes the following.

[0162] In one embodiment, in step S1, the organic solvent is a chloroalkane solvent and / or an amide solvent, such as a chloroalkane solvent. The chloroalkane solvent may be selected from one or more of dichloromethane, 1,2-dichloroethane, and chloroform, such as dichloromethane.

[0163] In step S1, the amount of organic solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, the molar volume ratio of the compound shown in formula A1 to the organic solvent is (0.1-5) mol:1 L, for example (0.1-1) mol:1 L, or even 0.4 mol:1 L.

[0164] In one embodiment, in step S1, the molar ratio of the compound shown in formula A2 to the compound shown in formula A1 is (1-3):1, for example, 1.2:1.

[0165] In one embodiment, in step S1, the acid is selected from one or more of methanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, sulfuric acid, phosphoric acid, and camphorsulfonic acid, for example, camphorsulfonic acid.

[0166] In one embodiment, in step S1, the molar ratio of the acid to the compound shown in formula A1 is (1-5):1, for example (1-3):1, or even 1.5:1.

[0167] In one embodiment, in step S1, the temperature of the condensation cyclization reaction is 0-30°C, for example, 25°C.

[0168] In step S1, the progress of the condensation cyclization reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), generally with the disappearance or cessation of the reaction of the compound shown in Formula A1 as the endpoint. The reaction time can be 2-16 hours, for example, 4 hours or 5 hours.

[0169] In step S1, after the condensation cyclization reaction is completed, a post-treatment may be included. This post-treatment can be a routine operation for this type of reaction, such as one or more of quenching, drying, concentration, and purification. The quenching solvent may be an aqueous solution of Na₂CO₃. The drying agent may be anhydrous sodium sulfate. The concentration may be vacuum distillation. The purification may be recrystallization, and the recrystallization solvent may be n-heptane.

[0170] In one embodiment, the compound represented by formula A1 is... The compound shown in formula A2 is

[0171] In one embodiment, the preparation method of the compound shown in formula A3 further includes a preparation method of the compound shown in formula A2, which includes the following steps S1-2d: under the action of a base and a Wittig reagent, the compound shown in formula A2-3 undergoes a Wittig reaction in an organic solvent as shown in the following formula to obtain the compound shown in formula A2.

[0172] Wherein, the Wittig reagent is methoxymethyltriphenylphosphine chloride or methoxymethyltriphenylphosphine bromide, R 4 R 5 and R 6 The definition is as described in any embodiment of this invention.

[0173] In the preparation method of the compound shown in Formula A2 (hereinafter referred to as steps S1-2d), the reaction conditions, reagent types and amounts of the Wittig reaction can be the conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably includes the following.

[0174] In steps S1-2d, the solvent is a conventional solvent for this type of reaction in the art. In one embodiment, the solvent is an ether solvent or a coal tar solvent, such as a coal tar solvent. The ether solvent may be selected from one or more of tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, and diethyl ether; the coal tar solvent may be selected from one or more of toluene, xylene, and trimethylbenzene, such as toluene.

[0175] The amount of organic solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, in steps S1-2d, the molar volume ratio of the compound shown in formula A2-3 to the organic solvent is (0.01-0.5) mol:1L, for example, 0.3 mol:1L.

[0176] In one embodiment, in steps S1-2d, the Wittig reagent is methoxymethyltriphenylphosphine chloride.

[0177] In one embodiment, in steps S1-2d, the molar ratio of the Wittig reagent to the compound shown in formula A2-3 is (1-5):1, for example (1-2):1, or even 1.5:1.

[0178] In one embodiment, in steps S1-2d, the base is an inorganic base; the inorganic base is sodium tert-butoxide, potassium tert-butoxide, potassium tert-pentoxide, or potassium neopentoxide, for example, potassium tert-butoxide.

[0179] In one embodiment, in steps S1-2d, the molar ratio of the base to the compound shown in formula A2-3 is (1-5):1, for example (1-2):1, or even 1.5:1.

[0180] In one embodiment, during steps S1-2d, the temperature of the Wittig reaction is 0-30°C, for example, 25°C.

[0181] In steps S1-2d, the progress of the Wittig reaction is monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), generally with the disappearance or cessation of reaction of the compounds shown in formulas A2-3 as the endpoint. The reaction time can be 2-16 h, for example 2 h or 3 h.

[0182] In steps S1-2d, after the Wittig reaction is completed, the following post-processing steps may be included. These post-processing steps can be routine post-processing operations for this type of reaction, such as one or more of extraction, concentration, and purification. The solvent for extraction can be ethyl acetate. The drying agent can be anhydrous sodium sulfate. The concentration can be vacuum distillation. The purification can be column chromatography (e.g., eluent of petroleum ether / ethyl acetate = 40:1 to 30:1).

[0183] In one embodiment, the compound represented by formula A2-3 is

[0184] In one embodiment, the preparation method of the compound shown in formula A2 further includes a preparation method of the compound shown in formula A2-3, which includes the following steps S1-2c: under the action of a catalyst, the compound shown in formula A2-2 and the compound shown in formula T1 undergo a substitution reaction as shown in the following formula in an organic solvent to obtain the compound shown in formula A2-3.

[0185] Among them, R b Halogen or two R b Together they form an oxygen group (=O), R 4 R 5 and R 6 The definition is as described in any embodiment of this invention.

[0186] In the preparation method of the compound shown in formula A2-3 (hereinafter referred to as step S1-2c), the reaction conditions, reagent types and amounts of the substitution reaction can be the conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably includes the following.

[0187] In steps S1-2c, the organic solvent is a conventional solvent for this type of reaction in the art. The solvent may be a nitrile solvent, a coal tar solvent, or an amide solvent, such as a nitrile solvent or a coal tar solvent. The nitrile solvent may be selected from one or more of acetonitrile, propionitrile, and butyronitrile, for example, acetonitrile; the coal tar solvent may be selected from one or more of toluene, xylene, and trimethylbenzene, for example, toluene; the amide solvent is N,N-dimethylformamide and / or N,N-dimethylacetamide.

[0188] In steps S1-2c, the amount of organic solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, the molar volume ratio of the compound shown in formula A2-2 to the organic solvent is (0.1-1) mol:1 L, for example, 0.5 mol:1 L or 0.6 mol:1 L.

[0189] In a certain scheme, in steps S1-2c, two R... b Together they form an oxo group (=O), for example, the compound shown in formula T1 is dibenzyl ketone, 4,4'-dimethoxybenzophenone or 4,4'-dimethoxybenzyl ketone, benzophenone, acetone or pentanone, such as acetone.

[0190] In a certain scheme, in steps S1-2c, two R... b Together they form an oxo group, and the catalyst is an acidic oxide, such as phosphorus pentoxide.

[0191] In one embodiment, in step S1-2c, the catalyst is an acidic oxide, and the molar ratio of the catalyst to the compound shown in formula A2-3 can be (1-8):1, for example (1-5):1, or even 2:1.

[0192] In a certain scheme, in steps S1-2c, R b Each is a halogen on its own; for example, the compound shown in formula T1 is diphenyl dichloromethane.

[0193] In a certain scheme, in steps S1-2c, R b Each is independently a halogen, and the catalyst is an inorganic base; for example, the inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, or potassium hydroxide, and potassium carbonate is another example.

[0194] In one embodiment, in step S1-2c, the catalyst is an inorganic base; the molar ratio of the catalyst to the compound shown in formula A2-3 can be (1-8):1, for example (1-5):1, or for example 2.5:1.

[0195] In one embodiment, in step S1-2c, the molar ratio of the compound shown in formula T1 to the compound shown in formula A2-2 is (1-5):1, for example (1-2):1, or even 1:1.

[0196] In one embodiment, the solvent is toluene, the compound represented by formula T1 is acetone, the catalyst is phosphorus pentoxide, and the temperature of the substitution reaction can be 50-100°C, for example, 75°C. After the substitution reaction, the following post-processing steps may be included. These post-processing steps can be routine post-processing operations for this type of reaction, such as one or more of quenching, extraction, drying, concentration, and purification. The quenching reagent is water. The extraction solvent can be ethyl acetate. The drying agent can be anhydrous sodium sulfate. The concentration can be vacuum distillation. The purification can be column chromatography (e.g., eluent: petroleum ether / ethyl acetate = 4:1).

[0197] In one embodiment, the solvent is acetonitrile, the compound represented by formula T1 is diphenyl dichloromethane, the catalyst is phosphorus pentoxide, and the temperature of the substitution reaction can be 10-50°C, for example, 35°C. After the substitution reaction, the following post-processing steps may be included. These post-processing steps can be conventional post-processing operations for this type of reaction, such as one or more of filtration, concentration, and purification. The concentration can be vacuum distillation. The purification can be recrystallization, and the solvent for recrystallization is a mixture of n-heptane and ethyl acetate, for example, n-heptane and ethyl acetate in a volume ratio of 5:1.

[0198] In steps S1-2c, the progress of the substitution reaction is monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally considered to end when the compound represented by formula A2-2 disappears or ceases to react. The reaction time can be 8-24 hours, for example, 12 hours or 16 hours.

[0199] In one embodiment, the compound represented by formula A2-2 is

[0200] This invention provides a method for preparing a compound as shown in formula A9 or formula A13, comprising the steps S10, S11 and S12:

[0201] S10: Under the action of a cyclizing agent, the compound shown in formula A6-2 undergoes a cyclization reaction in an organic solvent as shown in the following formula to give the compound shown in formula A7.

[0202] S11: Under the action of acid, the compound shown in Formula A7 undergoes an acidification reaction to obtain an acidification reaction product, and then under the action of an oxidizing agent, the acidification reaction product is oxidized in a solvent to obtain the compound shown in Formula A8.

[0203] S12 is selected from either Option 1 or Option 2:

[0204] Option 1: Under the action of a catalyst, the compound shown in Formula A8 undergoes a hydrogenation reaction with hydrogen in an organic solvent as shown in the following formula to obtain the compound shown in Formula A9.

[0205] Option 2 involves the compound of formula A8 undergoing a reduction reaction with hydrogen in an organic solvent under the action of a catalyst, as shown in the following formula, to obtain the compound of formula A13.

[0206] *, L, R 1 R 2 R 3 R 5 R 6 and R 7 The definition is as described in any embodiment of the present invention; the operations and conditions in step S10 may also be as described in any embodiment of the present invention.

[0207] In the preparation method of the compound shown in Formula A9 or Formula A13, the operation and conditions in step S11 may also be as described in any embodiment of the present invention. In steps S11 and S12, the reaction conditions, reagent types and amounts of the oxidation reaction, hydrogenation and reduction reaction may be the conventional conditions, reagent types and amounts of this type of reaction in the art. The present invention is preferred as follows.

[0208] In one embodiment, in step S12, the organic solvent is an alcohol solvent and / or an ester solvent. The alcohol solvent may be methanol and / or ethanol, for example, methanol. The ester solvent may be ethyl acetate; preferably, in embodiment 1, the solvent is an ester solvent; in embodiment 2, the solvent is an alcohol solvent.

[0209] In step S12, the amount of organic solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, the molar volume ratio of the compound shown in Formula A8 to the organic solvent is (0.01-1) mol:1 L, for example, 0.1 mol:1 L or 0.2 mol:1 L.

[0210] In one embodiment, in step S12, the catalyst is a Raney nickel and / or palladium catalyst, such as a palladium catalyst, or for example, 10% palladium on carbon, where "%" is the mass percentage of palladium relative to the total mass of palladium and carbon.

[0211] In one embodiment, in step S12, the mass percentage of the catalyst to the compound shown in Formula A8 is 30-50%, for example 20%.

[0212] In one scheme, in step S12, in scheme 1, the pressure of the hydrogenation reaction is 1 to 5 atm, for example 2 atm.

[0213] In one scheme, in step S12, in scheme 2, the pressure of the reduction reaction is 10 to 30 atm, for example, 20 atm.

[0214] In one scheme, in step S12, in scheme 1, the temperature of the hydrogenation reaction is 20-35°C, for example, 25°C.

[0215] In one scheme, in step S12, in scheme 2, the temperature of the hydrogenation reaction is 20-35°C, for example, 30°C.

[0216] In step S12, the progress of the hydrogenation or reduction reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and the reaction endpoint is generally defined as the disappearance of the compound represented by Formula A8. The hydrogenation reaction can take 3 to 20 hours, for example, 8 hours or 12 hours.

[0217] In step S12, after the hydrogenation or reduction reaction is completed, the following post-processing steps may be included. These post-processing steps can be routine post-processing operations for such reactions, such as one or more of filtration and purification. The purification may be column chromatography.

[0218] In one scheme, the compound represented by formula A8 is The compound represented by formula A9 is

[0219] In one scheme, the compound represented by formula A8 is The compound shown in formula A13 is

[0220] In one embodiment, in step S11, the acid is an organic acid, such as one or more selected from acetic acid and formic acid, for example, acetic acid.

[0221] In one embodiment, in step S11, the molar volume ratio of the compound as shown in formula A7 to the acid is (0.1-5) mol:1L, for example, 0.3 mol / L.

[0222] In one embodiment, in step S11, the solvent is the acid or a mixture of the acid and water. The amount of solvent used is not specifically limited, as long as it does not affect the reaction.

[0223] In one embodiment, in step S11, the oxidant is hydrogen peroxide and / or m-chloroperoxybenzoic acid (mCPBA), for example, hydrogen peroxide.

[0224] In one embodiment, in step S11, the oxidant is hydrogen peroxide, the solvent is a mixture of the acid and water, and the hydrogen peroxide and water are added to the oxidation reaction system in the form of an aqueous hydrogen peroxide solution. For example, the mass percentage of hydrogen peroxide in the aqueous hydrogen peroxide solution is 20-50%, such as 35%.

[0225] In one embodiment, in step S11, the molar ratio of the oxidant to the compound shown in Formula A7 is (1-10):1, for example (4-7):1, or for example 5.5:1.

[0226] In one embodiment, in step S11, the temperature of the oxidation reaction is 10-30°C, for example, 25°C.

[0227] In step S11, the progress of the acidification and oxidation reactions can be monitored using conventional monitoring methods in the art (e.g., TLC or HPLC), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound represented by formula A7. The acidification reaction can take 0.1-1 h, for example, 0.5 h; the oxidation reaction can take 10-30 h, for example, 20 h.

[0228] In step S11, after the oxidation reaction is completed, the following post-processing steps may be included. These post-processing steps can be routine post-processing operations for this type of reaction, such as one or more of quenching, extraction, drying, concentration, and purification. The reagent for the quenching reaction can be sodium sulfite solution. The solvent for extraction can be ethyl acetate. The drying can be done using anhydrous sodium sulfate. The concentration can be achieved by vacuum distillation. The purification can be achieved by column chromatography.

[0229] In one scheme, in step S11, the compound shown in A7 is... The compound shown in A8 is Or the compound shown in A7 is The compound shown in A8 is

[0230] The present invention also provides a method for preparing a compound as shown in Formula A12, comprising the steps S10, S11', S12' and S13:

[0231] S10: Under the action of a cyclizing agent, the compound shown in formula A6-2 undergoes a cyclization reaction in an organic solvent as shown in the following formula to give the compound shown in formula A7.

[0232] S11': The compound shown in Formula A7 undergoes a cycloaddition reaction with the compound shown in Formula T4 as shown in the following formula to give the compound shown in Formula A10.

[0233] S12': Under the action of a nucleophile, the compound shown in formula A10 undergoes a nucleophilic addition reaction in an organic solvent as shown in the following formula to give the compound shown in formula A11;

[0234] S13: Under the action of a catalyst, the compound shown in Formula A11 undergoes a hydrogenation reaction with hydrogen in an organic solvent as shown in the following formula to obtain the compound shown in Formula A12.

[0235] R 8 and R 9 Independently for H and C 1-10 Alkyl, C 3-7 cycloalkyl, C 6-14 aryl or 5-10 heteroaryl; the heteroatom of the 5-10 heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0236] R 10 C 1-10 Alkyl, C 3-7 cycloalkyl or C 6-14Aryl group; M is MgCl, MgBr or Li;

[0237] *, L, R 1 R 2 R 3 R 5 R 6 and R 7 The definition, operation, and conditions of step S10 can be as described in any embodiment of the present invention.

[0238] In step S11', the reaction conditions, reagent types, and amounts of the cycloaddition reaction can be the conventional conditions, reagent types, and amounts of this type of reaction in the art. The present invention preferably includes the following.

[0239] In one of the schemes, R 8 It is H or a 5-10 heteroaryl group, such as H.

[0240] In one of the schemes, R 9 C 1-10 Alkyl groups, such as methyl groups.

[0241] In one embodiment, the compound represented by Formula T4 is methyl vinyl ketone or 4-(2-thienyl)but-3-en-2-one, such as methyl vinyl ketone.

[0242] In one embodiment, in step S11', the molar ratio of the compound shown in formula T4 to the compound shown in formula A7 is (1 to 100):1, for example 10:1, or for example 50:1.

[0243] In one embodiment, the reaction system of the cycloaddition reaction also includes a solvent, such as a coal tar solvent, or toluene, xylene, or trimethylbenzene.

[0244] In one embodiment, the cycloaddition reaction system is solvent-free, for example, the compound represented by formula T4 reacts with the compound represented by formula A7 under solvent-free conditions.

[0245] In one embodiment, in step S11', the temperature of the cycloaddition reaction is 70-90°C, for example, 80°C.

[0246] In step S11', the progress of the cycloaddition reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and the reaction endpoint is generally defined as the disappearance of the compound represented by formula A7. The duration of the cycloaddition reaction can be 4-16 hours, for example, 8 hours.

[0247] In step S11', after the cycloaddition reaction is completed, the following post-processing steps may be included. These post-processing steps are routine post-processing operations for this type of reaction, such as concentration and purification. The concentration may be vacuum distillation. The purification may be column chromatography.

[0248] In one embodiment, the compound represented by formula A7 is

[0249] In one embodiment, the compound represented by formula A10 is...

[0250] The reaction conditions, reagent types, and amounts of the nucleophilic addition reaction can be the conventional conditions, reagent types, and amounts of this type of reaction in the art. The present invention preferably includes the following.

[0251] In one embodiment, in step S12', the nucleophilic addition reaction is carried out under the protection of an inert gas and / or nitrogen. The inert gas is a conventional protective gas in the art, such as argon. Preferably, the nucleophilic addition reaction is carried out under nitrogen protection.

[0252] In one scheme, in step S12', M is MgCl or MgBr.

[0253] In one scheme, in step S12', R 10 C 1-10 Alkyl groups, such as tert-butyl groups.

[0254] In one embodiment, in step S12', the nucleophile is tert-butylmagnesium chloride.

[0255] In one embodiment, in step S12', the molar ratio of the nucleophile to the compound shown in Formula A10 is (5-10):1, for example, 7:1.

[0256] In one embodiment, in step S12', the organic solvent is an ether solvent and / or an aromatic solvent, such as a mixture of ether solvents and aromatic solvents. The ether solvent may be tetrahydrofuran; the aromatic solvent may be toluene.

[0257] In one embodiment, in step S12', the solvent is a mixture of ether solvent and aromatic solvent, and the volume ratio of the ether solvent to the aromatic solvent is (1-5):(1-5), for example, 1.7:1; the ether solvent can be added to the nucleophilic addition reaction system in the form of a mixed solution with the Grignard reagent.

[0258] In step S12', the amount of organic solvent used is not specifically limited, as long as it does not affect the reaction. The molar volume ratio of the compound shown in Formula A10 to the organic solvent can be (0.01-1) mol:1 L, for example, 0.1 mol:1 L.

[0259] In one embodiment, in step S12', the temperature of the nucleophilic addition reaction is -5 to 35°C, for example 10 to 30°C, or for example 25°C.

[0260] In step S12', the progress of the nucleophilic addition reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound represented by Formula A10. The time for the nucleophilic addition reaction can be 4-30 hours, for example, 20 hours.

[0261] In step S12', after the nucleophilic addition reaction is completed, the following post-processing steps may be included. These post-processing steps are routine post-processing operations for this type of reaction, including one or more of quenching, extraction, drying, concentration, and purification. The quenching reagent is water. The extraction organic solvent may be ethyl acetate. The drying agent may be anhydrous sodium sulfate. The concentration may be vacuum distillation. The purification may be column chromatography.

[0262] In one embodiment, the compound represented by formula A11 is

[0263] The reaction conditions, reagent types, and amounts of the hydrogenation reaction can be the conventional conditions, reagent types, and amounts of this type of reaction in the art. The present invention preferably includes the following.

[0264] In one embodiment, in step S13, the catalyst is a Raney nickel and / or a palladium catalyst, such as a palladium catalyst, or for example, 10% palladium on carbon, where "%" is the mass percentage of palladium relative to the total mass of palladium and carbon.

[0265] In one embodiment, in step S13, the mass ratio of the catalyst to the compound shown in formula A11 is (0.03-0.5):1; for example, (0.03-0.2):1; or for example, 0.1:1.

[0266] In one embodiment, in step S13, the organic solvent is an ether and / or an alcohol solvent, such as an alcohol solvent. The alcohol solvent may be ethanol and / or isopropanol, for example, isopropanol.

[0267] In step S13, the amount of organic solvent used is not specifically limited, as long as it does not affect the reaction. In one embodiment, the molar volume ratio of the compound represented by formula A11 to the solvent is (0.01-1) mol:1 L, for example, 0.064 mol:1 L.

[0268] In one embodiment, in step S13, the hydrogenation reaction is carried out at a pressure of 5-30 atm, for example, 10 atm.

[0269] In one embodiment, in step S13, the temperature of the hydrogenation reaction is 10-35°C, for example, 25°C.

[0270] In step S13, the progress of the hydrogenation reaction can be monitored using conventional monitoring methods in the art (e.g., TLC or LCMS), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound represented by Formula A11. The hydrogenation reaction can take 8-16 hours, for example, 10 hours.

[0271] In one embodiment, the compound represented by formula A12 is

[0272] This invention provides a method for preparing a compound as shown in Formula A6, comprising the following step S7: under alkaline conditions, a compound as shown in Formula A5-1 and a compound as shown in Formula T3 are subjected to a substitution reaction as shown in the following formula in a solvent to obtain the compound as shown in Formula A6.

[0273] Where X is a halogen, -OTf, -OAc or -OMs;

[0274] L and R 7 The definition satisfies any of the following conditions:

[0275] (1) L is C 1-4 Alkylene, R 7 For H, C 3-7 cycloalkyl or C 6-14 Aryl;

[0276] (2) L is a single bond, R 7 C 3-7 cycloalkyl or C 6-14 Aryl;

[0277] R 1 R 2 R 3 R 4 R 5 and R 6 The definition is the same as that described in any embodiment of this invention.

[0278] The preparation method and conditions of the compound as shown in Formula A6 can be as described in any embodiment of the present invention.

[0279] This invention provides a method for preparing a compound as shown in Formula A8, comprising the following step S11:

[0280] Among them, L, R, R 1 R 2 R 3 R 5 and R 6 The definition is as described in any embodiment of the present invention; the conditions and operations of step S11 are as described in any embodiment of the present invention; preferably, the preparation method of the compound shown in formula A8 further includes the preparation method of the compound shown in formula A7.

[0281] This invention provides a method for preparing a compound as shown in Formula A7, comprising the following steps S1-2c, S1-2d and S1-S10:

[0282] Alternatively, it includes the following steps S7-S10,

[0283] Among them, "*", L, and R b , R, R 1 R 2 R 3 R 4 R 5 and R 6 The definition is as described in any embodiment of the present invention; the conditions and operations of S1-2c, S1-2d and steps S1-S10 are as described in any embodiment of the present invention.

[0284] This invention provides a method for preparing a compound as shown in Formula A5-1, comprising the following step S6: under the action of a deprotecting agent, the compound as shown in Formula A5 undergoes a deprotection reaction in a solvent as shown in the following formula to obtain the compound as shown in Formula A5-1.

[0285] Where R is C 1-10 Alkyl, C 3-10 cycloalkyl, C 6-12 Aryl or -C 1-4 Alkylene-C 6-12 Aryl; R 1 R 2 R 3 R 5 and R 6The definition is as described in any of the preceding schemes; the operation and conditions of the preparation method of the compound shown in Formula A5-1 may also be as described in any of the preceding schemes.

[0286] In one embodiment, the method for preparing the compound as shown in Formula A5-1 includes the following steps S1-2c, S1-2d, and S1-S6:

[0287] Among them, R, R 1 R 2 R 3 R 4 R 5 and R 6 The definition is as described in any embodiment of the present invention; the conditions and operations of steps S1, S2, S3, S4, S5 and S6 are as described in any embodiment of the present invention.

[0288] This invention provides a compound as shown in formula A2-3:

[0289] For example

[0290] This invention provides a compound as shown in Formula A2:

[0291] For example

[0292] This invention provides a compound as shown in Formula A3:

[0293] For example

[0294] This invention provides a compound as shown in Formula A3-1:

[0295] For example

[0296] This invention provides a compound as shown in Formula A3-2:

[0297] For example

[0298] This invention provides a compound as shown in Formula A4:

[0299] For example

[0300] This invention provides a compound as shown in Formula A5:

[0301] For example

[0302] This invention provides a compound as shown in Formula A5-1:

[0303] For example

[0304] This invention provides a compound as shown in Formula A6:

[0305] For example

[0306] This invention provides a compound as shown in Formula A6-1:

[0307] For example

[0308] This invention provides a compound as shown in Formula A6-1:

[0309] "*" indicates that the carbon atom is a chiral carbon with a configuration of R, S or a mixture thereof;

[0310] For example

[0311] The present invention also provides a method for preparing compounds as shown in formulas A2-3, A2, A3, A3-1, A3-2, A4, A5, A5-1, A6-1 or A6-2, which are respectively described in steps S1-2c, S1-2d, S1, S2, S3, S4, S5, S6, S8 or S9.

[0312] In this invention, a wedge-shaped solid line key is used. and wedge-shaped dashed key To represent the absolute configuration of the center of a solid, use a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key When a single bond on a carbon atom in a compound is indicated by a wavy line When indicated, it means that the carbon atom is a mixture of R and S.

[0313] Unless otherwise stated, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom in the double bond is attached to two different substituents (in a double bond containing a nitrogen atom, the lone pair of electrons on the nitrogen atom is considered as one of the substituents it is attached to), if the atoms in the double bond and their substituents in the compound are separated by a wavy line... The connection indicates that the compound exists as a mixture of two isomers: the (Z) type isomer and the (E) type isomer. For example, the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as a mixture of two isomers of formula (A-1) and formula (A-2).

[0314] In this invention, "alkyl" refers to a substance having a specified number of carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ...70, C70, C70 1-6 Alkyl, C 1-4 Alkyl groups are straight-chain or branched alkyl groups. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0315] In this invention, "alkylene" refers to a substituent formed by eliminating two hydrogen atoms from a saturated straight-chain or branched alkane. The two eliminated hydrogen atoms can be on the same carbon atom or on different carbon atoms (e.g., the two eliminated hydrogen atoms are on the carbon atoms at both ends). Thus, C1 alkylene (i.e., methylene) refers to -CH2-, and C2 alkylene (i.e., ethylene) refers to -CH2-CH2- or -CH(CH3)-. Examples of alkylene include methylene, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH2-CH3)-, -C(CH3)2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH2)-, -CH2-CH(CH2-CH2)-, or -CH(CH2-CH2-CH2)-.

[0316] In this invention, "cycloalkyl" refers to a monovalent saturated cycloalkyl group, preferably a monovalent saturated cycloalkyl group having 3-7 cyclic carbon atoms, more preferably 3-6 carbon atoms. Examples of cycloalkyl groups in this invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0317] In this invention, "aryl" refers to a group having a 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared p electrons in a cyclic array). Preferably, aryl groups have 6-14 carbon atoms, such as phenyl, naphthyl, phenanthryl, or anthracene.

[0318] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, and at least one ring is aromatic (conforming to Hückel's rule). Heteroaryl groups are linked to other segments of a molecule through aromatic or non-aromatic rings. Heteroaryl groups include, but are not limited to, furanyl, pyrroleyl, thiopheneyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and indoleyl.

[0319] The "-" at the end of a group indicates that the group is connected to other segments in the molecule through that site. For example, CH3-C(=O)- refers to an acetyl group.

[0320] In this invention, "room temperature" or "normal temperature" refers to 10-30°C, for example, 25°C.

[0321] In this invention, "ice water bath" or "ice salt bath" refers to -5 to 5°C, for example, 0°C.

[0322] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0323] The reagents and raw materials used in this invention are all commercially available.

[0324] The positive and progressive effects of this invention are as follows: This invention provides methods for preparing various opioid drugs and their intermediates. The intermediates provided by this invention can be used to synthesize multiple opioid drugs, including naltrexone, nalmefene, nalbuphine, and buprenorphine. The preparation methods provided by this invention have one or more of the following advantages: inexpensive and readily available raw materials, short synthesis steps, simple operation, easy process scale-up, and high product yield. Detailed Implementation

[0325] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0326] Example 1: The compound shown in Formula 1 (tert-butyl(4-hydroxy-3-methoxyphenethyl)carbamate)

[0327] The compound shown in Formula 1-1 (2-methoxy-4-(2-nitrovinyl)phenol)

[0328] In a clean 100L reactor, ethanol (70L), vanillin (10.0kg, 65.8mol, 1.0eq.), methylamine hydrochloride (222g, 3.3mol, 0.05eq.), and triethylamine (333g, 3.3mol, 0.05mol) were added sequentially at room temperature. After stirring for 5 minutes, nitromethane (4.41kg, 72.3mol, 1.1eq.) was added, and the system immediately turned into an orange-red solution. The mixture was stirred vigorously for 1-2 hours, followed by gentle stirring for 16 hours. A large amount of solid precipitated, and HPLC showed that vanillin had been completely consumed, indicating the end of the reaction. The reaction solution was filtered, and the filter cake was washed with ethanol (2L). The cake was then dried in an oven at 50°C for 24 hours to obtain the final product (compound 1-1) (10.3kg, 82% yield) as a deep yellow solid.

[0329] 1 H NMR (500MHz, CDCl3) δ7.96(d,J=13.3Hz,1H),7.52(d,J=13.5Hz,1H),7.14(d,J=7.7Hz,1H),7.04–6.94(m,2H),6.05(s,1H),3.96(s,3H).

[0330] 13 C NMR (126MHz, CDCl3) δ149.88,147.19,139.63,135.14,125.07,122.56,115.42,110.25,56.24.

[0331] HRMS (ESI) + ):194.0460.

[0332] Compounds such as those shown in Formula 1-2 (4-(2-aminoethyl)-2-methoxyphenol)

[0333] Compound 1-2 (57.7 g, 0.2956 mol, 1 eq.) was added to a 1-liter reaction vessel, followed by 480 mL of a 1:1 CH₂Cl₂ / MeOH mixed solvent. The mixture was then cooled to 0°C. NaBH₄ (17.4 g, 0.4611 mol, 1.56 eq.) was added in portions, and the mixture was allowed to return to room temperature after the addition was complete. Once the reaction was complete, the reaction system was cooled to 0°C, quenched with 1 M HCl solution, and the pH was adjusted to approximately 7. The organic solvent was evaporated, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and concentrated to obtain an oily substance. This oily substance was dissolved in 200 mL of methanol and transferred to a hydrogenation reactor. Palladium on carbon (6 g, 10 mol%) was added, and the mixture was hydrogenated at atmospheric pressure at 40°C overnight. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was concentrated and then mixed with dichloromethane (100 mL). After filtration and drying, a grayish-white powder product, 4-(2-aminoethyl)-2-methoxyphenol (39.0 g, 80% yield), was obtained.

[0334] 1 H NMR (500MHz, CD3OD) δ6.85 (s, 1H), 6.77 (d, J = 8.0Hz, 1H), 6.70 (dd, J = 8.0, 1.8Hz, 1H), 3.86 (s, 3H), 3.12 (t, J = 7.6Hz, 2H), 2.86 (t, J = 7.5Hz, 2H).

[0335] 13 C NMR (126MHz, CD3OD) δ147.88,145.39,127.85,120.87,115.12,111.88,54.98,40.93,33.17.HRMS (ESI + ):168.1022.

[0336] The compound shown in Formula 1 (tert-butyl(4-hydroxy-3-methoxyphenethyl)carbamate)

[0337] Dichloromethane (5 L) was added to a clean 20 L reactor, followed by an aqueous solution (6 L) of compounds 1-2 (1 kg, 5.95 mol, 1.0 eq.) and NaHCO3 (1 kg, 11.9 mol, 2.0 eq.). The system was cooled to 15 °C, and di-tert-butyl dicarbonate (1.43 kg, 6.5 mol, 1.1 eq.) was added in three batches. After the addition was complete, the system was heated to room temperature and stirred for 4 hours. After the reaction was complete, water (3 L) was added, and the mixture was separated. The aqueous phase was extracted once with dichloromethane (3 L), and the organic phases were combined. Most of the dichloromethane was distilled off, and the solvent was replaced with n-heptane. The system was filtered to obtain a white solid product 1 (1.53 kg, 96% yield).

[0338] 1 H NMR(400MHz, CDCl3)δ6.83(d,J=7.9Hz,1H),6.72–6.60(m,2H),5.77(s,1H),4.6 3(s,1H),3.85(s,3H),3.33(d,J=6.2Hz,2H),2.71(t,J=6.9Hz,2H),1.43(s,9H).

[0339] 13 C NMR (101MHz, CDCl3) δ156.06,146.68,144.28,130.83,121.43,114.54,111.39,79.32,55.93,42.06,35.89,28.50.

[0340] HRMS (ESI) + ):268.1550.

[0341] Example 2: The compound shown in Formula 2-4 (4-bromo-5-(2-methoxyvinyl)-2,2-dimethylbenzo[d][1,3]dioxole)

[0342] The compound shown in Formula 2-1 (2-bromo-3-hydroxy-4-methoxybenzaldehyde)

[0343] Dichloromethane (42 L) and isovandrin (6.0 kg, 39.4 mol, 1.0 eq.) were added to a clean, dry 100 L reactor. The system was cooled to 0 °C, and N-bromosuccinimide (NBS) (7.7 kg, 43.5 mol, 1.1 eq.) was added in portions. After the addition was complete, the system was heated to room temperature and reacted for 16 hours. After the reaction was complete, the system was cooled to 10 °C, and water (20 L) was added. The system was filtered, and the filter cake was washed with ethanol (6 L) and dried to give a white solid product 2-1 (7.9 kg, 86% yield).

[0344] 1 H NMR (500MHz, CD3OD) δ10.20(s,1H),7.47(d,J=8.6Hz,1H),7.05(d,J=8.5Hz,1H),3.96(s,3H).

[0345] 13C NMR (126MHz, CD3OD) δ191.20,153.23,127.05,121.49,113.22,109.36,55.52.

[0346] HRMS (ESI) + ):230.9642.

[0347] Compounds such as 2-bromo-3,4-dihydroxybenzaldehyde (as shown in Formula 2-2)

[0348] Dichloromethane (30 L), compound 2-1 (3.0 kg, 13 mol, 1.0 eq.), and aluminum trichloride (1.9 kg, 14.3 mol, 1.1 eq.) were added to a clean, dry 100 L reactor. Pyridine (4.1 kg, 52 mol, 4.0 eq.) was then added at room temperature. After the addition was complete, the system was refluxed for 16 hours. After the reaction was complete, the system was cooled to room temperature, and the reaction was quenched with water (6 L). HCl (6 N, 12 L) was added, and the system was stirred for 2 hours. Methyl tert-butyl ether (45 L) was added for extraction, and the organic phase was concentrated to give a pale white solid product 2-2 (2.8 kg, 100% yield).

[0349] 1 H NMR (400MHz, CD3OD) δ10.15 (s, 1H), 7.38 (d, J = 8.4Hz, 1H), 6.86 (d, J = 8.4Hz, 1H).

[0350] MS(ESI + ):216.94

[0351] Compound 4-bromo-2,2-dimethylbenzo[d][1,3]dioxole-5-carbaldehyde, as shown in Formulas 2-3

[0352] Compound 2-2 (30 g, 0.139 mol, 1.0 eq.) and phosphorus pentoxide (39 g, 0.278 mol, 2.0 eq.) were added to a clean, dry 500 mL three-necked flask. The system was purged with nitrogen three times. Toluene (240 mL) and acetone (10.2 mL, 0.139 mol, 1.0 eq.) were added at room temperature. After the addition was complete, the system was heated to 75 °C and reacted for 12 hours. After the reaction was complete, the system was cooled to 10 °C, and the reaction was quenched by slowly adding water (200 mL). The system was extracted twice with ethyl acetate (150 mL × 2). The organic phases were combined and concentrated, and column chromatography (eluent: petroleum ether / ethyl acetate = 4:1) was performed to give a pale yellow oily product 2-3 (13.8 g, 39% yield).

[0353] 1 H NMR (500MHz, CDCl3) δ10.14 (s, 1H), 7.54 (d, J = 8.2Hz, 1H), 6.77 (d, J = 8.2Hz, 1H), 1.77 (s, 6H). HRMS (ESI + ):256.9816.

[0354] The compound shown in Formula 2, 4-bromo-5-(2-methoxyvinyl)-2,2-dimethylbenzo[d][1,3]dioxole

[0355] In a clean, dry 250 mL three-necked flask under nitrogen atmosphere, methoxymethyltriphenylphosphine chloride (25.7 g, 0.075 mol, 1.5 eq.) and toluene (150 mL) were added. The system was cooled to 0 °C, and potassium tert-butoxide (8.4 g, 0.075 mol, 1.5 eq.) was added. The system was slowly heated to room temperature and stirred for 1 hour. Then, compounds 2-3 (13 g, 0.05 mol, 1.0 eq.) were added at room temperature. After the addition was complete, the system was reacted at room temperature for 2 hours. After the reaction was complete, water (100 mL) was added to the system, and the system was extracted twice with ethyl acetate (150 mL × 2). The organic phases were combined and concentrated, and then column chromatography (eluent: petroleum ether / ethyl acetate = 40:1 to 30:1) was performed to give a colorless oily product 2 (13.5 g, 95% yield).

[0356] The cis-trans isomers were obtained with an E / Z ratio of 3:2.

[0357] Trans configuration (E): 1H NMR (500MHz, CDCl3) δ6.84(d,J=12.8Hz,1H),6.78(d,J=8.2Hz,1H),6.60(d,J=8.1Hz,1H),5.96(d,J=12.8Hz,1H),3.70(s,3H),1.71(s,6H).

[0358] Cis configuration (Z): 1 H NMR (500MHz, CDCl3) δ6.77(d,J=4.7Hz,1H),6.63(d,J=4.7Hz,1H),6.17(d,J=7.2Hz,1H),5.47(d,J=7.2Hz,1H),3.76(s,3H),1.71(s,6H).HRMS(ESI + ):285.0131.

[0359] Example 3: The compound shown in Formula 2A (4-bromo-5-(2-methoxyvinyl)-2,2-diphenylbenzo[d][1,3]dioxole)

[0360] Compound 4-bromo-2,2-diphenylbenzo[d][1,3]dioxole-5-carbaldehyde, as shown in Formula 2-3A

[0361] Acetonitrile (5 L) was added to a clean, dry 20 L reactor, followed by compound 2-2 (500 g, 2.3 mol, 1.0 eq.) and potassium carbonate (800 g, 5.8 mol, 2.5 eq.). Diphenyl dichloromethane (545 g, 2.3 mol, 1.0 eq.) was then added at room temperature. After the addition was complete, the system was heated to 35 °C and reacted for 16 hours. After the reaction was complete, the system was filtered to obtain diatomaceous earth, and the filtrate was evaporated to dryness to obtain an oily substance. This oily substance was slurried in a mixed solvent of n-heptane and ethyl acetate (5:1), and filtered to obtain a white solid product 2-3A (315 g, 36% yield).

[0362] 1 H NMR (500MHz, CDCl3) δ10.15 (s, 1H), 7.59–7.56 (m, 5H), 7.42–7.40 (m, 6H), 6.91 (d, J = 8.2Hz, 1H).

[0363] 13C NMR (101MHz, CDCl3) δ189.65,151.89,146.52,138.89,129.80,128.56,127.89,126.36,126.32,119.26,107.93,105.16.HRMS (ESI + ):381.0131.

[0364] The compound 4-bromo-5-(2-methoxyvinyl)-2,2-diphenylbenzo[d][1,3]dioxole, as shown in Formula 2A,

[0365] In a clean, dry 2L three-necked flask, under nitrogen atmosphere, methoxymethyltriphenylphosphine chloride (174.8 g, 0.51 mol, 1.5 eq.) and toluene (1.2 L) were added. The system was cooled to 0°C, and potassium tert-butoxide (57 g, 0.51 mol, 1.5 eq.) was added. The system was slowly heated to room temperature and stirred for 1.5 hours. Then, compound 2-3A (130 g, 0.34 mol, 1.0 eq.) was added at room temperature. After the addition was complete, the system was reacted at room temperature for 3 hours. After the reaction was complete, water (500 mL) was added to the system, and the system was extracted twice with ethyl acetate (350 mL × 2). The organic phases were combined and concentrated, and then passed through a column (eluent: petroleum ether / ethyl acetate = 30:1) to give a white solid product 2A (129 g, 93% yield).

[0366] The cis-trans isomers were obtained with an E / Z ratio of 5:3.

[0367] Trans configuration (E): 1 H NMR (400MHz, CDCl3) δ7.60–7.58(m,4H),7.37(dd,J=3.8,1.6Hz,6H),6.84(d,J=5. 8Hz,1H),6.82(s,1H),6.73(d,J=8.1Hz,1H),5.96(d,J=12.8Hz,1H),3.69(s,3H).

[0368] Cis configuration (Z): 1 H NMR(400MHz, CDCl3)δ7.58–7.56(m,4H),7.39(dd,J=5.2,3.7Hz,6H),6.82–6.81(m,1 H), 6.78 (d, J = 8.3Hz, 1H), 6.17 (d, J = 7.2Hz, 1H), 5.48 (d, J = 7.2Hz, 1H), 3.74 (s, 3H).

[0369] Cis / trans configuration (E / Z): 13C NMR (101MHz, CDCl3) δ149.59,148.15,146.18,145.85,145.38,144.97,139.79,130.35,129.38,129.34,128.85,128.39,128. 36,126.53,126.49,123.21,118.46,117.52,117.24,107.68,107.33,103.63,102.91,102.16,101.94,60.78,56.62.HRMS(ESI + ):409.0442.

[0370] Example 4: The compound shown in Formula 3 (tert-butyl 1-((4-bromo-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)methyl)-7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate)

[0371] In a clean, dry 20L reactor, 10L of dichloromethane and camphor sulfonic acid (1.3kg, 5.61mol, 1.5eq.) were added. Then, compound 1 (1.0kg, 3.74mol, 1.0eq.) and compound 2 (1.28kg, 4.49mol, 1.2eq.) were added at room temperature. After the addition was complete, the system was allowed to react at room temperature for 4 hours. After the reaction was complete, the system was cooled to 10℃, and an aqueous solution of Na₂CO₃ (595g, 5.61mol, 1.5eq.) was added. The system was extracted twice with dichloromethane (4L × 2). The organic phases were combined and concentrated, and the solvent was replaced with n-heptane. Filtration yielded a grayish-white solid product 3 (1.48kg, 76% yield).

[0372] 1 H NMR (500MHz, CDCl3) δ6.97(s,1H),6.60(s,1H),6.57(d,J=1.5Hz,1H),6.51(d,J=7.8Hz,1H),5.56(s,1H),5.30(dd,J=6.2,4.5Hz,1H),4. 37(dd,J=13.3,5.7Hz,1H),3.88(d,J=1.3Hz,3H),3.25–3.14(m,2H),2.94–2.84(m,2H),2.62(d,J=15.8Hz,1H),1.73(s,6H),1.14(s,9H).

[0373] HRMS (ESI)+ ):520.1331.

[0374] Example 5: The compound shown in Formula 3A (tert-butyl 1-((4-bromo-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)methyl)-7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate)

[0375] In a clean, dry 20L reactor, 10L of dichloromethane and camphor sulfonic acid (1.3kg, 5.61mol, 1.5eq.) were added. Then, compound 1 (1.0kg, 3.74mol, 1.0eq.) and compound 2A (1.84kg, 4.49mol, 1.2eq.) were added at room temperature. After the addition was complete, the system was allowed to react at room temperature for 5 hours. After the reaction was complete, the system was cooled to 10℃, and an aqueous solution of Na₂CO₃ (595g, 5.61mol, 1.5eq.) was added. The system was extracted twice with dichloromethane (4L × 2), the organic phases were combined and concentrated, and the solvent was replaced with n-heptane. Filtration yielded a grayish-white solid product 3A (1.48kg, 87% yield).

[0376] 1 H NMR (500MHz, CDCl3) δ7.65–7.56(m,4H),7.37(dd,J=6.2,4.1Hz,6H),6.99(s,1H),6.73(d,J=7.9Hz,1H),6.59(s,1H),6.55(d,J=7.9Hz,1H),5.54( s,1H),5.27(d,J=9.1Hz,1H),4.36(dd,J=13.3,5.6Hz,1H),3.88(s,3H),3 .24–3.14(m,2H),2.93–2.83(m,2H),2.61(d,J=13.3Hz,1H),0.87(s,9H).

[0377] 13C NMR (101MHz, CDCl3) δ154.42,146.09,145.69(d,J=15.1Hz),144.13,140.00,139.76,131.51,129.93,129.33(d,J=8.4Hz),128.32(d,J=9.4H z),126.46(d,J=9.4Hz),125.78,123.87,117.53,112.69,110.95,107.16,103.88,79.28,56.01,53.63,41.57,35.97,28.34,27.84.HRMS(ESI + ):644.1650.

[0378] Example 6: The compound shown in Formula 3-1 (1-((4-bromo-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol)

[0379] Compound 3 (100 g, 0.19 mol, 1.0 eq.) and ethyl acetate (400 mL) were added to a clean, dry 1 L three-necked flask. The system was cooled to 0 °C, and a methanol solution of HCl (4 N, 240 mL) was slowly added. After the addition was complete, the system was maintained at 0 °C for 3 hours. After the reaction was complete, the system was cooled to 10 °C, and a Na₂CO₃ aqueous solution (60 g, 0.57 mol, 3.0 eq.) was slowly added to quench the system. The system was extracted three times with ethyl acetate (500 mL × 3), the organic phases were combined and concentrated, and the system was replaced with n-heptane. The mixture was filtered to give a white solid product 3-1 (75.6 g, 95% yield).

[0380] 1 H NMR (500MHz, CDCl3) δ6.83(d,J=7.6Hz,1H),6.64(s,1H),6.61(d,J=7.9Hz,1H),6.56(s,1H),3.96(dd,J=13.5,6.4Hz,1H),3.84(s,3H) ,3.60–3.52(m,1H),3.41(dd,J=14.2,4.3Hz,1H),3.34–3.26(m,1H),3.14–3.04(m,2H),2.97(t,J=15.5Hz,1H),1.72(d,J=7.0Hz,6H).

[0381] HRMS (ESI) + ):420.0811.

[0382] Example 7: The compound shown in Formula 3-1A (1-((4-bromo-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol)

[0383] Compound 3A (100 g, 0.155 mol, 1.0 eq.) and ethyl acetate (400 mL) were added to a clean, dry 1 L three-necked flask. The system was cooled to 0 °C, and a methanol solution of HCl (4 N, 240 mL) was slowly added. After the addition was complete, the system was maintained at 0 °C for 3 hours. After the reaction was complete, the system was cooled to 10 °C, and a Na₂CO₃ aqueous solution (57.5 g, 0.54 mol, 3.5 eq.) was slowly added to quench the system. The system was extracted three times with ethyl acetate (500 mL × 3), the organic phases were combined and concentrated, and the system was replaced with n-heptane. The mixture was filtered to give a white solid product 3-1A (75.6 g, 96% yield).

[0384] 1 H NMR (500MHz, CDCl3) δ7.61 (ddd, J=5.6, 4.2, 1.8Hz, 4H), 7.46–7.31 (m, 6H), 6.94(s,1H),6.80–6.73(m,2H),6.56(s,1H),4.15(dd,J=10.8,2.4Hz,1H), 3.82(s,3H),3.29(dd,J=13.9,2.9Hz,1H),3.23–3.17(m,1H),2.94–2.88(m ,1H),2.83(dd,J=13.8,10.8Hz,1H),2.74(qd,J=16.0,8.2Hz,2H).HRMS(ESI + ):544.1125.

[0385] Example 8: The compound shown in Formula 3-2 ((R)-1-((4-bromo-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol)

[0386] In a clean, dry 1L reactor purged with nitrogen, tetrahydrofuran (300 mL) and compound 3-1 (30 g, 0.071 mol, 1.0 eq.) were added. The system was cooled to 0 °C, and N-chlorosuccinimide (NCS) (9.53 g, 0.071 mol, 1.0 eq.) was added. After stirring for 10 minutes, potassium hydroxide (8 g, 0.14 mol, 2.0 eq.) was added, and the system was stirred for another hour. Subsequently, a formic acid / triethylamine mixed solvent was added. 60 mL of formic acid / triethylamine (molar ratio 5:2, volumes 24.2 mL:35.8 mL) and a transfer hydrogenation catalyst RuCl[(S,S)-Tsdpen](p-cymene)({[(S,S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) chloride, catalyst as shown in formula ATH-01, 0.01 eq.) were added. The system was heated to room temperature and reacted for 16 hours. After the reaction was completed, the system was concentrated, and then water (300 mL) was added. The system was extracted three times with ethyl acetate (300 mL × 3). The organic phases were combined and concentrated, and column chromatography (eluent: dichloromethane / methanol = 30:1 to 20:1) was performed to give a foamy solid product 3-2 (21.6 g, 72% yield).

[0387] 97% ee, AD-H column (packing material is silica gel coated with amylose-tris(3,5-xylylcarbamate)), 250*4.6mm, 5μm, mobile phase iPrOH / Heptane = 80:20; flow rate 0.5mL / min; t = 14.7min (minor), t = 25.4min (major).

[0388] 1 H NMR (500MHz, CDCl3) δ6.83(d,J=7.6Hz,1H),6.64(s,1H),6.61(d,J=7.9Hz,1H),6.56(s,1H),3.96(dd,J=13.5,6.4Hz,1H),3.84(s,3H) ,3.60–3.52(m,1H),3.41(dd,J=14.2,4.3Hz,1H),3.34–3.26(m,1H),3.14–3.04(m,2H),2.97(t,J=15.5Hz,1H),1.72(d,J=7.0Hz,6H).

[0389] HRMS (ESI) + ):420.0811.

[0390] Example 9: The compound shown in Formula 3-2A ((R)-1-((4-bromo-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-ol)

[0391] In a clean, dry 1L reactor, tetrahydrofuran (300mL) and compound 3-1A (30g, 0.055mol, 1.0eq.) were added. The system was cooled to 0℃, and N-chlorosuccinimide (NCS) (7.4g, 0.055mol, 1.0eq.) was added. After stirring for 10 minutes, potassium hydroxide (6.2g, 0.11mol, 2.0eq.) was added, and the system was stirred for another hour. Subsequently, a formic acid / triethylamine mixed solvent (60mL, 24.2mL:35.8mL) and a transfer hydrogenation catalyst RuCl[(S,S)-Tsdpen](p-cymene)({[(S,S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amino}(p-isopropyltoluene)ruthenium(II) chloride, 0.01eq.) were added, and the system was heated to room temperature and reacted for 16 hours. After the reaction was complete, the system was concentrated, and then water (300 mL) was added. The system was extracted three times with ethyl acetate (300 mL × 3). The organic phases were combined and concentrated, and then passed through a column (eluent: dichloromethane / methanol = 30:1 to 20:1) to give a foamy solid product 3-2A (22.5 g, 72% yield).

[0392] 92% ee, AD-H column, mobile phase iPrOH / Heptane = 80:20; flow rate 0.5 mL / min; t = 17.7 min (minor), t = 31.9 min (major)

[0393] 1 H NMR (500MHz, CDCl3) δ7.61(ddd,J=5.6,4.2,1.8Hz,4H),7.46–7.31(m,6H),6.94(s,1H),6.80–6.73(m,2H),6.56(s,1H),4.15(dd,J=10.8,2.4Hz, 1H),3.82(s,3H),3.29(dd,J=13.9,2.9Hz,1H),3.23–3.17(m,1H),2.94– 2.88(m,1H),2.83(dd,J=13.8,10.8Hz,1H),2.74(qd,J=16.0,8.2Hz,2H).

[0394] HRMS (ESI) +):544.1125.

[0395] Example 10: The compound shown in Formula 4 (tert-butyl(R)-1-((4-bromo-2,2-dimethylbenzo[d][1,3]dioxol-5-yl)methyl)-7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate)

[0396] In a clean, dry 250 mL three-necked flask, compound 3-2 (20 g, 0.0476 mol, 1.0 eq.) and dichloromethane (100 mL) were added, followed by an aqueous solution of sodium bicarbonate (8.0 g, 0.095 mol, 2.0 eq.) (40 mL), and then di-tert-butyl dicarbonate (12.5 g, 0.057 mol, 1.2 eq.). After the additions were complete, the system was allowed to react at room temperature for 8 hours. After the reaction was complete, water (100 mL) was added, and the system was extracted three times with ethyl acetate (150 mL × 3). The organic phases were combined and concentrated, and then crystallized from isopropanol to give a white solid product 4 (23.7 g, 96% yield).

[0397] 97% ee, OD-3 column; mobile phase iPrOH / Heptane = 40:60; flow rate 0.8 mL / min; t = 5.9 min (minor), t = 7.4 min (major).

[0398] 1 H NMR (500MHz, CDCl3) δ6.97(s,1H),6.60(s,1H),6.57(d,J=1.5Hz,1H),6.51(d,J=7.8Hz,1H),5.56(s,1H),5.30(dd,J=6.2,4.5Hz,1H),4. 37(dd,J=13.3,5.7Hz,1H),3.88(d,J=1.3Hz,3H),3.25–3.14(m,2H),2.94–2.84(m,2H),2.62(d,J=15.8Hz,1H),1.73(s,6H),1.14(s,9H).

[0399] HRMS (ESI) + ):520.1331.

[0400] Example 11: The compound shown in Formula 4A (tert-butyl(R)-1-((4-bromo-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)methyl)-7-hydroxy-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate)

[0401] In a clean, dry 2L three-necked flask, compound 3-2A (100 g, 0.183 mol, 1.0 eq.) and dichloromethane (1 L) were added, followed by an aqueous solution (200 mL) of sodium bicarbonate (30.8 g, 0.367 mol, 2.0 eq.), and then di-tert-butyl dicarbonate (48 g, 0.22 mol, 1.2 eq.). After the additions were complete, the system was allowed to react at room temperature for 8 hours. After the reaction was complete, water (300 mL) was added, and the system was extracted three times with ethyl acetate (350 mL × 3). The organic phases were combined and concentrated, and then crystallized from isopropanol to give a white solid product 4A (109 g, 93% yield).

[0402] 99% ee, OD-3 column; mobile phase iPrOH / Heptane = 40:60; flow rate 0.8 mL / min; t = 5.2 min (minor), t = 6.2 min (major).

[0403] 1 H NMR (500MHz, CDCl3) δ7.65–7.56(m,4H),7.37(dd,J=6.2,4.1Hz,6H),6.99(s,1H),6.73(d,J=7.9Hz,1H),6.59(s,1H),6.55(d,J=7.9Hz,1H),5.54( s,1H),5.27(d,J=9.1Hz,1H),4.36(dd,J=13.3,5.6Hz,1H),3.88(s,3H),3 .24–3.14(m,2H),2.93–2.83(m,2H),2.61(d,J=13.3Hz,1H),0.87(s,9H).

[0404] 13C NMR (101MHz, CDCl3) δ154.42, 146.09, 145.69 (d, J = 15.1Hz), 144.13, 140.00, 139.76, 131.51, 129.93, 129.33 (d, J = 8.4Hz), 128.32 (d, J = 9.4Hz), 126.46 (d, J = 9.4Hz), 125.78, 123.87, 117.53, 112.69, 110.95, 107.16, 103.88, 79.28, 56.01, 53.63, 41.57, 35.97, 28.34, 27.84.

[0405] HRMS (ESI) + ):644.1650.

[0406] Example 12: The compound shown in Formula 5 (tert-butyl(7R,11aS)-10-methoxy-2,2-dimethyl-9-oxo-7,9-dihydro-6H-7,11a-(epiminoethano)phenanthro[3,4-d][1,3]dioxole-14-carboxylate)

[0407] Compound 4 (10 g, 0.019 mol, 1.0 eq.), potassium carbonate (4.0 g, 0.029 mol, 1.5 eq.), palladium chloride (67 mg, 0.38 mmol, 0.02 eq.), and di-tert-butylcyclobutylphosphine (164 mg, 0.57 mmol, 0.03 eq.) were added to a clean, dry 250 mL three-necked flask. The system was purged with nitrogen three times, and then 100 mL of ultra-dry N,N-dimethylacetamide was added. After the addition was complete, the system was heated to 150 °C and reacted for 2 hours. After the reaction was complete, water (300 mL) was added, and the system was extracted three times with ethyl acetate (150 mL × 3). The organic phases were combined and concentrated, and then passed through a column (eluent: dichloromethane / methanol = 60:1 to 50:1) to give a pale yellow, foamy solid product 5 (5.18 g, 62% yield).

[0408] 1H NMR (500MHz, CDCl3) δ7.03 (s, 1H), 6.64 (d, J = 8.0Hz, 1H), 6.59 (d, J = 7.8Hz, 1H), 6.3 5(d,J=20.7Hz,1H),5.17(s,1H),5.00(s,1H),3.99(d,J=8.9Hz,1H),3.87(t,J=5.5 Hz,1H),3.74(s,3H),3.23–3.05(m,2H),2.92–2.78(m,1H),2.22(dd,J=16.9,8.8Hz ,1H),1.70(d,J=24.1Hz,6H),1.62(td,J=12.9,5.4Hz,2H),1.47(d,J=27.3Hz,9H).

[0409] HRMS (ESI) + ):462.1891.

[0410] Example 13: The compound shown in Formula 5A (tert-butyl(7R,11aS)-10-methoxy-9-oxo-2,2-diphenyl-7,9-dihydro-6H-7,11a-(epiminoethano)phenanthro[3,4-d][1,3]dioxole-14-carboxylate)

[0411] Compound 4A (10 g, 0.0155 mol, 1.0 eq.), potassium carbonate (3.2 g, 0.023 mol, 1.5 eq.), palladium chloride (55 mg, 0.31 mmol, 0.02 eq.), and diadamantyl n-butylphosphine (167 mg, 0.46 mmol, 0.03 eq.) were added to a clean, dry 250 mL three-necked flask. The system was purged with nitrogen three times, and then 100 mL of ultra-dry N,N-dimethylacetamide was added. After the addition was complete, the system was heated to 150 °C and reacted for 2 hours. After the reaction was complete, water (300 mL) was added, and the system was extracted three times with ethyl acetate (150 mL × 3). The organic phases were combined and concentrated, and then passed through a column (eluent: dichloromethane / methanol = 60:1 to 50:1) to give a pale yellow, foamy solid product 5A (4.98 g, 57% yield).

[0412] 1H NMR(500MHz, CDCl3)δ7.57(s,2H),7.55–7.49(m,2H),7.43(d,J=5.2Hz,3H),7.38–7.33(m,3H),7 .15(s,1H),6.79(d,J=8.0Hz,1H),6.66(d,J=7.5Hz,1H),6.36(d,J=20.5Hz,1H),5.18(s,1H),5.0 0(s,1H),3.96(d,J=9.2Hz,1H),3.85(d,J=7.8Hz,1H),3.66(s,3H),3.13(dd,J=45.3,21.6Hz,2H) ,2.80(dd,J=26.1,12.5Hz,1H),2.27(d,J=6.9Hz,1H),1.71–1.65(m,1H),1.47(d,J=28.7Hz,9H).

[0413] 13 C NMR (101MHz, CDCl3) δ181.07,158.68,151.65,146.27,143.74,139.91,129.51,129.44,128.49,128.41,126.21,126.17,122.32 ,121.78,119.91,118.42,118.22,117.15,108.19,80.65,60.45,59.73,54.90,53.70,52.49,42.69,39.27,38.47,38.15,28.47.

[0414] HRMS (ESI) + ):586.2204

[0415] Example 14: The compound shown in Formula 5-1 ((7R,11aS)-10-methoxy-2,2-dimethyl-6,7-dihydro-9H-7,11a-(epiminoethano)phenanthro[3,4-d][1,3]dioxol-9-one)

[0416] Compound 5 (5 g, 0.011 mol, 1.0 eq.) and ethyl acetate (30 mL) were added to a clean, dry 100 mL three-necked flask. The system was cooled to 0 °C, and a methanol solution of HCl (4 N, 18 mL) was slowly added. After the addition was complete, the system was maintained at 0 °C for 3 hours. After the reaction was complete, the system was cooled to 10 °C, and a Na₂CO₃ aqueous solution (4.0 g, 0.038 mol, 3.5 eq.) was slowly added to quench the system. The system was extracted three times with ethyl acetate (50 mL × 3), and the organic phases were combined and concentrated to give a white solid product 5-1 (3.4 g, 92% yield).

[0417] 1 H NMR (500MHz, CDCl3) δ7.04(s,1H),6.65–6.60(m,2H),6.30(s,1H),3.94(d,J=6.2Hz,1H),3.75(s,3H),3.32(dd,J=17.4,6.2Hz,1H),3.16 (d,J=17.5Hz,1H),2.89–2.82(m,2H),2.25(d,J=12.6Hz,1H),1.81–1.76(m,1H),1.73(s,3H),1.66(s,3H),1.62(dd,J=12.2,6.4Hz,1H).

[0418] HRMS (ESI) + ):340.1551.

[0419] Example 15: The compound shown in Formula 5A ((7R,11aS)-10-methoxy-2,2-diphenyl-6,7-dihydro-9H-7,11a-(epiminoethano)phenanthro[3,4-d][1,3]dioxol-9-one)

[0420] Compound 5A (10 g, 0.0177 mol, 1.0 eq.) and ethyl acetate (40 mL) were added to a clean, dry 100 mL three-necked flask. The system was cooled to 0 °C, and a methanol solution of HCl (4 N, 24 mL) was slowly added. After the addition was complete, the system was maintained at 0 °C for 3 hours. After the reaction was complete, the system was cooled to 10 °C, and a Na₂CO₃ aqueous solution (4.0 g, 0.038 mol, 3.5 eq.) was slowly added to quench the system. The system was extracted three times with ethyl acetate (50 mL × 3), and the organic phases were combined and concentrated to give a white, foamy solid product 5-1A (7.45 g, 91% yield).

[0421] 1H NMR (500MHz, CDCl3) δ7.59(dd,J=7.6,1.8Hz,2H),7.50(dd,J=7.3,2.2Hz,2H),7.42(dd,J =9.3,3.0Hz,3H),7.38–7.31(m,4H),7.17(s,1H),6.77(d,J=8.0Hz,1H),6.67(d,J=8.0Hz, 1H),6.31(s,1H),3.94(d,J=5.9Hz,1H),3.68(s,3H),3.32(dd,J=17.5,6.2Hz,1H),3.15( d,J=17.5Hz,1H),2.86–2.77(m,2H),2.30(d,J=12.4Hz,1H),1.68(td,J=12.3,5.3Hz,1H).

[0422] HRMS (ESI) + ):486.1680.

[0423] Example 16: The compound shown in Formula 6 ((7R,11aS)-14-(cyclopropylmethyl)-10-methoxy-2,2-dimethyl-6,7-dihydro-9H-7,11a-(epiminoethano)phenanthro[3,4-d][1,3]dioxol-9-one)

[0424] Compound 5-1 (3 g, 8.8 mmol, 1.0 eq.) and sodium bicarbonate (1.48 g, 17.6 mmol, 2.0 eq.) were added to a clean, dry 100 mL three-necked flask. The system was purged with nitrogen three times. Toluene (30 mL) and cyclopropylmethyl bromide (4.75 g, 35.2 mmol, 4.0 eq.) were then added. After the addition was complete, the system was heated to 100 °C and reacted for 24 hours. After the reaction was complete, water (50 mL) was added, and the system was extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated, and then passed through a column (eluent: dichloromethane / methanol = 30:1) to give a white, foamy solid product 6 (2.63 g, 76% yield).

[0425] 1H NMR (500MHz, CDCl3) δ7.03 (s, 1H), 6.60 (q, J = 8.1Hz, 2H), 6.33 (s, 1H), 3.94 (d, J = 5.7Hz, 1H), 3.74(s,3H),3.30(d,J=17.6Hz,1H),2.99(dd,J=17.7,5.8Hz,1H),2.95–2.89(m,1H),2.59–2 .50(m,2H),2.38(dd,J=12.5,6.9Hz,1H),2.06(d,J=12.7Hz,1H),1.83(dd,J=12.7,4.5Hz,1H ),1.73(s,3H),1.65(s,3H),0.90–0.83(m,1H),0.54(d,J=7.8Hz,2H),0.13(d,J=4.9Hz,2H).

[0426] HRMS (ESI) + ):394.2018.

[0427] Example 17: The compound shown in Formula 6A ((7R,11aS)-14-(cyclopropylmethyl)-10-methoxy-2,2-diphenyl-6,7-dihydro-9H-7,11a-(epiminoethano)phenanthro[3,4-d][1,3]dioxol-9-one)

[0428] Compound 5-1A (7 g, 0.015 mol, 1.0 eq.) and sodium bicarbonate (2.53 g, 0.03 mol, 2.0 eq.) were added to a clean, dry 100 mL three-necked flask. The system was purged with nitrogen three times. Toluene (60 mL) and cyclopropylmethyl bromide (8.1 g, 0.06 mol, 4.0 eq.) were then added. After the addition was complete, the system was heated to 100 °C and reacted for 24 hours. After the reaction was complete, water (50 mL) was added, and the system was extracted three times with ethyl acetate (100 mL × 3). The organic phases were combined and concentrated, and then passed through a column (eluent: dichloromethane / methanol = 40:1) to give a white, foamy solid product 6A (6.2 g, 80% yield).

[0429] 1H NMR(500MHz, CDCl3)δ7.59(dd,J=7.7,1.9Hz,2H),7.52–7.47(m,2H),7.45–7.38(m,3H),7.36–7.31(m,3H),7.16(s,1H ),6.76(d,J=8.0Hz,1H),6.64(d,J=8.0Hz,1H),6.34(s,1H),3.94(d,J=5.6Hz,1H),3.67(s,3H),3.29(d,J=17.7Hz,1H) ,3.00(dd,J=17.7,5.8Hz,1H),2.92–2.86(m,1H),2.52(dt,J=17.2,8.7Hz,2H),2.37(dd,J=12.6,6.8Hz,1H),2.11(d,J =12.0Hz,1H),1.87(td,J=12.6,4.6Hz,1H),0.87(dd,J=14.6,5.9Hz,1H),0.54(d,J=8.2Hz,2H),0.12(d,J=4.6Hz,2H).

[0430] 13 C NMR (101MHz, CDCl3) δ181.47,160.76,151.33,145.98,143.46,140.18,140.09,130.10,129.46,129.36,128.49,128.42 ,126.24,122.67,121.04,120.83,119.29,116.88,107.88,59.31,58.80,54.88,44.53,43.24,39.65,32.92,9.69,4.35.

[0431] HRMS (ESI) + ):540.2149.

[0432] Example 18: The compound shown in Formula 6-1 ((4bS,9R)-11-(cyclopropylmethyl)-3,4-dihydroxy-6-methoxy-9,10-dihydro-7H-9,4b-(epiminoethano)phenanthren-7-one)

[0433] Compound 6 (2 g, 5.0 mmol, 1.0 eq.) and water (3 mL) were added to a clean, dry 100 mL three-necked flask. The system was cooled to 10 °C, and trifluoroacetic acid (9 mL) was added. After the addition was complete, the system was heated to 80 °C and reacted for 24 hours. After the reaction was complete, the system was evaporated to dryness, and a suspension was formed by adding dichloromethane. The suspension was filtered to give a grayish-white solid product 6-1 (1.55 g, 88% yield).

[0434] Alternatively, compound 6A (5 g, 9.6 mmol, 1.0 eq.) and water (10 mL) were mixed, the system was cooled to 10 °C, and trifluoroacetic acid (30 mL) was added. After the addition was complete, the system was allowed to react at room temperature for 30 hours. After the reaction was complete, the system was evaporated to dryness, and dichloromethane was added to form a suspension. The suspension was filtered to give a grayish-white solid product 6-1 (3.22 g, 95% yield).

[0435] 1 H NMR(500MHz,CD3OD)δ7.87(s,1H),6.67(d,J=8.1Hz,1H),6.51(d,J=8.1Hz,1H),6.33(s,1H),4. 03(d,J=5.4Hz,1H),3.74(s,3H),3.34(s,3H),3.32(s,1H),3.29(s,1H),2.99(dd,J=17.8,5.7Hz ,1H),2.95–2.88(m,1H),2.60(dd,J=12.7,6.3Hz,1H),2.51–2.37(m,3H),1.71(td,J=12.9,4.4 Hz,1H),1.29(t,J=4.7Hz,1H),0.90(p,J=13.2Hz,1H),0.56(d,J=7.9Hz,2H),0.23–0.14(m,2H).

[0436] HRMS (ESI) + ):354.1701.

[0437] Example 19: The compound shown in Formula 6-2 ((4bS,9R)-11-(cyclopropylmethyl)-6-methoxy-9,10-dihydro-7H-9,4b-(epiminoethano)phenanthrene-3,4,7-triol)

[0438] Compound 6-1 (2 g, 5.6 mmol, 1.0 eq.) and anhydrous ethanol (20 mL) were added to a clean, dry 100 mL three-necked flask. Cerium trichloride heptahydrate (2.08 g, 5.6 mmol, 1.0 eq.) was added at room temperature, and the mixture was stirred at room temperature for 15 minutes. The system was cooled to 0 °C, and sodium borohydride (425 mg, 11.2 mmol, 2.0 eq.) was added. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, water (50 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined, dried, and concentrated to obtain a gray, foamy solid, 6-2 (2 g), which was used directly in the next reaction.

[0439] LCMS (ESI) + ):378.2.

[0440] Example 20: The compound shown in Formula 7 ((4R,7aR,12bS)-3-(cyclopropylmethyl)-7-methoxy-2,3,4,7a-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-ol)

[0441] Compound 6-2 (2 g) and 1,4-dioxane (20 mL) were added to a clean, dry, nitrogen-purged 50 mL three-necked flask, followed by the addition of N,N-dimethylformamide dimethyl acetal (6.67 g, 56 mmol, 10.0 eq.) at room temperature. After the addition was complete, the system was heated to 50 °C and reacted for 24 hours. After the reaction was complete, the system was directly concentrated and purified by column chromatography (eluent: dichloromethane / methanol = 30:1–20:1) to give a white, foamy solid product 7 (1.6 g, 85% yield).

[0442] 1 H NMR (500MHz, CDCl3) δ6.66(d,J=8.1Hz,1H),6.56(d,J=8.1Hz,1H),5.61(s,1H),5.31(s,1H),5.08(d,J=6.5Hz,1H),4.05(s,1H),3.63(s,3H),3.3 4(s,1H),2.99(d,J=33.4Hz,2H),2.80(s,1H),2.60(s,2H),2.24(s,1H), 1.77(d,J=11.8Hz,1H),0.99(s,1H),0.60(d,J=6.3Hz,2H),0.21(s,2H).

[0443] 13C NMR (101MHz, CDCl3) δ152.71,143.05,139.21,132.69,125.72,120.14,117.0 5,96.27,88.92,58.99,58.22,55.17,46.47,43.78,35.18,31.59,8.53,4.16.

[0444] HRMS (ESI) + ):360.1573.

[0445] Example 21: The compound shown in Formula 8 ((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one)

[0446] Compound 7 (1.0 g, 2.96 mmol, 1.0 eq.) and acetic acid (10 mL) were added to a clean, dry 100 mL three-necked flask. The system (pH = 2–4) was stirred at room temperature for 30 minutes. Then, the system was cooled to 10 °C, and hydrogen peroxide (35% aq., 1.58 g, 16.3 mmol, 5.5 eq.) was slowly added. After the addition was complete, the system was allowed to react at room temperature for 20 hours. After the reaction was complete, the system was quenched with sodium sulfite solution (2 mL), and water (30 mL) was added. The system was then extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined, dried, concentrated, and column filtered (eluent: dichloromethane / methanol = 50:1–40:1) to give a foamy white solid product 8 (874 mg, 87% yield).

[0447] 1 H NMR (500MHz, CDCl3) δ6.71–6.65(m,2H),6.57(d,J=8.2Hz,1H),6.19(d,J=10.1Hz,1H) ,4.74(s,1H),3.38(d,J=5.3Hz,1H),3.12(d,J=18.5Hz,1H),2.77(d,J=8.0Hz,1H),2.5 5(dd,J=18.7,6.0Hz,1H),2.45(td,J=12.4,6.1Hz,3H),2.27(td,J=12.2,3.7Hz,1H),1 .70(d,J=10.2Hz,1H),0.89–0.86(m,1H),0.58(d,J=7.9Hz,2H),0.17(d,J=4.7Hz,2H).

[0448] HRMS (ESI) + ):340.1553.

[0449] Example 22: The compound naltrexone ((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro-[3,2-e]isoquinolin-7(7aH)-one) shown in Formula 9

[0450] Compound 8 (500 mg, 1.47 mmol, 1.0 eq.), Pd / C (10 wt%, 50 mg), and ethyl acetate (8 mL) were added to a clean, dry 500 mL hydrogenation reactor. The system was purged with hydrogen three times, and then the hydrogen pressure was adjusted to 2 bar. The reaction was carried out at room temperature for 8 hours. After the reaction was completed, the system was filtered through diatomaceous earth, the filtrate was concentrated, and column chromatography (eluent: dichloromethane / methanol = 30:1–20:1) was performed to give a white solid product 9 (491 mg, 98% yield).

[0451] 1 H NMR (500MHz, CDCl3) δ6.72 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 7.9 Hz, 1H), 4.69 (s, 1H), 3.20 (d, J = 4. 8Hz,1H),3.11–2.98(m,2H),2.71(d,J=7.7Hz,1H),2.57(dd,J=18.3,5.5Hz,1H),2.49–2.37(m ,3H),2.32(d,J=14.4Hz,1H),2.17(dd,J=12.1,9.1Hz,1H),1.89(d,J=13.1Hz,1H),1.62(ddd, J=27.4,19.5,6.8Hz,2H),0.87(d,J=6.9Hz,1H),0.55(d,J=7.6Hz,2H),0.15(d,J=4.5Hz,2H).

[0452] 13 C NMR (126MHz, CDCl3) δ210.13,143.60,138.95,129.11,124.34,120.07,118.09,90.72,70.38 ,62.17,59.35,51.18,43.76,36.33,31.51,30.77,29.84,22.78,9.52,4.15,3.96.HRMS(ESI+ ):342.1703.

[0453] Example 23: The compound shown in Formula 10 (1-((4R,4aR,7R,7aR,12bS,14S)-3-(cyclopropylmethyl)-9-hydroxy-7-methoxy-1,2,3,4,7,7a-hexahydro-7,4a-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-14-yl)ethan-1-one)

[0454] Compound 7 (2 g, 5.9 mmol, 1.0 eq.) and methyl vinyl ketone (20 mL) were added to a clean, dry, nitrogen-purged 100 mL three-necked flask. After addition, the system was heated to 80 °C and refluxed for 8 hours. After the reaction was complete, the system was concentrated and purified by column chromatography (eluent: dichloromethane / methanol = 40:1) to give a white, foamy solid product 10 (1.95 g, 81% yield).

[0455] 1 H NMR (400MHz, CDCl3) δ6.58(d,J=7.8Hz,1H),6.44(d,J=7.7Hz,1H),5.82(d,J=8.5Hz ,1H),5.54(d,J=8.6Hz,1H),4.57(s,1H),3.53(s,3H),3.14–2.89(m,3H),2.70(d,J= 7.9Hz,1H),2.35(dd,J=28.7,18.0Hz,4H),2.11(s,3H),2.00–1.90(m,1H),1.80(d, J=12.1Hz,1H),1.32(dd,J=11.8,5.8Hz,1H),0.81(s,1H),0.49(s,2H),0.11(s,2H).

[0456] 13 C NMR (101MHz, CDCl3) δ209.78,146.67,137.64,136.31,134.01,127.54,125.71,119.90,116.66,116.20,94.75 ,81.31,59.76,57.04,53.53,53.09,50.64,48.37,44.04,43.21,33.44,30.17,30.05,23.26,9.39,4.19,3.47.

[0457] HRMS (ESI) +):430.1992.

[0458] Example 24: The compound shown in Formula 11 ((4R,4aR,7R,7aR,12bS,14R)-3-(cyclopropylmethyl)-14-((S)-2-hydroxy-3,3-dimethylbutan-2-yl)-7-methoxy-1,2,3,4,7,7a-hexahydro-7,4a-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-9-ol)

[0459] Compound 10 (1.0 g, 2.45 mmol, 1.0 eq.) was added to a clean, dry 100 mL three-necked flask. The system was purged with nitrogen three times, and toluene (10 mL) was added. The system was then cooled to 0 °C, and a THF solution of tert-butylmagnesium chloride (1.0 M, 17.1 mL, 17.1 mmol, 7.0 eq.) was added. The system was then slowly heated to room temperature and reacted for 20 hours. The starting material was not completely converted, so the system was quenched with water (20 mL), and then extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined, dried, and concentrated, and then passed through a column (eluent: dichloromethane / methanol = 20:1) to give a white solid product 11 (400 mg, 35% yield).

[0460] 1 H NMR (500MHz, CDCl3) δ6.61(d,J=8.1Hz,1H),6.49(d,J=8.1Hz,1H),5.99(d,J=8.8Hz,1H),5.65 (s,1H),5.44(d,J=8.9Hz,1H),4.56(s,1H),3.79(s,3H),3.49(d,J=6.5Hz,1H),3.09(d,J=18. 4Hz,1H),2.97(dd,J=12.5,8.8Hz,1H),2.66(dd,J=11.8,4.6Hz,1H),2.46–2.31(m,4H),2.15( t,J=8.6Hz,1H),1.97–1.80(m,2H),1.04–0.81(m,15H),0.59–0.44(m,2H),0.22–0.08(m,2H).

[0461] 13C NMR (126MHz, CDCl3) δ147.3,138.06,136.35,135.16,128.56,125.12,120.39,116.83,99.98,85.19,79.32,60.2 ,57.48,55.85,48.07,46.44,44.7,43.81,40.34,34.56,32.81,27.3,23.84,20.29,10.13,4.95,3.84.LCMS(ESI + ):488.3.

[0462] Example 25: The compound shown in Formula 12, buprenorphine ((4R,4aR,7S,7aR,12bS)-3-(cyclopropylmethyl)-6-(2-hydroxy-3,3-dimethylbutan-2-yl)-7-methoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-9-ol)

[0463] Compound 11 (300 mg, 0.64 mmol, 1.0 eq.), Pd / C (10 wt%, 30 mg), and isopropanol (10 mL) were added to a clean, dry 500 mL hydrogenation reactor. The system was purged with hydrogen three times, and then the hydrogen pressure was adjusted to 10 atm. The reaction was carried out at room temperature for 10 hours. After the reaction was completed, the system was filtered through diatomaceous earth, the filtrate was concentrated, and column chromatography (eluent: dichloromethane / methanol = 30:1–20:1) was performed to give a white solid product 12 (296 mg, 99% yield).

[0464] 1H NMR (500MHz, CDCl3) δ6.69(d,J=8.0Hz,1H),6.51(d,J=8.0Hz,1H),5.92(s,1H),4.45(s,1H),3.53(s,3H),2.98(d,J=18. 9Hz,2H),2.89(t,J=10.2Hz,1H),2.62(dd,J=11.5,4.7Hz,1H),2.26(dddd,J=36.9,30.5,15.9,7.8Hz,6H),1.98(td,J=1 2.6,5.4Hz,1H),1.84(t,J=12.4Hz,1H),1.75(td,J=12.8,6.0Hz,1H),1.70–1.57(m,1H),1.36(s,3H),1.31(d,J=13.8Hz ,2H),1.03(s,9H),0.88(t,J=5.9Hz,1H),0.80(s,1H),0.70(t,J=12.3Hz,1H),0.53–0.42(m,2H),0.11(d,J=3.6Hz,2H).

[0465] 13 C NMR (126MHz, CDCl3) δ145.56,137.36,132.72,128.51,119.74,116.50,97.23,80.98,79.67,59.66,58.43,52.67,46.64,43 .85,40.54,36.15,35.76,33.56,32.07,29.84,29.78,26.56,23.08,22.84,20.25,18.35,14.27,9.60,4.31,3.40.HRMS(ESI + ):468.3112.

[0466] Example 26: The compound shown in Formula 6B ((7R,11aS)-14-(cyclobutylmethyl)-10-methoxy-2,2-diphenyl-6,7-dihydro-9H-7,11a-(epiminoethano)phenanthro[3,4-d][1,3]dioxol-9-one)

[0467] Compound 5-1A (2.5 g, 5.4 mmol, 1.0 eq.) and potassium bicarbonate (1.6 g, 16.2 mmol, 3.0 eq.) were added to a clean, dry 100 mL three-necked flask. The system was purged with nitrogen three times. Acetonitrile (15 mL) and bromomethylcyclobutane (1.61 g, 10.8 mmol, 2.0 eq.) were then added. After the addition was complete, the system was heated to 80 °C and reacted for 16 hours. After the reaction was complete, water (50 mL) was added, and the system was extracted three times with ethyl acetate (100 mL × 3). The organic phases were combined and concentrated, and then passed through a column (eluent: dichloromethane / methanol = 40:1) to give a white, foamy solid product 6B (2.1 g, 75% yield).

[0468] 1 H NMR (500MHz, CDCl3) δ7.59(d,J=7.5Hz,2H),7.49(d,J=5.0Hz,2H),7.42(d,J=6.1Hz,3H),7.34 (d,J=4.8Hz,3H),7.15(s,1H),6.75(d,J=7.8Hz,1H),6.65(d,J=8.0Hz,1H),6.30(s,1H),3.68( s,1H),3.67(s,3H),3.30(d,J=17.5Hz,1H),3.02–2.93(m,1H),2.58(dd,J=14.6,8.6Hz,3H),2. 54–2.43(m,2H),2.09–2.02(m,3H),1.86(ddd,J=25.2,20.3,9.0Hz,3H),1.68(d,J=9.1Hz,2H).

[0469] HRMS (ESI) + ):532.2490.

[0470] Example 27: The compound shown in Formula 6-1A ((4bS,9R)-11-(cyclobutylmethyl)-3,4-dihydroxy-6-methoxy-9,10-dihydro-7H-9,4b-(epiminoethano)phenanthren-7-one)

[0471] Compound 6B (600 mg, 1.63 mmol, 1.0 eq.) and water (1.3 mL) were added to a clean, dry 100 mL three-necked flask. The system was cooled to 10 °C, and trifluoroacetic acid (4 mL) was added. After the addition was complete, the system was allowed to react at room temperature for 24 hours. After the reaction was complete, the system was evaporated to dryness, and a suspension was formed by adding dichloromethane. The suspension was filtered to give a grayish-white solid product 6-1A (320 mg, 77% yield).

[0472] 1 H NMR(500MHz,CD3OD)δ7.86(s,1H),6.68(d,J=8.0Hz,1H),6.52(d,J=8.0Hz,1H),6.30 (s,1H),3.77(d,J=5.7Hz,1H),3.74(s,3H),2.95(dd,J=17.8,5.5Hz,1H),2.63(dd,J= 14.3,7.3Hz,2H),2.59–2.54(m,1H),2.43(dd,J=17.4,12.6Hz,2H),2.10(d,J=7.7Hz ,2H),1.93(dd,J=18.4,9.0Hz,2H),1.86–1.78(m,2H),1.72(dd,J=19.9,10.8Hz,3H).

[0473] HRMS (ESI) + ):368.1860.

[0474] Example 28: The compound shown in Formula 6-2A ((4bS,9R)-11-(cyclobutylmethyl)-6-methoxy-9,10-dihydro-7H-9,4b-(epiminoethano)phenanthrene-3,4,7-triol)

[0475] Compound 6-1A (300 mg, 0.82 mmol, 1.0 eq.) and anhydrous ethanol (3 mL) were added to a clean, dry Shrek tube. Cerium trichloride heptahydrate (304 mg, 0.82 mmol, 1.0 eq.) was added at room temperature, and the mixture was stirred at room temperature for 15 minutes. The system was cooled to 0°C, and sodium borohydride (62 mg, 1.64 mmol, 2.0 eq.) was added. After the addition was complete, the system was allowed to react at room temperature for 1 hour. After the reaction was complete, water (15 mL) was added, and the system was extracted three times with ethyl acetate (50 mL × 3). The organic phases were combined, dried, and concentrated to obtain a gray, foamy solid, 6-2A (300 mg), which was used directly in the next reaction.

[0476] LCMS (ESI) + ):392.2.

[0477] Example 29: The compound shown in Formula 7A ((4R,7aR,12bS)-3-(cyclobutylmethyl)-7-methoxy-2,3,4,7a-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-ol)

[0478] Compound 6-2A (300 mg) and 1,4-dioxane (6 mL) were added to a clean, dry, nitrogen-purged 50 mL three-necked flask, followed by the addition of N,N-dimethylformamide dimethyl acetal (1 g, 8.2 mmol, 10.0 eq.) at room temperature. After the addition was complete, the system was heated to 50 °C and reacted for 24 hours. After the reaction was complete, the system was directly concentrated and purified by column chromatography (eluent: dichloromethane / methanol = 30:1–20:1) to give a white, foamy solid product 7A (190 mg, 66% yield).

[0479] 1 H NMR (600MHz, CDCl3) δ6.65(d,J=8.0Hz,1H),6.55(d,J=8.0Hz,1H),5.55(d,J=6.4Hz,1H),5.29(s ,1H),5.08(d,J=6.4Hz,1H),3.73(d,J=7.0Hz,1H),3.62(s,3H),3.33(d,J=18.0Hz,1H),2.89(t,J =11.7Hz,1H),2.71(m,4H),2.60(hept,J=7.4Hz,1H),2.23(ddd,J=12.7,12.7,4.9Hz,1H),2.10(m ,2H),1.91(m,1H),1.81(m,1H),1.74(pent,J=8.7Hz,2H),1.68(dd,J=12.4,1.8Hz,1H).HRMS(ESI + ):352.1915.

[0480] Example 30: The compound shown in Formula 8A ((4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a,9-dihydroxy-2,3,4,4a-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one)

[0481] Compound 7A (200 mg, 0.57 mmol, 1.0 eq.) and acetic acid (2 mL) were added to a clean, dry Shrek tube purged with nitrogen. The system was stirred at room temperature for 30 minutes, then cooled to 10°C, and hydrogen peroxide (35% aq., 0.3 g, 3.1 mmol, 5.5 eq.) was slowly added. After the addition was complete, the system was allowed to react at room temperature for 20 hours. After the reaction was complete, the system was quenched with sodium sulfite solution (1 mL), and water (10 mL) was added. The system was then extracted three times with ethyl acetate (30 mL × 3). The organic phases were combined, dried, concentrated, and column filtered (eluent: dichloromethane / methanol = 40:1) to give a foamy white solid product 8A (159 mg, 79% yield).

[0482] 1 H NMR (400MHz, CD3OD) δ6.94(d,J=10.2Hz,1H),6.69(s,2H),6.16(d,J=10.2Hz,1H),4.79(s,1H),3.81(d,J=6.1Hz,1H),3.54-3.39(m,2H),3.24-3. 13(m,2H),3.03(dd,J=19.8,6.3Hz,1H),2.89(td,J=12.7,3.4Hz,1H),2. 83-2.70(m,2H),2.35-2.13(m,2H),2.11-1.90(m,4H),1.89-1.81(m,1H).

[0483] HRMS (ESI) + ):354.1703.

[0484] Example 31: The compound shown in Formula 13, nalbuphine ((4R,4aS,7S,7aR,12bS)-3-(cyclobutylmethyl)-1,2,3,4,5,6,7,7a-octahydro-4aH-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7,9-triol)

[0485] Compound 8A (250 mg, 0.71 mmol, 1.0 eq.), Pd / C (10 wt%, 25 mg), and MeOH (5 mL) were added to a clean, dry 500 mL hydrogenation reactor. The system was purged with hydrogen three times, and then the hydrogen pressure was adjusted to 20 bar. The reaction was carried out at 30 °C for 12 hours. After the reaction was completed, the system was filtered through diatomaceous earth, the filtrate was concentrated, and column chromatography (eluent: dichloromethane / methanol = 30:1–20:1) was performed to give a white solid product 13 (184 mg, 73% yield).

[0486] 1 H NMR(400MHz,CDCl3)δ6.70(d,J=8.0Hz,1H),6.52(d,J=8.0Hz,1H),4.64(d,J=4.8Hz,1H),4.34–4.15(m,1H),3.06(d,J=18.8Hz,1H),2.90–2.77(m,1H),2.67–2.55(m,1H),2.53–2.40(m,4H),2.32–2.17(m,2H),2.10–2.00(m,2H),1.96–1.80(m,2H),1.74–1.61(m,4H),1.54(d,J=11.6Hz,1H),1.44–1.33(m,1H),1.17–1.04(m,1H).

[0487] 13 C NMR(101MHz,CDCl3)δ145.6,137.5,131.1,125.6,119.3,117.8,90.8,70.0,67.0,62.9,60.9,47.3,43.5,33.7,33.4,29.8,28.8,27.1,26.9,23.3,18.8.HRMS(ESI + ):358.2021。

Claims

A method for preparing a compound as shown in Formula A7, characterized in that, It includes the following step S10: S10: Under the action of a cyclizing agent, the compound shown in formula A6-2 undergoes a cyclization reaction in an organic solvent as shown in the following formula to give the compound shown in formula A7. Wherein, "*" indicates that when the carbon atom is chiral carbon, its configuration is R, S or a mixture thereof; R 1 For H, C 1-4 Alkyl or C 3-7 cycloalkyl; R 2 For H or C 1-4 alkyl; R 3 For H, C 1-4 Alkyl, C 3-7 cycloalkyl or C 6-14 Aryl; R 5 and R 6 Independently for H and C 1-4 Alkyl, C 3-7 cycloalkyl, C 6-14 Aryl or -OC 1-4 alkyl; L represents a single bond or C represents a single bond. 1-4 Alkylene; R 7 For H, C 3-7 cycloalkyl or C 6-14 Aryl. The method for preparing the compound as shown in Formula A7 according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The C 1-4 Alkyl and -OC 1-4 C in alkyl 1-4 Each alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; for example, methyl; (2) The C 3-7 Each cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example, cyclopropyl or cyclobutyl; (3) The C 6-14 Each aryl group can be anthracene, naphthyl, or phenyl; (4) The C 1-4 The alkylene group is methylene. For example, methylene; (5) In step S10, the cyclization reaction is carried out under the protection of an inert gas and / or nitrogen; for example, the inert gas is argon; preferably, the cyclization reaction is carried out under the protection of nitrogen. (6) In step S10, the organic solvent is a chloroalkane solvent and / or an ether solvent, such as an ether solvent; the chloroalkane solvent may be selected from one or more of dichloromethane, 1,2-dichloroethane and chloroform, such as dichloromethane; the ether solvent may be selected from one or more of 1,4-dioxane, tetrahydrofuran and methyltetrahydrofuran, such as 1,4-dioxane; (7) In step S10, the molar volume ratio of the compound as shown in formula A6-2 to the solvent is (0.05-5) mol:1L, for example 0.1 mol:1L or 0.3 mol:1L; (8) In step S10, the cyclizing agent is selected from one or more of N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide dinepentyl acetal, tert-butoxybis(dimethylamino)methane, N,N-dimethylformamide ditert-butyl acetal, N,N-dimethylformamide diethyl acetal and 1,1-diisopropoxytrimethylamine, for example N,N-dimethylformamide dimethyl acetal; (9) In step S10, the molar ratio of the cyclizing agent to the compound shown in formula A6-2 is (1-20):1, for example (5-15):1, or even 10:1; (10) In step S10, the temperature of the cyclization reaction is 40-80°C, for example 50°C; (11) In step S10, after the cyclization reaction is completed, the following post-processing steps are also included. The post-processing steps include one or more of concentration and purification. The concentration can be vacuum distillation. The purification can be column chromatography. The eluent for column chromatography can be dichloromethane / methanol, for example, with a volume ratio of (20-30):

1. Preferably, the method for preparing the compound as shown in Formula A7 satisfies one or more of the following conditions: (1)R 1 R 2 R 3 R 5 and R 6 For H; (2)R 2 C 1-4 Alkyl; for example, methyl; (3) L is C 1-4 Alkylene; for example, methylene; (4)R 7 C 3-7 Cycloalkyl; for example, cyclopropyl or cyclobutyl; More preferably, in step S10, the compound shown in formula A6-2 is The compound shown in Formula A7 is Alternatively, the compound shown in Formula A6-2 is The compound shown in Formula A7 is The method for preparing the compound as shown in Formula A7 according to claim 1, characterized in that, The method for preparing the compound shown in Formula A7 further includes a method for preparing the compound shown in Formula A6-2, wherein... The process includes the following step S9: Under the action of a reducing agent and a Lewis acid, the compound shown in formula A6-1 undergoes a reduction reaction in an organic solvent as shown in the following formula to obtain the compound shown in formula A6-2. *, L, R 1 R 2 R 3 R 5 R 6 and R 7 The definition is as described in claim 1 or 2; Preferably, step S9 satisfies one or more of the following conditions: (1) In step S9, the organic solvent is an alcohol solvent, for example, the organic solvent is selected from one or more of methanol, ethanol and isopropanol, for example, ethanol; (2) In step S9, the molar volume ratio of the compound as shown in formula A6-1 to the organic solvent is (0.1-2) mol:1L, for example 0.3 mol:1L; (3) In step S9, the reducing agent is selected from one or more of alkali metal borohydrides, lithium aluminum hydride, diisobutyl aluminum hydride and sodium dihydrobis(dimethoxyethoxy)aluminate, for example, alkali metal borohydrides; the alkali metal borohydrides can be selected from one or more of sodium borohydride, lithium borohydride and potassium borohydride, for example, sodium borohydride; (4) In step S9, the molar ratio of the reducing agent to the compound shown in formula A6-1 is (1-5):1, for example (1-3):1, or for example 2:1; (5) In step S9, the Lewis acid is selected from one or more of indium trichloride, aluminum trichloride, boron trichloride, cerium trichloride and boron trifluoride, such as cerium trichloride; the cerium trichloride may be anhydrous cerium trichloride and / or cerium trichloride hydrate, such as cerium trichloride hydrate, or cerium trichloride heptahydrate; (6) In step S9, the molar ratio of the Lewis acid to the compound shown in formula A6-1 is (1-5):1, for example (1-3):1, or for example 1:1; (7) In step S9, the temperature of the reduction reaction is 10-30℃, for example 25℃; (8) Step S9 includes the following steps: dissolving the compound as shown in Formula A6-1 in the organic solvent to form a mixture solution, adding the Lewis acid to the mixture solution and stirring, and then adding the reducing agent to carry out a reduction reaction; The Lewis acid is preferably added at 25°C; the reducing agent is preferably added at 0°C. (9) After the reduction reaction is completed, a post-processing step is also included, which includes one or more of quenching, extraction, drying and concentration; the solvent for quenching may be water; the solvent for extraction may be ethyl acetate; the drying agent may be anhydrous sodium sulfate; the concentration may be vacuum distillation. (10) The compound shown in Formula A6-1 is The method for preparing the compound as shown in Formula A7 according to claim 3, characterized in that, The method for preparing the compound shown in Formula A6-2 further includes a method for preparing the compound shown in Formula A6-1, wherein... The process includes the following step S8: Under the action of acid, the compound represented by formula A6 undergoes a hydrolysis reaction in a solvent as shown in the following formula to obtain the compound represented by formula A6-1. Among them, R 4 Each independently is C 1-4 Alkyl, C 6-14 aryl or aryl with one or more R 4a Replacement C 6-14 Aryl; R 4a Each independently is C 1-4 Alkyl or -OC 1-4 alkyl; L, R 1 R 2 R 3 R 5 R 6 and R 7 The definition is as described in claim 1 or 2; Preferably, step S8 satisfies one or more of the following conditions: (1) In step S8, the solvent is water and / or an alcohol solvent, such as water; the alcohol solvent may be methanol and / or ethanol; (2) In step S8, the molar volume ratio of the compound as shown in formula A6 to the solvent is (0.1-5) mol:1L, for example 1.3 mol:1L, 1.7 mol:1L or 1 mol:1L; (3) In step S8, the acid is selected from one or more of trifluoroacetic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid and trifluoromethanesulfonic acid, such as hydrochloric acid and / or trifluoroacetic acid, or trifluoroacetic acid; (4) In step S8, the molar ratio of the acid to the compound shown in formula A6 is (5-500):1, for example (10-100):1, or for example 24:1, 33:1 or 42:1; (5) In step S8, the temperature of the hydrolysis reaction is -5 to 100℃; R 4 Each independently is C 1-4 When alkyl groups are involved, the hydrolysis reaction can be carried out at a temperature of 50-100°C; for example, 80°C; R 4 Each independently is C 6-14 When aryl is used, the hydrolysis reaction can be carried out at a temperature of 10-30°C, for example, 25°C; (6) After the hydrolysis reaction is completed, the following post-processing steps may be included, including one or more of filtration, concentration and purification; the concentration may be vacuum distillation; the purification may be crystallization, and the solvent for crystallization may be dichloromethane; (7)R 4 Each independently is C 1-4 Alkyl or C 6-14 Aryl, for example R 4 Each can be independently phenyl or methyl, for example R 4 Simultaneously, it is either phenyl or R 4 It is also methyl; Preferably, the compound shown in Formula A6 is Or the compound shown in Formula A6 is The method for preparing the compound as shown in Formula A7 according to claim 4, characterized in that, The method for preparing the compound shown in Formula A6-1 further includes a method for preparing the compound shown in Formula A6, wherein... The process includes the following step S7: In the presence of a base, the compound shown in formula A5-1 and the compound shown in formula T3 undergo a substitution reaction in a solvent as shown in the following formula to obtain the compound shown in formula A6. Where X is a halogen, -OTf, -OAc or -OMs; L and R 7 The definition satisfies any of the following conditions: (1) L is C 1-4 Alkylene, R 7 For H, C 3-7 cycloalkyl or C 6-14 Aryl; (2) L is a single bond, R 7 C 3-7 cycloalkyl or C 6-14 Aryl; R 1 R 2 R 3 R 5 and R 6 The definition is as described in claim 1 or 2; R 4 The definition is as described in claim 4; Preferably, step S7 satisfies one or more of the following conditions: (1) In step S7, the substitution reaction is carried out under the protection of an inert gas and / or nitrogen; for example, the inert gas is argon; preferably, the substitution reaction is carried out under the protection of nitrogen. (2) In step S7, the solvent is a benzene solvent, a nitrile solvent, a pyrrolidone solvent, or an amide solvent, such as a benzene solvent or a nitrile solvent; the benzene solvent may be selected from one or more of toluene, xylene, and mesitylene, such as toluene; the nitrile solvent may be acetonitrile; the pyrrolidone solvent may be N-methylpyrrolidone; the amide solvent may be N,N-dimethylacetamide and / or N,N-dimethylformamide; (3) In step S7, the molar volume ratio of the compound as shown in formula A5-1 to the solvent is (0.01-0.5) mol:1L, for example 0.25 mol:1L, 0.3 mol:1L or 0.4 mol:1L; (4) In step S7, X is F, Cl, Br or I, for example Br; for example, the compound shown in formula T3 is iodomethane, iodoethane, cyclopropylmethyl bromide, cyclobutylmethyl iodide, bromomethylcyclobutane, cyclopentylmethyl bromide or cyclohexylmethyl bromide, or for example cyclopropylmethyl bromide or bromomethylcyclobutane. (5) In step S7, the molar ratio of the compound shown in formula T3 to the compound shown in formula A5-1 is (1-5):1, for example 2:1 or 4:

1. (6) In step S7, the base is an organic base and / or an inorganic base, such as an inorganic base; the organic base may be an organic amine, such as triethylamine; the inorganic base may be selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate or cesium carbonate, such as potassium bicarbonate or sodium bicarbonate. (7) In step S7, the molar ratio of the base to the compound shown in formula A5-1 is (1-10):1, for example (2-5):1, or for example 2:1 or 3:1; (8) In step S7, the temperature of the substitution reaction is 50-120°C, for example 80°C or 100°C; (9) In step S7, after the substitution reaction is completed, the following post-processing steps are also included, which include one or more of extraction, drying, concentration and purification; the solvent for extraction can be ethyl acetate; the drying agent can be anhydrous sodium sulfate; the concentration can be vacuum distillation; the purification can be column chromatography, for example, the column chromatography eluent is dichloromethane and methanol; (10) In step S7, the compound shown in formula A5-1 is The compound shown in Formula T3 is cyclopropylmethyl bromide; or the compound shown in Formula A5-1 is... The compound shown in Formula T3 is bromomethylcyclobutane. The method for preparing the compound as shown in Formula A7 according to claim 5, characterized in that, The method for preparing the compound shown in Formula A6 further includes a method for preparing the compound shown in Formula A5-1, which includes the following step S6: under the action of a deprotecting agent, the compound shown in Formula A5 undergoes a deprotection reaction in a solvent as shown in the following formula to obtain the compound shown in Formula A5-1. Where R is C 1-10 Alkyl, C 3-10 cycloalkyl, C 6-12 Aryl or -C 1-4 Alkylene-C 6-12 Aryl; R 1 R 2 R 3 R 5 and R 6 The definition is as described in claim 1 or 2; R 4 The definition is as described in claim 4; Preferably, step S6 satisfies one or more of the following conditions: (1) In step S6, the solvent is an ester solvent and / or an alcohol solvent, for example, the solvent is a mixture of an ester solvent and an alcohol solvent; the ester solvent may be ethyl acetate; the alcohol solvent may be methanol or ethanol, for example, methanol; (2) In step S6, the molar volume ratio of the compound as shown in formula A5 to the solvent is (0.01-1) mol:1L, for example 0.2 mol:1L or 0.3 mol:1L; (3) In step S6, the deprotection reagent is an acid or a base; the acid can be selected from one or more of HCl, H2SO4, CH3COOH, H3PO4, trifluoroacetic acid and methanesulfonic acid, such as HCl; the base can be selected from one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide and sodium tert-butoxide; when the solvent is a mixed solvent of ester solvent and alcohol solvent, the alcohol solvent and the deprotection reagent are added to the reaction system in the form of a deprotection reagent solution, such as a methanol solution of HCl; (4) In step S6, the molar ratio of the deprotecting agent to the compound shown in Formula A5 is (1-100):1, for example (3-10):1, or for example 5:1 or 6.5:1; (5) In step S6, the temperature of the deprotection reaction is -10 to 20°C, for example, 0°C; (6) In step S6, after the deprotection reaction is completed, the following post-processing steps are also included, which include one or more of quenching, extraction, drying and concentration; the quenching reagent may be an aqueous solution of Na2CO3; the extraction solvent may be ethyl acetate; the drying agent may be anhydrous sodium sulfate; the concentration may be vacuum distillation; (7) R is C 1-4 Alkyl, C 3-6 cycloalkyl, C 6-12 Aryl or -C 1-4 Alkylene-C 6-12 Aryl; for example, R is C 1-4 Alkyl or -C 1-4 Alkylene-C 6-12 Aryl, such as tert-butyl or benzyl, and tert-butyl; Preferably, in step S6, the compound shown in formula A5 is The method for preparing the compound as shown in Formula A7 according to claim 6, characterized in that, The compound shown in Formula A5-1 also includes a method for preparing the compound shown in Formula A5, wherein... The process includes the following step S5: In the presence of a palladium catalyst, a phosphine ligand as shown in Formula T2, and a base, the compound shown in Formula A4 undergoes a dearomatization reaction in an organic solvent as shown in the following formula to obtain the compound shown in Formula A5: Among them, R 11 R 12 and R 13 Independently for C 1-10 Alkyl, C 1-10 cycloalkyl or with one or more C 1-4 Alkyl-substituted C 3-10 cycloalkyl; R 1 R 2 R 3 R 5 and R 6 The definition is as described in claim 1 or 2; R 4 The definition of R is as described in claim 4; the definition of R is as described in claim 6; Preferably, step S5 satisfies one or more of the following conditions: (1) In step S5, the dearomatization reaction is carried out under the protection of an inert gas and / or nitrogen; for example, the inert gas is argon; preferably, the dearomatization reaction is carried out under the protection of nitrogen. (2) In step S5, the organic solvent is a sulfoxide solvent, an amide solvent, or a coal tar solvent, such as an amide solvent; the amide solvent may be selected from one or more of N-pyrrolidone, N,N-dimethylformamide, and N,N-dimethylacetamide, such as N,N-dimethylacetamide; the coal tar solvent may be selected from one or more of toluene, xylene, trimethylbenzene, and nitrotoluene; (3) In step S5, the molar volume ratio of the compound as shown in formula A4 to the organic solvent is (0.01-0.5) mol:1L, for example 0.2 mol:1L; (4) In step S5, the palladium catalyst is selected from one or more of 1,5-cyclooctadiene palladium chloride, tris(benzylacetone)palladium chloride, bis(acetonitrile)palladium chloride, palladium chloride, palladium trifluoromethanesulfonate and palladium acetate, for example palladium chloride; (5) In step S5, the molar ratio of the palladium catalyst to the compound shown in Formula A4 is (0.01-0.5):1, for example 0.02:1; (6)R 11 R 12 and R 13 Independently for C 1-10 Alkyl or C 1-10 Cycloalkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, such as tert-butyl, n-butyl, cyclobutyl or adamantyl. Preferably, the phosphine ligand represented by Formula T2 is one or more of the following: di-tert-butylcyclobutylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, diadamantyl-n-butylphosphine, diadamantyl-isopropylphosphine, diadamantyl-propylphosphine, diadamantyl-cyclopropylphosphine, diadamantyl-cyclobutylphosphine, diadamantyl-cyclopentylphosphine, diadamantyl-cyclohexylphosphine, and diadamantyl-cycloheptylphosphine; for example, di-tert-butylcyclobutylphosphine. (7) In step S5, the molar ratio of the phosphine ligand shown in formula T2 to the compound shown in formula A4 is (0.01-0.5):1, for example (0.01-0.1):1, or for example 0.03:1; (8) In step S5, the base is an inorganic base; the inorganic base may be selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate and potassium phosphate, for example, potassium carbonate; (9) In step S5, the molar ratio of the base to the compound shown in formula A4 is (1-10):1, for example (1-3):1, or for example 1.5:1; (10) In step S5, the temperature of the dearomatic cyclization reaction is 80℃-180℃, for example 120℃-170℃, or for example 150℃; (11) In step S5, after the dearomatic cyclization reaction is completed, the following post-processing steps are also included, which include one or more of extraction, drying, concentration and purification; the solvent for extraction can be ethyl acetate; the drying agent can be anhydrous sodium sulfate; the concentration can be vacuum distillation; the purification can be column chromatography. (12) The compound shown in Formula A4 is The method for preparing the compound as shown in Formula A7 according to claim 7, characterized in that, The method for preparing the compound shown in Formula A5 further includes a method for preparing the compound shown in Formula A4, which includes the following step S4: under the action of a base, the compound shown in Formula A3-2 and the compound shown in Formula T1 undergo a substitution reaction in a solvent as shown in the following formula to obtain the compound shown in Formula A4. Where: R a Halogen or R 1 R 2 R 3 R 5 and R 6 The definition is as described in claim 1 or 2; R 4 The definition of R is as described in claim 4; the definition of R is as described in claim 6; Preferably, step S4 satisfies one or more of the following conditions: (1) In step S4, the solvent is an organic solvent or a mixture of an organic solvent and water, for example, a mixture of an organic solvent and water; the organic solvent may be a chloroalkane solvent, a coal tar solvent, or an amide solvent, for example, a chloroalkane solvent; the chloroalkane solvent may be selected from one or more of dichloromethane, 1,2-dichloroethane, and chloroform, for example, dichloromethane; the coal tar solvent may be selected from one or more of toluene, xylene, or mesitylene; the amide solvent is N-methylpyrrolidone and / or N,N-dimethylacetamide; when the solvent is a mixture of an organic solvent and water, the volume ratio of the organic solvent to water is (1-10):1, for example (1-8):1, or for example 2.5:1 or 5:1; (2) In step S4, the molar volume ratio of the compound shown in formula A3-2 to the solvent is (0.01-1) mol:1L, for example 0.15 mol:1L or 0.3 mol:1L; (3) In step S4, R a It is chlorine; (4) In step S4, the compound shown in formula T1 is benzyl chloroformate, phenyl chloroformate, methyl chloroformate, ethyl chloroformate or di-tert-butyl dicarbonate, for example di-tert-butyl dicarbonate. (5) In step S4, the molar ratio of the compound shown in formula T1 to the compound shown in formula A3-2 is (1-3):1, for example 1.2:1; (6) In step S4, the base is an inorganic base; the inorganic base may be selected from one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and cesium carbonate, such as sodium bicarbonate; (7) In step S4, the molar ratio of the base to the compound shown in formula A3-2 is (1-10):1, for example (1-5):1, or for example 2:1; (8) In step S4, the temperature of the substitution reaction is 20-35°C, for example 25°C; (9) In step S4, after the substitution reaction is completed, the following post-processing steps are also included, which include one or more of extraction, drying, concentration and purification; the solvent for extraction may be ethyl acetate; the drying agent may be anhydrous sodium sulfate; the concentration may be vacuum distillation; the purification may be crystallization, for example, using isopropanol crystallization; (10) In step S4, the compound shown in formula A3-2 is The method for preparing the compound as shown in Formula A7 according to claim 8, characterized in that, The method for preparing the compound shown in Formula A4 also includes a method for preparing the compound shown in Formula A3-2, wherein... The process includes the following steps, S3: the compound shown in formula A3-1 undergoes a halogenation reaction with a halogenating agent in an organic solvent, followed by an elimination reaction under the action of a base, and finally an asymmetric transfer hydrogenation catalytic reaction under the action of a hydrogen source and a catalyst to obtain the compound shown in formula A3-2. R 1 R 2 R 3 R 5 and R 6 The definition is as described in claim 1 or 2; R 4 The definition is as described in claim 4; Preferably, step S3 satisfies one or more of the following conditions: (1) In step S3, the organic solvent is an ether solvent and / or an alcohol solvent, such as an ether solvent; the ether solvent may be selected from one or more of tetrahydrofuran, 1,4-dioxane, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether or anisole, such as tetrahydrofuran; (2) In step S3, the molar volume ratio of the compound as shown in formula A3-1 to the organic solvent is (0.01-1) mol:1L, for example 0.2 mol:1L; (3) In step S3, the halogenated reagent is N-chlorosuccinimide, N-bromosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin or trichloroisocyanuric acid, such as N-chlorosuccinimide; (4) In step S3, the molar ratio of the halogenated reagent to the compound shown in formula A3-1 is (0.9-1.5):1, for example 1:1; (5) In step S3, the temperature of the halogenation reaction is -10 to 20°C, for example, 0°C; (6) In step S3, the base is an inorganic base; for example, the inorganic base is selected from one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide and sodium methoxide, and potassium hydroxide is another example. (7) In step S3, the molar ratio of the base to the compound shown in formula A3-1 is (1-10):1, for example (1-5):1, or for example 2:1; (8) In step S3, the temperature of the elimination reaction is 0-35°C, for example 20°C; (9) In step S3, the hydrogen source is a mixed solvent of formic acid and triethylamine; for example, the molar ratio of formic acid and triethylamine is (0.5-5):1, such as 2.5:1 or 1:1; preferably, the molar volume ratio of the compound shown in formula A3-1 to the hydrogen source is (0.5-10) mol:1L, such as (0.5-3) mol:1L, or for example 0.9:1 or 1.2:1; (10) In step S3, the catalyst is a Noyori-type transfer hydrogenation catalyst, for example, the catalyst is selected from any of the following: For example, a catalyst as shown in formula ATH-01; (11) In step S3, the molar ratio of the catalyst to the compound shown in formula A3-1 is (0.0001-0.5):1, for example (0.001-0.1):1, or even 0.01:1; (12) In step S3, the temperature of the asymmetric transfer hydrogenation catalytic reaction is 0-35°C, for example 25°C; (13) In step S3, after the asymmetric transfer hydrogenation catalytic reaction is completed, the following post-processing steps are also included, which include one or more of extraction, drying, concentration and purification; the solvent for extraction can be ethyl acetate; the drying agent can be anhydrous sodium sulfate; the concentration can be vacuum distillation; the purification can be column chromatography or crystallization. (14) The compound shown in Formula A3-1 is The method for preparing the compound as shown in Formula A7 according to claim 9, characterized in that, The method for preparing the compound shown in Formula A3-2 further includes a method for preparing the compound shown in Formula A3-1, wherein... The process includes the following step S2: Under the action of a deprotecting agent, the compound shown in Formula A3 undergoes a deprotection reaction in a solvent as shown in the following formula to obtain the compound shown in Formula A3-1. R 1 R 2 R 3 R 5 and R 6 The definition is as described in claim 1 or 2; R 4 The definition of R is as described in claim 4; the definition of R is as described in claim 6; Preferably, step S2 satisfies one or more of the following conditions: (1) In step S2, the solvent is an ester solvent and / or an alcohol solvent, for example, the solvent is a mixture of an ester solvent and an alcohol solvent; the ester solvent may be ethyl acetate; the alcohol solvent may be methanol or ethanol, for example, methanol; (2) In step S2, the molar volume ratio of the compound as shown in formula A3 to the solvent is (0.01-1) mol:1L, for example 0.2 mol:1L or 0.3 mol:1L; (3) In step S2, the deprotection reagent is an acid or a base; the acid can be selected from one or more of HCl, H2SO4, CH3COOH, H3PO4, trifluoroacetic acid and methanesulfonic acid, such as HCl; the base can be selected from one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide and sodium tert-butoxide; when the solvent is a mixed solvent of ester solvent and alcohol solvent, the alcohol solvent and the deprotection reagent are added to the reaction system in the form of a deprotection reagent solution, such as a methanol solution of HCl; (4) In step S2, the molar ratio of the deprotecting agent to the compound shown in formula A3 is (1-100):1, for example (3-10):1, or for example 5:1 or 6:1; (5) In step S2, the temperature of the deprotection reaction is -10 to 20°C, for example, 0°C; (6) In step S2, after the deprotection reaction is completed, the following post-processing steps are also included, which include one or more of quenching, extraction, drying, concentration and purification; the quenching reagent can be an aqueous solution of Na2CO3; the extraction solvent can be ethyl acetate; the drying agent can be anhydrous sodium sulfate; the concentration can be vacuum distillation; the purification can be crystallization; for example, using n-heptane crystallization; (7) The compound shown in Formula A3 is The method for preparing the compound as shown in Formula A7 according to claim 10, characterized in that, The method for preparing the compound shown in formula A3-1 further includes a method for preparing the compound shown in formula A3, which includes the following step S1: Under the action of acid, the compound shown in formula A1 and the compound shown in formula A2 undergo a condensation cyclization reaction as shown in the following formula in an organic solvent to obtain the compound shown in formula A3. Among them, R 1 R 2 R 3 R 5 and R 6 The definition is as described in claim 1 or 2; R 4 The definition of R is as described in claim 4; the definition of R is as described in claim 6; Preferably, step S1 satisfies one or more of the following conditions: (1) In step S1, the organic solvent is a chloroalkane solvent and / or an amide solvent, such as a chloroalkane solvent; the chloroalkane solvent may be selected from one or more of dichloromethane, 1,2-dichloroethane and chloroform, such as dichloromethane; (2) In step S1, the molar volume ratio of the compound as shown in formula A1 to the organic solvent is (0.1-5) mol:1L, for example (0.1-1) mol:1L, or for example 0.4 mol:1L; (3) In step S1, the molar ratio of the compound shown in formula A2 to the compound shown in formula A1 is (1-3):1, for example 1.2:1; (4) In step S1, the acid is selected from one or more of methanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, sulfuric acid, phosphoric acid and camphorsulfonic acid, for example camphorsulfonic acid; (5) In step S1, the molar ratio of the acid to the compound shown in formula A1 is (1-5):1, for example (1-3):1, or even 1.5:1; (6) In step S1, the temperature of the condensation cyclization reaction is 0-30°C, for example 25°C; (7) In step S1, after the condensation cyclization reaction is completed, the following post-processing steps are also included. The post-processing steps include one or more of quenching, drying, concentration and purification. The solvent for quenching can be an aqueous solution of Na2CO3. The drying agent can be anhydrous sodium sulfate. The concentration can be vacuum distillation. The purification can be recrystallization. The solvent for recrystallization can be n-heptane. (8) The compound shown in formula A1 is The compound shown in formula A2 is The method for preparing the compound as shown in Formula A7 according to claim 11, characterized in that, The method for preparing the compound shown in formula A3 further includes a method for preparing the compound shown in formula A2, which includes the following steps S1-2d: under the action of a base and a Wittig reagent, the compound shown in formula A2-3 undergoes a Wittig reaction in an organic solvent as shown in the following formula to obtain the compound shown in formula A2. Wherein, the Wittig reagent is methoxymethyltriphenylphosphine chloride or methoxymethyltriphenylphosphine bromide, R 5 and R 6 The definition is as described in claim 1 or 2; R 4 The definition is as described in claim 4; Preferably, steps S1-2d satisfy one or more of the following conditions: (1) In steps S1-2d, the organic solvent is an ether solvent or a coal tar solvent, such as a coal tar solvent; the ether solvent may be selected from one or more of tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether and diethyl ether; the coal tar solvent may be selected from one or more of toluene, xylene and trimethylbenzene, such as toluene; (2) In steps S1-2d, the molar volume ratio of the compound shown in formula A2-3 to the organic solvent is (0.01-0.5) mol:1L, for example 0.3 mol:1L; (3) In steps S1-2d, the Wittig reagent is methoxymethyltriphenylphosphine chloride; (4) In steps S1-2d, the molar ratio of the Wittig reagent to the compound shown in formula A2-3 is (1-5):1, for example (1-2):1, or even 1.5:1; (5) In steps S1-2d, the base is an inorganic base; the inorganic base may be sodium tert-butoxide, potassium tert-butoxide, potassium tert-pentoxide or potassium neopentoxide, for example, potassium tert-butoxide; (6) In steps S1-2d, the molar ratio of the base to the compound shown in formula A2-3 is (1-5):1, for example (1-2):1, or even 1.5:1; (7) In steps S1-2d, the temperature of the Wittig reaction is 0-30°C, for example 25°C; (8) In steps S1-2d, after the Wittig reaction is completed, the following post-processing steps are also included, which include one or more of extraction, concentration and purification; the solvent for extraction can be ethyl acetate; the drying agent can be anhydrous sodium sulfate; the concentration can be vacuum distillation; the purification can be column chromatography. (9) The compound shown in formula A2-3 is The method for preparing the compound as shown in Formula A7 according to claim 12 is characterized in that, The method for preparing the compound shown in formula A2 further includes a method for preparing the compound shown in formula A2-3, which includes the following steps S1-2c: under the action of a catalyst, the compound shown in formula A2-2 and the compound shown in formula T1 undergo a substitution reaction as shown in the following formula in an organic solvent to obtain the compound shown in formula A2-3. Among them, R b Halogen or two R b Together they form an oxygen group, R 5 and R 6 The definition is as described in claim 1 or 2; R 4 The definition is as described in claim 4; Preferably, steps S1-2c satisfy one or more of the following conditions: (1) In steps S1-2c, the organic solvent is a nitrile solvent, a coal tar solvent, or an amide solvent, such as a nitrile solvent or a coal tar solvent; the nitrile solvent may be selected from one or more of acetonitrile, propionitrile, and butyronitrile, such as acetonitrile; the coal tar solvent may be selected from one or more of toluene, xylene, and trimethylbenzene, such as toluene; the amide solvent is N,N-dimethylformamide and / or N,N-dimethylacetamide; (2) In step S1-2c, the molar volume ratio of the compound as shown in formula A2-2 to the organic solvent is (0.1-1) mol:1L, for example 0.5 mol:1L or 0.6 mol:1L; (3) In steps S1-2c, the two R b Together they form an oxo group, for example, the compound shown in Formula T1 is dibenzyl ketone, 4,4'-dimethoxybenzophenone or 4,4'-dimethoxybenzyl ketone, benzophenone, acetone or pentanone, for example acetone; the catalyst can be an acidic oxide, for example phosphorus pentoxide; the molar ratio of the catalyst to the compound shown in Formulas A2-3 can be (1-8):1, for example (1-5):1, or for example 2:1; (4) In step S1-2c, R b Each component is independently a halogen, for example, the compound shown in formula T1 is diphenyl dichloromethane; the catalyst can be an inorganic base; for example, the inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, or potassium hydroxide, or potassium carbonate; the molar ratio of the catalyst to the compound shown in formulas A2-3 can be (1-8):1, for example (1-5):1, or for example 2.5:1; (5) In step S1-2c, the molar ratio of the compound shown in formula T1 to the compound shown in formula A2-2 is (1-5):1, for example (1-2):1, or even 1:1; (6) The compound shown in formula A2-2 is A method for preparing a compound as shown in formula A9 or formula A13, characterized in that, It includes the following steps S10, S11 and S12: S10: Under the action of a cyclizing agent, the compound shown in formula A6-2 undergoes a cyclization reaction in an organic solvent as shown in the following formula to give the compound shown in formula A7. S11: Under the action of acid, the compound shown in Formula A7 undergoes an acidification reaction to obtain an acidification reaction product, and then under the action of an oxidizing agent, the acidification reaction product is oxidized in a solvent to obtain the compound shown in Formula A8. S12 is selected from either Option 1 or Option 2: Option 1: Under the action of a catalyst, the compound shown in Formula A8 undergoes a hydrogenation reaction with hydrogen in an organic solvent as shown in the following formula to obtain the compound shown in Formula A9. Option 2 involves the compound of formula A8 undergoing a reduction reaction with hydrogen in an organic solvent under the action of a catalyst, as shown in the following formula, to obtain the compound of formula A13. *, L, R 1 R 2 R 3 R 5 R 6 and R 7 The definition is as described in claim 1 or 2; the operations and conditions in step S10 may also be as described in claim 1 or 2. The method for preparing the compound as described in claim 14, as shown in formula A9 or formula A13, is characterized in that, It meets one or more of the following conditions: (1) In step S12, the organic solvent is an alcohol solvent and / or an ester solvent; the alcohol solvent may be methanol and / or ethanol, for example, methanol; the ester solvent may be ethyl acetate; preferably, in Scheme 1, the solvent is an ester solvent; in Scheme 2, the solvent is an alcohol solvent; (2) In step S12, the molar volume ratio of the compound as shown in formula A8 to the organic solvent is (0.01-1) mol:1L, for example 0.1 mol:1L or 0.2 mol:1L; (3) In step S12, the catalyst is Raney nickel and / or palladium catalyst, such as palladium catalyst, or for example 10% palladium on carbon, where "%" is the mass percentage of palladium to the total mass of palladium and carbon; (4) In step S12, the mass percentage of the catalyst to the compound shown in Formula A8 is 30-50%, for example 20%; (5) In step S12, in scheme 1, the pressure of the hydrogenation reaction is 1-5 atm, for example 2 atm; (6) In step S12, in scheme 2, the pressure of the reduction reaction is 10-30 atm, for example 20 atm; (7) In step S12, in scheme 1, the temperature of the hydrogenation reaction is 20-35°C, for example 25°C; (8) In step S12, in scheme 2, the temperature of the hydrogenation reaction is 20-35°C, for example 30°C; (9) In step S12, after the hydrogenation reaction or reduction reaction is completed, the following post-processing steps are further included, the post-processing steps include one or more of filtration and purification; the purification may be column chromatography. (10) The compound shown in Formula A8 is The compound shown in Formula A9 is Or the compound shown in formula A8 is The compound shown in Formula A13 is (11) In step S11, the acid is an organic acid, such as one or more selected from acetic acid and formic acid, such as acetic acid; (12) In step S11, the molar volume ratio of the compound as shown in formula A7 to the acid is (0.1-5) mol:1L, for example 0.3 mol / L; (13) In step S11, the solvent is the acid or a mixture of the acid and water; (14) In step S11, the oxidant is hydrogen peroxide and / or m-chloroperoxybenzoic acid, for example, hydrogen peroxide; when the oxidant is hydrogen peroxide, the solvent is a mixed solvent of the acid and water, and the hydrogen peroxide and the water are added to the oxidation reaction system in the form of an aqueous hydrogen peroxide solution, for example, the mass percentage of hydrogen peroxide in the aqueous hydrogen peroxide solution is 20-50%, for example, 35%; (15) In step S11, the molar ratio of the oxidant to the compound shown in Formula A7 is (1-10):1, for example (4-7):1, or for example 5.5:1; (16) In step S11, the temperature of the oxidation reaction is 10-30°C, for example 25°C; (17) In step S11, after the oxidation reaction is completed, the following post-processing steps are further included, which include one or more of quenching reaction, extraction, drying, concentration and purification; the reagent for quenching reaction may be sodium sulfite solution; the solvent for extraction may be ethyl acetate; the drying agent may be anhydrous sodium sulfate; the concentration may be vacuum distillation; the purification may be column chromatography. (18) In step S11, the compound shown in formula A7 is A method for preparing a compound as shown in Formula A12, characterized in that, It includes the following steps S10, S11', S12' and S13: S10: Under the action of a cyclizing agent, the compound shown in formula A6-2 undergoes a cyclization reaction in an organic solvent as shown in the following formula to give the compound shown in formula A7. S11': The compound shown in Formula A7 undergoes a cycloaddition reaction with the compound shown in Formula T4 as shown in the following formula to give the compound shown in Formula A10. S12': Under the action of a nucleophile, the compound shown in formula A10 undergoes a nucleophilic addition reaction in an organic solvent as shown in the following formula to give the compound shown in formula A11; S13: Under the action of a catalyst, the compound shown in Formula A11 undergoes a hydrogenation reaction with hydrogen in an organic solvent as shown in the following formula to obtain the compound shown in Formula A12. R 8 and R 9 Independently for H and C 1-10 Alkyl, C 3-7 cycloalkyl, C 6-14 aryl or 5-10 heteroaryl; the heteroatom of the 5-10 heteroaryl group is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R 10 C 1-10 Alkyl, C 3-7 cycloalkyl or C 6-14 Aryl; M is MgCl, MgBr, or Li; *, L, R 1 R 2 R 3 R 5 R 6 and R 7 The definition is as described in claim 1 or 2; the operations and conditions in step S10 may also be as described in claim 1 or 2. The method for preparing the compound as shown in Formula A12 according to claim 16 is characterized in that, It meets one or more of the following conditions: (1)R 8 It is H or a 5-10 heteroaryl group, such as H; R 9 It can be C 1-10 Alkyl, such as methyl; preferably, the compound shown in Formula T4 is methyl vinyl ketone or 4-(2-thienyl)but-3-en-2-one, such as methyl vinyl ketone; or, for example, the methyl vinyl ketone reacts with the compound shown in Formula A7 under solvent-free conditions; (2) In step S11', the molar ratio of the compound shown in formula T4 to the compound shown in formula A7 is (1-100):1, for example 10:1, or for example 50:1; (3) In step S11', the temperature of the cycloaddition reaction is 70-90℃, for example 80℃; (4) In step S11', after the cycloaddition reaction is completed, the following post-processing steps are also included, the post-processing steps include concentration and purification; the concentration can be vacuum distillation; the purification can be column chromatography; (5) The compound represented by formula A7 is The compound represented by formula A10 is (6) In step S12', the nucleophilic addition reaction is carried out under the protection of an inert gas and / or nitrogen; for example, the inert gas is argon; preferably, the nucleophilic addition reaction is carried out under the protection of nitrogen. (7) In step S12', M is MgCl or MgBr; R 10 It can be C 1-10 Alkyl group, such as tert-butyl; preferably, the nucleophile is tert-butylmagnesium chloride; (8) In step S12', the molar ratio of the nucleophile to the compound as shown in Formula A10 is (5-10):1, for example 7:1; (9) In step S12', the organic solvent is an ether solvent and / or an aromatic solvent, such as a mixed solvent of ether solvent and aromatic solvent; the ether solvent may be tetrahydrofuran; the aromatic solvent may be toluene; when the organic solvent is a mixed solvent of ether solvent and aromatic solvent, the volume ratio of the ether solvent and the aromatic solvent may be (1-5):(1-5), for example 1.7:1; the ether solvent may be added to the nucleophilic addition reaction system in the form of a mixed solution with the Grignard reagent; (10) In step S12', the molar volume ratio of the compound as shown in formula A10 to the organic solvent is (0.01-1) mol:1L, for example 0.1 mol:1L; (11) In step S12', the temperature of the nucleophilic addition reaction is -5 to 35°C, for example 10 to 30°C, or for example 25°C; (12) In step S12', after the nucleophilic addition reaction is completed, the following post-processing steps are also included, which include one or more of quenching, extraction, drying, concentration and purification; the quenching reagent may be water; the organic solvent for extraction may be ethyl acetate; the drying agent may be anhydrous sodium sulfate; the concentration may be vacuum distillation; the purification may be column chromatography. (12) The compound shown in formula A11 is (13) In step S13, the catalyst is Raney nickel and / or palladium catalyst, such as palladium catalyst, or for example 10% palladium on carbon, where "%" is the mass percentage of palladium to the total mass of palladium and carbon; (14) In step S13, the mass ratio of the catalyst to the compound as shown in Formula A11 is (0.03-0.2):1; for example, 0.1:1; (15) In step S13, the organic solvent is an ether and / or an alcohol solvent, such as an alcohol solvent; the alcohol solvent may be ethanol and / or isopropanol, such as isopropanol; (16) In step S13, the molar volume ratio of the compound as shown in formula A11 to the organic solvent is (0.01-1) mol: 1 L, for example 0.064 mol: 1 L; (17) In step S13, the hydrogenation reaction is carried out at a pressure of 5-30 atm, for example 10 atm; (18) In step S13, the temperature of the hydrogenation reaction is 10-35°C, for example 25°C; (19) In step S13, after the nucleophilic addition reaction is completed, the following post-processing steps are also included, the post-processing steps include one or more of filtration, concentration and purification; the concentration may be vacuum distillation; the purification may be column chromatography. (20) The compound shown in formula A12 is A method for preparing a compound as shown in Formula A7, characterized in that, It includes the following steps S1-2c, S1-2d and S1-S10. Alternatively, it includes the following steps S7-S10, Among them, "*", L, and R 1 R 2 R 3 R 5 R 6 and R 7 The definition is as described in claim 1 or 2; R 4 The definition of R is as described in claim 4, and the definition of R is as described in claim 6. b The definition is as described in claim 13. A method for preparing a compound as shown in Formula A6, characterized in that, It includes the following step S7: under alkaline conditions, the compound shown in formula A5-1 and the compound shown in formula T3 are subjected to a substitution reaction in a solvent as shown in the following formula to obtain the compound shown in formula A6. Where X is a halogen, -OTf, -OAc or -OMs; L and R 7 The definition satisfies any of the following conditions: (1) L is C 1-4 Alkylene, R 7 For H, C 3-7 cycloalkyl or C 6-14 Aryl; (2) L is a single bond, R 7 C 3-7 cycloalkyl or C 6-14 Aryl; R 1 R 2 R 3 R 5 and R 6 The definition is as described in claim 1 or 2; R 4 The definition is as described in claim 4; the operation and conditions of step S7 are as described in claim 5. A method for preparing a compound as shown in Formula A8, characterized in that, It includes the following step S11: Among them, L and R 1 R 2 R 3 R 5 and R 6 The definition of is as described in claim 1 or 2; the definition of R is as described in claim 6; the conditions and operations of step S11 are as described in claim 15; preferably, the method for preparing the compound as shown in formula A8 further includes the method for preparing the compound as shown in formula A7 as described in claim 1. A method for preparing a compound as shown in Formula A5-1, characterized in that, It includes the following step S6: Under the action of a deprotecting agent, the compound shown in Formula A5 undergoes a deprotection reaction in a solvent as shown in the following formula to obtain the compound shown in Formula A5-1. Where R is C 1-10 Alkyl, C 3-10 cycloalkyl, C 6-12 Aryl or -C 1-4 Alkylene-C 6-12 Aryl; R 1 R 2 R 3 R 5 and R 6 The definition is as described in claim 1 or 2; R 4 The definition is as described in claim 4; The operation and conditions for preparing the compound as shown in Formula A5-1 are as described in claim 6. A compound as shown in formulas A2-3, A2, A3, A3-1, A3-2, A4, A5, A5-1, A6, A6-1, and A6-2: in, *, L, R 1 R 2 R 3 R 5 R 6 and R 7 The definition is as described in claim 1 or 2; R 4 The definition of is as described in claim 4, and the definition of R is as described in claim 6; For example

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