Opioid derivatives, intermediates thereof and preparation methods thereof

Abstract

The present invention discloses an opioid derivative, an intermediate thereof and a preparation method thereof. The present invention provides a preparation method of a compound represented by formula A6. The preparation method comprises the following step S7: under the action of a palladium catalyst, a phosphine ligand represented by formula L1 and a base, carrying out the dearomatization cyclization reaction shown below on the compound represented by formula A5 in an organic solvent to obtain the compound represented by formula A6. By using the synthesis route and intermediate of the present invention, it is possible to prepare opioid compounds starting from cheap and easily available vanillin and isovanillin, providing the possibility for its large-scale production.

Description

Technical Field

[0001] The present invention relates to an opioid derivative, an intermediate thereof and a preparation method thereof. Background Art

[0002] Naltrexone, whose chemical structural formula is is a pure opioid receptor antagonist, which has blocking effects on μ-, δ-, and κ-opioid receptors, can significantly weaken or completely block opioid receptors and has a long action time. It is a type of oral drug approved by the FDA in 1984 and can be used to block dependence on opioid drugs and alcohol.

[0003] Buprenorphine, whose chemical structural formula is is a partial agonist of opioid receptors and has analgesic effects on postoperative pain, cancer-induced cancer pain, burns, angina pectoris or limb pain caused by over-fatigue, etc. Moreover, the drug has a long duration, generally 6 - 8 hours. At the same time, it can also be used for maintenance treatment of drug addiction and can break the sense of tension in the human body.

[0004] Structurally, the naltrexone molecule has a relatively complex pentacyclic skeleton and four consecutive chiral centers, while buprenorphine contains a more complex hexacyclic skeleton and has seven consecutive chiral centers. However, naltrexone and buprenorphine have similar main skeletons and can be divergently synthesized through a common intermediate. Currently, the synthesis of naltrexone and buprenorphine compounds is mainly semi-synthesis starting from the alkaloid thebaine extracted from opium poppy and achieved through further chemical transformation. There is no reported chemical synthesis method for preparing naltrexone and buprenorphine starting from common compounds as raw materials. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the above-mentioned defects in the prior art, and thus provides an opioid derivative, an intermediate thereof and a preparation method thereof.

[0006] On the one hand, the present invention provides a preparation method of a compound represented by formula A6, which comprises the following step S7:

[0007] Under the action of a palladium catalyst, a phosphine ligand represented by formula L1 and a base, carry out the following shown dearomatization cyclization reaction of the compound represented by formula A5 in an organic solvent to obtain the compound represented by formula A6, that's all.

[0008]

[0009] Wherein, R 1 and R 2 are independently H, C 1～10 alkyl, C 1～10Alkoxy, C 3～10 Cycloalkyl or C 6～20 Aryl;

[0010] R 3 Independently for C 1～7 Alkyl, C 3～7 Cycloalkyl or C 6～20 Aryl;

[0011] R 5 , R 6 and R 7 Independently for C 1～10 Alkyl, C 3～10 Substituted cycloalkyl or C 1～10 Alkyl substituted C 3～10 Substituted cycloalkyl.

[0012] In the method for preparing the compound represented by formula A6 (hereinafter referred to as step S7), the reaction conditions, reagent types and amounts of the dearomatization cyclization reaction may be conventional conditions, reagent types and amounts of this type of reaction in the art, and the present invention preferably has the following.

[0013] In step S7, the dearomatization cyclization reaction can be carried out under the protection of an inert gas. The inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, and also nitrogen.

[0014] In step S7, the palladium catalyst may be one or more of palladium chloride, bis(acetonitrile)palladium chloride, palladium trifluoromethanesulfonate and palladium acetate, for example, palladium chloride.

[0015] In step S7, the molar ratio of the palladium catalyst to the compound represented by formula A5 can be 0.01 to 0.5, for example, 0.1.

[0016] In step S7, the phosphine ligand represented by formula L1 may be one or more of tri-tert-butylphosphine, tricyclohexylphosphine and di(1-adamantyl)-n-butylphosphine, for example, di(1-adamantyl)-n-butylphosphine.

[0017] In step S7, the molar ratio of the phosphine ligand represented by formula L1 to the compound represented by formula A5 may be 0.01 to 0.5, for example, 0.1 to 0.5.

[0018] In step S7, the base may be an alkali metal carbonate, such as potassium carbonate.

[0019] In step S7, the organic solvent may be a sulfoxide solvent and / or an amide solvent, preferably an amide solvent. The amide may be N,N-dimethylformamide (DMF) and / or N,N-dimethylacetamide (DMA), preferably N,N-dimethylformamide.

[0020] In step S7, the amount of the organic solvent may not be specifically limited as long as the reaction is not affected. The volume-mass ratio of the organic solvent to the compound represented by formula A5 may be 5 to 100 mL / g, for example, 10 to 30 mL / g.

[0021] In step S7, the temperature of the dearomatizing cyclization reaction may be 80°C to 180°C, for example, 100°C to 130°C, and for another example, 120°C.

[0022] In step S7, the progress of the dearomatizing cyclization reaction can be monitored by conventional monitoring methods in the art (such as TLC or LCMS). Generally, the disappearance or non-reaction of the compound represented by formula A5 is taken as the end point of the reaction. The reaction time can be 8 to 24 hours, for example, 12 hours.

[0023] In step S7, after the dearomatizing cyclization reaction, the following post-treatment steps may further be included. The post-treatment steps can be conventional post-treatment operations for such reactions, for example, including one or more of extraction, drying, concentration, and purification. The solvent for the extraction can be dichloromethane. The drying can be drying with anhydrous sodium sulfate. The concentration can be distillation under reduced pressure. The purification can be column chromatography.

[0024] Step S7 may include the following steps: adding the organic solvent to a mixture of the palladium catalyst, the phosphine ligand represented by formula L1, the base, and the compound represented by formula A5, and carrying out the dearomatizing cyclization reaction.

[0025] In a certain embodiment of the present invention, R 1 may be H.

[0026] In a certain embodiment of the present invention, R 2 may be H.

[0027] In a certain embodiment of the present invention, R 3 may be C 3～7 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and for another example, cyclopropyl.

[0028] In a certain embodiment of the present invention, the compound represented by formula A6 is preferably

[0029] In a certain embodiment of the present invention, the compound represented by formula A5 is preferably

[0030] In a certain embodiment of the present invention, the preparation method of the compound represented by Formula A6 may further include the preparation method of the compound represented by Formula A5 below, which comprises the following Step S6: Under the action of a deprotection reagent, perform the following deprotection reaction on Formula A5-3 in an organic solvent to obtain the compound represented by Formula A5, that's all.

[0031]

[0032] Wherein, R 1 、R 2 and R 3 are as defined above, and P is a hydroxyl protecting group.

[0033] In a certain embodiment of the present invention, in the preparation method of the compound represented by Formula A5 (hereinafter referred to as Step S6), the reaction conditions, types of reagents and their dosages of the deprotection reaction can be the conventional conditions, types of reagents and their dosages for this type of reaction in the art. The present invention preferably uses the following.

[0034] In Step S6, the deprotection reaction can be carried out under the protection of an inert gas. The inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, or nitrogen for example.

[0035] In Step S6, the deprotection reagent can be tetrabutylammonium fluoride.

[0036] In Step S6, the molar ratio of the deprotection reagent to the compound represented by Formula A5-3 can be 1 to 5, such as 1.1.

[0037] In Step S6, the organic solvent can be an ether solvent and / or a chlorinated hydrocarbon solvent, preferably an ether solvent. The ether solvent can be one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether (MTBE), preferably tetrahydrofuran.

[0038] In Step S6, the dosage of the organic solvent may not be specifically limited as long as it does not affect the reaction. The volume-mass ratio of the organic solvent to the compound represented by Formula A5-3 can be 5 to 100 mL / g, such as 10 to 30 mL / g, or 23 mL / g for example.

[0039] In Step S6, the temperature of the deprotection reaction can be 10 to 50 °C, such as 20 to 35 °C.

[0040] In Step S6, the progress of the deprotection reaction can be monitored by conventional monitoring methods in the art (such as TLC or LCMS). Generally, when the compound represented by Formula A5-3 disappears or no longer reacts, it is taken as the end point of the reaction. The reaction time can be 1 to 5 hours, such as 1 hour.

[0041] In step S6, after the deprotection reaction, the following post-treatment steps may further be included. The post-treatment steps may be conventional post-treatment operations for such reactions, for example, including one or more of extraction, drying, concentration, and purification. The solvent for the extraction may be dichloromethane. The drying may be drying with anhydrous sodium sulfate. The concentration may be vacuum distillation. The purification may be column chromatography.

[0042] Step S6 may include the following steps: The compound represented by formula A5-3 is dissolved in the organic solvent to form a mixed solution, and the deprotection reagent is added to the mixed solution (preferably dropwise at 0 °C) to carry out the deprotection reaction.

[0043] In a certain embodiment of the present invention, P may be a conventional hydroxyl protecting group in the art, such as a silyl ether protecting group or a carbonate protecting group, preferably a silyl ether protecting group. The silyl ether protecting group may be a trimethylsilyl ether protecting group, a tert-butyldimethylsilyl ether protecting group, or a tert-butyldiphenylsilyl ether protecting group (TBDPS), preferably a tert-butyldiphenylsilyl ether protecting group. The carbonate protecting group may be COOEt or COOMe.

[0044] In a certain embodiment of the present invention, the compound represented by formula A5-3 is preferably

[0045] In a certain embodiment of the present invention, the method for preparing the compound represented by formula A5 may further include the method for preparing the compound represented by formula A5-3, which includes the following step S5: Under the action of a base, the compound represented by formula A5-2 and the compound represented by formula B5-2 are subjected to the following substitution reaction in an organic solvent to obtain the compound represented by formula A5-3, that is,

[0046]

[0047] wherein, the definitions of R 1 、R 2 、R 3 and P are the same as those described above.

[0048] In the method for preparing the compound represented by formula A5 (hereinafter referred to as step S5), the reaction conditions, types of reagents, and amounts of reagents for the substitution reaction may be conventional conditions, types of reagents, and amounts of reagents for this type of reaction in the art. The present invention preferably has the following.

[0049] In step S5, the substitution reaction may be carried out under the protection of an inert gas. The inert gas may be a conventional protective gas in the art, such as nitrogen and / or argon, or nitrogen for example.

[0050] In step S5, the base may be an organic base, preferably triethylamine.

[0051] In step S5, the molar ratio of the base to the compound represented by formula A5-2 can be 1 to 3, such as 2.

[0052] In step S5, the organic solvent can be chloroalkanes and / or amides, preferably chloroalkanes. The chloroalkane solvent can be one or more of dichloromethane, 1,2-dichloroethane, and chloroform, preferably dichloromethane.

[0053] In step S5, the amount of the organic solvent does not need to be specifically limited as long as it does not affect the reaction. The volume-mass ratio of the organic solvent to the compound represented by formula A5-2 can be 5 to 100 mL / g, such as 10 to 30 mL / g, or 13 mL / g for example.

[0054] In step S5, the molar ratio of the compound represented by formula B5-2 to the compound represented by formula A5-2 can be 1 to 3, such as 2.

[0055] In step S5, the temperature of the substitution reaction can be 10 to 50 °C, such as 20 to 35 °C.

[0056] In step S5, the progress of the substitution reaction can be monitored by conventional monitoring methods in the art (such as TLC or LCMS). Generally, when the compound represented by formula A5-2 disappears or no longer reacts, it is taken as the end point of the reaction. The reaction time can be 4 to 12 hours, such as 6 hours.

[0057] In step S5, after the substitution reaction, the following post-treatment steps may further be included. The post-treatment steps can be conventional post-treatment operations for such reactions, such as including one or more of extraction, drying, concentration, and purification. The solvent for extraction can be dichloromethane. The drying can be drying with anhydrous sodium sulfate. The concentration can be vacuum distillation. The purification can be column chromatography.

[0058] Step S5 may include the following steps: dissolving the compound represented by formula A5-2 in the organic solvent to form a mixed solution, and adding (preferably dropwise at 0 °C) the compound represented by formula B5-2 and a base deprotection reagent to the mixed solution to carry out the substitution reaction.

[0059] In a certain embodiment of the present invention, the compound represented by formula A5-2 is preferably

[0060] In one embodiment of the present invention, the method for preparing the compound represented by Formula A5-3 may further include the method for preparing the compound represented by Formula A5-2, which comprises the following step S4: Under the action of a rhodium catalyst and a ligand, the compound represented by Formula A5-1 is subjected to the following asymmetric hydrogenation reaction with hydrogen in an organic solvent to obtain the compound represented by Formula A5-2, that is,

[0061]

[0062] wherein, R 1 、R 2 and P are as defined above.

[0063] In the method for preparing the compound represented by Formula A5-2 (hereinafter referred to as step S4), the reaction conditions, types of reagents and their amounts of the asymmetric hydrogenation reaction may be the conventional conditions, types of reagents and their amounts for this type of reaction in the art. Preferably, the present invention is as follows.

[0064] In step S4, the organic solvent may be one or more of alcohol solvents, ether solvents, aromatic hydrocarbon solvents, nitrile solvents, halogenated alkane solvents, sulfoxide solvents and amide solvents, preferably alcohol solvents. The alcohol solvent may be one or more of methanol, ethanol, n-propanol and isopropanol, preferably methanol.

[0065] In step S4, the amount of the organic solvent used may not be specifically limited as long as it does not affect the reaction. The volume-mass ratio of the organic solvent to the compound represented by Formula A5-1 may be 1 to 20 mL / g, such as 2.5 to 10 mL / g, or 7.5 mL / g for example.

[0066] In step S4, the rhodium catalyst may be Rh(nbd) 2 BF 4 .

[0067] In step S4, the molar ratio of the rhodium catalyst to the compound represented by Formula A5-1 may be 0.001 to 0.1, such as 0.01 for example.

[0068] In step S4, the ligand may be (2R,2’R,3R,3’R)-WingPhos

[0069] In step S4, the molar ratio of the ligand to the compound represented by Formula A5-1 may be 0.001 to 0.1, such as 0.01 for example.

[0070] In step S4, the asymmetric hydrogenation reaction may be carried out under a certain pressure, and the pressure of the asymmetric hydrogenation reaction may be the conventional pressure for this type of reaction in the art, such as 1 atm to 50 atm, or 400 psi for example.

[0071] In step S4, the temperature of the asymmetric hydrogenation reaction can be 10°C to 50°C, for example, 35°C.

[0072] In step S4, the progress of the asymmetric hydrogenation reaction can be monitored by conventional monitoring methods in the art (such as TLC or LCMS). Generally, the reaction end point is determined when the compound shown in formula A5-1 disappears or no longer reacts. The reaction time can be 10 - 24 hours, for example, 15 hours.

[0073] In step S4, after the asymmetric hydrogenation reaction, the following post-treatment steps may further be included. The post-treatment steps can be conventional post-treatment operations for such reactions, for example, including one or more of hydrogen replacement, concentration, and purification. The concentration can be vacuum distillation. The purification can be column chromatography.

[0074] In a certain embodiment of the present invention, the compound shown in formula A5-1 is preferably

[0075] In a certain embodiment of the present invention, the preparation method of the compound shown in formula A5-2 may further include the preparation method of the compound shown in the following formula A5-1, which includes the following step S3: In the presence of POCl 3 Under the action of, the compound shown in formula A4 is subjected to the following cyclization reaction in an organic solvent to obtain the compound shown in formula A5-1, that is,

[0076]

[0077] Wherein, R 1 、R 2 and P are as defined above.

[0078] In the preparation method of the compound shown in formula A5-1 (hereinafter referred to as step S3), the reaction conditions, types of reagents, and amounts thereof of the cyclization reaction can be conventional conditions, types of reagents, and amounts thereof for this type of reaction in the art. The present invention preferably has the following.

[0079] In step S3, the cyclization reaction can be carried out under the protection of an inert gas. The inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, and for example, nitrogen.

[0080] In step S3, the molar ratio of POCl 3 to the compound shown in formula A4 can be 2.0 - 4.0, for example, 3.0.

[0081] In step S3, the organic solvent may be a chloroalkane solvent and / or an amide solvent, preferably a chloroalkane solvent. The chloroalkane solvent may be one or more of dichloromethane, 1,2-dichloroethane, and chloroform, preferably dichloromethane.

[0082] In step S3, the amount of the organic solvent used may not be specifically limited as long as it does not affect the reaction. The volume-mass ratio of the organic solvent to the compound represented by formula A4 may be 5 to 20 mL / g, such as 8 mL / g.

[0083] In step S3, the temperature of the cyclization reaction may be 50 to 85 °C, such as 75 °C.

[0084] In step S3, the progress of the cyclization reaction can be monitored by conventional monitoring methods in the art (such as TLC or HPLC). Generally, the end point of the reaction is taken when the compound represented by formula A4 disappears. The reaction time may be 1 to 12 hours, such as 3 hours.

[0085] In step S3, after the cyclization reaction, the following post-treatment steps may further be included. The post-treatment steps may be conventional post-treatment operations for such reactions, such as including one or more of extraction, drying, concentration, and purification. The solvent for extraction may be dichloromethane. The drying may be drying with anhydrous sodium sulfate. The concentration may be vacuum distillation.

[0086] In a certain embodiment of the present invention, the compound represented by formula A4 is preferably

[0087] In a certain embodiment of the present invention, the method for preparing the compound represented by formula A5-1 may further include the method for preparing the following compound represented by formula A4, which includes the following step S2: Under the action of a base and a hydroxy protecting agent P-Hal, the compound represented by formula A3 is subjected to the following condensation reaction in an organic solvent to obtain the compound represented by formula A4, that's all.

[0088]

[0089] wherein, R 1 , R 2 and P are as defined above, and Hal is a halogen.

[0090] In the method for preparing the compound represented by formula A4 (hereinafter referred to as step S2), the reaction conditions, types of reagents, and amounts used of the condensation reaction may be conventional conditions, types of reagents, and amounts used for this type of reaction in the art. The present invention preferably is as follows.

[0091] In step S2, the condensation reaction can be carried out under the protection of an inert gas. The inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, and also nitrogen.

[0092] In step S2, the base may be an organic base, such as a pyridine base or an imidazole base, such as imidazole.

[0093] In step S2, the molar ratio of the base to the compound represented by formula A3 can be 1 to 3, for example, 2.

[0094] In step S2, the hydroxyl protecting agent P-Hal can be tri-tert-butylsilicon chloride or tert-butyldiphenylsilicon chloride, preferably tert-butyldiphenylsilicon chloride.

[0095] In step S2, the molar ratio of the hydroxyl protecting agent P-Hal to the compound represented by formula A3 can be 1 to 2, for example, 1.2.

[0096] In step S2, the organic solvent may be chlorinated alkanes and / or amides, preferably chlorinated alkanes. The chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1,2-dichloroethane and chloroform, preferably dichloromethane.

[0097] In step S2, the amount of the organic solvent is not specifically limited as long as it does not affect the reaction. The volume mass ratio of the organic solvent to the compound represented by formula A3 can be 1 to 10 mL / g, for example 3 to 6 mL / g.

[0098] In step S2, the temperature of the condensation reaction may be 10-30°C, for example 20°C.

[0099] In step S2, the progress of the condensation reaction can be monitored by conventional monitoring methods in the art (such as TLC or LCMS), and the disappearance of the compound represented by formula A3 is generally used as the end point of the reaction. The condensation reaction time can be 5-12 hours, for example 8 hours.

[0100] In step S2, after the condensation reaction, the following post-treatment step may be further included, and the post-treatment step may be a conventional post-treatment operation for such a reaction, for example, one or more of extraction, drying, concentration and purification. The solvent for the extraction may be dichloromethane. The drying may be drying over anhydrous sodium sulfate. The concentration may be reduced pressure distillation. The purification may be column chromatography.

[0101] In a certain embodiment of the present invention, the compound represented by formula A3 is preferably

[0102] In a certain embodiment of the present invention, the preparation method of the compound represented by formula A4 may further include the preparation method of the compound represented by formula A3 below, which comprises the following step S1: Under the action of a catalyst, the compound represented by formula 1 and the compound represented by formula A2 are subjected to the condensation reaction shown below in an organic solvent to obtain the compound represented by formula A3, that's all.

[0103]

[0104] Wherein, R 1 and R 2 are as defined above.

[0105] In the preparation method of the compound represented by formula A3 (hereinafter referred to as step S1), the reaction conditions, types and amounts of reagents of the condensation reaction can be the conventional conditions, types and amounts of reagents for this type of reaction in the art. The present invention preferably adopts the following.

[0106] In step S1, the condensation reaction can be carried out under the protection of an inert gas. The inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, or nitrogen for example.

[0107] In step S1, the catalyst can be one or more of "dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP)", 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and carbonyldiimidazole (CDI), and "dicyclohexylcarbodiimide and 4-dimethylaminopyridine" is preferred. The molar ratio of the dicyclohexylcarbodiimide to the 4-dimethylaminopyridine can be 1 to 2, such as 1.

[0108] In step S1, the molar ratio of the catalyst to the compound represented by formula A2 can be 1 to 3, such as 2.4.

[0109] In step S1, the molar ratio of the compound represented by formula A1 to the compound represented by formula A2 can be 1 to 3, such as 1.05.

[0110] In step S1, the organic solvent can be chloroalkanes and / or amides, and chloroalkanes are preferred. The chloroalkane solvent can be one or more of dichloromethane, 1,2-dichloroethane and chloroform, and dichloromethane is preferred. The amount of the organic solvent does not need to be specifically limited as long as the reaction is not affected.

[0111] In step S1, the temperature of the condensation reaction can be 10 to 30 °C, such as 20 °C.

[0112] In step S1, the progress of the condensation reaction can be monitored by conventional monitoring methods in the art (such as TLC or LCMS), and generally, the disappearance of the compound represented by formula A2 is taken as the end point of the reaction. The time of the condensation reaction can be 8 to 24 hours, such as 12 hours.

[0113] In step S1, after the condensation reaction, the following post-treatment steps may further be included. The post-treatment steps can be conventional post-treatment operations for such reactions, for example, including one or more of extraction, drying, concentration, and purification. The solvent for extraction can be dichloromethane. The drying can be drying with anhydrous sodium sulfate. The concentration can be vacuum distillation. The purification can be column chromatography.

[0114] In a certain embodiment of the present invention, the compound represented by formula A2 is preferably

[0115] In a certain embodiment of the present invention, the preparation method of the compound represented by formula A3 may further include the preparation method of the compound represented by the following formula A2, which includes the following step S0: Under the action of an oxidant, the compound represented by formula A2-3 is subjected to a Pinnick oxidation reaction in an organic solvent to obtain the compound represented by formula A2.

[0116]

[0117] Wherein, R 1 and R 2 are as defined above.

[0118] In the preparation method of the compound represented by formula A2 (hereinafter referred to as step S0), the reaction conditions, types of reagents, and amounts thereof of the Pinnick oxidation reaction can be conventional conditions, types of reagents, and amounts thereof for this type of reaction in the art. The present invention preferably is as follows.

[0119] In step S0, the oxidant can be an inorganic oxidant commonly used in the Pinnick oxidation reaction, preferably sodium chlorite.

[0120] In step S0, the molar ratio of the oxidant to the compound represented by formula A2-3 can be 1 to 3, such as 1.2.

[0121] In step S0, the solvent can be a mixed solvent of an organic solvent and water. Among them, the organic solvent can be one or more of ether solvents or alcohol solvents, such as one or more of tetrahydrofuran, 1,4-dioxane, and tert-butanol, preferably tert-butanol. The volume ratio of the organic solvent to water can be 1:(5 to 10), such as 1:7.5.

[0122] In step S0, the amount of the solvent may not be specifically limited as long as it does not affect the progress of the reaction. The volume-mass ratio of the solvent to the compound represented by formula A2-3 may be 5 to 20 mL / g.

[0123] In step S0, the temperature of the Pinnick oxidation reaction may be 15 to 35 °C, such as 20 °C.

[0124] In step S0, the progress of the Pinnick oxidation reaction can be monitored by conventional monitoring methods in the art (such as TLC or LCMS), and generally, the disappearance of the compound represented by formula A2-3 is taken as the end point of the reaction.

[0125] In step S0, after the Pinnick oxidation reaction, the following post-treatment steps may further be included. The post-treatment steps can be conventional post-treatment operations for such reactions, for example, including one or more of extraction, drying, concentration, and purification. The solvent for extraction can be dichloromethane. The drying can be drying with anhydrous sodium sulfate. The concentration can be vacuum distillation. The purification can be pulping with petroleum ether.

[0126] In a certain embodiment of the present invention, the method for preparing the compound represented by formula A2 may further include the method for preparing the compound represented by the following formula A2-3, which includes the following steps: subjecting the compound represented by formula A2-2 to the following carbon-carbon bond forming reaction to obtain the compound represented by formula A2;

[0127] Among them, the carbon-carbon bond forming reaction includes the following steps: (i) Under the action of a base, subjecting the compound represented by formula A2-2 and a chloroacetate in an organic solvent to a Darzens reaction to obtain a Darzens reaction product; (ii) Under the action of a base, subjecting the Darzens reaction product to a hydrolysis reaction to obtain a hydrolysis reaction product; (iii) Under the action of an acid, subjecting the hydrolysis reaction product to a decarboxylation reaction in a solvent to obtain the compound represented by formula A2-3, that's all.

[0128]

[0129] Wherein, R 1 and R 2 are as defined above.

[0130] In the method for preparing the compound represented by formula A2-3, in the carbon-carbon bond forming reaction, the reaction conditions, types of reagents, and amounts of the Darzens reaction, hydrolysis reaction, and decarboxylation reaction can be conventional conditions, types of reagents, and amounts of this type of reaction in the art. The present invention preferably is as follows.

[0131] In the carbon-increasing reaction, the Darzens reaction can be carried out under the protection of an inert gas. The inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, or nitrogen for example.

[0132] In the carbon-increasing reaction, in the Darzens reaction, the chloroacetate can be methyl chloroacetate or ethyl chloroacetate, such as ethyl chloroacetate for example.

[0133] In the carbon-increasing reaction, in the Darzens reaction, the equivalent of the chloroacetate is 1.2 to 2.0, such as 1.3 for example.

[0134] In the carbon-increasing reaction, in the Darzens reaction, the base can be sodium alkylate or potassium alkylate, such as one or more of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide and potassium tert-butoxide, or sodium methoxide for example.

[0135] In the carbon-increasing reaction, in the Darzens reaction, the molar ratio of the base to the compound represented by formula A2-2 can be 1.2 to 2.0, such as 1.3 for example.

[0136] In the carbon-increasing reaction, in the Darzens reaction, the organic solvent can be an alcohol solvent and / or an ether solvent, such as an alcohol solvent, or methanol for example. The amount of the organic solvent used does not need to be specifically limited as long as it does not affect the reaction.

[0137] In the carbon-increasing reaction, the temperature of the Darzens reaction can be 0 to 35 °C, such as 25 °C for example.

[0138] In the carbon-increasing reaction, the time of the Darzens reaction can be 1 to 5 hours, such as 3 hours for example.

[0139] In the carbon-increasing reaction, the Darzens reaction can include the following steps: the compound represented by formula A2-2 is dissolved in the organic solvent to form a mixed solution, and the chloroacetate and the base are added to the mixed solution (preferably under an ice-water bath or an ice-salt bath) to carry out the Darzens reaction.

[0140] In the carbon-increasing reaction, in the hydrolysis reaction, the base can be a hydroxide of an alkali metal, such as sodium hydroxide and / or potassium hydroxide, preferably potassium hydroxide.

[0141] In the carbon-increasing reaction, in the hydrolysis reaction, the molar ratio of the base to the compound represented by formula A2-2 can be 1 to 3, such as 1.3 for example.

[0142] In the carbon-increasing reaction, the temperature of the hydrolysis reaction can be 10 to 30 °C, such as 25 °C for example.

[0143] In the carbon increment reaction, the time of the hydrolysis reaction can be 3 to 5 hours, such as 4 hours.

[0144] In the carbon increment reaction, the decarboxylation reaction can be carried out under the protection of an inert gas. The inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, and for another example, nitrogen.

[0145] In the carbon increment reaction, in the decarboxylation reaction, the acid can be one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, and potassium dihydrogen phosphate, and preferably potassium dihydrogen phosphate.

[0146] In the carbon increment reaction, in the decarboxylation reaction, the acid can be a 10-50% acid solution, such as a 50% potassium dihydrogen phosphate solution.

[0147] In the carbon increment reaction, in the decarboxylation reaction, the molar ratio of the acid to the compound represented by formula A2-2 can be 1.5 to 5.0, such as 1.5.

[0148] In the carbon increment reaction, in the decarboxylation reaction, the solvent can be a mixed solvent of an organic solvent and water, wherein the organic solvent can be one or more of an alcohol solvent, an ether solvent, or an amide solvent, and preferably a mixed solvent of an ether solvent and water, such as a mixed solvent of tetrahydrofuran and water.

[0149] In the carbon increment reaction, the temperature of the decarboxylation reaction can be 60 °C.

[0150] In the carbon increment reaction, the progress of the decarboxylation reaction can be monitored by a conventional monitoring method in the art (such as TLC or LCMS), and generally, the disappearance of the hydrolysis reaction product is taken as the end point of the reaction. The time of the decarboxylation reaction can be 8 to 36 hours, such as 24 hours.

[0151] In a certain embodiment of the present invention, the compound represented by formula A2-2 is preferably

[0152] In a certain embodiment of the present invention, the compound represented by formula A2-3 is preferably

[0153] On the other hand, the present invention also provides a method for preparing a compound represented by formula A7, which includes the following step S8: under the action of a hydrogen source and a palladium catalyst, carrying out the following debenzylation protection reaction on the compound represented by formula A6 in an organic solvent to obtain the compound represented by formula A7, that's all.

[0154]

[0155] R 1 、R 2 and R3 The definition is the same as described above.

[0156] In the preparation method of the compound represented by Formula A7 (hereinafter referred to as Step S8), the reaction conditions, types of reagents and their dosages for the debenzylation protection reaction can be the conventional conditions, types of reagents and their dosages for this type of reaction in the art. Preferably, the following are provided in the present invention.

[0157] In Step S8, the compound represented by Formula A6 can be prepared according to the preparation method of the compound represented by Formula A6 as described above.

[0158] In Step S8, the debenzylation protection reaction can be carried out under the protection of an inert gas. The inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, or for example, nitrogen.

[0159] In Step S8, the hydrogen source is hydrogen and / or sodium hydride, for example, sodium hydride.

[0160] In Step S8, the molar ratio of the hydrogen source to the compound represented by Formula A6 can be 1.05 - 2.0, for example, 1.5.

[0161] In Step S8, the palladium catalyst is one or more of dry palladium on carbon, palladium hydroxide, palladium chloride and palladium acetate, for example, palladium chloride.

[0162] In Step S8, the molar ratio of the palladium catalyst to the compound represented by Formula A6 can be 0.02 - 0.1, for example, 0.05.

[0163] In Step S8, the organic solvent is an ether solvent or an amide solvent, preferably an ether solvent, for example, tetrahydrofuran.

[0164] In Step S8, the dosage of the organic solvent may not be specifically limited as long as it does not affect the reaction. The volume - mass ratio of the organic solvent to the compound represented by Formula A6 can be 10 - 50 mL / g, or for example, 20 - 30 mL / g.

[0165] In Step S8, the temperature of the debenzylation protection group removal reaction can be 40 - 70 °C, for example, 50 °C.

[0166] In Step S8, the progress of the debenzylation protection group removal reaction can be monitored by a conventional monitoring method in the art (such as TLC or LCMS). Generally, the disappearance of the compound represented by Formula A6 is taken as the end point of the reaction. The time for the debenzylation protection reaction can be 4 - 24 hours, for example, 6 hours.

[0167] In a certain embodiment of the present invention, the compound represented by Formula A6 is preferably

[0168] In a certain embodiment of the present invention, the compound represented by Formula A7 is preferably

[0169] In step S8, after the debenzylation protection reaction, the following post-treatment steps may further be included. The post-treatment steps may be conventional post-treatment operations for such reactions, for example, including one or more of adjusting the system pH, extraction, drying, concentration, and purification. The pH adjustment may be carried out using a saturated potassium dihydrogen phosphate solution. The adjusted system pH may be 6. The extraction solvent may be dichloromethane. Anhydrous sodium sulfate may be used for drying. The concentration may be carried out by vacuum distillation. The purification may be column chromatography.

[0170] On the other hand, the present invention also provides a method for preparing a compound represented by Formula A9, which includes the following step S11: Under the action of an acid, acidify the aqueous suspension of the compound represented by Formula A8 to obtain an acidification reaction product, and then under the action of an oxidizing agent, carry out an oxidation reaction on the acidification reaction product in an organic solvent to obtain the compound represented by Formula A9, that is,

[0171]

[0172] wherein, the definitions of R 1 、R 2 and R 3 are the same as those described above.

[0173] In the method for preparing the compound represented by Formula A9 (hereinafter referred to as step S11), the reaction conditions, reagent types, and dosages of the acidification reaction and the oxidation reaction may be conventional conditions, reagent types, and dosages for this type of reaction in the art. The present invention preferably uses the following.

[0174] In step S11, in the acidification reaction, the acid may be one or more of sulfuric acid, hydrochloric acid, acetic acid, and formic acid, such as hydrochloric acid and / or acetic acid. The hydrochloric acid may be 5% - 20% hydrochloric acid, such as 10% hydrochloric acid. The acetic acid may be 5% - 20% acetic acid, such as 10% acetic acid.

[0175] In step S11, in the acidification reaction, the amount of the acid is preferably such that the system pH is about 1 - 2, such as pH 2.

[0176] In step S11, the acidification reaction is carried out under ice-water bath or ice-salt bath conditions, such as an ice-water bath, or for example, at 0°C.

[0177] In step S11, after the acidification reaction, the following post-treatment steps may further be included. The post-treatment steps may be conventional post-treatment operations for such reactions, for example, including one or more of extraction, drying, and concentration. The extraction solvent may be dichloromethane. Anhydrous sodium sulfate may be used for drying. The concentration may be carried out by vacuum distillation.

[0178] In step S11, in the oxidation reaction, the oxidizing agent can be hydrogen peroxide and / or meta-chloroperoxybenzoic acid, such as meta-chloroperoxybenzoic acid (mCPBA).

[0179] In step S11, in the oxidation reaction, the molar ratio of the oxidizing agent to the compound represented by formula A8 can be 1 to 2, such as 1.1.

[0180] In step S11, in the oxidation reaction, the organic solvent can be a chloroalkane solvent. The chloroalkane solvent can be one or more of dichloromethane, 1,2-dichloroethane, and chloroform, preferably dichloromethane.

[0181] In step S11, the temperature of the oxidation reaction can be 10 to 30 °C, such as 25 °C.

[0182] In step S11, the progress of the oxidation reaction can be monitored by conventional monitoring methods in the art (such as TLC or HPLC). Generally, the disappearance of the compound represented by formula A8 is taken as the end point of the reaction. The reaction time can be 3 to 8 hours, such as 4 hours.

[0183] In step S11, after the oxidation reaction, the following post-treatment steps can also be included. The post-treatment steps can be conventional post-treatment operations for such reactions, such as including one or more of adjusting the system pH, extraction, drying, concentration, and purification. The pH can be adjusted using saturated sodium bicarbonate. The pH of the system can be 8. The solvent for extraction can be dichloromethane. Anhydrous sodium sulfate can be used for drying. The concentration can be vacuum distillation. The purification can be column chromatography.

[0184] In a certain embodiment of the present invention, the compound represented by formula A8 is preferably

[0185] In a certain embodiment of the present invention, the compound represented by formula A9 is preferably

[0186] In a certain embodiment of the present invention, the preparation method of the compound represented by formula A9 can further include the preparation method of the following compound represented by formula A8, which includes the following step S10: Under the action of a cyclizing agent, the compound represented by formula A8-1 is subjected to the following cyclization reaction in an organic solvent to obtain the compound represented by formula A8, that's all.

[0187]

[0188] Wherein, R 1 、R 2 and R 3 are as defined above.

[0189] In the preparation method of the compound represented by Formula A8 (hereinafter referred to as Step S10), the reaction conditions, types of reagents and their dosages for the cyclization reaction can be the conventional conditions, types of reagents and their dosages for this type of reaction in the art. The present invention preferably adopts the following.

[0190] In Step S10, the cyclization reaction can be carried out under the protection of an inert gas. The inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, or nitrogen for example.

[0191] In Step S10, the cyclization reagent can be one or more of N,N-dimethylformamide dimethyl acetal, p-toluic acid, sodium methoxide and sodium ethoxide, and N,N-dimethylformamide dimethyl acetal is preferred.

[0192] In Step S10, the organic solvent can be a chloroalkane solvent. The chloroalkane solvent can be one or more of dichloromethane, 1,2-dichloroethane and chloroform, and dichloromethane is preferred. The dosage of the organic solvent does not need to be specifically limited as long as it does not affect the reaction.

[0193] In Step S10, the temperature of the cyclization reaction can be 20 - 35 °C, such as 25 °C.

[0194] In Step S10, the progress of the cyclization reaction can be monitored by conventional monitoring methods in the art (such as TLC or LCMS). Generally, the disappearance of the compound represented by Formula A8-1 is taken as the end point of the reaction. The time of the reduction reaction can be 8 - 24 hours, such as 10 hours.

[0195] In Step S10, after the cyclization reaction, the following post-treatment steps may further be included. The post-treatment steps can be the conventional post-treatment operations for such reactions, such as including one or more of extraction, drying, concentration and purification. The solvent for extraction can be dichloromethane. The drying can be drying with anhydrous sodium sulfate. The concentration can be vacuum distillation. The purification can be column chromatography.

[0196] In a certain embodiment of the present invention, the compound represented by Formula A8-1 is preferably

[0197] In a certain embodiment of the present invention, the preparation method of the compound represented by Formula A8 may further include the preparation method of the compound represented by the following Formula A8-1, which includes the following Step S9: Under the action of a reducing agent, the compound represented by Formula A7 is subjected to the following reduction reaction in an organic solvent to obtain the compound represented by Formula A8-1, that's all.

[0198]

[0199] Wherein, R1 , R 2 and R 3 are defined as described above.

[0200] In the preparation method of the compound shown by formula A8-1 (hereinafter referred to as step S9), the reaction conditions, reagent types and dosages of the reduction reaction can be the conventional conditions, reagent types and dosages of this type of reaction in the art. The present invention preferably has the following.

[0201] In step S9, the reduction reaction can be carried out under the protection of an inert gas. The inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, or nitrogen for example.

[0202] In step S9, the compound shown by formula A7 can be prepared according to the preparation method of the compound shown by formula A7 as described above.

[0203] In step S9, the reducing agent can be an alkali metal borohydride and / or lithium aluminum hydride. The alkali metal borohydride can be sodium borohydride and / or lithium borohydride, and lithium borohydride is preferred.

[0204] In step S9, the molar ratio of the reducing agent to the compound shown by formula A7 can be 3 to 6, such as 5.0.

[0205] In step S9, the organic solvent can be an ether solvent, such as tetrahydrofuran. The dosage of the organic solvent does not need to be specifically limited as long as it does not affect the reaction.

[0206] In step S9, the temperature of the reduction reaction can be -5 to 35 °C, such as 10 to 30 °C, or 25 °C for example.

[0207] In step S9, the progress of the reduction reaction can be monitored by a conventional monitoring method in the art (such as TLC or LCMS), and generally the disappearance of the compound shown by formula 7 is taken as the end point of the reaction. The time of the reduction reaction can be 10 to 18 hours, such as 12 hours.

[0208] Step S9 may include the following steps: dissolving the compound shown by formula A7 in the organic solvent to form a mixed solution, adding (preferably adding at 0 °C) the reducing agent to the mixed solution, and carrying out the reduction reaction.

[0209] In a certain aspect of the present invention, the compound shown by formula A7 is preferably

[0210] On the other hand, the present invention also provides an application of a compound shown by formula A9 as an intermediate in the preparation of a compound shown by formula A10 or A11, which includes the following Scheme 1 or Scheme 2:

[0211] Scheme 1, which comprises the following step S12: Under the action of a catalyst, the compound represented by formula A9 reacts with hydrogen in an organic solvent to undergo a hydrogenation reaction to obtain the compound represented by formula A10, and that's it.

[0212]

[0213] wherein, R 1 , R 2 and R 3 are defined as described above;

[0214] Scheme 2, which comprises the following step S12 and step S13. Step S12 is the same as that in Scheme 1;

[0215] Step S13: Under the action of a deprotecting reagent, the compound represented by formula A10 undergoes a deprotection reaction in an organic solvent to obtain the compound represented by formula A11, and that's it.

[0216]

[0217] wherein, R 1 , R 2 and R 3 are defined as described above.

[0218] In the above-mentioned Scheme 1 and Scheme 2, the reaction conditions, types of reagents and their dosages for the hydrogenation reaction and the deprotection reaction can be the conventional conditions, types of reagents and their dosages for this type of reaction in the art. The present invention preferably uses the following.

[0219] In step S12, the catalyst can be Raney nickel and / or a palladium catalyst. Preferably, it is a palladium catalyst. More preferably, it is 5% palladium / barium sulfate, and the "%" is the mass percentage of palladium in the total mass of palladium and barium sulfate.

[0220] In step S12, the mass percentage of the catalyst to the compound represented by formula A9 can be 30-50%.

[0221] In step S12, the organic solvent can be an alcohol solvent. The alcohol solvent can be methanol and / or ethanol. Preferably, it is methanol.

[0222] In step S12, the dosage of the organic solvent does not need to be specifically limited as long as it does not affect the reaction.

[0223] In step S12, the pressure of the hydrogenation reaction can be 1-1.5 atm, for example, 1 atm.

[0224] In step S12, the temperature of the hydrogenation reaction can be 20-35 °C, for example, 25 °C.

[0225] In step S12, the progress of the hydrogenation reaction can be monitored by conventional monitoring methods in the art (such as TLC or LCMS). Generally, the disappearance of the compound represented by formula A9 is taken as the end point of the reaction. The time of the hydrogenation reaction can be 3 to 10 hours, for example, 8 hours.

[0226] In step S12, after the hydrogenation reaction, the following post-treatment steps may further be included. The post-treatment steps can be conventional post-treatment operations for such reactions, for example, including one or more of extraction, drying, concentration, and purification. The solvent for extraction can be dichloromethane. Anhydrous sodium sulfate can be used for drying. The concentration can be vacuum distillation. The purification can be column chromatography.

[0227] In a certain embodiment of the present invention, the compound represented by formula A9 is preferably

[0228] In step S13, the deprotection reaction can be carried out under the protection of an inert gas. The inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, or nitrogen for example.

[0229] In step S13, the deprotection reagent can be boron trichloride and / or boron tribromide, preferably boron tribromide.

[0230] In step S13, the molar ratio of the deprotection reagent to the compound represented by formula A10 can be 5 to 10, for example, 8.

[0231] In step S13, the organic solvent can be chlorinated alkanes, preferably dichloromethane. The amount of the organic solvent used does not need to be specifically limited as long as it does not affect the reaction.

[0232] In step S13, the temperature of the deprotection reaction is -20 to 25 °C, for example, 10 °C.

[0233] In step S13, the progress of the deprotection reaction can be monitored by conventional monitoring methods in the art (such as TLC or LCMS). Generally, the disappearance of the compound represented by formula A10 is taken as the end point of the reaction. The time of the deprotection reaction can be 5 to 10 hours, for example, 8 hours.

[0234] In step S13, after the deprotection, the following post-treatment steps may further be included. The post-treatment steps can be conventional post-treatment operations for such reactions, for example, including one or more of extraction, drying, concentration, and purification. The solvent for extraction can be dichloromethane. Anhydrous sodium sulfate can be used for drying. The concentration can be vacuum distillation. The purification can be column chromatography.

[0235] In a certain embodiment of the present invention, the compound represented by formula A10 is preferably

[0236] On the other hand, the present invention also provides a method for preparing a compound represented by Formula B2-3, which comprises the following steps: subjecting the compound represented by Formula B2-2 to a carbon-increasing reaction as shown below to obtain the compound represented by Formula B2-3, that is,

[0237]

[0238] wherein, R 8 and R 9 are independently H, C 1～10 alkyl, C 1～10 alkoxy, C 3～10 cycloalkyl, benzyl or C 6～20 aryl; R 10 is halogen, C 1～6 alkyl, C 1～6 cycloalkyl or C 6～20 aryl; R 11 and R 12 are independently H, C 1～10 alkyl, C 1～10 alkoxy, C 3～10 cycloalkyl or C 6～20 aryl;

[0239] The conditions and operations of the carbon-increasing reaction are the same as those described above.

[0240] In a certain embodiment of the present invention, R 8 can be C 1～10 alkyl, such as C 1～4 alkyl, and for another example, methyl.

[0241] In a certain embodiment of the present invention, R 9 can be benzyl.

[0242] In a certain embodiment of the present invention, R 10 can be halogen, such as Br.

[0243] In a certain embodiment of the present invention, R 11 can be H.

[0244] In a certain embodiment of the present invention, R 12 can be H.

[0245] In a certain embodiment of the present invention, the compound represented by Formula B2-2 is preferably

[0246] In a certain embodiment of the present invention, the compound represented by Formula B2-3 is preferably

[0247] On the other hand, the present invention also provides a method for preparing a compound represented by formula A5-1, which comprises the following step S3: It comprises the following step S3: In the presence of POCl 3 , the compound represented by formula A4 is subjected to the following cyclization reaction in an organic solvent to obtain the compound represented by formula A5-1, that's all.

[0248]

[0249] Wherein, R 1 , R 2 and P are as defined above, and the conditions and operations of the cyclization reaction are as defined above.

[0250] On the other hand, the present invention provides a method for preparing a compound represented by formula A8-1, which comprises the following step S9: Under the protection of an inert gas, in the presence of a reducing agent, the compound represented by formula A7 is subjected to the following reduction reaction in an organic solvent to obtain the compound represented by formula A8-1, that's all.

[0251]

[0252] Wherein, R 1 , R 2 and R 3 are as defined above, and the conditions and operations of the reduction reaction are as defined above.

[0253] On the other hand, the present invention also provides a method for preparing a compound represented by formula A13, which comprises the following step S15: In the presence of a nucleophile, the compound represented by formula A12 is subjected to the following nucleophilic addition reaction in an organic solvent to obtain the compound represented by formula A13, that's all;

[0254]

[0255] Wherein, R 1 , R 2 and R 3 are as defined above, R 4 is C 1～10 alkyl, C 3～10 cycloalkyl or C 6～20 aryl.

[0256] In the method for preparing the compound represented by formula A13 (hereinafter referred to as step S15), the reaction conditions, types of reagents and amounts of reagents of the nucleophilic addition reaction can be the conventional conditions, types of reagents and amounts of reagents for this type of reaction in the art. The present invention preferably uses the following.

[0257] In step S15, the nucleophilic addition reaction can be carried out under the protection of an inert gas; the inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, or nitrogen for example.

[0258] In step S15, the nucleophilic reagent can be a Grignard reagent and / or a lithium reagent, preferably a Grignard reagent.

[0259] In step S15, the molar ratio of the nucleophilic reagent to the compound represented by formula A12 can be 5 to 10, such as 7 for example.

[0260] In step S15, the organic solvent can be an ether solvent and / or a substituted aromatic hydrocarbon solvent, such as an aromatic hydrocarbon solvent, or toluene for example.

[0261] In step S15, the amount of the organic solvent used may not be specifically limited as long as it does not affect the reaction. The volume-mass ratio of the organic solvent to the compound represented by formula A12 can be the volume-mass ratio of such reactions in the art, such as 5 to 100 mL / g, or 40 to 60 mL / g for example.

[0262] In step S15, the temperature of the nucleophilic addition reaction can be -5 to 35 °C, such as 10 to 30 °C, or 25 °C for example.

[0263] In step S15, the progress of the nucleophilic addition reaction can be monitored by a conventional monitoring method in the art (such as TLC or LCMS). Generally, the disappearance or no longer reaction of the compound represented by formula A12 is taken as the end point of the reaction. The time of the nucleophilic addition reaction can be 4 to 10 hours, such as 6 hours for example.

[0264] In step S15, after the nucleophilic addition reaction, the following post-treatment steps may further be included. The post-treatment steps can be conventional post-treatment operations for such reactions, such as including one or more of quenching, extraction, drying, concentration and purification. The quenching can be quenching by adding a saturated ammonium chloride solution to the system. The organic solvent for extraction can be ethyl acetate. The solvent for washing can be saturated sodium chloride solution. The drying can use anhydrous sodium sulfate. The concentration can be vacuum distillation. The purification can be column chromatography.

[0265] In a certain embodiment of the present invention, R 4 can be C 1～4 alkyl, preferably tert-butyl.

[0266] In a certain embodiment of the present invention, the compound represented by formula A12 is preferably

[0267] In a certain embodiment of the present invention, the compound represented by formula A13 is preferably

[0268] In a certain embodiment of the present invention, the preparation method of the compound represented by formula A13 may further include the preparation method of the compound represented by formula A12 below, which comprises the following step S14: performing a cycloaddition reaction on the compound represented by formula A8 and methyl vinyl ketone to obtain the compound represented by formula A12, that's all.

[0269]

[0270] R 1 、R 2 and R 3 are as defined above.

[0271] In the preparation method of the compound represented by formula A12 (hereinafter referred to as step S14), the reaction conditions, types of reagents and their dosages of the cycloaddition reaction can be the conventional conditions, types of reagents and their dosages for this type of reaction in the art. The present invention preferably has the following.

[0272] In step S14, the compound represented by formula A8 can be prepared according to the preparation method of the compound represented by formula A8 as described above.

[0273] In step S14, the volume-mass ratio of the methyl vinyl ketone to the compound represented by formula A8 can be 0.5 - 5 mL / 100 mg, such as 3 mL / 100 mg.

[0274] In step S14, the temperature of the cycloaddition reaction can be 70 - 90 °C, such as 80 °C.

[0275] In step S14, the progress of the cycloaddition reaction can be monitored by a conventional monitoring method in the art (such as TLC or LCMS), and generally, the disappearance of the compound represented by formula A8 is taken as the end point of the reaction. The time of the cycloaddition reaction can be 4 - 16 hours, such as 6 hours.

[0276] In step S14, after the cycloaddition reaction, the following post-treatment steps may further be included. The post-treatment steps can be the conventional post-treatment operations for such reactions, directly concentrating and purifying. The concentration can be vacuum distillation. The purification can be column chromatography.

[0277] In a certain embodiment of the present invention, the compound represented by formula A8 is preferably

[0278] On the other hand, the present invention also provides a preparation method of a compound represented by formula A14, which comprises the following step S16: under the action of a catalyst, performing the following hydrogenation reaction on the compound represented by formula A13 in an organic solvent and hydrogen to obtain the compound represented by formula A14, that's all.

[0279] The hydrogenation reaction is carried out under a pressure of 5 to 30 atm, for example, 10 atm.

[0280]

[0281] Among them, R 1 , R 2 , R 3 and R 4 are as defined above.

[0282] In the preparation method of the compound represented by formula A14 (hereinafter referred to as step S16), the reaction conditions, types of reagents and their dosages of the hydrogenation reaction can be the conventional conditions, types of reagents and their dosages for this type of reaction in the art. The present invention preferably uses the following.

[0283] In step S16, the compound represented by formula A13 can be prepared according to the preparation method of the compound represented by formula A13 as described above.

[0284] In step S16, the catalyst can be a metal catalyst, such as a palladium catalyst, and for example, palladium on carbon.

[0285] In step S16, the molar ratio of the catalyst to the compound represented by formula A13 can be 0.03 - 0.2; for example, 0.1.

[0286] In step S16, the organic solvent can be an ether solvent and / or an alcohol solvent, such as an alcohol solvent, and for example, ethanol and / or isopropanol, and further for example, isopropanol.

[0287] In step S16, the dosage of the organic solvent does not need to be specifically limited as long as it does not affect the reaction.

[0288] In step S16, the temperature of the hydrogenation reaction can be 50 - 80 °C, for example, 70 °C.

[0289] In step S16, the progress of the hydrogenation reaction can be monitored by conventional monitoring methods in the art (such as TLC or LCMS). Generally, the disappearance or no longer reaction of the compound represented by formula A13 is used as the end point of the reaction. The time of the hydrogenation reaction can be 8 - 16 hours, for example, 10 hours.

[0290] In a certain embodiment of the present invention, the compound represented by formula A13 is preferably

[0291] In a certain embodiment of the present invention, the compound represented by formula A14 is preferably

[0292] On the other hand, the present invention also provides a method for preparing a compound represented by formula A15, which comprises the following step S17: under the action of a base and a thiol, the compound represented by formula A14 is subjected to the following demethylation reaction in an organic solvent to obtain the compound represented by formula A15, that is,

[0293]

[0294] wherein, R 1 、R 2 、R 3 and R 4 are as defined above.

[0295] In the method for preparing the compound represented by formula A15 (hereinafter referred to as step S17), the reaction conditions, types of reagents and their amounts for the demethylation reaction can be the conventional conditions, types of reagents and their amounts for this type of reaction in the art. The present invention preferably has the following.

[0296] In step S17, the compound represented by formula A14 can be prepared according to the method for preparing the compound represented by formula A14 as described above.

[0297] In step S17, the demethylation reaction can be carried out under the protection of an inert gas; the inert gas can be a conventional protective gas in the art, such as nitrogen and / or argon, or nitrogen for example.

[0298] In step S17, the base can be an alcohol base, such as sodium tert-butoxide and / or potassium tert-butoxide.

[0299] In step S17, the thiol can be an alkyl thiol, such as n-dodecyl mercaptan.

[0300] In step S17, the molar ratio of the base to the compound A14 can be 1.8 to 3.0, such as 2.0.

[0301] In step S17, the organic solvent can be an amide and / or sulfoxide solvent, such as DMSO and / or DMF.

[0302] In step S17, the amount of the organic solvent used may not be specifically limited as long as it does not affect the reaction.

[0303] In step S17, the temperature of the demethylation reaction can be 100 to 130 °C, such as 120 °C.

[0304] In step S17, the progress of the demethylation reaction can be monitored by a conventional monitoring method in the art (such as TLC or LCMS), and generally, the disappearance or no longer reaction of the compound represented by formula A14 is used as the end point of the reaction. The time of the reduction reaction can be 1 to 3 hours, such as 2 hours.

[0305] Step S17. After the demethylation reaction, the following post-treatment steps may further be included. The post-treatment steps may be conventional post-treatment operations for such reactions, for example, including one or more of extraction, drying, concentration, and purification. The solvent for the extraction may be ethyl acetate. The drying may be drying with anhydrous sodium sulfate. The concentration may be vacuum distillation. The purification may be column chromatography.

[0306] In a certain embodiment of the present invention, the compound represented by formula A14 is preferably

[0307] In a certain embodiment of the present invention, the compound represented by formula A15 is preferably

[0308] On the other hand, the present invention also provides a method for preparing a compound represented by formula A8, which includes the following steps S1 to step S10:

[0309]

[0310] wherein the definitions of R 1 , R 2 , R 3 and P are the same as defined above, and the conditions and operations of steps S1 to step S10 are the same as defined above.

[0311] On the other hand, the present invention also provides a method for preparing a compound represented by formula A11, which includes the following steps S11 to step S13:

[0312]

[0313] wherein the definitions of R 1 , R 2 and R 3 are the same as defined above, and the conditions and operations of steps S11 to step S13 are the same as defined above.

[0314] On the other hand, the present invention also provides a method for preparing a compound represented by formula A15, which includes the following steps S14 to step S17:

[0315]

[0316] wherein the definitions of R 1 , R 2 , R 3 and R 4 are the same as defined above, and the conditions and operations of steps S14 to step S17 are the same as defined above.

[0317] On the other hand, the present invention also provides a compound represented by formula A5-1:

[0318]

[0319] Among them, R 1 and R 2 and P are defined as described above.

[0320] On the other hand, the present invention also provides a compound represented by Formula A5-2:

[0321]

[0322] Among them, R 1 and R 2 and P are defined as described above.

[0323] On the other hand, the present invention also provides a compound represented by Formula A5-3:

[0324]

[0325] Among them, R 1 and R 2 and R 3 and P are defined as described above.

[0326] On the other hand, the present invention also provides a compound represented by Formula A5:

[0327]

[0328] Among them, R 1 and R 2 and R 3 are defined as described above.

[0329] On the other hand, the present invention also provides a compound represented by Formula A6:

[0330]

[0331] Among them, R 1 and R 2 and R 3 are defined as described above.

[0332] On the other hand, the present invention also provides a compound represented by Formula A7:

[0333]

[0334] Among them, R 1 and R 2 and R 3 are defined as described above.

[0335] On the other hand, the present invention also provides a compound represented by Formula A8:

[0336]

[0337] Among them, R 1 and R 2 and R 3 are defined as described above.

[0338] On the other hand, the present invention also provides a compound represented by Formula A8:

[0339]

[0340] Among them, R 1 and R 2 and R 3 are defined as described above.

[0341] On the other hand, the present invention also provides a compound represented by Formula A9:

[0342]

[0343] Among them, R 1 and R 2 and R 3 are defined as described above.

[0344] On the other hand, the present invention also provides a compound represented by Formula A10:

[0345]

[0346] Among them, R 1 and R 2 and R 3 are defined as described above.

[0347] On the other hand, the present invention also provides a compound represented by Formula A12:

[0348]

[0349] Among them, R 1 and R 2 and R 3 are defined as described above.

[0350] On the other hand, the present invention also provides a compound represented by Formula A13:

[0351]

[0352] Among them, R 1 and R 2 and R 3 and R 4 are defined as described above.

[0353] In one embodiment of the present invention, the compounds represented by Formula A5-1, A5-2, A5-3, A5, A6, A7, A8-1, A8, A9, A10, A12 or A13 may each be selected from the following compounds:

[0354]

[0355] In the present invention, "alkyl" includes straight-chain alkyl and branched-chain alkyl.

[0356] In the present invention, "alkoxy" refers to the group -O-R X , where R X is alkyl as defined above.

[0357] In the present invention, "cycloalkyl" refers to a monovalent saturated cyclic alkyl group, preferably a monovalent saturated cyclic alkyl group having 3 to 7 ring carbon atoms, more preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0358] In the present 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, the aryl has 6 to 14 carbon atoms, such as phenyl, naphthyl, phenanthryl, or anthracenyl.

[0359] In the present invention, "room temperature" or "ambient temperature" refers to 10 to 30 °C, such as 25 °C.

[0360] In the present invention, "ice bath" or "ice-salt bath" refers to -5 to 5 °C, such as 0 °C.

[0361] On the basis of conforming to common general knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0362] The reagents and raw materials used in the present invention are all commercially available.

[0363] The positive and progressive effects of the present invention are as follows: By using the synthesis route and intermediates of the present invention, it is possible to prepare opioid compounds starting from cheap and easily available vanillin and isovanillin, providing the possibility for its large-scale production. Detailed Embodiments

[0364] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the examples described herein. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0365] Example 1: The compound represented by Formula 1 (4-(2-aminoethyl)-2-methoxyphenol)

[0366]

[0367] 2-Methoxy-4-(2-nitrovinyl)phenol:

[0368] Add 250 mL of nitromethane (5 mL of nitromethane / 1 g of vanillin) to the reaction kettle, preheat to 110 °C, add vanillin (50 g, 0.3286 mol, 1 eq.), after complete dissolution, add ethylenediamine (0.25 mL, 0.003744 mol, 0.01 eq.), transfer to a 1 L round-bottom flask while it is hot after reacting for 2 h, distill under reduced pressure until there is no solvent, add 100 mL of a mixed solvent of MeOH / H 2 O = 1:1 and slurry for 2 h, filter, wash the filter cake twice with 50 mL of the MeOH / H 2 O mixed solvent, collect the filter cake and dry it to obtain an orange-yellow powdery nitroalkene product, 2-methoxy-4-(2-nitrovinyl)phenol (57.7 g, 90% yield).

[0369] 1 H NMR (500 MHz, CDCl 3 ) δ 7.96 (d, J = 13.3 Hz, 1H), 7.52 (d, J = 13.5 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.04–6.94 (m, 2H), 6.05 (s, 1H), 3.96 (s, 3H).

[0370] 13 C NMR (126 MHz, CDCl 3 ) δ 149.88, 147.19, 139.63, 135.14, 125.07, 122.56, 115.42, 110.25, 56.24.

[0371] HRMS (ESI+): m / z calculated for C 9 H 8 NO 4 [M + H] + : 194.0459, found: 194.0460.

[0372] 4-(2-Aminoethyl)-2-methoxyphenol:

[0373] Add 2-methoxy-4-(2-nitrovinyl)phenol (57.7 g, 0.2956 mol, 1 eq.) to the reaction kettle, add 480 mL of a mixed solvent of THF / MeOH = 7:1, and cool down to 0 °C. Add NaBH 4 (17.4 g, 0.4611 mol, 1.56 eq.) portionwise. After addition, let it return to room temperature for reaction naturally. After the reaction is complete, cool the reaction system to 0 °C, add 1 M HCl solution to quench the reaction and adjust the pH to about 7. Evaporate the organic solvent, then add ethyl acetate for extraction, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain an oily substance. Dissolve the oily substance with methanol, transfer it to a hydrogenation kettle, and add palladium-carbon (6 g, 10 mol%). Hydrogenate under atmospheric pressure and react at 40 °C overnight. After the reaction is complete, filter through diatomaceous earth, wash the filter cake with methanol three times, combine the filtrates, distill under reduced pressure, add dichloromethane for slurrying, filter, wash the filter cake with dichloromethane, collect and dry the filter cake to obtain a grayish-white powdery phenethylamine product, 4-(2-aminoethyl)-2-methoxyphenol (39.0 g, 80% yield).

[0374] 1 H NMR (500 MHz, CD 3 OD) δ 6.85 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.70 (dd, J = 8.0, 1.8 Hz, 1H), 3.86 (s, 3H), 3.12 (t, J = 7.6 Hz, 2H), 2.86 (t, J = 7.5 Hz, 2H).

[0375] 13 C NMR (126 MHz, CD 3 OD) δ 147.88, 145.39, 127.85, 120.87, 115.12, 111.88, 54.98, 40.93, 33.17.

[0376] HRMS (ESI+): m / z calculated for C 9 H 14 NO 2 [M + H] + : 168.1019, found: 168.1022.

[0377] Example 2: The compound shown in Formula 2 (2-(3-(benzyloxy)-2-bromo-4-methoxyphenyl)acetic acid)

[0378]

[0379] The compound shown in Formula 2-1 (2-bromo-3-hydroxy-4-methoxybenzaldehyde)

[0380] Dissolve 3-hydroxy-4-methoxybenzaldehyde (10.0 g, 0.0657 mol, 1.0 eq.) in 100 mL of DCM, cool down to 0 °C, and add NBS (12.8 g, 0.0723 mol, 1.1 eq.) in portions. After reacting at low temperature for 1 hour, return to room temperature and continue the reaction. After the reaction is completed, cool down to 10 °C, add saturated sodium chloride solution, stir for 0.5 hour and then filter. Wash the filter cake with water twice and dry to obtain Compound 2 (14.6 g, 96% yield). The organic phase in the filtrate can be combined in several batches and purified by recrystallization to obtain Compound 2-1.

[0381] 1 H NMR (500 MHz, CD 3 OD) δ10.20 (s, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 3.96 (s, 3H).

[0382] 13 C NMR (126 MHz, CD 3 OD) δ191.20, 153.23, 127.05, 121.49, 113.22, 109.36, 55.52.

[0383] HRMS (ESI+): m / z calculated for C 8 H 8 BrO 3 [M+H] + : 230.9651, found: 230.9642.

[0384] The compound shown in Formula 2-2 (3-(benzyloxy)-2-bromo-4-methoxybenzaldehyde)

[0385] Dissolve Compound 2-1 (14.6 g, 0.0631 mol, 1.0 eq.) in 100 mL of DMF, cool down to 0 °C, and add K 2 CO 3(10.5 g, 0.0757 mol, 1.2 eq.) and BnBr (8.2 mL, 0.0694 mol, 1.1 eq.) were reacted at low temperature for 1 h and then continued to react at room temperature. After the reaction was completed, the mixture was filtered, and the filter cake was washed with dichloromethane. After most of the filtrate was evaporated, saturated sodium chloride solution and triethylamine (0.96 mL, 0.00694 mol, 0.11 eq.) were added, and the mixture was stirred for 0.5 h. The mixture was extracted with dichloromethane three times, and the dichloromethane was evaporated to obtain an oily substance. After adding saturated sodium chloride solution and stirring, a white solid was obtained. The solid was filtered and dried to obtain compound 2-2 (18.8 g, 93% yield).

[0386] 1 H NMR (500 MHz, CDCl 3 ) δ 10.26 (s, 1H), 7.75 (s, 1H), 7.55 (d, J = 7.3 Hz, 2H), 7.38 (dt, J = 23.4, 7.2 Hz, 3H), 6.98 (d, J = 8.7 Hz, 1H), 5.05 (s, 2H), 3.96 (s, 4H).

[0387] 13 C NMR (126 MHz, CDCl 3 ) δ 191.20, 158.90, 145.20, 136.72, 128.63, 128.55, 128.47, 127.49, 126.73, 123.69, 111.03, 74.93, 56.45.

[0388] HRMS (ESI+): m / z calculated for C 15 H 13 BrNaO 3 [M + Na] + : 342.9940, found: 342.9943.

[0389] The compound shown in Formula 2-3 (2-(3-(benzyloxy)-2-bromo-4-methoxyphenyl)acetaldehyde)

[0390] Compound 2-2 (18.8 g, 0.0587 mol, 1.0 eq.) was weighed into a 500 mL three-necked flask. Nitrogen was evacuated and replaced three times. 100 mL of ultra-dry methanol was added. The temperature was lowered to 0 °C. Ethyl chloroacetate (8.0 mL, 0.0763 mol, 1.3 eq.) and a methanol solution of sodium methoxide (15.2 mL, 0.0763 mol, 1.3 eq.) were added slowly, and the reaction was carried out at low temperature. After the reaction was completed, KOH solution (4.3 g, 0.0763 mol, 1.3 eq.) was added. The mixture was stirred at room temperature for about 0.5 h. A large amount of white solid precipitated. It was placed in the refrigerator and allowed to stand for 0.5 h, then filtered. The filter cake was washed twice with a cold mixed solvent of methanol:dichloromethane = 1:1, and the filter cake was dried to obtain the organic potassium salt. The organic potassium salt was added to KH 2 PO 4 (12.0 g, 0.0881 mol, 1.5 eq.) in a THF / H 2 O mixed solution. The temperature was raised to 60 °C and the reaction was carried out for 24 h. It was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic solvent was evaporated to dryness to obtain the oily compound 2-3 (14.2 g, 72% yield)

[0391] 1 H NMR (500 MHz, CDCl 3 ) δ 9.73 (d, J = 1.7 Hz, 1H), 7.55 (d, J = 7.3 Hz, 2H), 7.41–7.32 (m, 3H), 6.98 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.04 (s, 2H), 3.88 (s, 3H), 3.83 (d, J = 1.2 Hz, 2H).

[0392] 13 C NMR (126 MHz, CDCl 3 ) δ 199.12, 153.33, 145.86, 137.15, 128.58, 128.48, 128.26, 126.71, 125.59, 121.26, 111.61, 74.73, 56.29, 50.26.

[0393] HRMS (ESI+): m / z calculated for C 16 H 15 BrNaO 3 [M+Na] + : 357.0097, found: 357.0093.

[0394] The compound shown in Formula 2 (2-(3-(benzyloxy)-2-bromo-4-methoxyphenyl)acetic acid)

[0395]

[0396] Transfer compound 2-3 (14.2 g, 0.0423 mol, 1.0 eq.) to a 500 mL egg-shaped flask, add 20 mL of tert-butanol and 10 mL of isoprene, cool to 0 °C, and slowly add NaClO 2 (4.6 g, 0.0508 mol, 1.2 eq.) and NaH 2 PO 4 (40.6 g, 0.3384 mol, 8.0 eq.) in a mixed aqueous solution (150 mL), and then react at room temperature. After the reaction is completed, extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate the solvent to obtain an oil, triturate with petroleum ether, filter, wash the filter cake once with petroleum ether, and dry the filter cake to obtain a white powdery compound 2 (13.5 g, 91% yield).

[0397] 1 1H NMR (500 MHz, CDCl 3 ) δ 7.56 (d, J = 7.5 Hz, 2H), 7.36 (dt, J = 27.4, 7.3 Hz, 3H), 7.04 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.03 (s, 2H), 3.87 (s, 3H), 3.82 (s, 2H).

[0398] 13 13C NMR (126 MHz, CDCl 3 ) δ 177.31, 153.17, 145.60, 137.22, 128.52, 128.43, 128.17, 126.58, 126.51, 121.39, 111.30, 74.65, 56.21, 41.15.

[0399] HRMS (ESI+): m / z calculated for C 16 H 15 BrNaO 4 [M+Na] + : 373.0046, found: 373.0051.

[0400] Example 3 Compound of Formula 3 (2-(3-(benzyloxy)-2-bromo-4-methoxyphenyl)-N-(4-hydroxy-3-methoxyphenethyl)acetamide)

[0401]

[0402] Into a clean and dry round-bottomed flask equipped with a magnetic stirrer were added the compound of Formula 2 (10.7 g, 30.5 mmol) and the compound of Formula 1 (5.35 g, 32 mmol). The entire system was evacuated and backfilled with nitrogen three times. Dry dichloromethane (50 mL) was added, and the system was cooled to 0 °C. Dicyclohexylcarbodiimide (7.0 g, 36.6 mmol) and 4-dimethylaminopyridine (6.4 mL, 36.6 mmol) were slowly added dropwise. After the addition was complete, the system was stirred at 0 °C for 30 minutes and then at room temperature for 12 hours. After the reaction was complete, water (50 mL) was added to quench the reaction. The system was extracted with dichloromethane three times (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: a mixed solvent of ethyl acetate / petroleum ether = 1:1) to obtain the product compound 3 as a white solid (11.8 g, 78% yield).

[0403] 1 H NMR (500 MHz, CDCl 3 ) δ 7.55 (d, J = 7.1 Hz, 2H), 7.38 (t, J = 7.3 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 1.7 Hz, 1H), 6.52 (dd, J = 8.0, 1.7 Hz, 1H), 5.59 (s, 1H), 5.41 (s, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 3.63 (s, 2H), 3.44 (q, J = 6.8 Hz, 2H), 2.66 (t, J = 6.9 Hz, 2H).

[0404] 13 C NMR (126 MHz, CDCl 3)δ170.05,153.20,146.76,145.78,144.35,137.19,130.53,128.54,128.44,128.23,127.77,126.57,121.40,121.23,114.47,111.76,111.23,74.67,56.28,56.04,43.89,40.90,35.27.

[0405] HRMS(ESI+):m / z calculated for C 25 H 27 BrNO 5 [M+H] + :500.1067,found:500.1072.

[0406] Example 4: The compound of formula 4 (2-(3-(benzyloxy)-2-bromo-4-methoxyphenyl)-N-(4-((tert-butyldiphenylsilyl)oxy)-3-methoxyphenethyl)acetamide)

[0407]

[0408] In a clean and dry round-bottom flask equipped with a magnetic stirrer, the compound of formula 3 (1.28 g, 2.66 mmol) and imidazole (362 mg, 5.32 mmol) were charged. The whole system was evacuated and replaced with nitrogen three times. Dry dichloromethane (6 mL) was added, and tert-butyldiphenylsilyl chloride (0.83 mL, 3.2 mmol) was slowly added dropwise at room temperature. After the addition was completed, the system was stirred at room temperature for 8 hours. After the reaction was complete, water (20 mL) was added to quench the reaction. The system was extracted with dichloromethane three times (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (the eluent was a mixed solvent of ethyl acetate / petroleum ether = 1:1), and the product compound 4 (1.76 g, 90% yield) was obtained as a white foamy solid.

[0409] 1 H NMR(500MHz,CDCl 3) δ 7.71 (d, J = 6.6 Hz, 4H), 7.55 (d, J = 6.8 Hz, 2H), 7.44–7.31 (m, 9H), 6.94 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 7.9 Hz, 1H), 6.52 (s, 1H), 6.32 (d, J = 7.3 Hz, 1H), 5.43 (s, 1H), 5.02 (s, 2H), 3.82 (s, 3H), 3.61 (s, 2H), 3.52 (s, 3H), 3.39 (d, J = 6.0 Hz, 2H), 2.60 (t, J = 6.3 Hz, 2H), 1.11 (s, 9H).

[0410] 13 C NMR (126 MHz, CDCl 3 ) δ 169.92, 153.05, 150.53, 145.55, 143.61, 137.06, 135.42, 133.66, 131.92, 129.66, 128.53, 128.39, 128.19, 127.66, 127.54, 126.54, 121.17, 120.55, 120.10, 112.74, 111.56, 74.59, 56.15, 55.40, 43.79, 40.84, 35.19, 26.73, 19.84.

[0411] HRMS (ESI+): m / z calculated for C 41 H 44 BrNO 5 SiNa [M+Na] + : 760.2064, found: 760.2068.

[0412] Example 5: The compound of formula 5 ((R)-(1-(3-(benzyloxy)-2-bromo-4-methoxybenzyl)-7-hydroxy-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)(cyclopropyl)methanone)

[0413]

[0414] The compound shown in Formula 5-1, 1-(3-(benzyloxy)-2-bromo-4-methoxybenzyl)-7-((tert-butyldiphenylsilyl)oxy)-6-methoxy-3,4-dihydroisoquinoline

[0415]

[0416] In a clean and dry Schlenk tube equipped with a magnetic stir bar, add Compound 4 (500 mg, 0.68 mmol). Evacuate and backfill the system with nitrogen three times. Add dry dichloroethane (4 mL). Slowly add phosphorus oxychloride (0.19 mL, 2.0 mmol) dropwise at room temperature. After the addition is complete, heat the system to 75 °C and stir for 3 hours. After the reaction is complete, cool the system to room temperature and quench the reaction by adding saturated sodium bicarbonate (10 mL). Extract the system with dichloromethane three times (30 mL × 3). Combine the organic phases and dry over anhydrous sodium sulfate. Concentrate to obtain a pale yellow foamy solid 5-1. The product does not require further purification and is directly used for the next step.

[0417] HRMS(ESI+): m / z calculated for C 21 H 23 BrNO 6 [M+H] + : 464.0703, found: 464.0707.

[0418] The compound shown in Formula 5-2, (R)-1-(3-(benzyloxy)-2-bromo-4-methoxybenzyl)-7-((tert-butyldiphenylsilyl)oxy)-6-methoxy-1,2,3,4-tetrahydroisoquinoline

[0419]

[0420] In a clean and dry 25 mL round-bottom flask equipped with a magnetic stir bar, add (2R,2’R,3R,3’R)-WingPhos (2.0 mg, 3.2 μmol) and Rh(nbd) 2 BF 4(2.1 mg, 3.2 μmol), then methanol (1.5 mL) was added and stirred at room temperature for 15 minutes. Subsequently, a methanol solution of compound 5-1 (200 mg, 0.28 mmol) was added, and the mixture was placed in an autoclave and purged with hydrogen three times. The entire system was reacted at 35 °C and 400 psi for 15 h. After the reaction was completed, the mixture was concentrated to obtain the target product 5-2 (180 mg, 90% yield).

[0421] 80% ee: Chiral OD-H column, iPrOH / Hexane = 90:10, 1.0 mL / min, 210 nm UV detector, t1 = 14.48 min (minor), t2 = 17.56 min (Major).

[0422] HRMS(ESI+): m / z calculated for C 41 H 45 BrNO 4 Si[M+H] + : 722.2296, found: 722.2300.

[0423] The compound shown in Formula 5-3 ((R)-(1-(3-(benzyloxy)-2-bromo-4-methoxybenzyl)-7-((tert-butyldiphenylsilyl)oxy)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)(cyclopropyl)meth-Anone)

[0424]

[0425] In a clean and dry round-bottom flask equipped with a magnetic stirrer, compound 5-2 (457 mg, 0.68 mmol) was charged. The entire system was purged with nitrogen three times. Dry dichloromethane (6 mL) was added, and the system was cooled to 0 °C. Cyclopropylcarbonyl chloride (0.12 mL, 1.36 mmol) and triethylamine (0.19 mL, 1.36 mmol) were slowly added dropwise. After the addition was completed, the system was warmed to room temperature and stirred for 6 hours. After the reaction was complete, water (20 mL) was added to quench the reaction. The system was extracted with dichloromethane three times (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: a mixed solvent of ethyl acetate / petroleum ether = 1:1) to obtain the product compound 5-3 as a white foamy solid (330 mg, 61% yield).

[0426] 1 H NMR(400MHz,CDCl3 ) δ 7.75 (dd, J = 22.3, 6.1 Hz, 4H), 7.59 (d, J = 7.0 Hz, 2H), 7.41 (dt, J = 22.3, 6.9 Hz, 9H), 6.77 (d, J = 11.1 Hz, 2H), 6.68 (d, J = 8.1 Hz, 1H), 6.56 (s, 1H), 5.09 (d, J = 9.5 Hz, 1H), 4.98 (s, 2H), 4.78 (d, J = 8.1 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.09–2.99 (m, 1H), 2.92–2.73 (m, 3H), 2.59 (d, J = 15.3 Hz, 1H), 1.16 (s, 9H), 0.92 (s, 1H), 0.63 (d, J = 5.0 Hz, 1H), 0.37 (d, J = 6.1 Hz, 2H), 0.00 (d, J = 5.7 Hz, 1H).

[0427] 13 C NMR (101 MHz, CDCl 3 ) δ 172.81, 152.76, 149.79, 145.51, 143.72, 137.23, 135.71, 135.66, 133.61, 133.40, 130.31, 129.90, 128.66, 128.48, 128.31, 127.80, 127.31, 127.06, 120.79, 118.55, 112.66, 111.63, 74.79, 56.32, 56.00, 54.94, 42.62, 35.33, 28.27, 26.88, 19.89, 10.69, 7.62, 7.31.

[0428] HRMS (ESI+): m / z calculated for C 41 H 47 BrNO 7 Si [M + H] + : 790.2558, found: 790.2559.

[0429] The compound shown in Formula 5 ((R)-(1-(3-(benzyloxy)-2-bromo-4-methoxybenzyl)-7-hydroxy-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)(cyclopropyl)methanone)

[0430]

[0431] In a clean and dry round-bottom flask equipped with a magnetic stir bar, compound 5-3 (260 mg, 0.33 mmol) was charged. The entire system was evacuated and backfilled with nitrogen three times. Dry THF (6 mL) was added, and the system was cooled to 0 °C. Tetrabutylammonium fluoride (0.39 mL, 0.39 mmol, 1 N) was slowly added dropwise. After the addition was complete, the system was warmed to room temperature and stirred for 1 h. The system was directly concentrated and purified by column chromatography (eluent: a mixed solvent of ethyl acetate / petroleum ether = 1:2), to give the product compound 5 as a white foamy solid (170 mg, 94% yield).

[0432] 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (t, J = 10.4 Hz, 2H), 7.35 (dt, J = 21.8, 6.7 Hz, 3H), 7.00 (s, 1H), 6.79 (q, J = 8.4 Hz, 2H), 6.60 (s, 1H), 5.59 (s, 1H), 5.40 (d, J = 10.1 Hz, 1H), 5.00 (s, 2H), 4.81 (dd, J = 12.8, 4.9 Hz, 1H), 3.84 (t, J = 14.0 Hz, 6H), 3.44–3.34 (m, 1H), 3.11 (ddd, J = 33.9, 18.8, 11.2 Hz, 2H), 2.92–2.79 (m, 1H), 2.65 (d, J = 15.3 Hz, 1H), 1.11 (d, J = 4.3 Hz, 1H), 0.86 (d, J = 53.8 Hz, 1H), 0.67 (dd, J = 15.0, 6.2 Hz, 1H), 0.42 (dd, J = 14.4, 7.8 Hz, 2H), 0.09 (dd, J = 13.2, 6.8 Hz, 1H).

[0433] 13 C NMR (101 MHz, CDCl 3 ) δ 172.90, 152.87, 145.88, 145.59, 144.26, 137.15, 130.20, 129.43, 128.64, 128.49, 128.29, 127.18, 126.15, 120.84, 112.75, 111.74, 110.96, 74.83, 56.33, 56.10, 55.21, 42.80, 35.54, 28.32, 10.80, 7.69, 7.39.

[0434] HRMS (ESI+): m / z calculated for C 29 H 31 BrNO 5 [M+H] +:552.1380, found:552.1375.

[0435] Example 6: The compound of formula 6 (4bS,9R)-4-(benzyloxy)-11-(cyclopropanecarbonyl)-3,6-dimethoxy-9,10-dihydro-7H-9,4b-(epiminoethano)phenan-thren-7-one)

[0436]

[0437] In a clean and dry 250 mL Schlenk tube, palladium chloride (106 mg, 0.6 mmol), di(1-adamantyl)n-butylphosphine (215 mg, 0.6 mmol), potassium carbonate (2.5 g, 18 mmol) and compound 5 (3.3 g, 6.0 mmol) were added. The whole system was evacuated and replaced with nitrogen three times, and then N,N-dimethylformamide (100 mL) was added. The whole reaction system was stirred at 120 °C for 12 hours. After the reaction was completed, the system was cooled to room temperature, dichloromethane (100 mL) was added, the crude system was filtered through diatomaceous earth, concentrated and purified by column chromatography (the eluent was a mixed solvent of dichloromethane / methanol = 150:1 to 100:1), and the yellow solid product compound 6 (1.75 g, 63% yield) was obtained.

[0438] 1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (d, J = 6.9 Hz, 2H), 7.42 (t, J = 6.9 Hz, 2H), 7.37 (d, J = 6.7 Hz, 1H), 7.27 (d, J = 13.2 Hz, 1H), 6.88 (q, J = 8.4 Hz, 2H), 6.34 (d, J = 6.9 Hz, 1H), 5.52 (d, J = 3.5 Hz, 1H), 5.33 (dd, J = 20.9, 9.7 Hz, 1H), 5.13 (dd, J = 40.8, 11.6 Hz, 1H), 4.34–4.01 (m, 1H), 3.89 (s, 3H), 3.39 (d, J = 21.1 Hz, 3H), 3.20 (dd, J = 15.1, 10.6 Hz, 1H), 3.12 (d, J = 17.8 Hz, 1H), 3.01–2.62 (m, 1H), 2.42 (dd, J = 49.6, 13.2 Hz, 1H), 1.83 (s, 1H), 1.00 (dd, J = 16.3, 10.9 Hz, 2H), 0.92–0.66 (m, 3H).

[0439] 1313C NMR(101MHz,CDCl 3 )δ180.94,172.78,159.45,151.94,151.65,146.34,137.49,130.58,128.73,128.57,128.16,127.36,127.24,124.48,124.31,122.09,121.99,120.27,119.73,112.39,74.22,60.40,56.02,54.82,51.83,44.16,40.66,39.24,38.93,37.81,14.24,12.16,11.58,7.75.

[0440] HRMS(ESI+):m / z calculated for C 29 H 30 NO 5 [M+H] + :472.2118,found:472.2117.

[0441] Example 7: Compound of formula 7 ((4bS,9R)-11-(cyclopropanecarbonyl)-4-hydroxy-3,6-dimethoxy-9,10-dihydro-7H-9,4b-(epiminoethano)phenanthren-7-one)

[0442]

[0443] Add palladium chloride (15 mg, 0.085 mmol) and sodium hydride (102 mg, 2.55 mmol, in 60% mineral oil) to a clean and dry round-bottom flask. The whole system was evacuated and replaced with nitrogen three times, and then a solution of compound 6 (750 mg, 1.7 mmol) in tetrahydrofuran (20 mL) was added. The whole reaction system was stirred at 50 °C for 6 hours. After the reaction was completed, the system was cooled to room temperature, water (20 mL) and saturated potassium dihydrogen phosphate solution (10 mL) were added to adjust the pH of the system to 6. The crude system was extracted with dichloromethane three times (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: a mixed solvent of dichloromethane / methanol = 100:1), to obtain the product compound 7 as a yellow foamy solid (442 mg, 73% yield).

[0444] 1 1H NMR(400MHz,CDCl 3)δ 7.54 (s, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 17.0 Hz, 2H), 5.52 (s, 1H), 5.20 (s, 1H), 4.34 (dd, J = 13.6, 4.2 Hz, 1H), 4.03 (dd, J = 12.6, 4.4 Hz, 1H), 3.86 (d, J = 11.3 Hz, 3H), 3.73 (s, 3H), 3.41–3.03 (m, 3H), 2.62 (dd, J = 28.3, 11.7 Hz, 2H), 1.14–0.61 (m, 5H).

[0445] 13 C NMR (101 MHz, CDCl 3 )δ 181.10, 172.87, 172.64, 159.59, 151.64, 145.66, 143.73, 128.65, 127.67, 122.83, 122.03, 119.99, 119.84, 119.29, 109.97, 56.39, 54.98, 53.51, 51.92, 43.91, 40.82, 40.16, 38.82, 37.96, 37.69, 37.07, 12.18, 11.61, 7.74.

[0446] HRMS (ESI+): m / z calculated for C 22 H 24 NO 5 [M + H] + : 382.1649, found: 382.1648.

[0447] Example 8: The compound of formula 8 ((4R,7aR,12bS)-3-(cyclopropylmethyl)-7,9-dimethoxy-2,3,4,7a-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline)

[0448]

[0449] Under a nitrogen atmosphere, at 0 °C, a solution of lithium aluminum hydride (2.1 mL, 2.1 mmol, 1 N) was added to a solution of the debenzylated product 7 (160 mg, 0.42 mmol) in tetrahydrofuran. The entire system was stirred at 0 °C for 1 hour and then warmed to room temperature and stirred for 12 hours. After the reaction was complete, the reaction was quenched by adding saturated potassium sodium tartrate (5 mL), and the system was extracted three times with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give a pale yellow foamy solid (crude product), which was directly used in the next reaction.

[0450] The above-obtained crude product was transferred to a clean and dry Schlenk tube. The system was evacuated and backfilled with nitrogen three times, and dry dichloromethane (5 mL) was added at room temperature. Then, N,N-dimethyl dimethyl acetal (0.28 mL, 2.1 mmol) was added. The entire system was stirred at room temperature for 10 hours, concentrated directly, and purified by column chromatography (eluent: a mixed solvent of dichloromethane / methanol = 30:1) to give the yellow foamy solid product compound 8 (87 mg, 59% yield).

[0451] 1 H NMR(500MHz,CD 3 OD)δ6.81(d,J=8.2Hz,1H),6.73(d,J=8.3Hz,1H),6.02(d,J=6.6Hz,1H),5.42(s,1H),5.24(d,J=6.6Hz,1H),4.70(d,J=6.9Hz,1H),3.84(s,3H),3.66(s,3H),3.55(t,J=13.8Hz,2H),3.44(d,J=7.6Hz,1H),3.25(d,J=6.9Hz,3H),2.45(td,J=13.9,4.9Hz,1H),1.95(d,J=13.5Hz,1H),1.25–1.15(m,1H),0.85–0.75(m,2H),0.52(d,J=4.5Hz,2H).

[0452] 13 C NMR(126MHz,CD 3 OD)δ156.11,146.06,144.74,133.46,125.55,121.29,115.92,96.27,89.00,61.65,57.26,55.86,45.95,30.74,7.10,5.02,4.78.

[0453] HRMS(ESI+):m / z calculated for C 22 H 26 NO3 [M+H] + : 352.1907, found: 352.1910.

[0454] Example 9: The compound of formula 9 ((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-2,3,4,4a-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one)

[0455]

[0456] Under the condition of an open ice-water bath, 10% dilute hydrochloric acid was added to the suspended aqueous solution (5 mL) of compound 8 (51 mg, 0.13 mmol) until the pH was 2. Then the whole system was extracted with dichloromethane five times (10 mL × 5), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated and dried to obtain its hydrochloride salt.

[0457] Meta-chloroperoxybenzoic acid (30 mg, 0.17 mmol) was added portionwise to the acetic acid aqueous solution (5 mL, 10% aqueous solution) of this hydrochloride salt. After the addition was completed, the system was raised to room temperature and stirred for 4 hours. After the reaction was completed, saturated sodium bicarbonate (10 mL) was slowly added to adjust the pH of the system to 8. The system was extracted with dichloromethane four times (10 mL × 4). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (the eluent was a mixed solvent of dichloromethane / methanol = 100:1), and the product compound 9 (31 mg, 67% yield) was obtained as a yellow foamy solid.

[0458] 1 H NMR (400 MHz, CDCl 3 ) δ 6.64 (dt, J = 26.8, 8.1 Hz, 3H), 6.18 (d, J = 10.0 Hz, 1H), 4.71 (s, 1H), 3.83 (s, 3H), 3.37 (d, J = 4.9 Hz, 1H), 3.13 (d, J = 18.6 Hz, 1H), 2.83–2.70 (m, 1H), 2.56 (dd, J = 18.5, 5.5 Hz, 1H), 2.44 (t, J = 9.7 Hz, 3H), 2.25 (t, J = 10.8 Hz, 1H), 1.69 (d, J = 12.2 Hz, 1H), 0.88 (d, J = 5.7 Hz, 1H), 0.58 (d, J = 7.0 Hz, 2H), 0.17 (d, J = 3.4 Hz, 2H).

[0459] 1313C NMR(101MHz,CDCl 3 )δ194.36,147.71,144.52,142.81,134.77,130.80,125.07,119.62,115.33,87.25,67.71,61.85,59.19,57.01,47.34,43.70,29.73,23.24,9.41,4.17,3.94.

[0460] HRMS(ESI+):m / z calculated for C 21 H 24 NO 4 [M+H] + :354.1700,found:354.1705.

[0461] Example 10: Compound of formula 10 ((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-9-methoxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one)

[0462]

[0463] To a clean and dry 25 mL round-bottom flask were added compound 9 (31 mg, 0.088 mmol) and palladium / barium sulfate (5% on BaSO 4 , 15 mg, 8 mol%), followed by addition of methanol (5 mL). The whole system was evacuated and backfilled with hydrogen three times (atmospheric pressure: 1 atm), and the reaction was carried out at room temperature for 8 hours under this atmospheric pressure condition. After completion of the reaction, it was directly concentrated and purified by column chromatography (eluent: a mixed solvent of dichloromethane / methanol = 100:1), to obtain the product compound A10 as a colorless oil (30 mg, 96% yield).

[0464] 1 1H NMR(400MHz,CDCl 3)δ 6.68 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 4.67 (s, 1H), 3.88 (s, 3H), 3.21 (s, 1H), 3.10–2.95 (m, 2H), 2.77–2.53 (m, 2H), 2.41 (d, J = 6.1 Hz, 3H), 2.29 (d, J = 14.3 Hz, 1H), 2.13 (dd, J = 11.8, 9.5 Hz, 1H), 1.88 (d, J = 12.7 Hz, 1H), 1.60 (dd, J = 28.9, 12.8 Hz, 2H), 0.87 (d, J = 3.7 Hz, 1H), 0.55 (d, J = 7.2 Hz, 2H), 0.15 (d, J = 3.6 Hz, 2H).

[0465] 13 C NMR (101 MHz, CDCl 3 )δ 208.53, 145.15, 143.07, 129.63, 124.94, 119.49, 115.18, 90.50, 70.27, 62.21, 59.32, 57.00, 50.88, 43.81, 36.26, 31.62, 30.74, 29.78, 22.80, 9.43, 4.11, 3.94.

[0466] HRMS (ESI+): m / z calculated for C 21 H 26 NO 4 [M + H] + : 356.1856, found: 356.1860.

[0467] Example 11: The compound Naltrexone of formula 11 ((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)

[0468]

[0469] In a clean and dry Schlenk tube, add compound 10 (11 mg, 0.031 mmol). The system is evacuated and filled with nitrogen three times, and then dry dichloromethane (3 mL) is added. The whole system is cooled to -20 °C, and then boron tribromide (24 μL, 0.25 mmol) is slowly added dropwise. The system is warmed to 10 °C and stirred for 5 hours. After the reaction is completed, the system is cooled to 0 °C, saturated ammonium chloride (5 mL) is added, and the system is extracted with dichloromethane four times (10 mL × 4). The organic phases are combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (the eluent is a mixed solvent of dichloromethane / methanol = 50:1), to obtain the white solid product 11 (6 mg, 56% yield).

[0470] 1 H NMR(500MHz,CDCl 3 )δ6.72(d,J=8.0Hz,1H),6.58(d,J=7.9Hz,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).

[0471] 13 C NMR(126MHz,CDCl 3 )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.

[0472] HRMS(ESI+):m / z calculated for C 20 H 24 NO 4 [M+H] + :342.1700,found:342.1703.

[0473] Example 12: Compound 1-((4R,12bS)-3-(cyclopropylmethyl)-7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-14-yl)ethan-1-one of Formula 12

[0474]

[0475] Compound 8 (100 mg, 0.285 mmol) was added to a clean and dry Schlenk tube. The system was evacuated and backfilled with nitrogen three times, and methyl vinyl ketone (3 mL) was added. The system was heated to 80 °C and stirred for 6 hours. After the reaction was completed, the system was cooled to room temperature, concentrated and purified by column chromatography (the eluent was a mixed solvent of dichloromethane / methanol = 60:1), to obtain the white foamy solid product 12 (78 mg, 65% yield).

[0476] 1 H NMR (500 MHz, CDCl 3 ) δ 6.61 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 7.9 Hz, 1H), 5.88 (d, J = 8.6 Hz, 1H), 5.58 (d, J = 8.7 Hz, 1H), 4.58 (s, 1H), 3.80 (s, 3H), 3.59 (s, 4H), 3.10 (d, J = 18.4 Hz, 1H), 2.97 (dd, J = 21.7, 8.8 Hz, 2H), 2.73 (d, J = 7.2 Hz, 1H), 2.41 (t, J = 18.2 Hz, 4H), 2.14 (s, 3H), 1.98 (s, 1H), 1.84 (d, J = 12.2 Hz, 1H), 1.44–1.32 (m, 1H), 0.82 (s, 1H), 0.50 (t, J = 7.3 Hz, 2H), 0.13 (s, 2H).

[0477] 13 C NMR (126 MHz, CDCl 3 ) δ 209.51, 149.78, 148.06, 141.89, 136.19, 134.22, 128.17, 125.97, 119.46, 116.17, 113.58, 95.34, 81.38, 59.77, 57.04, 56.68, 53.57, 50.74, 48.18, 44.11, 43.19, 33.53, 30.64, 30.01, 23.32, 9.38, 4.30, 3.47.

[0478] HRMS(ESI+): m / z calculated for C 26 H 32 NO 4 [M + H] + : 422.2326, found: 422.2331.

[0479] Example 13: Compound of formula 13 (2 - ((4R,4aS,7S,7aR,12bS)-3-(cyclopropylmethyl)-7,9 - dimethoxy - 1,2,3,4,7,7a - hexahydro - 4a,7 - ethano - 4,12 - methanobenzofuro[3,2 - e]isoquinolin - 14 - yl)-3,3 - dimethylbutan - 2 - ol)

[0480]

[0481] In a clean and dry Schlenk tube, compound 12 (54 mg, 0.128 mmol) was added. The system was evacuated and filled with nitrogen three times and dry toluene (3 mL) was added. The whole system was cooled to 0 °C, and tert - butylmagnesium chloride (1.7 M, 0.53 mL, 0.897 mmol) was slowly added dropwise. Subsequently, the system was warmed to room temperature and stirred for 5 hours. After the reaction was completed, the system was cooled to 0 °C and saturated ammonium chloride (5 mL) was added. The system was extracted with ethyl acetate four times (15 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (eluent: a mixed solvent of petroleum ether / ethyl acetate = 10:1), to obtain the colorless oily product compound 13 (36 mg, 59% yield), and at the same time the starting material was recovered (8 mg, 15% yield). Therefore, the yield based on the starting material for this reaction was (71%, brsm).

[0482] 1 H NMR(500 MHz, CDCl 3)δ 6.61 (d, J = 8.1 Hz, 1H), 6.49 (d, J = 8.1 Hz, 1H), 5.99 (d, J = 8.8 Hz, 1H), 5.65 (s, 1H), 5.44 (d, J = 8.9 Hz, 1H), 4.56 (s, 1H), 3.79 (d, J = 20.6 Hz, 6H), 3.49 (d, J = 6.5 Hz, 1H), 3.09 (d, J = 18.4 Hz, 1H), 2.97 (dd, J = 12.5, 8.8 Hz, 1H), 2.66 (dd, J = 11.8, 4.6 Hz, 1H), 2.46–2.31 (m, 4H), 2.15 (t, J = 8.6 Hz, 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).

[0483] 13 C NMR (126 MHz, CDCl 3 )δ 148.18, 141.79, 135.65, 134.87, 128.61, 124.93, 119.34, 113.81, 99.11, 84.61, 78.51, 60.50, 59.66, 56.93, 56.87, 55.36, 47.23, 45.98, 44.22, 43.20, 39.82, 34.10, 32.30, 26.78, 23.23, 19.75, 9.63, 4.47, 3.30.

[0484] HRMS (ESI+): m / z calculated for C 30 H 42 NO 4 [M + H] + : 480.3108, found: 480.3111.

[0485] Example 14: Compound of formula 14 (2 - ((4R, 4aR, 7S, 7aR, 12bS) - 3 - (cyclopropylmethyl) - 7, 9 - dimethoxy - 1, 2, 3, 4, 5, 6, 7, 7a - octahydro - 4a, 7 - ethano - 4, 12 - methanobenzofuro[3, 2 - e]isoquinolin - 6 - yl) - 3, 3 - dimethylbutan - 2 - ol)

[0486]

[0487] In a clean and dry 25 mL round-bottom flask, add compound 13 (18 mg, 0.038 mmol), 10% Pd / C (5 mg, 0.0047 mmol) and isopropanol (5 mL). Place it in a reaction kettle, evacuate and replace the system with hydrogen three times and raise the hydrogen pressure to 10 atm. Subsequently, heat the system to 70 °C and react for 14 hours under this hydrogen pressure. After the reaction is completed, filter the system through diatomaceous earth and rinse with dichloromethane. Concentrate the organic phase to obtain the white foam solid product compound 14 (18 mg, 99% yield). The product is directly used for the subsequent reaction without purification.

[0488] 1 H NMR(500MHz,CDCl 3 )δ6.70(d,J=8.1Hz,1H),6.55(d,J=8.1Hz,1H),5.92(s,1H),4.43(d,J=1.5Hz,1H),3.87(s,3H),3.55(s,3H),3.03–2.95(m,2H),2.93–2.85(m,1H),2.60(dd,J=11.7,5.2Hz,1H),2.38–2.19(m,4H),2.15(t,J=9.8Hz,1H),1.97(td,J=12.7,5.6Hz,1H),1.87–1.74(m,2H),1.67(dd,J=12.9,2.4Hz,1H),1.36(s,3H),1.03(s,9H),0.88(t,J=6.9Hz,1H),0.79(td,J=13.2,6.7Hz,1H),0.75–0.67(m,1H),0.53–0.42(m,2H),0.11(d,J=3.5Hz,2H).

[0489] 13 C NMR(126MHz,CDCl 3 )δ147.04,141.79,133.06,129.08,119.26,114.18,96.88,80.90,79.50,59.68,58.43,57.01,52.73,46.33,44.04,43.83,40.53,36.08,35.91,33.59,29.89,29.84,26.57,23.00,20.21,18.32,9.66,4.31,3.39.

[0490] HRMS(ESI+):m / z calculated for C 30 H 44 NO 4 [M+H]+ : 482.3265, found: 482.3269.

[0491] Example 15: Compound 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) of Formula 15

[0492]

[0493] Add potassium tert-butoxide (11 mg, 0.1 mmol) to a clean and dry Schlenk tube. The system is evacuated and replaced with nitrogen three times and dry N,N-dimethylformamide (1.5 mL) is added. The system is heated to 50 °C, and then n-dodecyl mercaptan (24 μL, 0.1 mmol) is added. The system is stirred for 5 minutes, and a solution of compound 14 (18 mg, 0.037 mmol) in N,N-dimethylformamide (1.5 mL) is added. The whole system is heated to 120 °C and reacted for 2 hours. After the reaction is completed, the system is cooled to room temperature and the pH is adjusted to 4 with potassium dihydrogen phosphate solution (50%, 5 mL), and then the pH is adjusted to 9 with saturated sodium bicarbonate solution. The system is extracted with ethyl acetate four times (10 mL × 4). The organic phases are combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (the eluent is a mixed solvent of petroleum ether / ethyl acetate = 4:1), and the final product buprenorphine (14 mg, 81% yield) is obtained.

[0494] 1 H NMR (500 MHz, CDCl 3)δ6.69(d, J = 8.0 Hz, 1H), 6.51(d, J = 8.0 Hz, 1H), 5.92(s, 1H), 4.45(s, 1H), 3.53(s, 3H), 2.98(d, J = 18.9 Hz, 2H), 2.89(t, J = 10.2 Hz, 1H), 2.62(dd, J = 11.5, 4.7 Hz, 1H), 2.26(dddd, J = 36.9, 30.5, 15.9, 7.8 Hz, 6H), 1.98(td, J = 12.6, 5.4 Hz, 1H), 1.84(t, J = 12.4 Hz, 1H), 1.75(td, J = 12.8, 6.0 Hz, 1H), 1.70–1.57(m, 1H), 1.36(s, 3H), 1.31(d, J = 13.8 Hz, 2H), 1.03(s, 9H), 0.88(t, J = 5.9 Hz, 1H), 0.80(s, 1H), 0.70(t, J = 12.3 Hz, 1H), 0.53–0.42(m, 2H), 0.11(d, J = 3.6 Hz, 2H).

[0495] 13 C NMR(126 MHz, CDCl 3 )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.

[0496] HRMS(ESI+): m / z calculated for C 29 H 42 NO 4 [M + H] + : 468.3108, found: 468.3112.

Claims

1. A method for preparing a compound represented by formula A6, characterized in that, the preparation method comprises the following step S7: Under the action of a palladium catalyst, a phosphine ligand represented by formula L1, and a base, the compound represented by formula A5 is subjected to the following dearomatizing cyclization reaction in an organic solvent to obtain the compound represented by formula A6, that's all. wherein, R 1 and R 2 are H; R 3 is C 3～7 cycloalkyl; The phosphine ligand represented by formula L1 is di(1-adamantyl)n-butylphosphine; The palladium catalyst is palladium chloride or dichloro(phenyl cyanide)palladium(II).

2. The preparation method according to claim 1, characterized in that, in step S7, the molar ratio of the palladium catalyst to the compound represented by formula A5 is 0.01 - 0.5; and / or, in step S7, the molar ratio of the phosphine ligand represented by formula L1 to the compound represented by formula A5 is 0.01 - 0.5; and / or, in step S7, the base is an alkali metal carbonate; and / or, in step S7, the organic solvent is a sulfoxide solvent and / or an amide solvent; and / or, in step S7, the volume-mass ratio of the organic solvent to the compound represented by formula A5 is 5 - 100 mL / g; and / or, in step S7, the temperature of the dearomatizing cyclization reaction is 80°C - 180°C; and / or, in step S7, the reaction time of the dearomatizing cyclization reaction is 8 - 24 hours; and / or, step S7 comprises the following steps: adding the organic solvent to a mixture of the palladium catalyst, the phosphine ligand represented by formula L1, the base, and the compound represented by formula A5, and carrying out the dearomatizing cyclization reaction.

3. The preparation method according to claim 2, characterized in that, in step S7, the palladium catalyst is palladium chloride; and / or, in step S7, the molar ratio of the palladium catalyst to the compound represented by formula A5 is 0.1; and / or, in step S7, the molar ratio of the phosphine ligand represented by formula L1 to the compound represented by formula A5 is 0.1 - 0.5; and / or, in step S7, the base is potassium carbonate; and / or, in step S7, the organic solvent is N,N-dimethylformamide and / or N,N-dimethylacetamide; and / or, in step S7, the volume-mass ratio of the organic solvent to the compound represented by formula A5 is 10 - 30 mL / g; and / or, in step S7, the temperature of the dearomatizing cyclization reaction is 100°C - 130°C; and / or, in step S7, the reaction time of the dearomatizing cyclization reaction is 12 hours; and / or, R 3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

4. The preparation method according to claim 3, characterized in that, in step S7, the organic solvent is N,N-dimethylformamide; and / or, the compound represented by Formula A6 is and / or, the compound represented by Formula A5 is 5. The preparation method according to claim 1, characterized in that, the preparation method further comprises the following steps: Step S4: Under the action of a rhodium catalyst and a ligand, the compound represented by formula A5-1 is subjected to the following asymmetric hydrogenation reaction with hydrogen in an organic solvent to obtain the compound represented by formula A5-2, that's all. Step S5: Under the action of a base, carry out the following substitution reaction on the compound shown by formula A5-2 and the compound shown by formula B5-2 in an organic solvent to obtain the compound shown by formula A5-3, and that's it. Step S6: Under the action of a deprotection reagent, carry out the following deprotection reaction on formula A5-3 in an organic solvent to obtain the compound shown by formula A5, and that's it. Among them, R 1 , R 2 and R 3 are defined as described in claim 1, and P is a hydroxyl protecting group.

6. The preparation method according to claim 5, characterized in that in Step S4, the organic solvent is one or more of an alcohol solvent, an ether solvent, an aromatic hydrocarbon solvent, a nitrile solvent, a halogenated alkane solvent, a sulfoxide solvent, and an amide solvent; and / or, in Step S4, the volume-mass ratio of the organic solvent to the compound shown by formula A5-1 is 1-20 mL / g; And / or, in step S4, the rhodium catalyst is Rh(nbd) 2 BF 4 ; and / or, in Step S4, the molar ratio of the rhodium catalyst to the compound shown by formula A5-1 is 0.001-0.1; and / or, in Step S4, the ligand is (2R,2’R,3R,3’R)-WingPhos; and / or, in Step S4, the molar ratio of the ligand to the compound shown by formula A5-1 is 0.001-0.1; and / or, in Step S4, the pressure of the asymmetric hydrogenation reaction is 1 atm to 50 atm; and / or, in Step S4, the temperature of the asymmetric hydrogenation reaction is 10°C to 50°C; and / or, in Step S4, the reaction time of the asymmetric hydrogenation reaction is 10 - 24 hours; and / or, in Step S5, the base is an organic base; and / or, in Step S5, the molar ratio of the base to the compound shown by formula A5-2 is 1-3; and / or, in Step S5, the organic solvent is a chloroalkane and / or an amide; and / or, in Step S5, the volume-mass ratio of the organic solvent to the compound shown by formula A5-2 is 5-100 mL / g; and / or, in Step S5, the molar ratio of the compound shown by formula B5-2 to the compound shown by formula A5-2 is 1-3; and / or, in Step S5, the temperature of the substitution reaction is 10-50°C; and / or, in Step S5, the reaction time of the substitution reaction is 4-12 hours; and / or, Step S5 includes the following steps: dissolve the compound shown by formula A5-2 in the organic solvent to form a mixture solution, add the compound shown by formula B5-2 and a base deprotection reagent to the mixture solution, and carry out the substitution reaction; and / or, in Step S6, the deprotection reagent is tetrabutylammonium fluoride; and / or, in Step S6, the molar ratio of the deprotection reagent to the compound shown by formula A5-3 is 1-5; and / or, in Step S6, the organic solvent is an ether solvent and / or a chloroalkane solvent; and / or, in Step S6, the volume-mass ratio of the organic solvent to the compound shown by formula A5-3 is 5-100 mL / g; and / or, in Step S6, the temperature of the deprotection reaction is 10-50°C; And / or, in step S6, the reaction time of the deprotection reaction is 1 to 5 hours; And / or, step S6 includes the following steps: the compound shown by formula A5-3 is dissolved in the organic solvent to form a mixed solution, and the deprotection reagent is added to the mixed solution to carry out the deprotection reaction; And / or, P is a silyl ether protecting group or a carbonate protecting group.

7. The preparation method according to claim 6, characterized in that in step S4, the organic solvent is one or more of methanol, ethanol, n-propanol and isopropanol; And / or, in step S4, the volume-mass ratio of the organic solvent to the compound shown by formula A5-1 is 2.5 to 10 mL / g; And / or, in step S4, the molar ratio of the rhodium catalyst to the compound shown by formula A5-1 is 0.01; And / or, in step S4, the molar ratio of the ligand to the compound shown by formula A5-1 is 0.01; And / or, in step S4, the pressure of the asymmetric hydrogenation reaction is 400 psi; And / or, in step S4, the temperature of the asymmetric hydrogenation reaction is 35 °C; And / or, in step S4, the reaction time of the asymmetric hydrogenation reaction is 15 hours; And / or, in step S5, the base is triethylamine; And / or, in step S5, the molar ratio of the base to the compound shown by formula A5-2 is 2; And / or, in step S5, the organic solvent is one or more of dichloromethane, 1,2-dichloroethane and chloroform; And / or, in step S5, the volume-mass ratio of the organic solvent to the compound shown by formula A5-2 is 10 to 30 mL / g; And / or, in step S5, the molar ratio of the compound shown by formula B5-2 to the compound shown by formula A5-2 is 2; And / or, in step S5, the temperature of the substitution reaction is 20 to 35 °C; And / or, in step S5, the reaction time of the substitution reaction is 6 hours; And / or, in step S6, the molar ratio of the deprotection reagent to the compound shown by formula A5-3 is 1.1; And / or, in step S6, the organic solvent is one or more of tetrahydrofuran, dioxane, ether and methyl tert-butyl ether; And / or, in step S6, the volume-mass ratio of the organic solvent to the compound shown by formula A5-3 is 10 to 30 mL / g; And / or, in step S6, the temperature of the deprotection reaction is 20 to 35 °C; And / or, in step S6, the reaction time of the deprotection reaction is 1 hour; And / or, P is a trimethylsilyl ether protecting group, a tert-butyldimethylsilyl ether protecting group, a tert-butyldiphenylsilyl ether protecting group, COOEt or COOMe.

8. The preparation method according to claim 7, characterized in that in step S4, the organic solvent is methanol; And / or, in step S4, the volume-mass ratio of the organic solvent to the compound shown by formula A5-1 is 7.5 mL / g; And / or, in step S5, the organic solvent is dichloromethane; And / or, in step S5, the volume-to-mass ratio of the organic solvent to the compound represented by formula A5-2 is 13 mL / g; And / or, in step S6, the organic solvent is tetrahydrofuran; And / or, in step S6, the volume-to-mass ratio of the organic solvent to the compound represented by formula A5-3 is 23 mL / g; And / or, P is a tert-butyldiphenylsilyl ether protecting group.

9. The preparation method according to claim 5, characterized in that The preparation method further comprises the following step S3: in the presence of POCl 3 , subject the compound shown by formula A4 to the cyclization reaction shown below in an organic solvent to obtain the compound shown by formula A5-1, and that's it. wherein, R 1 and R 2 are defined as described in claim 1, and P is defined as described in claim 5.

10. The preparation method according to claim 9, characterized in that In step S3, the molar ratio of the POCl 3 to the compound represented by formula A4 is 2.0 to 4.0; And / or, in step S3, the organic solvent is a chloroalkane solvent and / or an amide solvent; And / or, in step S3, the volume-to-mass ratio of the organic solvent to the compound represented by formula A4 is 5-20 mL / g; And / or, in step S3, the temperature of the cyclization reaction is 50-85 °C; And / or, in step S3, the reaction time of the cyclization reaction is 1-12 hours; and / or, the compound represented by formula A4 is the compound represented by formula A5-1 is 11. The preparation method according to claim 10, characterized in that In step S3, the molar ratio of the POCl 3 to the compound represented by formula A4 is 3.0; And / or, in step S3, the organic solvent is one or more of dichloromethane, 1,2-dichloroethane, and chloroform; And / or, in step S3, the volume-to-mass ratio of the organic solvent to the compound represented by formula A4 is 8 mL / g; And / or, in step S3, the temperature of the cyclization reaction is 75 °C; And / or, in step S3, the reaction time of the cyclization reaction is 3 hours.

12. The preparation method according to claim 11, characterized in that In step S3, the organic solvent is dichloromethane.

13. The preparation method according to claim 9, characterized in that The preparation method further comprises the following steps: Step S0: Under the action of an oxidant, subject the compound represented by formula A2-3 to a Pinnick oxidation reaction in an organic solvent to obtain the compound represented by formula A2, that's all; Step S1: Under the action of a catalyst, subject the compound represented by formula 1 and the compound represented by formula A2 to a condensation reaction in an organic solvent as shown below to obtain the compound represented by formula A3, that's all; Step S2: Under the action of a base and a hydroxyl protecting agent P-Hal, subject the compound represented by formula A3 to a condensation reaction in an organic solvent as shown below to obtain the compound represented by formula A4, that's all; wherein, R 1 and R 2 are defined as described in claim 1, P is defined as described in claim 5, and Hal is a halogen.

14. The preparation method according to claim 13, characterized in that In step S0, the oxidant is sodium chlorite; And / or, in step S0, the molar ratio of the oxidant to the compound represented by formula A2-3 is 1-3; And / or, in step S0, the solvent is a mixed solvent of an organic solvent and water; And / or, in step S0, the volume-to-mass ratio of the organic solvent to the compound represented by formula A2-3 is 5-20 mL / g; And / or, in step S0, the temperature of the Pinnick oxidation reaction is 15-35 °C; And / or, in step S1, the catalyst is one or more of "dicyclohexylcarbodiimide and 4-diaminopyridine", 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and carbonyldiimidazole; And / or, in step S1, the molar ratio of the catalyst to the compound represented by formula A2 is 1 to 3; And / or, in step S1, the molar ratio of the compound represented by formula 1 to the compound represented by formula A2 is 1 to 3; And / or, in step S1, the organic solvent is a chloroalkane and / or an amide; And / or, in step S1, the temperature of the condensation reaction is 10 to 30 °C; And / or, in step S1, the reaction time of the condensation reaction is 8 to 24 hours; And / or, in step S2, the base is an organic base; And / or, in step S2, the molar ratio of the base to the compound represented by formula A3 is 1 to 3; And / or, in step S2, the hydroxy protecting agent P-Hal is tert-butyldimethylsilyl chloride or tert-butyldiphenylsilyl chloride; And / or, in step S2, the molar ratio of the hydroxy protecting agent P-Hal to the compound represented by formula A3 is 1 to 2; And / or, in step S2, the organic solvent is a chloroalkane and / or an amide; And / or, in step S2, the volume-to-mass ratio of the organic solvent to the compound represented by formula A3 is 1 to 10 mL / g; And / or, in step S2, the temperature of the condensation reaction is 10 to 30 °C; And / or, in step S2, the reaction time of the condensation reaction is 5 to 12 hours.

15. The preparation method according to claim 14, wherein, in step S0, the molar ratio of the oxidant to the compound represented by formula A2-3 is 1.2; And / or, in step S0, the organic solvent is one or more of an ether solvent or an alcohol solvent; And / or, in step S0, the volume ratio of the organic solvent to water is 1:(5 to 10); And / or, in step S0, the temperature of the Pinnick oxidation reaction is 20 °C; And / or, in step S1, the catalyst is "dicyclohexylcarbodiimide and 4-diaminopyridine"; And / or, in step S1, the molar ratio of the catalyst to the compound represented by formula A2 is 2.4; And / or, in step S1, the molar ratio of the compound represented by formula 1 to the compound represented by formula A2 is 1.05; And / or, in step S1, the organic solvent is one or more of dichloromethane, 1,2-dichloroethane, and chloroform; And / or, in step S1, the temperature of the condensation reaction is 20 °C; And / or, in step S1, the reaction time of the condensation reaction is 12 hours; And / or, in step S2, the base is a pyridine base or an imidazole base; And / or, in step S2, the molar ratio of the base to the compound represented by formula A3 is 2; And / or, in step S2, the hydroxy protecting agent P-Hal is tert-butyldiphenylsilyl chloride; And / or, in step S2, the molar ratio of the hydroxyl protecting agent P-Hal to the compound represented by formula A3 is 1.2; And / or, in step S2, the organic solvent is one or more of dichloromethane, 1,2-dichloroethane, and chloroform; And / or, in step S2, the volume-mass ratio of the organic solvent to the compound represented by formula A3 is 3 - 6 mL / g; And / or, in step S2, the temperature of the condensation reaction is 20 °C; And / or, in step S2, the reaction time of the condensation reaction is 8 hours.

16. The preparation method according to claim 15, characterized in that, in step S0, the organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, and tert-butanol; And / or, in step S0, the volume ratio of the organic solvent to water is 1:7.5; And / or, in step S1, the molar ratio of dicyclohexylcarbodiimide to 4-diaminopyridine is 1 - 2; And / or, in step S1, the organic solvent is dichloromethane; And / or, in step S2, the base is imidazole; And / or, in step S2, the organic solvent is dichloromethane.

17. The preparation method according to claim 16, characterized in that, in step S0, the organic solvent is tert-butanol.

18. The preparation method according to claim 13, characterized in that, the preparation method further includes a preparation method of the compound represented by formula A2-3 below, which includes the following steps: subject the compound represented by formula A2-2 to the following carbon-increasing reaction to obtain the compound represented by formula A2; wherein, the carbon-increasing reaction includes the following steps: (i) Under the action of a base, carry out a Darzens reaction on the compound represented by formula A2-2 and chloroacetate in an organic solvent to obtain a Darzens reaction product; (ii) Under the action of a base, carry out a hydrolysis reaction on the Darzens reaction product to obtain a hydrolysis reaction product; (iii) Under the action of an acid, carry out a decarboxylation reaction on the hydrolysis reaction product in a solvent to obtain the compound represented by formula A2-3, that's all; Among them, R 1 and R 2 are defined as described in claim 1.

19. The preparation method according to claim 18, characterized in that, in the carbon-increasing reaction, in the Darzens reaction, the chloroacetate is methyl chloroacetate or ethyl chloroacetate; And / or, in the carbon-increasing reaction, in the Darzens reaction, the equivalent of the chloroacetate is 1.2 - 2.0; And / or, in the carbon-increasing reaction, in the Darzens reaction, the base is sodium alkyl alcoholate or potassium alkyl alcoholate; And / or, in the carbon-increasing reaction, in the Darzens reaction, the molar ratio of the base to the compound represented by formula A2-2 is 1.2 - 2.0; And / or, in the carbon-increasing reaction, in the Darzens reaction, the organic solvent is an alcohol solvent and / or an ether solvent; And / or, in the carbon-increasing reaction, in the Darzens reaction, the temperature is 0 - 35 °C; And / or, in the carbon-increasing reaction, in the Darzens reaction, the reaction time is 1 - 5 hours; And / or, in the carbon increment reaction, the Darzens reaction includes the following steps: the compound shown in Formula A2-2 is dissolved in the organic solvent to form a mixed solution, and the chloroacetate and the base are added to the mixed solution to carry out the Darzens reaction; And / or, in the carbon increment reaction, in the hydrolysis reaction, the base is a hydroxide of an alkali metal; And / or, in the carbon increment reaction, in the hydrolysis reaction, the molar ratio of the base to the compound shown in Formula A2-2 is 1 to 3; And / or, in the carbon increment reaction, the temperature of the hydrolysis reaction is 10 to 30; And / or, in the carbon increment reaction, the reaction time of the hydrolysis reaction is 3 to 5 hours; And / or, in the carbon increment reaction, in the decarboxylation reaction, the acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, and potassium dihydrogen phosphate; And / or, in the carbon increment reaction, in the decarboxylation reaction, the acid is a 10 to 50% acid solution; And / or, in the carbon increment reaction, in the decarboxylation reaction, the molar ratio of the acid to the compound shown in Formula A2-2 is 1.5 to 5.0; And / or, in the carbon increment reaction, in the decarboxylation reaction, the solvent is a mixed solvent of an organic solvent and water; And / or, in the carbon increment reaction, the temperature of the decarboxylation reaction is 60 °C; And / or, in the carbon increment reaction, the reaction time of the decarboxylation reaction is 8 to 36 hours; and / or, the compound represented by Formula A2-2 is the compound represented by Formula A2-3 is 20. The preparation method according to claim 19, characterized in that, in the carbon increment reaction, in the Darzens reaction, the chloroacetate is ethyl chloroacetate; And / or, in the carbon increment reaction, in the Darzens reaction, the equivalent of the chloroacetate is 1.3; And / or, in the carbon increment reaction, in the Darzens reaction, the base is one or more of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; And / or, in the carbon increment reaction, in the Darzens reaction, the molar ratio of the base to the compound shown in Formula A2-2 is 1.3; And / or, in the carbon increment reaction, in the Darzens reaction, the organic solvent is methanol; And / or, in the carbon increment reaction, the temperature of the Darzens reaction is 25 °C; And / or, in the carbon increment reaction, the reaction time of the Darzens reaction is 3 hours; And / or, in the carbon increment reaction, in the hydrolysis reaction, the base is sodium hydroxide and / or potassium hydroxide; And / or, in the carbon increment reaction, in the hydrolysis reaction, the molar ratio of the base to the compound shown in Formula A2-2 is 1.3; And / or, in the carbon increment reaction, the temperature of the hydrolysis reaction is 25 °C; And / or, in the carbon increment reaction, the reaction time of the hydrolysis reaction is 4 hours; And / or, in the carbon increment reaction, in the decarboxylation reaction, the acid is potassium dihydrogen phosphate; And / or, in the carbon increment reaction, in the decarboxylation reaction, the acid is a 50% potassium dihydrogen phosphate solution; And / or, in the carbon addition reaction and the decarboxylation reaction, the organic solvent is one or more of alcohol solvents, ether solvents or amide solvents; And / or, in the carbon addition reaction, the reaction time of the decarboxylation reaction is 24 hours.

21. The preparation method according to claim 20, characterized in that in the carbon addition reaction and the Darzens reaction, the base is sodium methoxide; And / or, in the carbon addition reaction and the decarboxylation reaction, the organic solvent is an ether solvent.

22. The preparation method according to claim 21, characterized in that in the carbon addition reaction and the decarboxylation reaction, the organic solvent is tetrahydrofuran.

23. A preparation method of a compound represented by formula A7, characterized in that the preparation method comprises the following step S8: under the action of a hydrogen source and a palladium catalyst, carrying out the following debenzylation protection reaction on the compound represented by formula A6 in an organic solvent to obtain the compound represented by formula A7; R 1 、R 2 and R 3 are defined as described in claim 1 or claim 2; the preparation method of the compound represented by formula A7 further comprises the preparation method of the compound represented by formula A6, and the preparation method of the compound represented by formula A6 is as described in any one of claims 1 to 22.

24. The preparation method according to claim 23, characterized in that in step S8, the hydrogen source is hydrogen and / or sodium hydride; And / or, in step S8, the molar ratio of the hydrogen source to the compound represented by formula A6 is 1.05 - 2.0; And / or, in step S8, the palladium catalyst is one or more of dry palladium carbon, palladium hydroxide, palladium chloride and palladium acetate; And / or, in step S8, the molar ratio of the palladium catalyst to the compound represented by formula A6 is 0.02 - 0.1; And / or, in step S8, the organic solvent is an ether solvent or an amide solvent; And / or, in step S8, the volume-mass ratio of the organic solvent to the compound represented by formula A6 is 10 - 50 mL / g; And / or, in step S8, the temperature of the debenzylation protection reaction is 40 - 70 °C; And / or, in step S8, the reaction time of the debenzylation protection reaction is 4 - 24 hours; and / or, the compound represented by formula A6 is the compound represented by formula A7 is 25. The preparation method according to claim 24, characterized in that in step S8, the hydrogen source is sodium hydride; And / or, in step S8, the molar ratio of the hydrogen source to the compound represented by formula A6 is 1.5; And / or, in step S8, the palladium catalyst is palladium chloride; And / or, in step S8, the molar ratio of the palladium catalyst to the compound represented by formula A6 is 0.05; And / or, in step S8, the organic solvent is tetrahydrofuran; And / or, in step S8, the volume-mass ratio of the organic solvent to the compound represented by formula A6 is 20 - 30 mL / g; And / or, in step S8, the temperature of the debenzylation protection reaction is 50 °C; And / or, in step S8, the reaction time of the debenzylation protection reaction is 6 hours.

26. A preparation method of a compound represented by formula A9, characterized in that the preparation method comprises the following steps: Step S9: Under the action of a reducing agent, the compound represented by formula A7 is subjected to the following reduction reaction in an organic solvent to obtain the compound represented by formula A8-1, and that's it. Step S10: Under the action of a cyclizing agent, the compound of formula A8-1 is subjected to the following cyclization reaction in an organic solvent to obtain the compound represented by formula A8, and that's it. Step S11: Under the action of an acid, an acidification reaction is carried out on the water suspension of the compound represented by formula A8 to obtain an acidification reaction product, and then under the action of an oxidizing agent, the acidification reaction product is subjected to an oxidation reaction in an organic solvent to obtain the compound represented by formula A9, and that's it. wherein, R 1 , R 2 and R 3 are defined as described in claim 1 or 2; Step S9 further includes the preparation method of the compound represented by formula A7, and the preparation method of the compound represented by formula A7 is as described in any one of claims 23-25.

27. The preparation method according to claim 26, wherein, in step S9, the reducing agent is an alkali metal borohydride and / or lithium aluminum hydride; and / or, in step S9, the molar ratio of the reducing agent to the compound represented by formula A7 is 3-6; and / or, in step S9, the organic solvent is an ether solvent; and / or, in step S9, the temperature of the reduction reaction is -5-35 °C; and / or, in step S9, the reaction time of the reduction reaction is 10-18 hours; and / or, step S9 includes the following steps: dissolving the compound represented by formula A7 in the organic solvent to form a mixture solution, adding the reducing agent to the mixture solution, and carrying out the reduction reaction; and / or, the compound represented by Formula A7 is the compound represented by Formula A8-1 is 28. The preparation method according to claim 27, wherein, in step S9, the reducing agent is sodium borohydride and / or lithium borohydride; and / or, in step S9, the molar ratio of the reducing agent to the compound represented by formula A7 is 5.0; and / or, in step S9, the organic solvent is tetrahydrofuran; and / or, in step S9, the temperature of the reduction reaction is 10-30 °C; and / or, in step S9, the reaction time of the reduction reaction is 12 hours.

29. The preparation method according to claim 28, wherein, in step S9, the reducing agent is lithium borohydride; and / or, in step S9, the temperature of the reduction reaction is 25 °C.

30. The preparation method according to claim 26, wherein, in step S10, the cyclizing agent is one or more of N,N-dimethylformamide dimethyl acetal, p-toluic acid, sodium methoxide and sodium ethoxide; and / or, in step S10, the organic solvent is a chloroalkane solvent; and / or, in step S10, the temperature of the cyclization reaction is 20-35 °C; and / or, in step S10, the reaction time of the cyclization reaction is 8-24 hours.

31. The preparation method according to claim 30, wherein, in step S10, the cyclizing agent is N,N-dimethylformamide dimethyl acetal; and / or, in step S10, the organic solvent is one or more of dichloromethane, 1,2-dichloroethane and chloroform; And / or, in step S10, the temperature of the cyclization reaction is 25 °C; And / or, in step S10, the reaction time of the cyclization reaction is 10 hours.

32. The preparation method according to claim 26, characterized in that in step S11, in the acidification reaction, the acid is one or more of sulfuric acid, hydrochloric acid, acetic acid and formic acid; and / or, in step S11, in the acidification reaction, the amount of the acid is preferably such that the system pH is about 1 to 2; and / or, in step S11, the acidification reaction is carried out under ice-water bath or ice-salt bath conditions; and / or, in step S11, in the oxidation reaction, the oxidant is hydrogen peroxide and / or m-chloroperoxybenzoic acid; and / or, in step S11, in the oxidation reaction, the molar ratio of the oxidant to the compound represented by formula A8 is 1 to 2; and / or, in step S11, in the oxidation reaction, the organic solvent is a chloroalkane solvent; and / or, in step S11, the temperature of the oxidation reaction is 10 to 30 °C; and / or, in step S11, the reaction time of the oxidation reaction is 3 to 8 hours; and / or, the compound represented by formula A8 is the compound represented by formula A9 is 33. The preparation method according to claim 32, characterized in that in step S11, in the acidification reaction, the acid is hydrochloric acid and / or acetic acid; and / or, in step S11, in the oxidation reaction, the molar ratio of the oxidant to the compound represented by formula A8 is 1.1; and / or, in step S11, in the oxidation reaction, the organic solvent is one or more of dichloromethane, 1,2-dichloroethane and chloroform; and / or, in step S11, the temperature of the oxidation reaction is 25 °C; and / or, in step S11, the reaction time of the oxidation reaction is 4 hours.

34. The preparation method according to claim 33, characterized in that in step S11, in the oxidation reaction, the organic solvent is dichloromethane.

35. Use of a compound represented by formula A9 as an intermediate in the preparation of a compound represented by formula A10 or A11, characterized in that the use includes the following Scheme 1 or Scheme 2: Scheme 1. It includes the following step S12: Under the action of a catalyst, hydrogenate the compound represented by formula A9 with hydrogen in an organic solvent to obtain the compound represented by formula A10, that's all. Scheme 2. It includes the following steps S12 and step S13. Step S12 is the same as Scheme 1; Step S13: Under the action of a deprotecting reagent, carry out a deprotection reaction on the compound represented by formula A10 in an organic solvent to obtain the compound represented by formula A11, that's all. wherein, R 1 , R 2 and R 3 are defined as described in claim 1 or 2; Step S12 further includes the preparation method of the compound represented by formula A9, and the preparation method of the compound represented by formula A9 is as described in any one of claims 26-34.

36. The use according to claim 35, characterized in that in step S12, the catalyst is Raney nickel and / or a palladium catalyst; and / or, in step S12, the mass percentage of the catalyst to the compound represented by formula A9 is 30 to 50%; and / or, in step S12, the organic solvent is an alcohol solvent; And / or, in step S12, the pressure of the hydrogenation reaction is 1 to 1.5 atm; And / or, in step S12, the temperature of the hydrogenation reaction is 20 to 35 °C; And / or, in step S12, the reaction time of the hydrogenation reaction is 3 to 10 hours; And / or, in step S13, the deprotecting reagent is boron trichloride and / or boron tribromide; And / or, in step S13, the molar ratio of the deprotecting reagent to the compound represented by formula A10 is 5 to 10; And / or, in step S13, the organic solvent is chloroalkanes; And / or, in step S13, the temperature of the deprotection reaction is -20 to 25 °C; And / or, in step S13, the reaction time of the deprotection reaction is 5 to 10 hours; and / or, the compound represented by Formula A9 is the compound represented by Formula A10 is 37. The application according to claim 36, wherein, in step S12, the catalyst is a palladium catalyst; And / or, in step S12, the organic solvent is methanol and / or ethanol; And / or, in step S12, the pressure of the hydrogenation reaction is 1 atm; And / or, in step S12, the temperature of the hydrogenation reaction is 25 °C; And / or, in step S12, the reaction time of the hydrogenation reaction is 8 hours; And / or, in step S13, the deprotecting reagent is boron tribromide; And / or, in step S13, the molar ratio of the deprotecting reagent to the compound represented by formula A10 is 8; And / or, in step S13, the organic solvent is dichloromethane; And / or, in step S13, the temperature of the deprotection reaction is 10 °C; And / or, in step S13, the reaction time of the deprotection reaction is 8 hours.

38. The application according to claim 37, wherein, in step S12, the catalyst is 5% palladium / barium sulfate, and the "%" is the mass percentage of palladium in the total mass of palladium and barium sulfate.

39. A method for preparing a compound represented by formula A8-1, wherein, the preparation method comprises the following step S9: under the protection of an inert gas, under the action of a reducing agent, carrying out the following reduction reaction on the compound represented by formula A7 in an organic solvent to obtain the compound represented by formula A8-1, that's all. Among them, R 1 , R 2 and R 3 are defined as described in claim 1 or 2, and the conditions and operations of the reduction reaction are as described in any one of claims 26-29; Step S9 further includes the preparation method of the compound represented by formula A7, and the preparation method of the compound represented by formula A7 is as described in any one of claims 23-25.

40. A method for preparing a compound represented by formula A13, wherein, the preparation method comprises the following steps: Step S14: carrying out a cycloaddition reaction on the compound represented by formula A8 and methyl vinyl ketone to obtain a compound represented by formula A12, that's all. Step S15: under the action of a nucleophile, carrying out the following nucleophilic addition reaction on the compound represented by formula A12 in an organic solvent to obtain a compound represented by formula A13, that's all; wherein, R 1 , R 2 and R 3 are defined as described in claim 1 or 2, and R 4 is C 1～10 alkyl, C 3～10 cycloalkyl or C 6～20 aryl; Step S14 further includes the preparation method of the compound represented by formula A8, and the preparation method of the compound represented by formula A8 is as described in any one of claims 26-31.

41. The preparation method according to claim 40, wherein, In step S14, the volume-mass ratio of the methyl vinyl ketone to the compound represented by formula A8 is 0.5 to 5 mL / 100 mg; and / or, in step S14, the temperature of the cycloaddition reaction is 70 to 90 °C; and / or, in step S14, the reaction time of the cycloaddition reaction is 4 to 16 hours.

42. The preparation method according to claim 41, wherein, in step S14, the volume-mass ratio of the methyl vinyl ketone to the compound represented by formula A8 is 3 mL / 100 mg; and / or, in step S14, the temperature of the cycloaddition reaction is 80 °C; and / or, in step S14, the reaction time of the cycloaddition reaction is 6 hours.

43. The preparation method according to claim 40, wherein, in step S15, the nucleophile is a Grignard reagent and / or a lithium reagent; and / or, in step S15, the molar ratio of the nucleophile to the compound represented by formula A12 is 5 to 10; and / or, in step S15, the organic solvent is an ether solvent and / or a substituted aromatic hydrocarbon solvent; and / or, in step S15, the volume-mass ratio of the organic solvent to the compound represented by formula A12 is 5 to 100 mL / g; and / or, in step S15, the temperature of the nucleophilic addition reaction is -5 to 35 °C; and / or, in step S15, the reaction time of the nucleophilic addition reaction is 4 to 10 hours; and / or, R 4 is C 1～4 alkyl.

44. The preparation method according to claim 43, wherein, in step S15, the nucleophile is a Grignard reagent; and / or, in step S15, the molar ratio of the nucleophile to the compound represented by formula A12 is 7; and / or, in step S15, the organic solvent is toluene; and / or, in step S15, the volume-mass ratio of the organic solvent to the compound represented by formula A12 is 40 to 60 mL / g; and / or, in step S15, the temperature of the nucleophilic addition reaction is 10 to 30 °C; and / or, in step S15, the reaction time of the nucleophilic addition reaction is 6 hours; and / or, the compound represented by Formula A12 is the compound represented by Formula A13 is 45. The preparation method according to claim 44, wherein, in step S15, the temperature of the nucleophilic addition reaction is 25 °C.

46. A preparation method of a compound represented by formula A14, wherein, the preparation method comprises the following step S16: under the action of a catalyst, subjecting the compound represented by formula A13 to the following hydrogenation reaction with hydrogen in an organic solvent to obtain the compound represented by formula A14, that's all, the hydrogenation reaction is carried out under a pressure of 5 to 30 atm; wherein, R 1 , R 2 and R 3 are defined as described in claim 1 or 2, and R 4 is defined as described in any one of claims 40 and 43 - 44; Step S16 further includes the preparation method of the compound represented by formula A13, and the preparation method of the compound represented by formula A13 is as described in any one of claims 40-45.

47. The preparation method according to claim 46, wherein, in step S16, the hydrogenation reaction is carried out under a pressure of 10 atm; and / or, in step S16, the catalyst is a palladium catalyst; And / or, in step S16, the molar ratio of the catalyst to the compound represented by formula A13 is 0.03 - 0.2; And / or, in step S16, the organic solvent is an ether and / or alcohol solvent; And / or, in step S16, the temperature of the hydrogenation reaction is 50 - 80 °C; And / or, in step S16, the reaction time of the hydrogenation reaction is 8 - 16 hours; and / or, the compound represented by formula A13 is the compound represented by formula A14 is 48. The preparation method according to claim 47, wherein, in step S16, the catalyst is palladium on carbon; And / or, in step S16, the molar ratio of the catalyst to the compound represented by formula A13 is 0.1; And / or, in step S16, the organic solvent is ethanol and / or isopropanol; And / or, in step S16, the temperature of the hydrogenation reaction is 70 °C; And / or, in step S16, the reaction time of the hydrogenation reaction is 10 hours.

49. A preparation method of a compound represented by formula A15, which comprises the following step S17: Under the action of a base and a thiol, the compound represented by formula A14 is subjected to the following demethylation reaction in an organic solvent to obtain the compound represented by formula A15, that's all. Wherein, R 1 、R 2 and R 3 are defined as described in claim 1 or 2, and R 4 is defined as described in any one of claims 40 and 43 - 44; step S17 further includes the preparation method of the compound represented by formula A14, and the preparation method of the compound represented by formula A14 is as described in any one of claims 46 - 48.

50. The preparation method according to claim 49, wherein, in step S17, the base is an alcohol base; And / or, in step S17, the thiol is an alkyl thiol; And / or, in step S17, the molar ratio of the base to the compound A14 is 1.8 - 3.0; And / or, in step S17, the organic solvent is an amide and / or sulfoxide solvent; And / or, in step S17, the temperature of the demethylation reaction is 100 - 130 °C; And / or, in step S17, the reaction time of the demethylation reaction is 1 - 3 hours; and / or, the compound represented by formula A14 is the compound represented by formula A15 is 51. The preparation method according to claim 50, wherein, in step S17, the base is sodium tert - butoxide and / or potassium tert - butoxide; And / or, in step S17, the thiol is n - dodecyl mercaptan; And / or, in step S17, the molar ratio of the base to the compound A14 is 2.0; And / or, in step S17, the organic solvent is DMSO and / or DMF; And / or, in step S17, the temperature of the demethylation reaction is 120 °C; And / or, in step S17, the reaction time of the demethylation reaction is 2 hours.

52. A preparation method of a compound represented by formula A8, which comprises the following steps: Step S9: Under the protection of an inert gas, under the action of a reducing agent, the compound represented by formula A7 is subjected to the following reduction reaction in an organic solvent to obtain the compound represented by formula A8 - 1, that's all. Step S10: Under the action of a cyclizing agent, formula A8 - 1 is subjected to the following cyclization reaction in an organic solvent to obtain the compound represented by formula A8, that's all. Among them, in the above steps, R 1 , R 2 and R 3 are defined as described in claim 1 or 2; Step S9 further includes a method for preparing the compound represented by Formula A7, and the method for preparing the compound represented by Formula A7 is as described in any one of claims 23-25.

53. The preparation method according to claim 52, wherein, it includes the following steps S1 to step S10: wherein, R 1 , R 2 , R 3 are defined as described in claim 1 or 2; P is defined as described in claim 5, and the conditions and operations of steps S1 to S10 are as described in any one of claims 1-31.

54. A compound represented by Formula A5: wherein, R 1 、R 2 and R 3 are defined as described in claim 1 or 2.

55. The compound represented by Formula A5 according to claim 54, and the compound represented by Formula A5 is

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