CN111205296A

CN111205296A - Oxycodone compound and intermediate and preparation method thereof

Info

Publication number: CN111205296A
Application number: CN201911157445.XA
Authority: CN
Inventors: 汤文军; 徐斯尧
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shaoxing Yujun Biomedical Technology Co ltd
Priority date: 2018-11-22
Filing date: 2019-11-22
Publication date: 2020-05-29
Anticipated expiration: 2039-11-22
Also published as: WO2020103945A1; CN111205296B

Abstract

The invention discloses an oxycodone compound, an intermediate thereof and a preparation method thereof. The invention provides a preparation method of a compound shown as a formula A9, which comprises the following steps: under the action of a palladium catalyst and a phosphine ligand, carrying out dearomatization cyclization reaction shown as the formula A8b in an organic solvent under the action of a protective gas to obtain a compound shown as the formula A9; wherein the phosphine ligand is shown as a formula L1 and/or a formula L2. The preparation method can prepare important intermediate of oxycodone compound shown as formula A9 with high yield。

Description

Oxycodone compound and intermediate and preparation method thereof

Technical Field

The invention relates to an oxycodone compound and an intermediate and a preparation method thereof.

Background

Oxycodone (oxycodone) with the chemical structural formula

Is a semi-synthetic opioid drug extracted from thebaine (alkaloid). Oxycodone has been used clinically for over 80 years as a potent analgesic. Oxycodone has high bioavailability and multiple administration routes, so that oxycodone is widely applied clinically.

At present, the synthesis method of oxycodone compounds is mainly to extract morphine compounds from plants, and the morphine compounds are further modified. Chemical synthesis methods for preparing oxycodone from common compounds as starting materials have not been reported so far.

Disclosure of Invention

The invention provides an oxycodone compound different from the prior art, an intermediate and a preparation method thereof. The preparation method takes the common compound as the starting material to prepare the oxycodone compound, and has high yield and simple operation.

The invention solves the technical problems through the following technical scheme.

The invention provides a preparation method of a compound shown as a formula A9, which comprises the following steps:

under the action of a palladium catalyst and a phosphine ligand, carrying out dearomatization cyclization reaction shown as the formula A8b in an organic solvent under the action of a protective gas to obtain a compound shown as the formula A9; wherein the phosphine ligand is a phosphine ligand shown as a formula L1 and/or a phosphine ligand shown as a formula L2;

wherein R is¹And R²Independently H, C_1～10Alkyl radical, C_1～10Alkoxy radical, C_3～10Cycloalkyl or C_6～20Aryl radical, R³Is C_1～4An alkyl group.

In the dearomatization cyclization reaction, the protective gas may be a protective gas conventional in the art, preferably nitrogen and/or argon, more preferably nitrogen.

In the dearomatization cyclization reaction, the palladium catalyst may be a palladium catalyst conventional in such reactions in the art, preferably one or more of palladium chloride, palladium hydroxide, bis (acetonitrile) palladium chloride, palladium trifluoromethanesulfonate and palladium acetate, more preferably palladium chloride.

In the dearomatization cyclization reaction, the phosphine ligand is preferably a phosphine ligand shown as a formula L1.

In the dearomatization cyclization reaction, the organic solvent may be an organic solvent conventional in such reactions in the art, preferably one or more of an alcohol solvent, an ether solvent, an aromatic solvent, a nitrile solvent, a haloalkane solvent, a sulfoxide solvent and an amide solvent, preferably a sulfoxide solvent and/or an amide solvent, more preferably an amide solvent.

The amide solvent may be N, N-Dimethylformamide (DMF) and/or N, N-Dimethylacetamide (DMA).

In the dearomatization cyclization reaction, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected. The volume-to-mass ratio of the organic solvent to the compound represented by the formula A8b can be the volume-to-mass ratio of such reactions in the field, and is preferably 5-20 ml/g, for example 10 ml/g.

In the dearomatization cyclization reaction, the molar ratio of the palladium catalyst to the compound shown in formula A8b can be a molar ratio which is conventional in the reaction in the field, preferably 0.01 to 0.5, and more preferably 0.1 to 0.5.

In the dearomatization cyclization reaction, the molar ratio of the phosphine ligand to the compound shown as the formula A8b can be 0.01-0.5, preferably 0.1-0.5.

In the dearomatization cyclization reaction, the temperature of the dearomatization cyclization reaction can be 80-180 ℃, and can also be 100-130 ℃, for example 120 ℃.

In the dearomatization cyclization reaction, the progress of the dearomatization cyclization reaction can be monitored by a monitoring method (such as TLC or LCMS) which is conventional in the art, and the process is generally used as an end point of the reaction when the compound shown as the formula A8b disappears. The reaction time may be 10-24 hours, for example 14 hours).

Wherein, R is¹And said R²Independently is preferably H.

R³In (A), the C_1～4Alkyl is preferably C_1～2Alkyl groups, more preferably methyl groups.

The compound shown in the formula A8b is preferably

After the dearomatization cyclization reaction is finished, the method also comprises the following post-treatment steps: and (3) extracting, drying, concentrating and carrying out column chromatography on the reaction solution after the reaction is finished.

In a preferred embodiment, the mixture of the compound represented by formula A8b and the organic solvent is mixed with the catalyst, the ligand and the base. Preferably, the "catalyst, the ligand and the base" are added to the "mixture of the compound represented by formula A8b and the organic solvent". The mode of addition is preferably batchwise addition. The number of the addition in portions is preferably 2-5, and more preferably 3.

The preparation method of the compound shown in the formula A9 can also comprise the preparation method of the compound shown in the formula A8b, which is the method 1 or the method 2;

the method 1 comprises the following steps: under the action of a deprotection reagent, carrying out deprotection reaction shown as the following on a compound shown as a formula A8a-I in an organic solvent to obtain the compound shown as the formula A8 b;

wherein R is⁴Is a hydroxy protecting group; r¹、R²And R³As defined above;

the method 2 comprises the following steps: under the action of alkali, carrying out acylation reaction on a compound shown as a formula A8a-II and chloroformate in an organic solvent as shown in the specification to obtain a compound shown as a formula A8 b;

wherein R is¹、R²And R³The definition of (A) is as described above.

In method 1, the conditions for the deprotection reaction may be those conventional in such reactions in the art, and the following conditions are preferred in the present invention:

in method 1, the deprotection reagent may be tetrabutylammonium fluoride.

In the method 1, the molar ratio of the deprotection reagent to the compound A8a-I is 1-5, for example 1.1.

In the method 1, the organic solvent may be an ether solvent and/or a chlorinated hydrocarbon solvent, and an ether solvent is more preferable. The ether solvent may be one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether (MTBE), more preferably tetrahydrofuran.

In the method 1, the R¹And said R²Independently is preferably H.

In Process 1, R³In (A), the C_1～4Alkyl is preferably C_1～2Alkyl groups, more preferably methyl groups.

In Process 1, when R is in the formula A8a-I⁴In the case of a hydroxyl protecting group, the hydroxyl protecting group may be a hydroxyl protecting group which is conventional in the art, and is preferably a silyl ether protecting group (e.g., trimethylsilyl ether protecting group, t-butyldimethylsilyl ether protecting group, t-butyldiphenylsilyl ether protecting group (TBDPS)), and more preferably t-butyldiphenylsilyl ether protecting groupAnd (4) protecting the base.

In the method 1, the compound shown as the formula A8a-I is preferably

In method 2, the conditions for the acylation reaction can be those conventional in the art, and the following conditions are preferred in the present invention:

in the method 2, the organic solvent can be a chloroalkane solvent and/or an amide solvent, and the chloroalkane solvent is preferred. The chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1, 2-dichloroethane and chloroform, preferably dichloromethane.

In the method 2, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected.

In method 2, the base may be a conventional base for such reactions in the art, preferably a weak organic base, and further preferably triethylamine.

In the method 2, the molar ratio of the alkali to the compound shown in the formula A8a-II can be 1-3, for example, 1.41.

In method 2, the chloroformate may be one or more of methyl chloroformate, ethyl chloroformate, propyl chloroformate and butyl chloroformate, preferably methyl chloroformate.

In the method 2, the molar ratio of the chloroformate to the compound represented by formula A8a-II may be 0.9 to 1.1, for example, 0.96.

In the method 2, the R¹And said R²Independently is preferably H.

In Process 2, R³In (A), the C_1～4Alkyl is preferably C_1～2Alkyl groups, more preferably methyl groups.

In the method 2, the compound shown as the formula A8a-II is preferably

In the method 2, the reaction temperature may be 10 to 50 ℃, for example, 20 ℃, or, for example, 40 ℃.

In the preparation method of the compound shown in the formula A8b-I, the preparation method of the compound shown in the formula A8a-I can comprise the following steps:

under the action of rhodium catalyst and ligand, the compound shown as formula A7 and H₂Carrying out asymmetric hydrogenation reaction in an organic solvent as shown in the specification to obtain a compound as shown in a formula A8 a-I; the ligand is a ligand shown as a formula L3 and/or a ligand shown as a formula L4;

wherein R is⁴、R¹、R²And R³The definition of (A) is as described above.

In the asymmetric hydrogenation reaction, the rhodium catalyst may be a rhodium catalyst conventional in such reactions in the art, preferably one or more of bis (norbornadiene) rhodium (I) tetrafluoroborate, (acetylacetonato) dicarbonylrhodium, rhodium trifluoroacetate dimer, tris (acetonitrile) trichlororhodium, and acetylacetonato dicarbonylrhodium, more preferably bis (norbornadiene) rhodium (I) tetrafluoroborate.

In the asymmetric hydrogenation reaction, the ligand is preferably a ligand shown as a formula L4.

The asymmetric hydrogenation reaction is preferably carried out at a pressure which may be conventional in the art for such reactions, preferably from 1atm to 50atm, for example 300 psi.

The asymmetric hydrogenation reaction is preferably carried out in a reaction vessel (e.g., a high pressure reaction vessel).

In the asymmetric hydrogenation reaction, the organic solvent may be an organic solvent conventional in the reaction in the field, preferably 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 preferably an alcohol solvent.

The alcoholic solvent may be one or more of methanol, ethanol, n-propanol and isopropanol, preferably methanol.

In the asymmetric hydrogenation reaction, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected. The volume-to-mass ratio of the organic solvent to the compound represented by formula a7 may be a conventional volume-to-mass ratio for such reactions in the art, preferably 5 to 20ml/g, for example 10 ml/g.

In the asymmetric hydrogenation reaction, the molar ratio of the rhodium catalyst to the compound shown in formula a7 may be a molar ratio which is conventional in the art in such reactions, and is preferably 0.00005 to 0.0005, for example 0.00015.

In the asymmetric hydrogenation reaction, the molar ratio of the ligand to the compound shown in formula a7 may be 0.00005 to 0.0005, for example, 0.00015.

In the asymmetric hydrogenation reaction, the temperature of the asymmetric hydrogenation reaction may be a temperature conventional in such reactions in the art, preferably 10 ℃ to 50 ℃, e.g., 25 ℃.

Wherein, R is¹And said R²Independently is preferably H.

The compound shown in the formula A7 is preferably

The progress of the asymmetric hydrogenation reaction can be monitored by monitoring methods conventional in the art, (e.g., TLC or HPLC), and is generally determined as the end point of the reaction when the compound of formula A7 disappears. The reaction time may be 10 to 24 hours, for example 12 hours.

After the asymmetric hydrogenation reaction is finished, the following post-treatment steps can be further included: and (3) extracting, drying, concentrating and carrying out column chromatography on the reaction solution after the reaction is finished.

In the preparation method of the compound shown in the formula A8a-I, the preparation method of the compound shown in the formula A7 can comprise the following steps: in POCl₃Under the action of the organic solvent, the compound shown as the formula A6Carrying out a ring closure reaction to obtain a ring closure product; then, under the action of alkali, carrying out acylation reaction of the closed-loop compound and chloroformate in an organic solvent to obtain a compound shown as a formula A7;

wherein R is⁴、R¹、R²And R³The definition of (A) is as described above.

The conditions of the ring closure reaction may be those conventional in such reactions in the art, and the following conditions are preferred in the present invention:

wherein the POCl₃The molar ratio of the compound represented by the formula A6 to the compound represented by the formula A6 can be 1.0-1.5, for example 1.01.

Wherein, the organic solvent can be a chloroalkane solvent and/or an amide solvent, and the chloroalkane solvent is preferred. The chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1, 2-dichloroethane and chloroform, preferably dichloromethane.

The amount of the organic solvent is not particularly limited, as long as the reaction is not affected.

The conditions for the acylation reaction may be those conventional in the art for such reactions, and the following conditions are preferred in the present invention:

among them, the base may be a conventional base for such a reaction in the art, preferably an organic weak base, and further preferably triethylamine.

Wherein the molar ratio of the base to the compound shown in formula A6 can be 1-3, for example 1.41.

Wherein, the chloroformate can be one or more of methyl chloroformate, ethyl chloroformate, propyl chloroformate and butyl chloroformate, and methyl chloroformate is preferred.

Wherein the molar ratio of the chloroformate to the compound represented by formula a6 may be 0.9 to 1.1, for example, 0.96.

Wherein, R is¹And said R²Independently is preferably H.

Wherein R is³In (A), the C_1～4Alkyl is preferably C_1～2Alkyl groups, more preferably methyl groups.

Among them, the compound represented by the formula A6 is preferable

Wherein the reaction temperature can be 10-50 ℃, for example 20 ℃, and also for example 40 ℃.

After the acylation reaction is finished, the method also comprises the following post-treatment steps: and (3) extracting, drying and carrying out column chromatography on the reaction solution after the reaction is finished.

In the preparation method of the compound shown in the formula A8b, the preparation method of the compound shown in the formula A8a-II can comprise the following steps: under the action of a deprotection reagent, carrying out deprotection reaction shown as the following formula A8a-III in an organic solvent to obtain a compound shown as the formula A8 a-II;

wherein R is⁴、R¹And R⁴The definitions of (A) and (B) are as described above.

The conditions for the deprotection reaction may be those conventional in the art for such reactions, and the following conditions are preferred in the present invention:

in the deprotection reaction, the deprotection reagent can be tetrabutylammonium fluoride.

In the deprotection reaction, the molar ratio of the deprotection reagent to the compound A8a-III can be 1-5, for example, 1.1.

In the deprotection reaction, the organic solvent can be an ether solvent and/or a chlorinated hydrocarbon solvent, and preferably an ether solvent. The ether solvent may be one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether (MTBE), more preferably tetrahydrofuran.

Wherein, R is¹And said R²Independently is preferably H.

In the formula A8a-III, when R⁴In the case of a hydroxyl protecting group, the hydroxyl protecting group may be a silyl ether protecting group (e.g., trimethylsilyl ether protecting group, t-butyldimethylsilyl ether protecting group, t-butyldiphenylsilyl ether protecting group (TBDPS-), and more preferably a t-butyldiphenylsilyl ether protecting group.

The compound shown as the formula A8a-III is preferably

In the preparation method of the compound shown in the formula A8a-II, the preparation method of the compound shown in the formula A8a-III can comprise the following steps: under the action of a metal complex, carrying out asymmetric hydrogenation reaction on a compound shown as a formula A8a-IV in a solvent to obtain a compound shown as a formula A8 a-III; the metal complex is a complex shown as a formula L5;

wherein R is¹、R²And R⁴The definitions of (A) and (B) are as described above.

In the asymmetric hydrogenation reaction, the organic solvent may be an organic solvent conventional in the reaction in the field, preferably one or more of an alcohol solvent, an ether solvent, an aromatic hydrocarbon solvent, a nitrile solvent, a haloalkane solvent, a sulfoxide solvent and an amide solvent, preferably a halogenated solvent, and further preferably dichloromethane.

In the asymmetric hydrogenation reaction, the amount of the organic solvent used is not particularly limited as long as the reaction is not affected.

In the asymmetric hydrogenation reaction, the molar ratio of the metal complex to the compound shown in formula A8a-IV can be a molar ratio which is conventional in the reaction in the field, and is preferably 0.005-0.05, for example 0.02.

The asymmetric hydrogenation reaction is preferably carried out in the presence of a reducing agent. The reducing agent is preferably a weak organic base or weak organic acid. The weak organic base may be triethylamine. The weak organic acid may be formic acid. The molar ratio of the organic weak base to the compound shown in the formula A8a-IV is preferably 1.5-3.0, such as 1.8. The molar ratio of the weak organic acid to the compound shown in the formula A8a-IV is preferably 15-30, such as 21. The volume ratio of the weak organic acid to the weak organic base is preferably 2-5, such as 3.

Wherein, R is¹And said R²Independently is preferably H.

The post-treatment step of the asymmetric hydrogenation reaction may be a post-treatment step of an organic reaction, which is conventional in the art, and may include the following steps: and after the reaction is finished, adjusting the pH value of the reaction solution to 8-9, extracting, drying, filtering, concentrating and carrying out column chromatography. The reagent for adjusting the pH of the reaction solution may be a carbonate salt, and sodium bicarbonate is more preferable. The solvent used for the extraction may be ethyl acetate.

In the preparation method of the compound shown in the formula A8a-III, the preparation method of the compound shown in the formula A8a-IV can comprise the following steps: in POCl₃Under the action, carrying out a ring closure reaction on a compound shown as a formula A6 in an organic solvent to obtain the compound shown as a formula A8 a-IV;

in the ring-closing reaction, thePOCl₃The molar ratio of the compound represented by the formula A6 to the compound represented by the formula A6 can be 1.0-1.5, for example 1.01.

In the ring closing reaction, the organic solvent can be a chloroalkane solvent and/or an amide solvent, and the chloroalkane solvent is preferred. The chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1, 2-dichloroethane and chloroform, preferably dichloromethane.

In the ring-closing reaction, the amount of the organic solvent may not be particularly limited as long as the reaction is not affected.

The temperature of the ring closing reaction can be 30-50 ℃, for example 40 ℃.

The preparation methods of the compounds shown in the formulas A8a-IV and A7 and the preparation method of the compound shown in the formula A6 can comprise the following steps:

under the action of a catalyst, carrying out condensation reaction on a compound shown as a formula A5 and a compound shown as a formula A2 in an organic solvent to obtain a compound shown as a formula A6;

The conditions of the condensation reaction may be those conventional in the art for such reactions, and the following conditions are preferred in the present invention:

wherein the catalyst may be one or more of "Dicyclohexylcarbodiimide (DCC) and 4-Diaminopyridine (DMAP)", 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), and Carbonyldiimidazole (CDI), preferably "dicyclohexylcarbodiimide and 4-diaminopyridine". The molar ratio of the dicyclohexylcarbodiimide to the 4-diaminopyridine may be 1.0 to 2.

Wherein, the molar ratio of the catalyst to the compound shown in the formula A5 can be 1.0-3, such as 1.17.

Wherein, the molar ratio of the compound shown in the formula A2 to the compound shown in the formula A5 can be 1.0-3, such as 1.15.

Wherein, the organic solvent can be alkyl chloride and/or amide, and is preferably alkyl chloride. The chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1, 2-dichloroethane and chloroform, preferably dichloromethane.

Wherein the condensation reaction temperature can be 10-30 ℃, for example 20 ℃.

The progress of the condensation reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound represented by formula A5 disappears. The condensation reaction time can be 12-36 h, such as 30 h.

Wherein, R is¹And said R²Independently is preferably H.

Among them, the compound represented by the formula A5 is preferable

After the condensation reaction is finished, the method also comprises the following post-treatment steps: and (3) extracting, drying and carrying out column chromatography on the reaction solution after the reaction is finished.

The invention also provides a preparation method of the compound shown as the formula A8a-I, which comprises the following steps: under the action of rhodium catalyst and ligand, the compound shown as formula A7 and H₂Carrying out asymmetric hydrogenation reaction in an organic solvent as shown in the specification to obtain a compound as shown in a formula A8 a; the ligand is a ligand shown as a formula L3 and/or a ligand shown as a formula L4;

whereinR¹、R²、R³And R⁴The definitions of (A) and (B) are as described above.

Wherein the conditions in the asymmetric hydrogenation reaction are all as described above.

The invention also provides a preparation method of the compound shown in the formula A8a-III, which comprises the following steps: under the action of a metal complex, carrying out asymmetric hydrogenation reaction on a compound shown as a formula A8a-IV in a solvent to obtain a compound shown as a formula A8 a-III; the metal complex is a complex shown as a formula L5;

The asymmetric hydrogenation method of the invention can be used for obtaining hydrogenation products with high optical purity and/or high yield.

The invention also provides a preparation method of the compound shown in the formula A, which comprises the following steps:

s1: under the action of a catalyst, carrying out condensation reaction on a compound shown as a formula A5 and a compound shown as a formula A2 in an organic solvent to obtain a compound shown as a formula A6;

s2: in POCl₃Under the action, carrying out ring closure reaction on the compound shown as the formula A6 in an organic solvent to obtain a ring closure product;

then, under the action of alkali, reacting the closed-loop compound with chloroformate in an organic solvent to obtain a compound shown as a formula A7;

s3: under the action of a rhodium catalyst and a ligand, reacting the compound shown as the formula A7 with H₂Carrying out asymmetric hydrogenation reaction in an organic solvent as shown below to obtain a compound shown as a formula A8 a; the ligand is shown as a formula L3 and/or a formula L4A body;

s4: under the action of a deprotection reagent, carrying out deprotection reaction shown as the following formula A8a in an organic solvent to obtain a compound shown as a formula A8 b;

s5: under the action of a palladium catalyst and a phosphine ligand, carrying out dearomatization cyclization reaction shown as the following on the compound shown as the formula A8b in an organic solvent under the action of protective gas to obtain a compound shown as the formula A9; wherein the phosphine ligand is a phosphine ligand shown as a formula L1 and/or a phosphine ligand shown as a formula L2;

s6: under the action of a deprotection reagent, carrying out deprotection reaction shown as the following on the compound shown as the formula A9 in an organic solvent to obtain a compound shown as the formula A10;

s7: under the action of a reducing agent, carrying out the reduction reaction shown as the following on the compound shown as the formula A10 in an organic solvent to obtain a compound shown as the formula A11;

s8: under the action of a cyclization reagent, carrying out cyclization reaction on the compound shown as the formula A11 in an organic solvent to obtain a compound shown as the formula A12;

s9: under the action of an oxidant, carrying out an oxidation reaction on the compound shown as the formula A12 in an organic solvent to obtain a compound shown as the formula A13;

s10: under the action of a catalyst, carrying out hydrogenation reaction on the compound shown as the formula A13 in an organic solvent to obtain a compound shown as the formula A14;

s11: under the action of a reducing agent, carrying out the reduction reaction shown as the following on the compound shown as the formula A14 in an organic solvent to obtain a compound shown as the formula A15;

s12: under the action of an oxidant, carrying out an oxidation reaction shown as the following in an organic solvent on the compound shown as the formula A15 to obtain the compound shown as the formula A;

wherein R is¹、R²And R³The definitions of (A) and (B) are as described above.

In step S1, the condensation reaction conditions may be those conventional in such reactions in the art, and the following conditions are preferred in the present invention:

in step S1, the catalyst may be one or more of "Dicyclohexylcarbodiimide (DCC) and 4-Diaminopyridine (DMAP)", 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), and Carbonyldiimidazole (CDI), preferably "dicyclohexylcarbodiimide and 4-diaminopyridine". The molar ratio of the dicyclohexylcarbodiimide to the 4-diaminopyridine may be 1.0 to 2.

In step S1, the molar ratio of the catalyst to the compound represented by formula a5 may be 1.0 to 3, for example, 1.17.

In step S1, the molar ratio of the compound represented by formula a2 to the compound represented by formula a5 may be 1.0 to 3, for example, 1.15.

In step S1, the organic solvent may be a chlorinated alkane and/or an amide, preferably a chlorinated alkane. The chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1, 2-dichloroethane and chloroform, preferably dichloromethane.

In step S1, the amount of the organic solvent used may not be particularly limited as long as the reaction progress is not affected.

In step S1, the condensation reaction temperature may be 10 to 30 ℃, for example, 20 ℃.

In step S1, the progress of the condensation reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A5 disappears. The condensation reaction time can be 12-36 h, such as 30 h.

In step S1, R is¹And said R²Independently is preferably H.

In step S1, R³In (A), the C_1～4Alkyl is preferably C_1～2Alkyl radical, orMethyl is preferred for one step.

In step S1, the compound represented by formula A5 is preferably

In step S2, the conditions of the ring-closing reaction can be the conditions conventional in this type of reaction in the art, and the following conditions are preferred in the present invention:

in step S2, the POCl₃The molar ratio of the compound represented by the formula A6 to the compound represented by the formula A6 can be 1.0-1.5, for example 1.01.

In step S2, the organic solvent may be a chlorinated alkane solvent and/or an amide solvent, preferably a chlorinated alkane solvent. The chlorinated hydrocarbon solvent may be one or more of dichloromethane, 1, 2-dichloroethane and chloroform, preferably dichloromethane.

In step S2, the amount of the organic solvent used may not be particularly limited as long as the reaction progress is not affected.

In step S2, the base may be a conventional base for such reactions in the art, preferably a weak organic base, and further preferably triethylamine.

In step S2, the molar ratio of the base to the compound represented by formula a6 may be 1 to 3, for example, 1.41.

In step S2, the chloroformate may be one or more of methyl chloroformate, ethyl chloroformate, propyl chloroformate, and butyl chloroformate, preferably methyl chloroformate.

In step S2, the reaction temperature may be 10 to 50 ℃, for example, 20 ℃, or, for example, 40 ℃.

In step S2, the molar ratio of the chloroformate to the compound represented by formula a6 may be 0.9 to 1.1, for example, 0.96.

In step S2, R is¹And said R²Independently is preferably H.

In step S2, R³In (A), theC_1～4Alkyl is preferably C_1～2Alkyl groups, more preferably methyl groups.

The compound shown in the formula A6 is preferably

After step S2 is finished, the following post-processing steps may be further included: and (3) extracting, drying and carrying out column chromatography on the reaction solution after the reaction is finished.

In step S3, the conditions of the asymmetric hydrogenation reaction are the same as described above.

In step S4, the deprotection reaction conditions are the same as described above.

In step S5, the dearomatization cyclization reaction conditions are the same as described above.

In step S6, the conditions for the deprotection reaction may be those conventional in this type of reaction in the art, and the following conditions are preferred in the present invention:

in step S6, the deprotection reagent may be one or more of boron trichloride, boron tribromide and Pd/hydrogen, preferably boron trichloride.

In step S6, the molar ratio of the deprotecting reagent to the compound a9 may be 2 to 5, for example, 4.

In step S6, the organic solvent may be a chlorinated alkane. The chlorinated hydrocarbon solvent is preferably dichloromethane.

In step S6, the amount of the organic solvent used may not be particularly limited as long as the reaction progress is not affected.

In step S6, the deprotection reaction may be carried out at a temperature of-78 to-50 deg.C, for example-60 deg.C.

In step S6, the progress of the deprotection reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A9 disappears. The deprotection reaction time can be 1-3 h, such as 1.5 h.

In step S6, R is¹And said R²Independently is preferably H.

In step S6, R³In (A), the C_1～4Alkyl is preferably C_1～2Alkyl groups, more preferably methyl groups.

The compound shown in the formula A9 is preferably

After the deprotection reaction is finished, the method also comprises the following post-treatment steps: and (3) extracting, drying, concentrating and carrying out column chromatography on the reaction solution after the reaction is finished.

In step S7, the conditions of the reduction reaction can be conventional in the art, and the following conditions are preferred in the present invention:

in step S7, the reducing agent may be an alkali metal borohydride and/or lithium aluminum hydride, preferably an alkali metal borohydride. The alkali metal borohydride can be sodium borohydride and/or lithium borohydride, preferably sodium borohydride.

In step S7, the molar ratio of the reducing agent to the compound A10 can be 3-6.

In step S7, the organic solvent may be an alcohol solvent and/or a chloroalkane solvent, preferably an alcohol solvent. The alcoholic solvent may be methanol and/or ethanol, preferably methanol.

In step S7, the amount of the organic solvent used may not be particularly limited as long as the reaction progress is not affected.

In step S7, the temperature of the reduction reaction may be-5 to 5 ℃, for example, 0 ℃.

In step S7, the progress of the reduction reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A10 disappears. The time of the reduction reaction can be 1-3 h, such as 1.5 h.

In step S7, R is¹And said R²Independently is preferably H.

In step S7, R³In (A), the C_1～4Alkyl is preferably C_1～2Alkyl groups, more preferably methyl groups.

In step S7, the formula is shown in A10The compound is preferably

After the reduction reaction is finished, the method also comprises the following post-treatment steps: and (3) extracting, drying, concentrating and carrying out column chromatography on the reaction solution after the reaction is finished.

In step S8, the conditions of the cyclization reaction may be those conventional in the art, and the following conditions are preferred in the present invention:

in step S8, the cyclizing reagent may 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.

In step S8, the molar ratio of the cyclizing reagent to the compound represented by formula a11 may be 10 to 15.

In step S8, the organic solvent may be a chlorinated alkane solvent. The chloroalkane solvent may be one or more of dichloromethane, 1,2 dichloroethane and chloroform, preferably dichloromethane.

In step S8, the amount of the organic solvent used may not be particularly limited as long as the reaction progress is not affected.

In step S8, the temperature of the cyclization reaction may be-5 to 5 ℃, for example, 0 ℃.

In step S8, the progress of the cyclization reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A11 disappears. The time of the reduction reaction can be 5-12 h, such as 8 h.

In step S8, R is¹And said R²Independently is preferably H.

In step S8, R³In (A), the C_1～4Alkyl is preferably C_1～2Alkyl groups, more preferably methyl groups.

In step S8, the compound represented by formula A11 is preferably

After the cyclization reaction is finished, the method also comprises the following post-treatment steps: extracting the reaction solution, drying, concentrating and carrying out column chromatography.

In step S9, the conditions of the oxidation reaction can be conventional in the art, and the following conditions are preferred in the present invention:

in step S9, the oxidizing agent may be m-chloroperoxybenzoic acid (mCPBA).

In step S9, the molar ratio of the oxidant to the compound A12 may be 1-2, for example, 1.1.

In step S9, the organic solvent may be a chlorinated alkane solvent. The chloroalkane solvent may be one or more of dichloromethane, 1,2 dichloroethane and chloroform, preferably dichloromethane.

In step S9, the amount of the organic solvent used may not be particularly limited as long as the reaction progress is not affected.

In step S9, the temperature of the oxidation reaction may be 30 to 60 ℃, for example, 40 ℃.

In step S9, the progress of the oxidation reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A12 disappears. The time of the reduction reaction can be 3-8 h, such as 5 h.

In step S9, R is¹And said R²Independently is preferably H.

In step S9, R³In (A), the C_1～4Alkyl is preferably C_1～2Alkyl groups, more preferably methyl groups.

In step S9, the compound represented by formula A12 is preferably

After the oxidation reaction is finished, the method also comprises the following post-treatment steps: and (3) extracting, drying, concentrating and carrying out column chromatography on the reaction solution after the reaction is finished.

In step S10, the conditions of the hydrogenation reaction may be those conventional in such reactions in the art, and the following conditions are preferred in the present invention:

in step S10, the catalyst may be raney nickel and/or a palladium catalyst, preferably a palladium catalyst, more preferably palladium/carbon, and even more preferably 10% palladium/carbon, where "%" is the mass percentage of the palladium to the total mass of the palladium and the carbon.

In step S10, the mass percentage of the catalyst to the compound a13 may be 30 to 50%, for example, 36%.

In step S10, the organic solvent may be an alcohol solvent. The alcoholic solvent may be methanol and/or ethanol, preferably methanol.

In step S10, the amount of the organic solvent used may not be particularly limited as long as the reaction progress is not affected.

In the step S10, the pressure of the hydrogenation reaction may be 1 to 1.5 atm.

In step S10, the temperature of the hydrogenation reaction may be 30 to 60 ℃, for example, 40 ℃.

In step S10, the progress of the hydrogenation reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A13 disappears. The hydrogenation reaction time can be 3-8 h, such as 5 h.

In step S10, R is¹And said R²Independently is preferably H.

In step S10, R³In (A), the C_1～4Alkyl is preferably C_1～2Alkyl groups, more preferably methyl groups.

In step S10, the compound represented by formula A13 is preferably

After the hydrogenation reaction is finished, the method also comprises the following post-treatment steps: and (3) extracting, drying, concentrating and carrying out column chromatography on the reaction solution after the reaction is finished.

In step S11, the conditions of the reduction reaction can be conventional in the art, and the following conditions are preferred in the present invention:

in step S11, the reducing agent may be lithium aluminum hydride and/or an alkali metal borohydride, preferably sodium lithium aluminum hydride.

In step S11, the molar ratio of the reducing agent to the compound represented by formula a14 may be 3 to 8, for example, 6.

In step S11, the organic solvent may be an ether solvent. The ether solvent may be one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether (MTBE), preferably tetrahydrofuran.

In step S11, the amount of the organic solvent used may not be particularly limited as long as the reaction progress is not affected.

In step S11, the temperature of the reduction reaction may be 10 to 40 ℃, for example, 20 ℃.

In step S11, the progress of the reduction reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A14 disappears. The time of the reduction reaction can be 1-4 h, such as 2 h.

In step S11, R is¹And said R²Independently is preferably H.

In step S11, R³In (A), the C_1～4Alkyl is preferably C_1～2Alkyl groups, more preferably methyl groups.

In step S11, the compound represented by formula A14 is preferably

After the reduction reaction is finished, the method also comprises the following post-treatment steps: extracting the reaction solution, drying, concentrating and carrying out column chromatography.

In step S12, the operation and conditions of the oxidation reaction may be those conventional in the art for such reactions, and the following conditions are preferred in the present invention:

in step S12, the oxidant may be dessimutan oxidant (Dess-Martin) and/or hydrogen peroxide, preferably dessimutan oxidant.

In step S12, the molar ratio of the oxidant to the compound represented by formula a15 may be 1 to 3, for example, 1.5.

In step S12, the organic solvent may be an ether solvent and/or a halogenated alkane solvent, preferably a halogenated alkane solvent. The haloalkane solvent may be one or more of dichloromethane, 1, 2-dichloroethane and chloroform, preferably dichloromethane.

In step S12, the amount of the organic solvent used may not be particularly limited as long as the reaction progress is not affected.

In step S12, the temperature of the oxidation reaction may be 10 to 40 ℃, for example, 20 ℃.

In step S12, the progress of the oxidation reaction can be monitored by conventional monitoring methods in the art (e.g., TLC or LCMS), and is generally determined as the end point of the reaction when the compound of formula A15 disappears. The time of the reduction reaction can be 1-4 h, such as 2 h.

In step S12, R is¹And said R²Independently is preferably H.

The compound shown in the formula A15 is preferably

s6': under the action of a deprotection reagent, carrying out deprotection reaction shown as the following on the compound shown as the formula A9 in an organic solvent to obtain a compound shown as the formula A10;

s7': under the action of a reducing agent, carrying out the reduction reaction shown as the following on the compound shown as the formula A10 in an organic solvent to obtain a compound shown as the formula A11;

s8': under the action of a cyclization reagent, carrying out cyclization reaction on the compound shown as the formula A11 in an organic solvent to obtain a compound shown as the formula A12;

s9': under the action of an oxidant, carrying out an oxidation reaction on the compound shown as the formula A12 in an organic solvent to obtain a compound shown as the formula A13;

s10': under the action of a catalyst, carrying out hydrogenation reaction on the compound shown as the formula A13 in an organic solvent to obtain a compound shown as the formula A14;

s11': under the action of a reducing agent, carrying out the reduction reaction shown as the following on the compound shown as the formula A14 in an organic solvent to obtain a compound shown as the formula A15;

s12': under the action of an oxidant, carrying out an oxidation reaction shown as the following in an organic solvent on the compound shown as the formula A15 to obtain the compound shown as the formula A;

wherein the compound shown as the formula A9 is prepared according to any one method; the conditions and operations in steps S6 'to S12' are the same as those in steps S6 to S12; r¹、R²And R³The definitions of (A) and (B) are as described above.

The invention also provides a preparation method of the compound shown as the formula A6, which comprises the following steps:

wherein R is¹、R²And R⁴Is as defined aboveSaid (R)¹And R²Independently H, C_1～10Alkyl radical, C_1～10Alkoxy radical, C_3～10Cycloalkyl or C_6～20Aryl radical, R⁴As a hydroxyl protecting group).

The invention also provides a preparation method of the compound shown as the formula A7, which comprises the following steps: in POCl₃Under the action, carrying out ring closure reaction on a compound shown as a formula A6 in an organic solvent to obtain a ring closure product;

wherein R is¹、R²、R³And R⁴The definitions of (A) and (B) are as described above.

The conditions of the catalytic reaction are the same as those described above.

The invention also provides a preparation method of the compound shown as the formula A8b, which comprises the following steps: under the action of a deprotection reagent, carrying out deprotection reaction shown as the following formula A8a-I in an organic solvent to obtain a compound shown as the formula A8 b;

The deprotection reaction conditions were as described above.

The invention also provides a preparation method of the compound shown as the formula A10, which comprises the following steps: under the action of a deprotection reagent, carrying out deprotection reaction shown as the following on a compound shown as a formula A9 in an organic solvent to obtain a compound shown as a formula A10;

The deprotection reaction conditions were as described above.

The invention also provides a preparation method of the compound shown as the formula A11, which comprises the following steps: under the action of a reducing agent, carrying out a reduction reaction shown as the following on a compound shown as a formula A10 in an organic solvent to obtain a compound shown as a formula A11;

wherein R is¹、R²And R³Are as defined for (R)¹And R²Independently H, C_1～10Alkyl radical, C_1～10Alkoxy radical, C_3～10Cycloalkyl or C_6～20Aryl radical, R³Is C_1～4Alkyl groups).

The conditions of the reduction reaction are the same as those described above.

The invention also provides a preparation method of the compound shown as the formula A12, which comprises the following steps: under the action of a cyclization reagent, carrying out cyclization reaction on a compound shown as a formula A11 in an organic solvent to obtain a compound shown as a formula A12;

The conditions for the cyclization reaction are as described above.

The invention also provides a preparation method of the compound shown as the formula A13, which comprises the following steps: carrying out oxidation reaction on a compound shown as a formula A12 in an organic solvent under the action of an oxidant to obtain a compound shown as a formula A13;

The oxidation conditions were as described above.

The invention also provides a preparation method of the compound shown as the formula A14, which comprises the following steps: under the action of a catalyst, carrying out hydrogenation reaction on a compound shown as a formula A13 in an organic solvent as shown in the specification to obtain a compound shown as a formula A14;

The conditions for the hydrogenation reaction are as described above.

The invention also provides a preparation method of the compound shown as the formula A15, which comprises the following steps: under the action of a reducing agent, carrying out a reduction reaction shown as the following on a compound shown as a formula A14 in an organic solvent to obtain a compound shown as a formula A15;

The conditions of the reduction reaction are the same as those described above.

The invention also provides a preparation method of the compound shown in the formula A, which comprises the following steps: under the action of an oxidant, carrying out an oxidation reaction shown as the following in an organic solvent on a compound shown as a formula A15 to obtain the compound shown as the formula A;

wherein R is¹And R²The definitions of (A) and (B) are as described above.

The oxidation conditions were as described above.

The invention also provides a compound shown as the formula A6:

The invention also provides a compound shown as the formula A7:

wherein R is¹、R²、R³And R⁴The definitions of (A) and (B) are as described above. The invention also provides a compound shown as the formula A8 a-I:

wherein R is¹、R²、R³And R⁴The definitions of (A) and (B) are as described above. The invention also provides a compound shown as the formula A8 b:

The invention also provides a compound shown as the formula A9:

The invention also provides a compound shown as the formula A10:

The invention also provides a compound shown as the formula A11:

The invention also provides a compound shown as the formula A12:

The invention also provides a compound shown as the formula A13:

The invention also provides a compound shown as the formula A14:

The invention also provides a compound shown as the formula A15:

wherein R is¹And R²The definitions of (A) and (B) are as described above.

The invention also provides a compound shown as the formula A8 a-IV:

The invention also provides a compound shown as the formula A8 a-III:

The invention also provides a compound shown as the formula A8 a-II:

wherein R is¹And R²The definitions of (A) and (B) are as described above.

The invention also provides a compound shown as the formula A7:

The compounds represented by the formulae A7, A8a-I, A8a-II, A8a-III, A8a-IV, A8b, A9, A10, A11, A12, A13, A14 or A15 are preferably the following compounds:

in the present invention, chemical bond

Meaning that the radical attached to the chiral carbon atom is either above or below the plane, e.g. compounds

To represent

Or

The above-mentioned preparation methods of the compounds may be combined as desired to give a synthetic route of the compound represented by the formula A, A8-8-III, A or A (for example, A → A → A8-I, A → A8-IV → A8-III, A → A → A → A8-I → A, A → A8-IV → A8-III → A8-II → A, A → A → A → A → A → A → A → A8-IV → A → A8-II → A → A → A → A → A → A → A → A, etc.).

In the present invention, "C_1-10Alkyl "and" C_1-4Alkyl "includes both straight chain and branched chain alkyl groups.

In the present invention, "alkoxy" means a group-O-R^XWherein R is^XIs an alkyl group as defined above.

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

As used herein, "aryl" refers to a group having a 4n +2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array). Aryl of 6 to 14 carbon atoms, such as phenyl, naphthyl, phenanthryl, or anthracyl, is preferred.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents of the invention are self-made phosphine ligands shown in formulas L1-2 and ligands shown in formulas L3-4, and other reagents and raw materials are commercially available.

The positive progress effects of the invention are as follows: the preparation method of the invention takes common reagents as starting materials to prepare the oxycodone compounds, and has high yield and simple operation.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Example 1 Compound (2- (4- ((tert-butylpropylphenyl) oxy) -3-methoxyphenyl) ethan-1-amine) represented by the formula A2-1

A compound represented by the formula A1-1 (Tert-butyl (2-methoxy-4- (2-nitro) phenoxy) diphenylsilane)

Ammonium acetate (9.1g,118mmol) was slowly added in equal portions to a solution of vanillin (15g,98.5mmol) in nitromethane (1.0g, 1.93mmol, 1.0 equiv.) at 20 ℃. The reaction mixture was stirred at 100 ℃ for 3 hours, then cooled and spin dried. The resulting solution was extracted three times with a saturated solution of ammonium chloride and dichloromethane (300mL), the organic phases taken, the combined organic phases dried over sodium sulfate and recrystallized from methanol (30mL) to give the product as a yellow solid which was directly put to the next step.

Tert-butyldiphenylchlorosilane (25.7g,93.6mmol) was slowly added in equal portions to a solution of the product of the previous step and imidazole (6.4g,93.6mmol) in dichloromethane (135mL) at 20 ℃. The reaction mixture was stirred at 20 ℃ for 6 hours. The system was extracted three times with a saturated solution of ammonium chloride and dichloromethane (200mL), the organic phases taken, the combined organic phases dried over sodium sulfate and recrystallized from methanol (40mL) to give the product as a yellow solid (14.3g, 75% yield).

A compound (2- (4- ((tert-butylpropylsilylyl) oxy) -3-methoxyphenyl) ethan-1-amine) shown as a formula A2-1

Lithium aluminum hydride (4g,105mmol) was slowly added in equal portions to a solution of A-1(15g,35mmol) in anhydrous tetrahydrofuran (100mL) at-10 ℃. The reaction mixture was stirred at 20 ℃ for 50 minutes. The system was extracted three times with saturated solution of potassium sodium tartrate and ethyl acetate (100mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a pale yellow oil (7.7g, 55% yield).¹H NMR(500MHz,CDCl₃)δ7.62-7.30(m,10H),6.82(m,2H),6.67(d,J＝9Hz,1H),3.93(s,3H),2.84(dd,J＝6.8,13.6Hz,2H)，2.68(dd,J＝6.8,13.6Hz,2H),1.09(s,9H)；[M+H]⁺:406.61；Found:406.6.

Example 2 Compound (2- (3- (benzyloxy) -2-bromo-4-methoxyphenyl) acetic acid) represented by the formula A5-1

A compound represented by the formula A3-1 (2-bromo-3-hydroxy-4-methoxybenzadheride)

A solution of liquid bromine (3.7mL,0.0726mol) in acetic acid (12.5mL) was slowly added in equal portions to a solution of isovanillin (10g,66mmol), anhydrous sodium acetate (10.82g,0.132mol) and iron powder (0.3g,5.4mmol) in acetic acid (60mL) at 0 deg.C. After stirring the reaction mixture at 20 ℃ for 12h, the system was poured into deionized water (70mL) and stirred for 1h, and after filtration a viscous solid was obtained which was recrystallized from ethanol (50mL) to give the product as a white solid (11.93g, 79% yield).

A compound (3- (benzoyloxy) -2-bromo-4-methoxybenzadheride) represented by the formula A4-1

Potassium carbonate (10.8g,77.4mmol) was added in equal portions to a solution of A-3(12g,51.6mmol) and benzyl bromide (6.7mL) in dimethylformamide (120mL) at-10 deg.C in three portions. The reaction mixture was stirred at 20 ℃ for 8 hours. The system was extracted three times with a saturated solution of sodium chloride and dichloromethane (150mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a white solid (15.8g, 95% yield).

A compound (2- (3- (benzyloxy) -2-bromo-4-methoxyphenyl) acetic acid) as shown in formula A5-1

Ruthenium trichloride (830mg,4mmol) was added in equal portions to a solution of A-4(11.8g,33.6mmol) and sodium periodate (14.6g,67.2mmol) in dichloromethane, water, acetonitrile (300mL,1:1:1) at 0 ℃. The reaction mixture was stirred at 20 ℃ for 0.5 h. The system was extracted three times with a saturated solution of sodium chloride and dichloromethane (250mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a white oil (10.7g, 87% yield).¹H NMR(400MHz,d-DMSO)δ12.39(s,1H),7.53-7.34(m,5H),7.15(d,J＝8.0Hz,1H),7.05(d,J＝8.0Hz,1H),4.94(s,2H),3.85(s,3H),3.68(s,2H)；[M+H]⁺:352.20；Found:352.21.

Example 3 Compound (2- (3- (benzoyloxy) -2-bromo-4-methoxyphenyl) -N- (4- ((tert-butylpropylphenyl) oxy) -3-methoxyphenyl) acetamide) represented by formula A6-1

Dicyclohexylcarbodiimide (3.2g,15mmol) and 4-dimethylaminopyridine (1.4mg,15mmol) were added in equal portions to a solution of A5(4.52g,12.8mmol) and A-2(6g,14.8mmol) in dichloromethane (60mL) at 0 deg.C in three portions. The reaction mixture was stirred at 20 ℃ for 30 hours. The system was extracted three times with a saturated solution of sodium chloride and dichloromethane (150mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product (9.03g, 95% yield) as a white solid.¹H NMR(500MHz,d-DMSO)δ7.74–7.34(m,15H),7.03(m,2H),6.84(d,J＝8.0Hz,1H),6.80(s,1H),6.70(d,J＝8.0Hz,1H),5.13(s,2H),3.93(s,3H),3.83(s,3H),3.79(s,3H),2.74(dd,J＝6.8,13.6Hz,2H),2.58(dd,J＝6.8,13.6Hz,2H),1.09(s,9H)；[M+H]⁺:739.79；Found:739.79.

Example 4 Compound represented by the formula A7-1 (methyl (Z) -1- (3- (benzyloxy) -2-bromo-4-methoxybenzidine) -7- ((tert-butylphenylglycine) oxy) -6-methoxy-3, 4-dihydroquino line-2(1H) -carboxylate)

Phosphorus oxychloride (1.92g,13mmol) was added in equal portions to a solution of A-5(4.52g,12.8mmol) and A6-1(2g,2.7mmol) in dichloromethane (60mL) at 20 ℃. The reaction mixture was stirred at 40 ℃ for 5 hours. The system was extracted three times with a saturated solution of sodium chloride and dichloromethane (150mL), the organic phases taken and the combined organic phases dried over sodium sulfate to give the product as a white oil which was taken to the next step.

Methyl chloroformate (0.24g,2.6mmol) was added in equal portions to a solution of the product of the previous step and triethylamine (0.39g,3.9mmol) in dichloromethane (50mL) at 20 ℃. The reaction mixture was stirred at 20 ℃ for 1 hour. The system was extracted three times with a saturated solution of sodium chloride and dichloromethane (150mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product (9.03g, 95% yield) as a white solid.

Example 5 Compound represented by the formula A8a-I-1 (methyl (R) -1- (3- (phenyloxy) -2-bromo-4-methoxybenzyl) -7-hydroxy-6-methoxy-3,4-

Dihydroisoquinoline-2(1H)-carboxylate)

A7-1(0.5g, 3.2mmol), L4(0.15mg, 0.5. mu. mol), Rh (nbd) were placed in a glove box under nitrogen₂BF₄(0.19mg, 0.5. mu. mol), 5mL of anhydrous methanol was added to the hydrogenation flask, and the hydrogenation flask was transferred to the autoclave. After the reaction kettle is closed, the hydrogen is replaced for three times, the hydrogen is filled to 300psi, the reaction is carried out for 12 hours at the temperature of 25 ℃, and then the reaction is cooled to the room temperature. The hydrogen was vented, the reaction vessel was opened, concentrated and purified by column chromatography to give product A8a-I-1 as a white solid (0.49g, 96% yield, ee 95% ee).

Example 6 Compounds of formula A8b-1

A solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 0.4mL, 3.5mol) was added in three equal portions to the tetrahydrofuran mixture of the product of the previous step A8 a-I-1. The reaction mixture was stirred at 20 ℃ for 1 hour. The system was extracted three times with saturated solution of sodium chloride and dichloromethane (50mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a white solid (0.34g, 95% yield, 92% ee).

Example 7 Compound (Methyl (4bS,9R) -4- (benzyloxy) -3, 6-dimethoxy-7-oxo-9, 10-dihydo-7H-9, 4b- (epithioethane) phenanthrene-11-carboxylate) represented by the formula A9-1

Palladium chloride (0.21mmol,0.1equiv), L1(0.21mmol,0.1equiv) and potassium carbonate (6.3mmol,3equiv) were added in equal portions to a mixture of A8-1(1.15g,2.1mmol,1equiv) in dimethylformamide (120mL) under a nitrogen atmosphere. The reaction mixture was stirred at 120 ℃ for 14 hours. The system was extracted three times with saturated solution of sodium chloride and dichloromethane (50mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a white solid (0.53g, 65% yield).¹H NMR(500MHz,d-DMSO)δ7.42(s,1H),7.31(m,5H),6.71(d,J＝8.0Hz,1H),6.60(m,1H),6.25(m,1H),6.17(s,1H),5.15(s,2H),5.18and 5.00(br s,1H),3.91(s,3H),3.81-3.71(m,6H),3.18-3.26(m,2H),2.80-2.60(m,2H)；1.61(m,1H)；[M+H]⁺:462.51；Found:462.51.

Example 8 Compound represented by the formula A10-1 (Methyl (4bS,9R) -4-hydroxy-3, 6-dimethoxy-7-oxo-9, 10-dihydroxy-7H-9, 4b- (epiethano) Phenanthrene-11-carboxylate)

Boron trichloride (203mg,17.3mmol) was added in equal portions to a mixture of A9-1(200mg,0.43mmol) in dry dichloromethane (10mL) at 20 ℃ under nitrogen. The reaction mixture was stirred at-60 ℃ for 1.5 hours. The system was extracted three times with saturated solution of sodium chloride and dichloromethane (10mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a white solid (80mg, 50% yeild).¹H NMR(500MHz,CDCl₃)δ7.53(s,1H),6.77(d,J＝8.0Hz,1H),6.64(m,1H),6.37(m,1H),6.25(s,1H),5.28and 5.04(br s,1H),3.91(s,3H),3.80-3.70(m,6H),3.08-3.24(m,2H),2.83-2.62(m,2H)；1.63(m,1H)；[M+H]⁺:372.39；Found:372.39.

Example 9 Compound represented by the formula A11-1 (Methyl (4bS,9R) -4,7-dihydroxy-3, 6-dihydroxy-9, 10-dihydroxy-7H-9, 4b- (epiethano) Phenanthrene-11-carboxylate)

Sodium borohydride (48.3mg,1.32mmol) was added in three equal portions to a mixture of A10-1(80mg,0.22mmol) in dry methanol (2mL) at 0 deg.C under nitrogen. The reaction mixture was stirred at 0 ℃ for 1.5 hours. The system was extracted three times with a saturated solution of sodium chloride and dichloromethane (20mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a white solid (67mg, 83% yeild).

Example 10 Compound represented by the formula A12-1 (Methyl (4R,7aR,12bS) -7, 9-dimethoxy-1, 2,4,7a-tetrahydro-3H-4,12-methanobenzofuro [3,2-e ] isoquinoline-3-carboxylate)

N, N-dimethylformamide dimethyl acetal (213.9mg,2mmol) was added in equal portions to a mixture of A11-1(67mg,0.2mmol) in dry dichloromethane (2mL) at 0 ℃ under nitrogen atmosphere in three portions. The reaction mixture was stirred at 0 ℃ for 8 hours. The system was extracted three times with a saturated solution of sodium chloride and dichloromethane (25mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a white oil (55mg, 86% yield).

Example 11A Compound of formula A13-1

Under nitrogen, m-chloroperoxybenzoic acid (30mg,0.165mmol) was added in equal portions to a mixture of A12-1(55mg,0.15mmol) in dry dichloromethane (8mL) at 0 deg.C. The reaction mixture was stirred at 40 ℃ for 5 hours. The system was extracted three times with a saturated solution of sodium chloride and dichloromethane (10mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give product a13-1(50mg, 90% yeild) as a white oil.¹HNMR(400MHz,CDCl₃)δ6.72(m,2H),6.62(d,J＝8.4,1H),6.19(d,J8.4,1H),5.27(s,1H),4.52(s,1H),4.00(br s,1H),3.86(s,3H),3.78(s,3H),3.02(m,2H),2.94-2.80(m,2H),2.45(m,1H),1.71(dd,J 3.2and 13.2,1H)

Example 12 Compound represented by the formula A14-1 (Methyl (4R,4aS,7aR,12bS) -4 a-hydroxy-9-methoxy-7-oxo-1, 2,4,4a,5,6,7,7a-octahydro-3H-4,12-Methanobenzofuro [3,2-e ] isoquinoline-3-carboxylate)

10% Palladium on carbon (20mg) was added to a methanol (5mL) mixture of the product of the previous step A13-1 at 0 ℃ and stirred at 40 ℃ for 5 hours under a hydrogen atmosphere of 1 atm. The system was extracted three times with a saturated solution of sodium chloride and dichloromethane (10mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a white oil (43mg, 85% yield).¹HNMR(400MHz,CDCl₃)δ6.71(d,J 8.0,1H),6.66(d,J 8.0,1H),4.68(s,1H),4.60–4.52(br s,1H),3.91(s,3H),3.77(s,3H),3.16(d,J 14.4,1H),3.03(m,3H),2.95(d,J＝6.0,1H),2.57(dd,J＝6.0and 18.8,1H),2.82–2.46(m,2H),2.3(m,1H),1.91(m,1H),1.72(m,1H)

Example 13 Compound represented by the formula A15-1 ((4R,4aS,7aR,12bS) -9-methoxy-3-methyl-1,2,3,4,5,6,7,7a-octahydro-4aH-4,12-methanobenzofuro [3,2-e ] isoquinoline-4a,7-diol)

Lithium aluminum hydride (27.5mg,0.71mmol) was slowly added in three equal portions to a solution of A14-1(43mg,0.12mmol) in dry tetrahydrofuran (5mL) at-10 ℃. The reaction mixture was stirred at 20 ℃ for 2 hours. The system was extracted three times with ethyl acetate (10mL) and a saturated solution of potassium sodium tartrate, the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a pale yellow oil (17mg, 70% yield).¹H NMR(400MHz,CDCl₃)δ6.73(d,J＝8.4,1H),6.56(d,J＝8.4,1H),4.67(d,J＝4.4,1H),4.25(ddd,J＝4.4,14.4and 11.2,1H),3.81(s,3H),3.23,d,J＝18.4,1H),2.78(d,J＝6.4,1H),2.58(dd,J＝6.4and 18.4,1H),2.48–2.38(m,1H),2.36(s,3H),1.20–1.08(m,1H).

Example 14 Compound represented by the formula A-1 ((4R,4aS,7aR,12bS) -9-methoxy-3-methyl-1,2,3,4,5,6,7,7a-octahydro-4aH-4,12-methanobenzofuro [3,2-e ] isoquinoline-4a,7-diol)

Des-Martin oxidant (20mg,0.045mmol) was added slowly in equal portions to a solution of A15-1(10mg,0.03mmol) in anhydrous dichloromethane (1mL) at-10 deg.C in three portions. The reaction mixture was stirred at 20 ℃ for two hours. The system was extracted three times with saturated solution of ammonium chloride and ethyl acetate (10mL), the organic phases taken, the combined organic phases dried over sodium sulfate, concentrated and purified by column chromatography to give the product as a pale yellow oil (7mg, 60% yield).¹H NMR(400Hz,CDCl₃)δ6.71(d,J 8.0,1H),6.54(d,J 8.0,1H),5.02–4.90(br s,1H),4.67(s,1H),3.91(s,3H),3.16(d,J 14.4,1H),3.03(ddd,J 4.8,14.4and 14.4,1H),2.88(d,J6.0,1H),2.57(dd,J 6.0and 18.8,1H),2.52–2.36(m,5H),2.30(ddd,J 3.2,3.2and 14.4,1H),2.22–2.13(m,1H),1.88(ddd,J 2.8,4.8and 13.2,1H),1.68–1.55(m,2H)[M+H]⁺:316.15；Found:316.15.

Example 15 preparation of a phosphine ligand of formula L1

Preparation of a Compound of formula L1-1

Potassium fluoride (1.16g,20.0mmol, 4.0equiv) was weighed into a Schlenk tube, baked under vacuum for 5min, and cooled under nitrogen. After the reaction tube was cooled, Compound L2-2(1.8g,5mmol, 1.0equiv), 9-Anthranilic acid (6.66g,15mmol,3.0equiv), Pd was added to the reaction tube₂(dba)₃(91.6mg,0.10mmol,2.0 mol%), BIDIME (82.6mg,0.25mmol,5.0 mol%), nitrogen purged three times and then redistilled toluene (10mL) added. Heating and stirring at 100 ℃ for 12 h. After the TLC detection reaction, the reaction mixture was cooled to room temperature, water (10mL) and ethyl acetate (20mL) were added to separate layers, the aqueous phase was extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed three times with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain compound 6-4(1.83g,4.74mmol, 95%) as a yellow solid.¹H NMR(400MHz,CDCl₃)δ8.52(s,1H),8.04(d,J＝8.5Hz,1H),7.99(m,1H),7.76(m,1H),7.66(t,J＝7.5Hz,1H),7.58(d,J＝8.5Hz,1H),7.40-7.50(m,3H),7.37(m,1H),7.16(dd,J＝8.4,3.1Hz,1H),7.09(dd,J＝7.4,3.4Hz,1H),4.47(m,2H),0.45(d,J＝16.3Hz,9H)；³¹P NMR(162MHz,CDCl3)δ62.4；¹³CNMR(100MHz,CDCl3)δ166.2(d,J＝18.7Hz),141.8(d,J＝6.3Hz),134.6(d,J＝1.6Hz),134.1(d,J＝2.0Hz),131.3,131.0,130.3(d,J＝2.7Hz),128.7,128.1,127.8,127.6,126.1,126.0,125.9,125.7,125.4,124.8,115.8(d,J＝88Hz),113.6(d,J＝5.2Hz),65.9(d,J＝60.2Hz),33.2(d,J＝71.5Hz),23.6；ESI-MS:m/z 387[M+H]+.

Preparation of phosphine ligands of formula L1

Compound L1-1(1.83g,4.47mmol,1.0equiv) was placed in a Schlenk tube, and THF (20mL) was added after purging nitrogen three times. To this reaction system was added Ti (OiPr)₄(2.6mL,8.94mmol,2.0equiv) and PMHS (3.0 mL). The reaction solution was put in an oil bath at 60 ℃ for 12 hours. After the reaction was completed by 31P NMR, the reaction mixture was cooled to room temperature under a nitrogen atmosphere, and most of the THF solvent was removed by oil pump. Degassed 30% aqueous sodium hydroxide (25mL) was added dropwise to the reaction system. The reaction system was heated at 60 ℃ with stirring for 30min, cooled to room temperature, and degassed Et under nitrogen₂O (15 mL. times.3) was extracted three times, and the organic phase was dried over anhydrous sodium sulfate. Filtered, concentrated, passed through a neutral alumina column under nitrogen, and then dried by suction to obtain yellow solid L2(1.52g,4.11mmol, 92%).¹H NMR(400MHz,CDCl3)δ8.49(s,1H),8.04(d,J＝7.7Hz,1H),8.02(d,J＝7.1Hz,1H),7.86(d,J＝8.8Hz,1H),7.79(d,J＝8.7Hz,1H),7.35-7.52(m,5H),7.10(dd,J＝8.1,0.7Hz,1H),7.05(dd,J＝7.4,3.2Hz,1H),4.85(dd,J＝12.5,1.8Hz,1H),4.61(dd,J＝26.2,12.7Hz,1H),0.45(d,J＝12.3Hz,9H)；³¹P NMR(162MHz,CDCl3)δ-9.9；¹³C NMR(100MHz,CDCl3)164.3,142.2,142.0,136.3,131.5,131.3,131.0,130.8,128.6,128.4,127.1,127.0,126.9,125.5,125.4,12.3,125.1,125.0,124.9,110.5,70.7(d,J＝26.7Hz),30.6(d,J＝19.6Hz),26.9(d,J＝14.3Hz)；ESI-MS:m/z 371[M+H]+。

Example 16 preparation of a phosphine ligand of formula L2

Preparation of a Compound of formula L2-2

Adding compound L2-1(26.2g,100mmol, 1.0equiv) into dichloromethane (300mL) under the protection of nitrogen, dropwise adding triethylamine (56mL,400mmol,4.0equiv) into the system, moving to an ice-water bath after the raw materials are completely dissolved, and reacting Tf at 0 DEG C₂NPh (39.3g,110mmol,1.1equiv) was added to the reaction system in one pot. After naturally warming to room temperature for 2 hours, the reaction was quenched by adding water (200mL), the reaction was separated into layers, and the aqueous layer was extracted three times with dichloromethane (150 mL. times.3). The organic phases were combined, washed three times with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give compound 6-2(34.1g,95.2mmol, 95%) as a white solid.¹H NMR(500MHz,CDCl3)δ7.58(t,J＝8.3Hz,1H),7.03(dd,J＝8.2,3.5Hz,1H),7.00(dd,J＝8.5,2.4Hz,1H),4.67(dd,J＝14.2,2.1Hz,1H),4.46(dd,J＝14.1,11.1Hz,1H),1.21(d,J＝16.8Hz,9H)；31P NMR(162MHz,CDCl₃)δ75.6；¹³C NMR(125MHz,CDCl₃)δ167.1(d,J＝16.8Hz),150.0,137.1,120.3,117.8,114.7(d,J＝4.4Hz),114.2(d,J＝4.3Hz),66.9(d,J＝59.3Hz),34.7(d,J＝72.0Hz),24.2；ESI-MS:m/z 359[M+H]+。

Preparation of a Compound of formula L2-3

Potassium fluoride (1.16g,20.0mmol, 4.0equiv) was weighed into a Schlenk tube, baked under vacuum for 5min, and cooled under nitrogen. After the reaction tube was cooled, compound 6-2(1.8g,5mmol, 1.0equiv),2, 6-dimethoxyphenylboronic acid (1.8g,10mmol,2.0equiv), Pd2(dba)3(91.6mg,0.10mmol,2.0 mol%), BIDIME (82.6mg,0.25mmol,5.0 mol%) and a double distilled 1, 4-dioxane (10mL) were added after nitrogen gas was purged three times. Heating and stirring at 100 ℃ for 12 h. After the TLC detection reaction, the reaction mixture was cooled to room temperature, dioxane was pumped off, water (10mL) and dichloromethane (20mL) were added for layer separation, the aqueous phase was extracted with dichloromethane (20 mL. times.3), the organic phases were combined, washed three times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain compound 6-3(1.3g,3.74mmol, 75%) as a white solid.¹H NMR(500MHz,CDCl₃):δ7.46(t,J＝7.9Hz,1H),7.28(t,J＝8.4Hz,1H),6.89(m,2H),6.64(d,J＝8.4Hz,1H),6.55(d,J＝8.4Hz,1H),4.47(dd,J＝13.8,1.8Hz,1H),4.34(dd,J＝13.7,10.5Hz,1H),3.77(s,3H),3.70(s,3H),0.87(d,J＝15.9Hz,9H)；31P NMR(162MHz,CDCl₃):δ62.4；13C NMR(125MHz,CDCl₃):δ165.2(d,J＝18.8Hz),158.5,157.3,138.1(d,J＝6.3Hz),134.0(d,J＝1.3Hz),129.8,125.0(d,J＝8.8Hz),117.4(d,J＝2.5Hz),114.8,114.0,112.4(d,J＝5.0Hz),104.3,103.1,65.3(d,J＝60.0Hz),55.8,55.3,33.4(d,J＝71.3Hz),23.6(d,J＝1.3Hz)；ESIMS:m/z 347[M+H]+。

Preparation of phosphine ligands of formula L2

Compound 6-3(1.3g,3.74mmol,1.0equiv) was placed in a Schlenk tube, and THF (15mL) was added after purging nitrogen three times. To this reaction system was added Ti (OiPr)₄(2.2mL,7.48mmol,2.0equiv) and PMHS (2.5 mL). The reaction solution was put in an oil bath at 60 ℃ for 12 hours.³¹After the reaction was completed by P NMR, the reaction mixture was cooled to room temperature under nitrogen, and most of the THF solvent was removed by an oil pump. Degassed 30% aqueous sodium hydroxide (20mL) was added dropwise to the reaction system. The reaction system was heated at 60 ℃ with stirring for 30min, cooled to room temperature, and degassed Et under nitrogen₂O (15 mL. times.3) was extracted three times, and the organic phase was dried over anhydrous sodium sulfate. Filtering, concentrating, passing through neutral alumina column under nitrogen protection, and draining to obtain white solid L1.¹HNMR(400MHz,CDCl3):δ7.29(m,2H),6.87(m,2H),6.65(d,J＝8.2Hz,1H),6.59(d,J＝8.3Hz,1H),4.81(dd,J＝12.5,1.8Hz,1H),4.53(dd,J＝25.2,12.5Hz,1H),3.77(s,3H),3.71(s,3H),0.73(d,J＝12.1Hz,9H)；³¹P NMR(162MHz,CDCl3):δ-7.9；¹³C NMR(100MHz,CDCl3):δ163.4,157.9,157.1,138.4(d,J＝22.3Hz),130.5,129.0,125.0(d,J＝16.4Hz),123.8(d,J＝5.4Hz),119.6,109.5,104.5,103.6,70.4(d,J＝33.8Hz),55.9,55.4,30.9(d,J＝23.2Hz),26.6(d,J＝18.1Hz)；ESI-MS:m/z 331[M+H]+。

Example 17 preparation of a ligand of formula L3

The ligand represented by the formula L3 is obtained according to the preparation method of the compound 1 in the example 1 in the patent CN 103087105A.

Example 18 preparation of a ligand of formula L4

Preparation of a Compound of formula L4-1

A1000 mL four-necked flask was taken, the flask was baked with a baking gun, protected with nitrogen, a thermowell and a low-temperature thermometer were inserted into one port, a mechanical stirring device was inserted into one port, a constant-pressure dropping funnel was installed into one port, and nitrogen gas was substituted 3 to 5 times. Carefully withdraw 10mL of PCl from the syringe₃The flask was dropped dropwise into the pear until the analytical balance showed 20g (145.6mmol, 1 equivalent), taken out, protected with nitrogen, dissolved by adding 40mL of THF which had been refluxed with sodium thread for three hours, poured into a four-necked flask, and the pear was rinsed with 15mL of tetrahydrofuran and transferred into the four-necked flask 3 times.

The apparatus was placed in an ice bath at-50 ℃ and 176.9mL (176.9mmol, 1 eq.) of tert-butylmagnesium chloride was taken out by a syringe, injected into a constant pressure dropping funnel and slowly added dropwise. After the dropwise addition, the ice bath device is removed, and the temperature is returned to room temperature. After the temperature is stabilized, the reaction is carried out for 2 hours. By using³¹And detecting the reaction by P-NMR, and directly putting the next step without separation if the reaction is finished.

The apparatus was placed in an ice bath at-50 ℃ and 154.9mL (154.9mmol, 1.1 eq.) of vinylmagnesium bromide was withdrawn by syringe and injected into a constant pressure dropping funnel and slowly added dropwise. After the dropwise addition, the ice bath device is removed, and the temperature is returned to room temperature. After the temperature is stabilized, the reaction is carried out for 2 hours. By using³¹And detecting the reaction by P-NMR, and directly putting the next step without separation if the reaction is finished.

A certain amount of deionized water is taken in a container, then the container is sealed, and nitrogen is injected into the container to remove trace oxygen dissolved in the water. 20mL of deionized water with peroxide removed was taken out with a syringe and injected into a constant pressure dropping funnel, slowlyAnd (4) dropwise adding. After the dropwise addition, the device is put into an oil bath kettle at 45 ℃ for reaction for 3h (or at room temperature for 20h), and the mixture is used³¹And detecting the reaction by P-NMR, and directly putting the next step without separation if the reaction is finished.

A saturated sodium hydroxide solution containing 29g of NaOH (725mmol, 5 equivalents) was taken, prepared with deionized water to remove peroxide, part of nitrogen gas was introduced into the container, nitrogen gas was used for protection, 100mL of a formaldehyde solution (1233mmol, 10 equivalents) and the freshly prepared NaOH solution were taken out by a syringe, injected into a constant pressure dropping funnel, and slowly added dropwise in an ice bath at-20 ℃. After the dropwise addition, the room temperature is recovered, the device is placed into an oil bath kettle at 50 ℃ for reaction for 3 hours, the reaction is detected by TLC (developing solvent: ethyl acetate and methanol volume ratio is 10:1, and potassium permanganate developer develops color), and after-treatment is carried out if the reaction is finished.

The apparatus was cooled to room temperature and the pH of the system was then adjusted to 1 with 2mol/L HCl solution. The organic phase was concentrated by several extractions with ethyl acetate and water. The organic phase was dried with saturated brine and anhydrous sodium sulfate. The organic phase was spin dried. Silica gel powder (200-mesh and 300-mesh) is added into the organic phase for sample mixing, pure ethyl acetate is used for column packing, dry method sample loading is carried out, column chromatography is carried out by eluent with the volume ratio of ethyl acetate to methanol being 20:1, and products are collected to obtain yellow viscous liquid with the yield of 5.502g and the yield of 27.5%.

L4-1：¹H NMR(500MHz,Chloroform-d)δ6.46-6.15(m,3H),4.15-4.10(d,J＝14.4Hz,1H),4.01-3.96(d,J＝14.4Hz,1H),1.19(d,J＝14.5Hz,9H)；¹³C NMR(126MHz,Chloroform-d)δ136.99,125.79,57.71,31.53,24.35；³¹P NMR(162MHz,Chloroform-d)δ45.59；ESI-MS:m/z 163.00[M+H]+.

Preparation of a Compound of formula L4-2

Under the protection of nitrogen, 10g (25mmol, 1 equivalent) of tert-butyl (hydroxymethyl) (vinyl) phosphine oxide was put into a baked Schlenk tube, 8g (2.7mL) of liquid bromine (50mmol, 2 equivalents) and 50mL of carbon tetrachloride were added, and the mixture was magnetically stirred at 0 ℃ for about 0.5h, then returned to room temperature, and reacted for 3 h. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol in a volume ratio of 20:1, color developed by potassium permanganate developer) and worked up after the reaction was complete. After the reaction was completed, the stirrer was taken out, and a saturated sodium sulfite solution was gradually added dropwise until the orange-red color disappeared. Then, the organic phase is separated, dried by anhydrous sodium sulfate, spin-dried and put into the next step.

4.8g of sodium tert-butoxide (50mmol, 2 eq.) are added and reacted with 50mL of tetrahydrofuran for 40 min. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol in a volume ratio of 20:1, color developed by potassium permanganate developer) and worked up after the reaction was complete. And after the reaction is finished, taking out the stirrer, adding a proper amount of silica gel powder, loading the mixture by a dry method, loading the mixture into a column by ethyl acetate, performing column chromatography by using an eluent with the volume ratio of ethyl acetate to methanol being 80:1, collecting a product, concentrating and spin-drying the product to obtain a yellow oily liquid with the yield of 7.5g and the yield of 75%.

L4-2：¹H NMR(500MHz,Chloroform-d)δ7.24-7.19(dd,J＝25.4,4.7Hz,1H),5.34-5.31(dd,J＝16.75,4.7Hz,1H),4.25(dd,J＝14.4,3.9Hz,1H),4.16(dd,J＝14.4,10.2Hz,1H),1.16(d,fJ＝16.0Hz,9H)；¹³C NMR(126MHz,Chloroform-d)δ163.89(d,J＝10.4Hz),91.75,91.05,64.39,63.93,32.25(d,J＝75.4Hz),24.37；³¹P NMR(162MHz,Chloroform-d)δ72.56.ESI-MS:m/z 161.0[M+H]+.

Preparation of a Compound of formula L4-3

1g (6.2473mmol, 1 equivalent) of 3- (tert-butyl) -2-hydro-1, 3-oxophosphoryl-3-oxide was placed in a Schlenk tube, 5mL of ethyl acetate and 0.1g of palladium on carbon (10%) were added, and after replacement of the hydrogen gas three times under one atmosphere, the mixture was magnetically stirred at an external temperature of 40 ℃ for about 6 hours, after which the temperature was returned to room temperature. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol in a volume ratio of 20:1, color developed by potassium permanganate developer) and worked up after the reaction was complete. And after the reaction is finished, taking out the stirrer, adding a proper amount of silica gel powder, loading the mixture by a dry method, loading the mixture into a column by ethyl acetate, performing column chromatography by using an eluent with the volume ratio of ethyl acetate to methanol being 20:1, collecting a product, concentrating and spin-drying the product to obtain a yellow oily liquid with the yield of 0.8904g and the yield of 89%.

L4-3：¹H NMR(500MHz,Chloroform-d)δ7.27(s,0H),4.19(ddd,J＝19.2,9.5,6.8Hz,1H),4.12(dd,J＝13.2,2.6Hz,1H),4.04(tt,J＝10.0,6.5Hz,1H),3.59(dd,J＝13.2,6.7Hz,1H),1.23(d,J＝15.1Hz,9H)；¹³C NMR(126MHz,Chloroform-d)δ68.11,64.19,63.71,31.79,31.28,24.27；³¹P NMR(162MHz,Chloroform-d)δ48.63,48.35,48.01,47.73.ESI-MS:m/z 163.05[M+H]⁺.

Preparation of a Compound of formula L4-4

10g (62.473mmol, 1 eq) of 3- (tert-butyl) -2-hydro-1, 3-oxo, phospho-penta-3-oxo were placed in a Schlenk tube under nitrogen, 100mL of tetrahydrofuran, 60.8mL of polymethylhydrosiloxane and 25.2mL of tetraisopropyl titanate (87.462mmol, 1.4 eq) were added and reacted at 70 ℃ for 4 h. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol in a volume ratio of 10:1, color developed by potassium permanganate developer) and the next step was carried out if the reaction was complete. After the reaction was completed, the reaction system was cooled to 0 ℃ and 3g of sulfur powder (93.7mmol, 1.5 equivalents) was slowly added dropwise and reacted at 0 ℃ for 1 hour at an external temperature. And detecting the reaction by TLC (developing solvent: petroleum ether and ethyl acetate volume ratio is 2:1, and potassium permanganate developer develops color), and adding water to quench the reaction when the reaction is finished. The mixture was extracted with dichloromethane and water, and the organic phase was separated and dried. Adding a proper amount of silica gel powder into the organic phase, loading the organic phase by a dry method, loading petroleum ether into a column, carrying out column chromatography by using an eluent with the volume ratio of the petroleum ether to the ethyl acetate being 20:1, collecting a product, concentrating and spin-drying to obtain a white solid product with the yield of 9.4g and the yield of 86%.

L4-4：¹H NMR(500MHz,Chloroform-d)δ4.47(d,J＝12.4Hz,1H),4.37–4.25(m,1H),4.01–3.94(m,1H),3.63(dd,J＝12.4,1.0Hz,1H),2.43(d,J＝10.3Hz,1H),2.05(d,J＝6.1Hz,1H),1.28(d,J＝16.7Hz,9H)；¹³C NMR(126MHz,Chloroform-d)δ77.27,77.02,76.76,70.80,70.44,69.02,33.54,33.19,30.12,29.70,24.98,24.96；³¹P NMR(162MHz,Chloroform-d)δ76.17.ESI-MS:m/z 179.04[M+H]⁺.

Preparation of a Compound of formula L4-5

Using a chiral preparation column AD-H column for separation. The specific method comprises the following steps:

preparation of column type: CHIRALPAK AD-H, Particle Size 5 μm; dimensions 4.6mm 250 mm;

mobile phase: isopropanol/n-hexane 5/95, flow rate: 1ml per minute; detection wavelength: 210 nm. Retention time: t is t₁7.1min (S configuration), t₂12.3min (R configuration).

Preparation of a Compound of formula L4-6

1g (5.6mmol, 1 equivalent) of R-3- (tert-butyl) -2-hydro-1, 3-oxo, phospho-pentan-3-thio was placed in a Schlenk tube, 5mL of methanol and 0.3mL of hydrogen peroxide (30%) were added, and the mixture was magnetically stirred at 30 ℃ for about 6 h. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol in a volume ratio of 20:1, color developed by potassium permanganate developer) and worked up after the reaction was complete. After the reaction is finished, taking out the stirrer, adding a proper amount of silica gel powder, loading the sample by a dry method, loading ethyl acetate into a column, and carrying out reaction by using a reaction mixture of ethyl acetate and methanol in a volume ratio of 20:1, carrying out column chromatography, collecting the product, concentrating and spin-drying to obtain a yellow oily liquid, wherein the yield is 0.86g and 95%.

L4-6：¹H NMR(500MHz,Chloroform-d)δ4.24-4.10(m,2H),4.12(dd,J＝13.2,2.6Hz,1H),4.08-4.01(m,1H),3.59-3.57(dd,J＝13.2,6.7Hz,1H),2.10-1.86(m,2H),1.24-1.21(d,J＝15.1Hz,9H)；¹³C NMR(126MHz,Chloroform-d)δ68.11,64.19,63.71,31.79,31.28,24.27；³¹P NMR(162MHz,Chloroform-d)δ48.63,48.35,48.01,47.73.ESI-MS:m/z 163.05[M+H]⁺.

Preparation of a Compound of formula L4-7

5g (30.8mmol, 1 eq) of S-3- (tert-butyl) -2-hydro-1, 3-oxo, phosphorus-penta-3-oxo were placed in a nitrogen atmosphere, 50mL of THF, 10mL of polymethylhydrosiloxane and 11.6mL of tetraisopropyl titanate (40mmol, 1.3 eq) were added and the reaction was carried out at 70 ℃ for 4 h. The reaction was checked by TLC (developing solvent: ethyl acetate and methanol in a volume ratio of 10:1, color developed by potassium permanganate developer) and the next step was carried out if the reaction was complete. After the reaction was completed, the reaction system was cooled to 0 ℃ and 36.9mL of 1M borane-tetrahydrofuran solution (36.9mmol, 1.2 eq.) was slowly added dropwise and reacted at 0 ℃ for 1h at ambient temperature. The reaction was checked by TLC (developer: petroleum ether to ethyl acetate volume ratio 6:1, color developed by potassium permanganate developer) and, if the reaction was complete, the reaction was quenched by addition of saturated aqueous sodium hydroxide. The mixture was extracted with dichloromethane, the organic phase was separated and dried. Adding a proper amount of silica gel powder into the organic phase, loading the organic phase by a dry method, loading petroleum ether into a column, carrying out column chromatography by using an eluent with the volume ratio of the petroleum ether to the ethyl acetate being 50:1, collecting a product, concentrating and spin-drying to obtain a white solid product, wherein the yield is 4.5g and 90 percent.

L4-7：¹H NMR(500MHz,Chloroform-d)δ4.43(dd,J＝12.3,3.2Hz,1H),4.27-4.19(m,1H),3.73-3.66(m,2H),2.10-2.01(m,2H),1.21-1.18(d,J＝15),0.9-0.21(m,3H)；¹³CNMR(126MHz,Chloroform-d)δ69.32,69.29,65.55,65.34,27.39,27.18,25.55,25.53,22.65,22.38；³¹P NMR(162MHz,Chloroform-d)δ48.18(dd,J＝100.6,45.4Hz).ESI-MS:m/z163.1[M+H]⁺.

Preparation of a Compound of formula L4-8

2g (12.3mmol, 1 eq) of S-3- (tert-butyl) -2-hydro-1, 3-oxo, phospho-penta-3-borane were placed in a Schlenk tube under nitrogen and 10mL of THF, 1.4mL of TMEDA (18.5mmol, 1.5 eq) were added. 10.9mL of 1.7M t-butyllithium (18.5mmol, 1.5 equiv.) were added dropwise at 2d/s magnetically stirred at-78 deg.C for about 15min, after which 4.1g of cupric chloride (30.8mmol, 2.5 equiv.) was added while maintaining at-78 deg.C, and the reaction was allowed to resume at room temperature for 45 min. The reaction was checked by TLC (developing solvent: petroleum ether and ethyl acetate in a volume ratio of 6:1, color developed by potassium permanganate developer) and post-treatment was carried out if the reaction was complete. After completion of the reaction, the mixture was extracted with ethyl acetate and a 10% aqueous solution of sodium hydroxide, and the organic phase was separated and dried. Adding appropriate amount of silica gel powder into the organic phase, loading sample by dry method, loading petroleum ether into column, performing column chromatography with eluent with volume ratio of petroleum ether to ethyl acetate of 100:1, collecting product, concentrating, and spin drying to obtain white solid with yield of 0.6g and 30.6%.

L4-8：¹H NMR(500MHz,Chloroform-d)δ4.39-4.37(dd,2H),4.27-4.24(m,2H),3.74(m,2H),2.21-2.20(m,2H),2.08-2.07(m,2H),1.25(d,J＝13.9Hz,18H),0.81-0.25(m,6H)；¹³C NMR(101MHz,Chloroform-d)δ73.67,70.12,28.34,28.08,25.71,22.58,22.26.；³¹PNMR(162MHz,Chloroform-d)δ59.04.ESI-MS:m/z 321.21[M+H]⁺.

Single crystal X-ray diffraction thereof: space group is P21212, cell parameter

α -90 °, β -90 °, γ -90 °, unit cell volume

Preparation of a ligand of formula L4

100mg (0.31mmol, 1 eq.) of (2R, 2' R, 3S, 3' S) -3,3' -di-tert-butyl-2, 2' -bis (1, 3-oxo, phospho-pentanyl) -3,3' -diborane was placed in a Schlenk tube under nitrogen, and 6mL of toluene and 105mg of 1, 4-diazabicyclo [2.2.2] octane (0.94mmol, 3 eq.) were added. Magnetically stir at 60 ℃ for about 2 h. The vacuum pump reduced the pressure to remove most of the toluene solvent. Degassed water (5mL) was carefully added to the residue. Degassed ether (5mL) was added to the mixture at room temperature, stirred at 60 ℃ for 0.5h, separated to give an organic phase, dried over sodium sulfate, concentrated, and chromatographed on an anhydrous oxygen-free neutral alumina column (petroleum ether/ether ═ 3:1) to give the desired ligand (2R, 2'R, 3S, 3' S) -3,3 '-di-tert-butyl-2, 2' -bis (1, 3-oxo, phospho-pentayoke) (68mg, 75%) as a colorless oil.

L4：¹H NMR(500MHz,Chloroform-d)δ4.79-4.77(d,J＝3.72,2H),4.20-4.17(m,4H),2.16(m,4H),1.24-1.19(d,J＝15)；³¹P NMR(162MHz,Chloroform-d)δ2.51.ESI-MS:m/z291.21[M+H]⁺。

EXAMPLE 19 preparation of Compound A8a-IV-1

Compound A8a-IV-1 was prepared by reference to the preparation method of step 1) in the compound represented by the formula A7-1 in example 4.

EXAMPLE 20 preparation of Compound A8a-III-1

Adding A8a-IV-1(2mmol) into a 20mL Schlenk tube, replacing the tube with nitrogen for 3 times, adding a dichloromethane solution (10mL) with a catalyst amount of L5((S, S) -TsDPEN-RuCl, 0.04mmol), draining the solvent under vacuum, adding a mixture of 2mL triethylamine and formic acid (the volume ratio is 1/3) in an ice-water bath and stirring, moving the mixture to room temperature, adding a saturated sodium bicarbonate solution after the reaction is finished, adjusting the pH value to 8-9, extracting the mixture with ethyl acetate, combining organic phases, drying the combined organic phases through anhydrous sodium sulfate, filtering, removing the solvent through rotary evaporation, and purifying the combined organic phases through column chromatography to obtain the product. (1.33g, 90% yield, ee 92%).

¹HNMR(500MHz,d-DMSO)δ7.70-7.33(m,15H),7.00(m,2H),6.80(d,J＝8.0Hz,1H),6.71(s,1H),5.13(s,2H),4.10(t,1H),3.91(s,3H),3.83(s,3H),2.84-2.74(m,4H),2.58(dd,J＝6.8,13.6Hz,2H),1.09(s,9H)；[M+H]+:723.79；Found:723.79.

EXAMPLE 21 preparation of Compound A8a-II-1

Preparation of Compound A8a-II-1 with reference to the preparation of the compound represented by the formula A8b-1 in example 6.

EXAMPLE 22 preparation of Compound A8b-1

Compound A8b-1 was prepared by referring to the synthetic method in step 2) of the compound represented by formula a7-1 in example 4.

Claims

1. A method for preparing a compound shown as a formula A9, which is characterized by comprising the following steps:

2. The process according to claim 1, characterized in that in the dearomatization cyclization reaction, the protective gas is nitrogen and/or argon, preferably nitrogen;

and/or, in the dearomatization cyclization reaction, the palladium catalyst is one or more of palladium chloride, palladium hydroxide, palladium bis (acetonitrile) chloride, palladium trifluoromethanesulfonate and palladium acetate, preferably palladium chloride;

and/or in the dearomatization cyclization reaction, the phosphine ligand is shown as a formula L1;

and/or in the dearomatization cyclization reaction, the organic solvent is one or more of an alcohol solvent, an ether solvent, an aromatic solvent, a nitrile solvent, a halogenated alkane solvent, a sulfoxide solvent and an amide solvent, preferably the sulfoxide solvent and/or the amide solvent, and more preferably the amide solvent;

and/or in the dearomatization cyclization reaction, the volume-mass ratio of the organic solvent to the compound shown in the formula A8b is 5-20 ml/g;

and/or in the dearomatization cyclization reaction, the molar ratio of the palladium catalyst to the compound shown in the formula A8b is 0.01-0.5, preferably 0.1-0.5;

and/or in the dearomatization cyclization reaction, the molar ratio of the phosphine ligand to the compound shown as the formula A8b is 0.01-0.5, preferably 0.1-0.5;

and/or in the dearomatization cyclization reaction, the temperature of the dearomatization cyclization reaction is 80-180 ℃;

and/or, said R¹And said R²Independently is H;

and/or, R³In (A), the C_1～4Alkyl is C_1～2Alkyl groups, more preferably methyl groups.

3. The process according to claim 1 or 2, further comprising a process for the preparation of the compound of formula A8b, which is process 1 or process 2;

wherein, in the above compounds, R⁴Is a hydroxy protecting group; r¹、R²And R³Is as defined in claim 1 or 2.

4. The method according to claim 3, wherein in the method 1, the deprotecting agent is tetrabutylammonium fluoride;

and/or in the method 1, the molar ratio of the deprotection reagent to the compound A8a is 1-5;

and/or, in the method 1, the organic solvent is an ether solvent and/or a chlorinated hydrocarbon solvent, more preferably an ether solvent, further preferably one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether, and still further preferably tetrahydrofuran;

and/or, in method 1, in formula A8a-I, when R is⁴When the hydroxyl protecting group is a hydroxyl protecting group, the hydroxyl protecting group is a silyl ether protecting group, and a tert-butyl diphenyl silyl ether protecting group is further preferable;

and/or, in method 2, the organic solvent is a chlorinated alkane solvent, further preferably one or more of dichloromethane, 1, 2-dichloroethane and chloroform, further more preferably dichloromethane;

and/or, in the method 2, the base is an organic weak base, and triethylamine is further preferred;

and/or in the method 2, the molar ratio of the alkali to the compound shown as the formula A8a-II is 1-3;

and/or, in method 2, the chloroformate is one or more of methyl chloroformate, ethyl chloroformate, propyl chloroformate and butyl chloroformate, preferably methyl chloroformate;

and/or in the method 2, the molar ratio of the chloroformate to the compound shown in the formula A8a-II is 0.9-1.1.

5. The production method according to claim 3 or 4,

in the method 1, the preparation method of the compound shown in the formula A8a-I comprises the following steps: under the action of rhodium catalyst and ligand, the compound shown as formula A7 and H₂Carrying out asymmetric hydrogenation reaction in an organic solvent to obtain the compound shown as the formula A8 a-I; the ligand is a ligand shown as a formula L3 and/or a ligand shown as a formula L4;

and/or, in the method 2, the preparation method of the compound shown in the formula A8a-II comprises the following steps: under the action of a deprotection reagent, carrying out deprotection reaction shown as the following formula A8a-III in an organic solvent to obtain a compound shown as the formula A8 a-II-;

wherein R is⁴As defined in claim 3 or 4; r¹、R²And R³Is as defined in claim 1 or 2.

6. The method according to claim 5,

in the asymmetric hydrogenation reaction, the rhodium catalyst is one or more of bis (norbornadiene) rhodium (I) tetrafluoroborate, (acetylacetonato) dicarbonyl rhodium, rhodium trifluoroacetate dimer, tris (acetonitrile) trichlororhodium and acetylacetonato dicarbonyl rhodium, preferably bis (norbornadiene) rhodium (I) tetrafluoroborate;

and/or, in the asymmetric hydrogenation reaction, the ligand is represented by formula L4;

and/or, the asymmetric hydrogenation reaction is carried out under a certain pressure, and the pressure of the asymmetric hydrogenation reaction is 1 atm-50 atm;

and/or in the asymmetric hydrogenation reaction, 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, preferably the alcohol solvent, more preferably one or more of methanol, ethanol, n-propanol and isopropanol, and still more preferably methanol;

and/or in the asymmetric hydrogenation reaction, the volume-mass ratio of the organic solvent to the compound shown in the formula A7 is 5-20 ml/g;

and/or in the asymmetric hydrogenation reaction, the molar ratio of the rhodium catalyst to the compound shown as the formula A7 is 0.00005-0.0005;

and/or in the asymmetric hydrogenation reaction, the molar ratio of the ligand to the compound shown as the formula A7 is 0.00005-0.0005;

and/or in the asymmetric hydrogenation reaction, the temperature of the asymmetric hydrogenation reaction is 10-50 ℃;

and/or in the deprotection reaction, the deprotection reagent is tetrabutylammonium fluoride;

and/or in the deprotection reaction, the molar ratio of the deprotection reagent to the compound A8a-III is 1-5;

and/or, in the deprotection reaction, the organic solvent may be an ether solvent and/or a chlorinated hydrocarbon solvent, preferably an ether solvent, and further preferably tetrahydrofuran.

7. The method according to claim 5,

in the method 1, the preparation method of the compound shown as the formula A7 comprises the following stepsThe method comprises the following steps: in POCl₃Under the action, carrying out ring closure reaction on the compound shown as the formula A6 in an organic solvent to obtain a ring closure product; then, under the action of alkali, carrying out acylation reaction of the closed-loop compound and chloroformate in an organic solvent to obtain a compound shown as a formula A7;

and/or, in the method 2, the preparation method of the compound shown in the formula A8a-III comprises the following steps: under the action of a metal complex, carrying out asymmetric hydrogenation reaction on a compound shown as a formula A8a-IV in a solvent to obtain a compound shown as a formula A8 a-III; the metal complex is a complex shown as a formula L5;

wherein R is¹、R²And R³As defined in claim 1 or 2; r⁴Is as defined in claim 3 or 4.

8. The method according to claim 7,

the POCl₃The molar ratio of the compound to the compound shown as the formula A6 is 1.0-1.5;

and/or the organic solvent is a chloroalkane solvent and/or an amide solvent, preferably a chloroalkane solvent, and further preferably dichloromethane;

and/or the base is organic weak base, and triethylamine is further preferred;

and/or the molar ratio of the alkali to the compound shown as the formula A6 is 1-3;

and/or, the chloroformate is one or more of methyl chloroformate, ethyl chloroformate, propyl chloroformate and butyl chloroformate, preferably methyl chloroformate;

and/or the molar ratio of the chloroformate to the compound shown in the formula A6 is 0.9-1.1;

and/or in the asymmetric hydrogenation reaction, 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, preferably the halogenated alkane solvent, and more preferably dichloromethane;

and/or in the asymmetric hydrogenation reaction, the molar ratio of the metal complex to the compound shown as the formula A8a-IV is 0.005-0.05;

and/or, the asymmetric hydrogenation reaction is carried out in the presence of a reducing agent; the reducing agent is preferably organic weak base and organic weak acid, and further can be triethylamine and formic acid; the molar ratio of the organic weak base to the compound shown in the formula A8a-IV is preferably 1.5-3.0; the molar ratio of the organic weak acid to the compound shown in the formula A8a-IV is preferably 15-30; the volume ratio of the weak organic acid to the weak organic base is preferably 2-5.

9. The process of claim 7, wherein the process for the preparation of the compound of formula A8a-IV comprises the steps of: in POCl₃Under the action, carrying out a ring closure reaction on a compound shown as a formula A6 in an organic solvent to obtain the compound shown as a formula A8 a-IV;

wherein R is¹And R²As defined in claim 1 or 2; r⁴Is as defined in claim 3 or 4.

10. The method of claim 9, wherein the POCl is present in the ring-closing reaction₃The molar ratio of the compound to the compound shown as the formula A6 is 1.0-1.5;

and/or, in the ring closing reaction, the organic solvent can be a chloroalkane solvent and/or an amide solvent, preferably the chloroalkane solvent, and further preferably dichloromethane.

11. The process of claim 7 or 9, wherein the process for the preparation of the compound of formula a6 comprises the steps of: under the action of a catalyst, carrying out condensation reaction on a compound shown as a formula A5 and a compound shown as a formula A2 in an organic solvent to obtain a compound shown as a formula A6;

12. A method for preparing a compound represented by formula A8a-I, comprising the steps of: under the action of rhodium catalyst and ligand, the compound shown as formula A7 and H₂Carrying out asymmetric hydrogenation reaction in an organic solvent as shown in the specification to obtain a compound as shown in a formula A8 a; the ligand is a ligand shown as a formula L3 and/or a ligand shown as a formula L4;

alternatively, a method of preparing a compound of formula A8a-III, comprising the steps of: under the action of a metal complex, carrying out asymmetric hydrogenation reaction on a compound shown as a formula A8a-IV in a solvent to obtain a compound shown as a formula A8 a-III; the metal complex is a complex shown as a formula L5;

13. A preparation method of a compound shown as a formula A is characterized by comprising the following steps:

wherein the compound shown in the formula A9 is prepared according to the preparation method of any one of claims 1 to 11; r¹、R²And R³Is as defined in claimThe method according to claim 1 or 2.

14. The method of claim 13, wherein in step S6', the deprotection reagent is one or more of boron trichloride, boron tribromide and Pd/hydrogen, preferably boron trichloride;

and/or in step S6', the molar ratio of the deprotection reagent to the compound A9 is 2-5;

and/or, in step S6', the organic solvent is a chloroalkane, more preferably dichloromethane;

and/or, in the step S6', the temperature of the deprotection reaction is-78 to-50 ℃;

and/or, in step S7', the reducing agent is an alkali metal borohydride and/or lithium aluminum hydride, preferably an alkali metal borohydride, more preferably sodium borohydride and/or lithium borohydride, and still more preferably sodium borohydride;

and/or in step S7', the molar ratio of the reducing agent to the compound A10 is 3-6;

and/or, in step S7', the organic solvent is an alcohol solvent and/or a chloroalkane solvent, preferably an alcohol solvent, more preferably methanol and/or ethanol, and still more preferably methanol;

and/or in the step S7', the temperature of the reduction reaction is-5 ℃;

and/or, in step S8', the cyclizing reagent is one or more of N, N-dimethylformamide dimethyl acetal, p-toluic acid, sodium methoxide and sodium ethoxide, preferably N, N-dimethylformamide dimethyl acetal;

and/or in the step S8', the molar ratio of the cyclization reagent to the compound shown in the formula A11 is 10-15;

and/or, in step S8', the organic solvent is a chlorinated alkane solvent, more preferably one or more of dichloromethane, 1,2 dichloroethane and chloroform, and still more preferably dichloromethane;

and/or in the step S8', the temperature of the cyclization reaction is-5 ℃;

and/or, in step S9', the oxidizing agent is m-chloroperoxybenzoic acid;

and/or in step S9', the molar ratio of the oxidant to the compound A12 is 1-2;

and/or, in step S9', the organic solvent is a chlorinated alkane solvent, more preferably one or more of dichloromethane, 1,2 dichloroethane and chloroform, and still more preferably dichloromethane;

and/or in the step S9', the temperature of the oxidation reaction is 30-60 ℃;

and/or, in step S10', the catalyst is raney nickel and/or a palladium catalyst, preferably a palladium catalyst, further preferably palladium/carbon, further preferably 10% palladium/carbon, and the "%" is the mass percentage of the palladium to the total mass of the palladium and the carbon;

and/or in the step S10', the mass percent of the catalyst and the compound A13 is 30-50%;

and/or, in step S10', the organic solvent is an alcohol solvent, more preferably methanol and/or ethanol, and still more preferably methanol;

and/or in the step S10', the pressure of the hydrogenation reaction is 1-1.5 atm;

and/or in the step S10', the temperature of the hydrogenation reaction is 30-60 ℃;

and/or in the step S10', the hydrogenation reaction time is 3-8 h;

and/or, in step S11', the reducing agent is lithium aluminum hydride and/or an alkali metal borohydride, preferably sodium lithium aluminum hydride;

and/or in the step S11', the molar ratio of the reducing agent to the compound shown in the formula A14 is 3-8;

and/or, in step S11', the organic solvent is an ether solvent, further preferably one or more of tetrahydrofuran, dioxane, diethyl ether and methyl tert-butyl ether, further preferably tetrahydrofuran;

and/or in the step S11', the temperature of the reduction reaction is 10-40 ℃;

and/or in step S12', the oxidant is dessimutan oxidant and/or hydrogen peroxide, preferably dessimutan oxidant;

and/or in the step S12', the molar ratio of the oxidant to the compound shown in the formula A15 is 1-3;

and/or, in step S12', the organic solvent is an ether solvent and/or a halogenated alkane solvent, preferably a halogenated alkane solvent, more preferably one or more of dichloromethane, 1, 2-dichloroethane and chloroform, and still more preferably dichloromethane;

and/or in the step S12', the temperature of the oxidation reaction is 10-40 ℃.

15. A compound represented by:

wherein R is¹、R²And R³As defined in claim 1 or 2; r⁴As defined in claim 3 or 4;

preferred are the following compounds: