CN114105875B

CN114105875B - Synthesis method of morphine derivative dihydro etorphine

Info

Publication number: CN114105875B
Application number: CN202111475921.XA
Authority: CN
Inventors: 秦勇; 薛芳琳; 叶贞飞; 薛斐; 宋颢
Original assignee: Sichuan University
Current assignee: Sichuan University
Priority date: 2021-12-06
Filing date: 2021-12-06
Publication date: 2023-11-03
Anticipated expiration: 2041-12-06
Also published as: CN114105875A

Abstract

The invention belongs to the field of chemical drug synthesis, and particularly relates to a novel synthesis method of morphine derivative dihydroetorphine. The method is based on a possible biogenic route of the morphine derivative, takes intramolecular oxidation dearomatization Heck reaction as a key reaction through a bionic synthesis strategy, synthesizes thebaine analogue intermediate, and realizes the high-efficiency synthesis of the morphine derivative dihydro etorphine through the steps of adding with a propyl Grignard reagent, removing a secondary amine protecting group, introducing a nitrogen methyl, removing an oxygen methyl and the like through Diels-Alder reaction, catalytic hydrogenation and the like. Compared with the existing route, the synthetic route has few steps and high total yield, and obviously saves the production cost.

Description

Synthesis method of morphine derivative dihydro etorphine

Technical Field

The invention relates to the field of medicine synthesis, in particular to a synthesis method of morphine derivative dihydro etorphine.

Background

Morphine drugs such as hydrocodone, oxycodone, buprenorphine, naloxone, naltrexone, dihydroetorphine and the like are clinically used as opioid receptor agonists mainly for the treatment of moderate, severe pain and palliative conditions caused by severe wounds, burns, fractures, cancers and the like, and as opioid receptor antagonists for the treatment of respiratory depression and withdrawal from addiction to opioid drugs and alcohol, and are a basic drug category recognized by the world health organization. It is counted that morphine drugs occupy 7 varieties in the drugs with the global prescription dosage ranking of top 200 in 2016, and have irreplaceable effects and extremely important clinical values in the drug market. According to the statistics of the IQVIA database, the total production amount of the global morphine drugs in 2018 is approximately 390 tons, the sales amount of the preparation reaches 145 hundred million dollars, and under the condition that the clinical consumption of the morphine drugs in China only accounts for 2% of the world, the sales scale of the morphine drugs in China reaches 44 hundred million yuan. Thus, it is expected that with the increasing population of our country and the increasing importance of palliative treatment, as well as the popularization of treatments for respiratory depression, withdrawal from drugs and alcohol addiction, the market demand for such drugs will grow rapidly (World Health Organization, "18th WHO essential medicines list" (Geneva, switzerland, 2013); seya, m.j.; gelders, s.f.; achara, o.u.; milani, b.; scholten, w.k.; paint pallat, j.care pharmacothers.2011, 25,6).

Morphine is prepared by taking morphine (morphine) mother nucleus as basic skeleton, extracting morphine and thebaine and its analogues from agricultural poppy, and semisynthesis to obtain its derivative. It is counted that about 10 kilohectares of poppy are legally planted annually worldwide for extracting 800 tons of raw material (mainly morphine) to meet legal pharmaceutical production and scientific research requirements (International Narcotics Control Board, "nartic drugs: estimated world requirements for 2015-statics for 2013", 2014). However, poppy planting not only has the problem of occupying a large amount of farmland and illegal planting, but also can be affected by factors such as plant diseases and insect pests, climate, politics and the like, and supply sources have variability and instability. In addition, although the synthesis and conversion efficiency of thebaine to other morphine-like drugs is high, thebaine is contained in plants in a low amount, resulting in high cost of the drugs synthesized from thebaine semi-synthesis. Therefore, the existing industrial production method of morphine drugs not only occupies a large amount of farmland, has complex production procedures and high cost, but also has long control process and complex procedures, and is easy to cause serious social problems caused by insufficient control. Therefore, the development of a new method for industrially producing morphine drugs based on a total synthesis method has important significance.

The dihydro etorphine is a semisynthetic morphine derivative developed in China, has the analgesic effect which is 12000 times of that of morphine, has smaller side effect, and is clinically used for relieving pain of moderately severe pain and treating opioid addiction. The method for synthesizing the dihydro etorphine reported in the current literature is prepared by taking thebaine as a starting material and mainly through the steps of Diels-Alder reaction of thebaine and butenone, catalytic hydrogenation reduction of double bond, addition of ketone and propyl Grignard reagent, introduction of n-propyl, removal of oxymethyl and the like. The method uses natural product thebai as a synthesis starting point, and does not fundamentally solve the problem of semi-synthesis by using thebai as a raw material. Therefore, the full synthesis of the dihydroetorphine is carried out by raw materials with simple structure and commercial availability, the development of a preparation method with shorter synthetic route and higher efficiency is still necessary.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a novel method for preparing dihydroetorphine, which has the characteristics of easily available raw materials, higher synthesis efficiency, shorter steps and lower cost.

The aim of the invention is realized by the following technical scheme:

a method of synthesizing dihydroetorphine comprising the steps of:

A)

Providing a compound 17, wherein the compound 17 is subjected to intramolecular oxidation to remove an aromatic Heck reaction to generate a compound 18;

B)

the compound 18 is subjected to removal of hydroxyl protecting groups R ₁ Reacting to obtain a compound 19;

C)

the compound 19 undergoes a reduction reaction to produce a compound 20;

D)

cyclizing the compound 20 to generate an intermediate I;

E)

the intermediate I generates a compound 22 through Diels-Alder reaction with butenone;

F)

the compound 22 is subjected to catalytic hydrogenation reaction to reduce double bonds, so as to generate a compound 23;

G)

the compound 23 is subjected to addition reaction with a propyl Grignard reagent to generate a compound 24;

H)

the compound 24 is subjected to secondary amine protecting group R removal reaction to generate a compound 25;

I)

the compound 25 undergoes reductive amine methylation to produce a compound 26;

J)

selectively removing methyl on benzene ring of the compound 26 to obtain Dihydroetorphine (Dihydroetorphine);

in the above formula, X is a halogen atom. R is R ₁ The hydroxyl protecting group I is selected based on the compatibility of functional groups and avoiding side reactionsAnd (3) selecting.

R is a secondary amine protecting group, and the secondary amine protecting group used in the invention is mainly selected based on the compatibility of functional groups and avoids side reactions, such as unnecessary side reactions caused in the processes of subsequent oxidation dearomatization Heck reaction, cyclization reaction and the like.

In certain embodiments, the hydroxy protecting group i is one selected from the group consisting of p-methoxybenzyl, benzyl, acetyl, benzyloxycarbonyl, methoxymethylene, methyl, triisopropylsilyl, triethylsilyl, and t-butyldiphenylsilyl;

in certain embodiments, the secondary amine protecting group R is selected from one of benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, methyl formate, t-butoxycarbonyl, benzyl, p-methoxybenzyl, benzyloxycarbonyl, trifluorosulfonyl, methanesulfonyl, and trimethylbenzenesulfonyl.

In certain embodiments, in step E), the Diels-Alder reaction solvent is selected from one of toluene, isopropanol, ethanol;

in certain embodiments, in step E), the Diels-Alder reaction is at a temperature of 50 to 110 ℃.

In certain embodiments, in step F), the catalyst for the catalytic hydrogenation reaction is selected from one of palladium on carbon and palladium hydroxide;

in certain embodiments, in step F), the reaction solvent of the catalytic hydrogenation reaction is selected from one or more of methanol, ethanol, methylene chloride, ethylene dichloride, ethyl acetate, isopropanol, formic acid, acetic acid, and water;

In certain embodiments, in step F), the hydrogen pressure of the catalytic hydrogenation reaction is from 1 to 25atm;

in certain embodiments, in step F), the catalytic hydrogenation reaction is carried out at a temperature of from 0 to 80 ℃.

In certain embodiments, in step F), the catalyst for the catalytic hydrogenation reaction is palladium on carbon; the molar ratio of the compound 22 to the catalyst is 1:0.05-0.3;

in certain embodiments, in step F), the reaction solvent of the catalytic hydrogenation reaction is selected from methanol and acetic acid;

in certain embodiments, in step F), the hydrogen pressure of the catalytic hydrogenation reaction is from 5 to 10atm;

in certain embodiments, in step F), the catalytic hydrogenation reaction is carried out at a temperature of from 10 to 40 ℃.

In certain embodiments, in step G), the propyl grignard reagent is propyl magnesium chloride or propyl magnesium bromide;

in certain embodiments, in step G), the reaction solvent of the addition reaction is selected from one of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, dioxane, and toluene;

in certain embodiments, in step G), the reaction temperature of the addition reaction is from-20 to 110 ℃.

In certain embodiments, in step H), when the secondary amine protecting group is selected from p-toluenesulfonyl:

The reactant for removing the secondary amine protecting group R is one of red aluminum, lithium aluminum hydride, magnesium powder and sodium-naphthalene;

and/or the reaction solvent for removing the secondary amine protecting group R is selected from one of tetrahydrofuran, ethylene glycol dimethyl ether and toluene;

and/or the temperature of the reaction for removing the secondary amine protecting group R is 25-80 ℃.

the reaction reagent for removing the secondary amine protecting group R is lithium aluminum hydride, and the molar ratio of the compound 24 to the reaction reagent is 1:3-6;

and/or, in the step H), the reaction solvent is tetrahydrofuran;

and/or, in the step H), the reaction temperature is 40-70 ℃.

In certain embodiments, in step I), the reagent of the reductive amine methylation reaction is selected from one of paraformaldehyde sodium borohydride in combination with aqueous formaldehyde sodium borohydride in combination;

in certain embodiments, in step I), the reaction solvent of the reductive amine methylation reaction is selected from one of methanol, ethanol, tetrahydrofuran, and acetic acid;

in certain embodiments, in step I), the reaction temperature of the reductive amine methylation reaction is from 0 to 60 ℃.

In certain embodiments, in step I), the reagent for the reductive amine methylation reaction is sodium borohydride in combination with paraformaldehyde, and the molar ratio of the compound 25 to the reagent is 1:2-5;

in certain embodiments, in step I), the reaction solvent for the reductive amine methylation reaction is methanol;

in certain embodiments, in step I), the reaction temperature of the reductive amine methylation reaction is from 10 ℃ to 40 ℃.

In certain embodiments, in step J), the removal reagent for the selective methyl removal reaction is selected from one of boron tribromide, sodium hydrosulfide, sodium sulfide, sodium ethanethiol, thiophenol, sodium p-toluenesulfonate, t-dodecanethiol, potassium fluoride, sodium ethoxide, tetrabutylammonium fluoride, acetic acid, trifluoroacetic acid, hydrobromic acid, trimethyliodosilane, aluminum trichloride, cerium trichloride, ceric ammonium nitrate, camphorsulfonic acid, p-toluenesulfonic acid, phosphorus oxychloride, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, and hydrochloric acid;

in certain embodiments, in step J), the reaction solvent for the selective methyl removal reaction is selected from one or two of dimethyl sulfoxide, N-dimethylacetamide, azamethylpyrrolidone, methanol, N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, and acetic acid.

In certain embodiments, in step J), the removal reagent for the selective methyl removal reaction is sodium ethoxide and t-dodecyl mercaptan, or thiophenol and potassium carbonate, or thiophenol and cesium carbonate;

in certain embodiments, in step J), the reaction solvent for the selective methyl removal reaction is dimethyl sulfoxide.

In certain embodiments, in step B), the hydroxy protecting group R is removed ₁ Removal test usedThe agent is selected from one of sodium hydrosulfide, sodium sulfide, sodium ethanethiol, thiophenol, sodium p-toluenesulfonate, potassium fluoride, tetrabutylammonium fluoride, acetic acid, trifluoroacetic acid, hydrobromic acid, trimethyliodosilane, cerium trichloride, ceric ammonium nitrate, camphorsulfonic acid, p-toluenesulfonic acid, phosphorus oxychloride, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone and hydrochloric acid; the invention removes the hydroxyl protecting group R ₁ The removal reagent is mainly based on different hydroxyl protecting group removal R ₁ And selected. For example, those skilled in the art often use sodium hydrosulfide, sodium sulfide, sodium ethanethiol, thiophenol, sodium p-toluene thiophenol, etc. to remove methyl groups; the removal of silicon protecting groups, etc., by those skilled in the art, using potassium fluoride, tetrabutylammonium fluoride, tetraethylammonium fluoride, etc., are common removal methods in the art.

And/or, in step B), the hydroxy protecting group R is removed ₁ The reaction solvent is selected from one of N, N-dimethylacetamide, azomethylpyrrolidone, methanol, N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane and acetic acid; the invention removes the hydroxyl protecting group R ₁ The reaction solvent is also mainly based on the reasons of reducing side reaction, saving energy consumption, proceeding forward reaction, etc., and aims at different hydroxyl protecting group removal R ₁ The adaptability of the removal reagent is selected from the common reaction solvents in the field.

And/or, in the step B), the reaction temperature for removing the hydroxyl protecting group is-50-150 ℃. The invention removes the hydroxyl protecting group R ₁ The temperature used can be determined according to the removal of the hydroxy protecting group R ₁ The conditions of the reaction solvent, the removal reagent and the like are specifically selected, or the reasons of improving the yield, accelerating the reaction speed, reducing side reactions and the like are reasonably selected; if the removing reagent is hydrobromic acid, the temperature of the reaction solvent is N, N-dimethylformamide can be selected to be 0-70 ℃; when the removal reagent is trifluoroacetic acid and the reaction solvent is dichloromethane, the temperature can be selected to be-40-0 ℃.

In addition, the selection of protecting groups, the reaction reagents, the proportion, the reaction conditions and the like related to other reactions in the invention can be reasonably selected according to different conditions by a person skilled in the art, and are not described herein.

In certain embodiments, in step B), the molar ratio of compound 18 to removal agent is from 1:3 to 25; the removing reagent is hydrobromic acid, trifluoroacetic acid or sodium hydrosulfide;

and/or, in step B), the reaction solvent is dichloromethane, N-dimethylformamide or N, N-dimethylacetamide;

and/or, in step B), the hydroxy protecting group R is removed ₁ The reaction temperature is-40-150 ℃.

In certain embodiments, in S2, the reducing agent of the reduction reaction is selected from one of sodium borohydride, lithium tetrahydroaluminum, and lithium tri-tert-butyl tetrahydroaluminum;

and/or, in the step C), the reaction solvent of the reduction reaction is selected from one or two of methanol, ethanol, tetrahydrofuran and dichloromethane;

and/or, in the step C), the reaction temperature of the reduction reaction is-10-40 ℃.

In certain embodiments, in step C), the molar ratio of compound 19 to reducing agent is from 1:1.8 to 3;

and/or, in the step C), the reducing agent is sodium borohydride;

And/or, in the step C), the reaction solvent is methanol and methylene dichloride;

and/or, in the step C), the temperature of the reduction reaction is 0-25 ℃.

In certain embodiments, in step D), the reaction solvent of the cyclization reaction is selected from one of N, N-dimethylformamide, N-dimethylformamide dimethyl acetal, acetonitrile, tetrahydrofuran, dichloromethane, and 1, 4-dioxane;

in the step D), the cyclizing reagent of the cyclizing reaction is selected from one of N, N-dimethylformamide dineopentylacetal, N-dimethylformamide dimethyl acetal, N-dimethylformamide diethyl acetal and N, N-dimethylformamide diisopropyl acetal;

and/or, in the step D), the reaction temperature of the cyclization reaction is 0-130 ℃.

In certain embodiments, in step D), the molar ratio of compound 20 to cyclizing reagent is from 1:2 to 12;

and/or, in step D), the cyclizing reagent is N, N-dimethylformamide dimethyl acetal;

and/or, in step D), the reaction solvent is tetrahydrofuran, 1, 4-dioxane or N, N-dimethylformamide dimethyl acetal; the use of N, N-dimethylformamide dimethyl acetal accelerates the reaction rate.

And/or, in the step D), the reaction temperature of the cyclization reaction is 50-130 ℃.

In certain embodiments, in step a), the intramolecular oxidative dearomatization Heck reaction is performed in the presence of a reactant and a base.

In certain embodiments, in step a), the reactant is a complex, or, ligand ii and transition metal catalyst ii.

In certain embodiments, in step a), the complex is selected from Pd (PPh) ₃ ) ₄ 、Pd(PPh ₃ ) ₂ Cl ₂ 、Pd(PtBu ₃ ) ₂ 、 Pd(PCy ₃ ) ₂ 、Pd(PPhtBu ₂ ) ₂ Cl ₂ (1, 2-bis (diphenylphosphino) ethane)]Palladium dichloride, [1, 3-bis (diphenylphosphino) propane]Palladium dichloride and [1, 4-bis (diphenylphosphino) butane]One of palladium dichloride;

and/or the molar ratio of the compound 17, the complex and the alkali is 1:0.025-0.2:1-3.

In certain embodiments, in step a), the ligand ii is represented by formula (ii), or a stereoisomer, tautomer, or phosphonium hydrohalate corresponding to formula (ii);

wherein:

R ₄ and R is ₅ One selected from adamantyl or tert-butyl;

R ₆ one selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl, each of which is substituted with one or more hydrogen atoms, alkyl, halogen, cycloalkyl, aryl and heteroaryl, independently;

And/or, in step A), the transition metal catalyst II is selected from [ Pd (cinnamy) Cl] ₂ 、[Pd(allyl)Cl] ₂ 、Pd ₂ (dba) ₃ 、 Pd(OAc) ₂ 、Pd(Tfa) ₂ 、Pd(acac) ₂ 、Pd(MeCN) ₂ Cl ₂ 、Pd(PhCN) ₂ Cl ₂ 、PdCl ₂ 、Pd(Cp)(allyl)、 Pd(MeCN) ₄ (BF ₄ ) ₂ 、Pd(MeCN) ₄ (OTf) ₂ 、Pd(cod)Cl ₂ 、Pd(norbornadiene)Cl ₂ 、Pd(TMEDA)Cl ₂ And Pd (amphos) Cl ₂ One of the following;

and/or the mol ratio of the compound 17 to the ligand II to the transition metal catalyst II to the alkali is 1:0.05-0.5:0.05-0.15:2-4.

In certain embodiments, in step A), preferably, the ligand II is selected from

Or->Phosphonium hydrohalates->Wherein R is ₆ Selected from C _1～20 Alkyl or benzyl, X is a halogen atom.

More preferably, in step a), the ligand ii is selected from one of the following compounds:

in certain embodiments, in step a), the base is selected from one or two of potassium tert-butoxide, lithium carbonate, sodium carbonate, cesium carbonate, silver carbonate, potassium bicarbonate, potassium carbonate, potassium borofluoride, potassium phosphate, dipotassium hydrogen phosphate, sodium tert-butoxide, lithium tert-butoxide, sodium hydride, potassium hydride, sodium acetate, sodium methoxide, sodium benzoate, potassium benzoate, pyridine, triethylamine, cesium fluoride, potassium hydroxide, and pivalate;

and/or, in the step A), the reaction solvent of the intramolecular oxidation dearomatization Heck reaction is selected from anisole, benzotrifluoride, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-diethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, trimethylbenzene, dimethyl ether, ethanol, tertiary butanol, toluene, chlorobenzene, xylene, 1, 4-dioxane, diethylene glycol dimethyl ether, methyl tertiary butyl ether, tetrahydrofuran and ethylene glycol dimethyl ether;

And/or, in the step A), the concentration of the compound 17 in the intramolecular oxidation dearomatization Heck reaction is 0.05-2.5 mol/L;

and/or, in the step A), the temperature of the intramolecular oxidation de-aromatization Heck reaction is 50-160 ℃.

In certain embodiments, in step a), the base is potassium phosphate and potassium carbonate;

and/or, in the step A), the reaction solvent is one of N, N-dimethylformamide, N-dimethylacetamide and anisole;

and/or, in the step A), the concentration of the compound 17 in the intramolecular Heck reaction is 0.05-1 mol/L;

and/or, in the step A), the temperature of the intramolecular Heck reaction is 60-150 ℃.

In certain embodiments, the synthetic route for compound 17 is as follows:

wherein R is ₂ Is hydroxy protecting group II, X is halogen atom, R ₁₁ Is a hydroxyl protecting group I or a hydrogen atom, R ₁ Is a hydroxyl protecting group I;

when R is ₁₁ Protecting for hydroxy groupsThe protecting group I comprises the following steps:

1) Providing compound 15;

2) Removing hydroxyl protecting group II from the compound 15 to generate a compound 17;

when R is ₁₁ In the case of a hydrogen atom, step 2) is carried out after introducing a hydroxyl protecting group I into the compound 15.

In certain embodiments, the hydroxy protecting group ii is selected from one of p-methoxybenzyl, benzyl, acetyl, benzoyl, pivaloyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and triethylsilyl.

In certain embodiments, the halogen atom is selected from one of a chlorine atom, a bromine atom, and an iodine atom.

In certain embodiments, in step 2), the removal reagent used to remove the hydroxyl protecting group ii is selected from one or two of potassium carbonate, sodium methoxide, sodium hydroxide, potassium hydroxide, trifluoroacetic acid, hydrochloric acid, boron trichloride, acetic acid, tetrabutylammonium fluoride, tetraethylammonium fluoride, hydrobromic acid, potassium fluoride, and cesium fluoride;

and/or in the step 2), the reaction solvent used for removing the hydroxyl protecting group II is one or two selected from methanol, N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane and water;

and/or, in the step 2), the reaction temperature for removing the hydroxyl protecting group II is-20-90 ℃.

In certain embodiments, in step 2), the removal agent is potassium carbonate;

and/or, in the step 2), the reaction solvent is methanol;

and/or, in the step 2), the reaction temperature for removing the hydroxyl protecting group II is 40-60 ℃.

In certain embodiments, in step 2), the removal reagent is potassium fluoride;

and/or, in the step 2), the reaction solvent is acetonitrile and water;

and/or, in the step 2), the reaction temperature for removing the hydroxyl protecting group II is 0-60 ℃.

In certain embodiments, the synthetic route for compound 15 is as follows:

wherein R is ₂ Is a hydroxyl protecting group II, R ₂₂ Is a hydroxyl protecting group II or a hydrogen atom, X is a halogen atom, R ₁₁ Is a hydroxyl protecting group I or a hydrogen atom;

when R is ₂₂ When the hydroxyl protecting group II is a hydroxyl protecting group II, the method comprises the following steps:

a. providing compound 11;

b. subjecting the compound 11 to a Bischler-Napieralski reaction to obtain a compound 13;

c. subjecting the compound 13 to asymmetric transfer hydrogenation reaction to obtain a chiral tetrahydroisoquinoline compound 14;

d. the compound 14 is subjected to secondary amine protection to generate a compound 15;

when R is ₂₂ In the case of a hydrogen atom, the compound 11 is subjected to steps b, c and d after the introduction of a hydroxy protecting group II.

In certain embodiments, in step b, the Bischler-Napieralski reaction is performed in the presence of a condensing agent and a base; the molar ratio of the compound 11 to the condensing agent to the alkali is 1:0.9-1.3:1.5-2.5.

In certain embodiments, the condensing agent is selected from one of phosphine oxide, phosphorus pentoxide, and trifluoromethanesulfonic anhydride;

and/or in step b, the base is selected from one of 2-fluoropyridine, pyridine, 4-dimethylaminopyridine, lutidine and triethylamine;

And/or in the step b, the reaction solvent of the Bischler-Napieralski reaction is selected from one of dichloromethane, dichloroethane, tetrahydrofuran and toluene;

and/or in the step b, the temperature of the Bischler-Napieralski reaction is-50-40 ℃.

In certain embodiments, in step b, the condensing agent is triflic anhydride;

and/or, in step b, the base is 2-fluoropyridine;

and/or, in the step b, the reaction solvent is dichloromethane;

and/or in the step b, the temperature of the Bischler-Napieralski reaction is-30-35 ℃.

In certain embodiments, in step c, the asymmetric transfer hydrogenation reaction is performed in the presence of chiral ligand i, hydrogen source i, and metal catalyst i; the molar ratio of the compound 13, the metal catalyst I, the chiral ligand I and the hydrogen source I is preferably 1:0.001 to 0.01: 0.002-0.02: 1.2 to 3.

In certain embodiments, in step c, the chiral ligand I is selected from

One of the following;

and/or in the step c, the hydrogen source I is selected from one of formic acid, ammonium formate and a complex of formic acid and trialkylamine;

and/or, in step c, the metal catalyst I is selected from

One of the following;

And/or in the step c, the reaction solvent of the asymmetric hydrogenation reaction is selected from one of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, dimethyl ether, tert-butyl methyl ether, trifluoroethanol, anisole, N-dimethylformamide, benzotrifluoride, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, trimethylbenzene, ethanol, tert-butanol, toluene, chlorobenzene, xylene, 1, 4-dioxane, dichlorobenzene, hexafluoroisopropanol, methanol and isopropanol;

and/or, in the step c, the temperature of the transfer hydrogenation reaction is-10-40 ℃.

In certain embodiments, in step c, the hydrogen source i is a methanol and triethylamine complex;

and/or, in the step c, the reaction solvent is N, N-dimethylformamide;

and/or, in the step c, the temperature of the transfer hydrogenation reaction is 0-35 ℃.

In certain embodiments, in step d, the secondary amine protection is performed under basic conditions; the alkali used in the alkaline condition is selected from one of disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium carbonate, sodium carbonate, triethylamine, N-diisopropylethylamine, pyridine and 4-dimethylaminopyridine.

In certain embodiments, in step d, the reaction temperature of the secondary amine protection is from-10 to 50 ℃.

In certain embodiments, the method of preparing compound 11 comprises the steps of: providing a compound 9 and a compound 5, and carrying out an amino acid condensation reaction to obtain a compound 11I, wherein the reaction formula is as follows:

wherein R is ₃ Is methyl or hydrogen, X is halogen, R ₂₂ Is a hydrogen atom or a hydroxyl protecting group II.

In certain embodiments, the amine acid condensation reaction is performed in the presence of a condensing agent and a base; the molar ratio of the compound 9 to the compound 5 to the condensing agent to the alkali is 1-1.6:1-1.2:1.5-3.

In certain embodiments, the condensing agent is selected from one of O-benzotriazol-N, N '-tetramethylurea tetrafluoroboric acid, 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride, 2- (7-azobenzotriazol) -N, N' -tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, and benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate;

and/or the base is selected from one of triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine and pyridine;

and/or the temperature of the amine acid condensation reaction is-10-50 ℃.

In certain embodiments, the condensing agent O-benzotriazol-N, N' -tetramethylurea tetrafluoroboric acid;

And/or, the base is triethylamine;

and/or the temperature of the amine acid condensation reaction is 0-25 ℃.

In certain embodiments, R in the compound 11I ₃ The reaction formula of the compound 11 II obtained by substituting hydroxyl with the group protecting group I is as follows:

wherein R is ₁ Is a hydroxyl protecting group I, R ₂ Is a hydroxyl protecting group II. It is noted that the compound 11 includes all structural formulas of the compound 11 i and the compound 11 ii.

In certain embodiments, the method of preparing compound 9 comprises the steps of:

A. providing compound 6;

B. the compound 6 and nitromethane undergo a Henry reaction to generate a compound 7;

C. the compound 7 is subjected to double bond reduction reaction to generate a compound 8;

D. the compound 8 is subjected to nitroreduction reaction to generate a compound 9I.

In certain embodiments, in step B, the compound 6 is subjected to Henry's reaction with nitromethane under the catalysis of a base that is one or more of ethylenediamine, ammonium acetate, sodium hydroxide, piperidine, diethylamine, and morpholine.

In certain embodiments, in step C, the reducing agent of the double bond reduction reaction is selected from one of lithium aluminum hydride, sodium borohydride, palladium on carbon+hydrogen, raney nickel+hydrogen, lithium borohydride, red-Al, zinc powder, and iron powder; the Raney nickel and hydrogen are used as a catalyst, and hydrogen is used as a hydrogen source for hydrogenation reduction; palladium carbon and hydrogen refer to hydrogen reduction by hydrogenation with palladium carbon as a catalyst and hydrogen as a hydrogen source, and are all reducing agents commonly used by those skilled in the art.

And/or in the step C, the reaction solvent of the double bond reduction reaction is selected from one of ethanol, diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 1, 4-dioxane, toluene, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether;

and/or, in the step C, the temperature of the double bond reduction reaction is-10 ℃.

In certain embodiments, in step C, the molar ratio of compound 7 to reducing agent is from 1:1 to 3;

and/or, in the step C, the reducing agent is sodium borohydride;

and/or, in the step C, the reaction solvent is ethanol and tetrahydrofuran;

and/or, in the step C, the temperature of the reduction reaction is 0 ℃.

In certain embodiments, in step D, the reducing agent of the nitroreduction reaction is selected from one of lithium aluminum hydride, sodium borohydride, palladium on carbon+hydrogen, raney nickel+hydrogen, lithium borohydride, red-Al, zinc powder, and iron powder;

and/or in the step D, the reaction solvent of the nitroreduction reaction is selected from one of ethanol, diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 1, 4-dioxane, toluene, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether;

and/or, in the step D, the temperature of the nitroreduction reaction is-10-80 ℃.

In certain embodiments, in step D, the molar ratio of compound 8 to reducing agent is from 1:1 to 3;

and/or, in the step D, the reducing agent is Raney nickel+hydrogen;

and/or, in the step D, the reaction solvent is ethanol;

and/or, in the step D, the temperature of the reduction reaction is 10-80 ℃.

In certain embodiments, the compound 9I is further reacted via hydroxyl protection to form a compound 9 ii having the following formula:

wherein R is ₂ Is a hydroxyl protecting group II. It is noted that the compound 9 includes all structural formulas of the compound 9I and the compound 9 ii.

In certain embodiments, the hydroxy protection reaction of compound 9I is performed under basic conditions; the alkali adopted in the alkaline condition is one or two selected from 4-dimethylaminopyridine, sodium hydride, triethylamine, pyridine and imidazole;

and/or the reaction solvent for the hydroxyl protection reaction of the compound 9I is selected from one of dichloromethane, dichloroethane, tetrahydrofuran and toluene;

and/or the temperature of the hydroxyl protection reaction of the compound 9I is 0-40 ℃.

In certain embodiments, the method of preparing compound 5 comprises the steps of:

wherein R is ₃ Is methyl or a hydrogen atom;

(1) Providing compound 1;

(2) The compound 1 undergoes halogenation reaction to generate a compound 2;

(3) The compound 2 undergoes a Wittig reaction to generate a compound 3;

(4) The compound 3 undergoes hydrolysis reaction to generate a compound 4;

(5) The compound 4 undergoes an oxidation reaction to produce a compound 5.

The beneficial effects of the invention are as follows:

1. the invention provides a full synthesis method of dihydro etorphine, which ensures that a reaction substrate can be effectively converted into an expected product under the designed reaction condition, and achieves the high-efficiency synthesis effect of high chemical and optical yield (the shortest total 15 steps from the condensation reaction of compound 9 and compound 5 amino acid, the total yield is 16 percent, and 99.9%ee).

2. According to the method provided by the invention, the thebaine analogue intermediate is prepared, and the dihydro etorphine can be prepared by only simple conversion in several steps from the intermediate, so that the effects of high reaction yield and simplicity in operation are achieved.

3. In the full synthesis method of the dihydroetorphine, the intramolecular oxidation dearomatization Heck reaction in the process of preparing the intermediate is taken as a key reaction, and the reaction activity of a reaction site is high, so that a reaction substrate and a catalyst can be efficiently converted into an expected product after the reaction substrate and the catalyst act, the yield reaches 82 percent, and the method is remarkably improved compared with the prior report method.

4. The full synthesis method of the dihydroetorphine is simple to operate, and most of synthesis intermediates can be directly subjected to subsequent reactions without further separation and purification, so that continuous operation of multi-step reactions is realized. The synthesis efficiency is improved, the synthesis path is shortened, and the production cost is saved. The cost of the dihydro etorphine synthesized by the method is greatly reduced compared with the traditional synthesis modes of planting, extracting and semi-synthesizing.

5. The total synthesis method has mild reaction conditions, simple and convenient post-reaction treatment and easy operation, and is suitable for large-scale preparation of the medicine.

6. The total synthesis method of the invention can also be used for synthesizing other opioid medicines with similar structures, is beneficial to changing the current situation that the existing opioid medicines mainly rely on manually planting poppy to obtain thebaine, and is beneficial to the management and control and the safe production of the medicines.

7. The reagents used in the method provided by the invention are all common chemical reagents, and special preparation is not needed; meanwhile, the requirements of each reaction condition are not harsh, and the sensitivity to substances such as water, oxygen and the like is not high; in addition, the post-treatment of each reaction step is simple, and the operability is strong.

Detailed Description

The technical scheme of the present invention is described in further detail below, but the scope of the present invention is not limited to the following.

Example 1 preparation of Compound 5, R ₃ For H, X is bromine as an example, compound 5a was synthesized;

the method comprises the following steps:

isovanillin 1a (150 g,0.986mol,1.0 equiv.) was dissolved in dichloromethane (2500 mL) and cooled to 0 ℃ in an ice bath. Dibromohydantoin (155 g, 0.552 mol,0.55 equiv.) was added slowly thereto in portions with stirring, then the reaction solution was warmed to room temperature for reaction, and after TLC detected complete disappearance of starting material (about 4 hours), the reaction solution was cooled to 0 ℃, and saturated Na was added thereto ₂ S ₂ O ₃ The reaction was quenched with aqueous solution (500 mL), stirred at 0deg.C for 1h, the precipitate was completely precipitated, filtered, the filter cake (500 mL. Times.3) was washed with water, the resulting off-white solid 2a was collected, dried in an oven at 90deg.C for 5 hours, and then dried in vacuo (50deg.C) for 6 hours, and used directly in the next reaction (193 g, yield 85%).

Will Ph ₃ P ⁺ CH ₂ OMeCl ^- (88 g,2.59mol,3.1 equiv) was dispersed in dry tetrahydrofuran (2500 mL), and after ice-bath cooling to 0deg.C, t-BuOK (272 g,2.42mol,2.9 equiv) was slowly added thereto, and the reaction solution was stirred vigorously for 45 minutes in orange-red color. Compound 2a (193 g,0.835mol,1.0 equiv.) from the previous step was added slowly to the suspension in portions, and the reaction was carried out by natural heating at 0 ℃ to 20 ℃ after complete disappearance of starting material by TLC (about 1 hour). The reaction mixture was cooled to 0℃again, and water (1000 mL) was added thereto to quench the reaction. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (1000 ml×3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude brown-red compound 3a, which was used directly in the subsequent reaction without purification.

The crude compound 3a was dissolved in a 1M HCl/acetone (v/v=1:1, 3000 mL) mixture, heated to 80 ℃ for reaction, after complete disappearance of the starting material monitored by TLC (about 3 hours), cooled to room temperature, acetone was removed under reduced pressure, the resulting mixture was extracted with ethyl acetate (2000 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give crude brownish red compound 4a, which was used directly in the subsequent reaction without purification.

The crude product 4a is dissolved in t-BuOH/H ₂ O (v: v=1:1, 2000 ml), ice-bath cooled to 0 ℃, and NaH was added thereto in portions ₂ PO ₄ ·2H ₂ O (261 g,1.67mol,2.0 equiv.) was added to the mixture, and 2-methyl-2-butene (178mL,1.67mol,2.0 equiv) was added thereto, followed by stirring at 0℃for 10 minutes, and then NaClO was added thereto in portions slowly ₂ (151 g,1.67mol,2.0 equiv.) the reaction was strongly exothermic. After the addition, the temperature was naturally raised to 20℃and the reaction was carried out at 0℃after the TLC had detected the complete disappearance of starting material (about 3 hours), and the reaction mixture was again cooled to 0 ℃. The reaction was quenched by slowly adding saturated aqueous sodium bicarbonate until no bubbles were generated. t-BuOH was removed under reduced pressure, toluene (1000 mL) was added, stirring vigorously for 15 minutes, and the aqueous layer was separated, washed sequentially with toluene (1000 mL. Times.5), and dichloromethane (1000 mL. Times.5). The aqueous layer was adjusted to pH 5 with 1M HCl, then extracted with ethyl acetate (1000 mL. Times.5), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was dispersed in toluene (600 mL), stirred at room temperature for 2 hours, filtered, and the solid was collected and recrystallized from isopropanol to give compound 5a (87.0 g, three step yield 40%) as an off-white solid.

Example 2 preparation of Compound 5, R ₃ For Me, X is bromine, to synthesize Compound 5b;

the method comprises the following steps:

will Ph ₃ P ⁺ CH ₂ OMeCl ^- (911 g,2.66mol,3.1 equiv.) is dispersed in dry tetrahydrofuran (2500 mL), cooled to 0deg.C in an ice bath, t-BuOK (279 g,2.48mol,2.9 equiv.) is slowly added thereto, and the reaction solution is orange-red and vigorously stirred for 45 minutes. Compound 2b (210 g,0.857mol,1.0 equiv.) was slowly added to the suspension in portions, and the reaction was allowed to proceed to 20 ℃ naturally at 0 ℃ after complete disappearance of starting material monitored by TLC (about 1 hour). The reaction mixture was cooled to 0℃again, and water (1000 mL) was added thereto to quench the reaction. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (1000 mL. Times.3),the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude brown-red compound 3b, which was used directly in the subsequent reaction without purification.

The crude compound 3b was dissolved in a 1M HCl/acetone (v/v=1:1, 3000 mL) mixture, heated to 80 ℃ for reaction, after complete disappearance of the starting material monitored by TLC (about 3 hours), cooled to room temperature, acetone was removed under reduced pressure, the resulting mixture was extracted with ethyl acetate (2000 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give crude brownish red compound 4b which was used directly in the subsequent reaction without purification.

Dissolving the crude product 4b in t-BuOH/H ₂ O (v: v=1:1, 2000 ml), ice-bath cooled to 0 ℃, and NaH was added thereto in portions ₂ PO ₄ ·2H ₂ O (267 g,1.71mol,2.0 equiv.) was added to the mixture, 2-methyl-2-butene (181mL,1.71mol,2.0 equiv.) was added thereto, and after stirring at 0deg.C for 10 minutes, naClO was added thereto slowly in portions ₂ (155g,1.71mol,2.0 equiv) the reaction is strongly exothermic. After the addition, the temperature was naturally raised to 20℃and the reaction was carried out at 0℃after the TLC had detected the complete disappearance of starting material (about 3 hours), and the reaction mixture was again cooled to 0 ℃. The reaction was quenched by slowly adding saturated aqueous sodium bicarbonate until no bubbles were generated. t-BuOH was removed under reduced pressure, toluene (1000 mL) was added, stirring vigorously for 15 minutes, and the aqueous layer was separated, washed sequentially with toluene (1000 mL. Times.5), and dichloromethane (1000 mL. Times.5). The aqueous layer was adjusted to pH 5 with 1M HCl, then extracted with ethyl acetate (1000 mL. Times.5), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was dispersed in toluene (600 mL), stirred at room temperature for 2 hours, filtered, and the solid was collected and recrystallized from isopropanol to give compound 5b (99.0 g, three-step yield 42%) as an off-white solid.

Example 3 preparation of compound 9 i: by R ₂₂ Taking a hydrogen atom as an example, the compound 9a is synthesized by the following synthetic route:

The method comprises the following steps:

vanillin 6 (200 g,1.31mol,1.0 equiv) was added.) Dissolved in CH ₃ NO ₂ To this (1000 mL) was added ethylenediamine (1.0 mL) with stirring, heated to reflux, and after completion of the reaction (about 2 hours) as monitored by TLC, the reaction solution was cooled to room temperature and a large amount of yellow solid precipitated. The mixture was filtered, and the cake was washed successively with methanol/water (v/v=1:1) (200 ml×3) and absolute ethanol (200 mL ×2), and the solid was collected and dried under reduced pressure with a water pump to give compound 7 (bright yellow fine needle crystals, 185g, yield 72%).

Compound 7 (40.0 g,0.205mol,1.0 equiv.) is dissolved in a THF/EtOH mixed solution (v/v=1:1, 480 ml), ice-cooled to 0 ℃, and NaBH is added thereto slowly in portions with stirring ₄ (15.5 g,0.410mol,2.0 equiv.) for 3 hours at 0deg.C, TLC checked complete disappearance of starting material, to which was added aqueous acetic acid (CH) ₃ COOH/H ₂ O, v/v=1:4, 250 ml). After the organic solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate (300 ml×3), the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated, and the resulting crude product was filtered through a pad of silica gel (eluent PE: ea=2:1, v/v) to give compound 8 (yellow oil) which was directly used for the next reaction.

Compound 8 was dissolved in EtOH (400 mL), raney-Ni (about 4.0 g) was added, placed in a high pressure hydrogenation reactor and reacted at room temperature under 10atm hydrogen pressure for 10 hours, and TLC detected complete disappearance of starting material. A large amount of solid was precipitated from the reaction mixture, meOH (300 mL) was added, and after the mixture was heated to 70℃to dissolve the solid, the solid was filtered through celite while it was hot, and the cake was washed with MeOH (100 mL. Times.3). The filtrate was concentrated under reduced pressure until the solvent amount remained about 200mL, at which time a large amount of solids had precipitated. Cooling at room temperature for 3 hours, filtering, collecting a filter cake, vacuum drying (40 ℃) for 1 hour by a water pump, and vacuum drying at room temperature by an oil pump for about 0.5 hour to obtain a brown yellow solid compound 9a (22.2 g, two-step yield 55%). M.p. 139-141 ℃. ¹ H NMR(400MHz,CDCl ₃ ):δ6.84(d,J＝8.4Hz,1H),6.72–6.67(m,2H),3.87(s,3H),2.94(t,J＝ 6.8Hz,2H),2.68(t,J＝6.8Hz,2H). ¹³ C NMR(100MHz,CDCl ₃ ):δ146.5,144.0,131.6,121.4, 114.4,111.3,55.9,43.6,39.6.IR(neat):ν _max ＝2512,1610,1496,1469,1232,1153,1128,1033, 812cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₉ H ₁₄ NO ₂ ⁺ ,168.1019；found,168.1025.

EXAMPLE 4 preparation of Compound 9 II, R ₂₂ For TBDPS as an example, compound 9b was synthesized as follows:

compound 9a (20.0 g,0.120mol,1.0 equiv.) and imidazole (12.2 g, 0.178 mol,1.5 equiv.) were dissolved in dry CH ₂ Cl ₂ To (250 mL) was added TBDPSCl (34.5 g,0.125mol,1.05 equiv.) after stirring at room temperature for 10 minutes. After 5 hours at room temperature, the reaction was complete by TLC. To which saturated NH is added ₄ The reaction was quenched with aqueous Cl (300 mL) and the resulting mixture was filtered through celite, the filtrate was separated, the aqueous layer was taken up in CH ₂ Cl ₂ Extraction (100 ml×2), combining the organic layers, washing with saturated aqueous NaCl (100 ml×2), drying over anhydrous magnesium sulfate, filtration, concentration of the filtrate under reduced pressure, purification of the crude product by column chromatography on silica gel (dichloromethane/methanol=6:1, v/v, containing 0.5% aqueous ammonia) afforded compound 9b (41.3 g, yield 85%). ¹ H NMR(400MHz,CDCl ₃ ):δ7.72–7.70(m,4H),7.41–7.32(m,6H),6.64(d,J＝8.0Hz, 1H),6.59(s,1H),6.47(dd,J＝8.0,1.6Hz,1H),3.55(s,3H),2.88(t,J＝6.8Hz,2H),2.62(t,J＝ 6.8Hz,2H),1.11(s,9H). ¹³ C NMR(100MHz,CDCl ₃ ):δ150.4,143.5,135.4,134.8,133.6,132.5, 129.5,127.6,127.4,120.6,120.0,113.0,55.4,43.2,38.9,26.7,19.7.IR(neat):ν _max ＝3053,2933, 2858,1587,1513,1264cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₅ H ₃₂ NO ₂ Si ⁺ ,406.2197；found,406.2190.

EXAMPLE 5 preparation of Compound 9 II, R ₂₂ For TBS as an example, compound 9c was synthesized by the route:

synthetic route reference example 4, differing in the factTBSCl was added to example 5 to give Compound 9c as an oil. ¹ H NMR(400MHz,CDCl ₃ ):δ6.77(d,J＝8.0Hz,1H),6.68–6.63(m,2H),3.79(s,3H),2.93(t,J＝ 6.8Hz,2H),2.67(t,J＝6.8Hz,2H),1.30(s,2H),0.99(s,9H),0.14(s,6H). ¹³ C NMR(100MHz, CDCl ₃ ):δ150.8,143.3,133.2,120.9,120.7,112.8,55.5,43.6,39.7,25.7,18.4,–4.66.IR(neat): ν _max ＝2929,2856,1578,1463,1275,1156,1126,1034,838cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₁₅ H ₂₈ NO ₂ Si ⁺ ,282.1884；found,282.1881.

Example 6 preparation of Compound 11, R ₂₂ TBDPS, X is bromine, R ₁₁ Taking a hydrogen atom as an example, the compound 11a is synthesized by the following synthetic route:

the method comprises the following steps:

Compound 9b (51.3 g,0.126mol,1.1 equiv.) compound 5a (30.0 g,0.115mol,1.0 equiv.) and TBTU (44.3 g,0.138mol,1.2 equiv.) were dissolved in dry CH ₂ Cl ₂ (300 mL). Triethylamine (40.0 mL,0.287mol,2.5equiv) was added in an ice bath, followed by warming to room temperature and reaction for 4 hours, TLC checked complete disappearance of starting material, and quenched by addition of saturated aqueous ammonium chloride (300 mL). Separating the organic layer from the aqueous layer with CH ₂ Cl ₂ The organic layers were combined by extraction (400 mL. Times.1), washed successively with water (200 mL. Times.1) and saturated sodium chloride solution (100 mL. Times.1), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was dissolved in ethyl acetate (300 mL) and successively treated with 0.1M HCl (100 mL. Times.2), saturated NaHCO ₃ (100 mL. Times.2), water (100 mL. Times.1), and saturated sodium chloride solution (100 mL. Times.1). Dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/acetone=4:1, v/v) to give 11a as a white foam (67.1 g, 90% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.71–7.68(m,4H), 7.42–7.32(m,6H),6.71(q,J＝8.0Hz,2H),6.56(d,J＝8.0Hz,1H),6.49(d,J＝2.0Hz,1H), 6.29(dd,J＝8.0,2.0Hz,1H),6.01(s,1H),5.35(t,J＝4.0Hz,1H),3.84(s,3H),3.59(s,2H),3.50 (s,3H),3.38(q,J＝6.0Hz,2H),2.59(t,J＝6.9Hz,2H),1.10(s,9H). ¹³ C NMR(100MHz, CDCl ₃ ):δ170.0,150.6,146.5,143.7,135.5,133.8,132.0,129.7,127.8,127.6,122.1,120.7,120.1, 112.9,111.3,109.9,56.5,55.5,43.7,40.8,35.2,26.8,19.9.IR(neat):ν _max ＝3297,3050,2932, 2857,1650,1605,1512,1488,1111,1034,700cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₃₄ H ₃₉ ⁷⁹ BrNO ₅ Si ⁺ ,648.1775；found,648.1778；C ₃₄ H ₃₉ ⁸¹ BrNO ₅ Si ⁺ ,650.1755；found,650.1763.

EXAMPLE 7 preparation of Compound 11, R ₂₂ TBDPS, X is bromine, R ₁₁ For Me as an example, compound 11b was synthesized by the following route:

compound 9b (64.9 g,0.160mol,1.1 equiv.) compound 5b (40.0 g,0.145mol,1.0 equiv.) and TBTU (55.9 g,0.174mol,1.2 equiv.) were dissolved in dry CH ₂ Cl ₂ (400 mL). Triethylamine (50.6 mL,0.364mol,2.5equiv) was added in an ice bath, followed by warming to room temperature and TLC checked complete disappearance of starting material and quenched by addition of saturated aqueous ammonium chloride (400 mL). Separating the organic layer from the aqueous layer with CH ₂ Cl ₂ The organic layers were combined by extraction (500 mL. Times.1), washed successively with water (300 mL. Times.1) and saturated sodium chloride solution (200 mL. Times.1), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was dissolved in ethyl acetate (400 mL) and sequentially with 0.1M HCl (150 mL. Times.2), saturated NaHCO ₃ (150 mL. Times.2), water (150 mL. Times.1), and saturated sodium chloride solution (150 mL. Times.1). Dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/acetone=4:1, v/v) to give 11b as a white foam (87.7 g, 91% yield). ¹ H NMR(400MHz,CDCl ₃ ):δ7.70–7.68(m,4H),7.43 –7.37(m,2H),7.37–7.30(m,4H),6.93(d,J＝8.0Hz,1H),6.76(d,J＝8.0Hz,1H),6.57(d,J＝ 8.0Hz,1H),6.51(d,J＝1.8Hz,1H),6.31(dd,J＝8.0,1.6Hz,1H),5.38(t,J＝4.8Hz,1H),3.820 (s,3H,overlapped),3.818(s,3H,overlapped),3.59(s,2H),3.51(s,3H),3.39(q,J＝6.0Hz,2H), 2.60(t,J＝6.8Hz,2H),1.10(s,9H). ¹³ C NMR(100MHz,CDCl ₃ ):δ169.8,152.8,150.5,146.8, 143.6,135.3,133.6,131.8,129.6,127.6,127.4,126.3,120.7,120.5,120.0,112.7,111.5,60.4,56.0,55.3,43.6,40.7,35.1,26.6,19.7.IR(neat):ν _max ＝3311,3052,2934,2858,1663,1512,1486,1265, 1034,733,701cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₃₅ H ₄₁ 79BrNO ₅ Si ⁺ ,662.1932；found, 662.1930；C ₃₅ H ₄₁ ⁸¹ BrNO ₅ Si ⁺ ,664.1911；found,664.1922.

Example 8 preparation of Compound 11, R ₂₂ Is a hydrogen atom, X is bromine, R ₁₁ For Me as an example, compound 11c was synthesized by the following route:

compound 9a (2.00 g,0.012mol,1.1 equiv.) compound 5b (3.00 g, 0.0111 mol,1.0 equiv.) and TBTU (4.24 g,0.013mol,1.2 equiv.) were dissolved in dry CH ₂ Cl ₂ (30 mL). Triethylamine (3.8 mL,0.027mol,2.5equiv) was added in an ice bath, followed by reaction at room temperature for 13 hours, TLC detected complete disappearance of starting material, and quenched by addition of saturated aqueous ammonium chloride (30 mL). Separating the organic layer from the aqueous layer with CH ₂ Cl ₂ Extraction (20 mL. Times.3), combining the organic layers, followed by 1M HCl (50 mL. Times.2), saturated NaHCO ₃ (50 mL. Times.1), saturated sodium chloride solution (50 mL. Times.1). Dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether/acetone=3:1, v/v) to give 11c as a white foam (3.5 g, 75% yield). ¹ H NMR(400MHz,CDCl ₃ ): δ6.96–6.50(m,5H),5.83(s,1H),5.52(s,1H),3.85(s,6H,overlapped),3.82–3.81(m,3H),3.60(m,2H),3.45–3.40(m,2H),2.67–2.64(m,2H). ¹³ C NMR(100MHz,CDCl ₃ ):δ169.9,152.8, 146.7,146.6,144.2,130.3,127.5,126.3,121.2,120.7,114.3,111.5,111.0,60.4,56.0,55.8,43.6, 40.7,35.1.IR(neat):ν _max ＝3307,1650,1598,1523,1488,1271,1031cm ^-1 .HRMS(m/z):[M+ H] ⁺ calculated for C ₁₉ H ₂₃ ⁷⁹ BrNO ₅ ⁺ ,424.0754；found,424.0748；C ₁₉ H ₂₃ ⁸¹ BrNO ₅ ⁺ ,426.0734；found, 426.0731.

Example 9 preparation of Compound 11, R ₂₂ TBS, X is bromine, R ₁₁ Taking a hydrogen atom as an example, the compound 11d is synthesized by the following synthetic route:

the synthetic route for compound 11d is shown above, and the synthetic procedure is as described in example 6. ¹ H NMR(400MHz, CDCl ₃ ):δ6.77–6.73(m,2H),6.67(d,J＝8.0Hz,1H),6.59–6.58(m,1H),6.48–6.46(m,1H), 6.09(s,1H),5.39(m,1H),3.90(s,3H),3.75(s,3H),3.62(s,2H),3.44(q,J＝6.8Hz,2H),2.66(t, J＝6.8Hz,2H),0.98(s,9H),0.13(s,6H). ¹³ C NMR(100MHz,CDCl ₃ ):δ169.9,150.9,146.4, 143.6,143.5,132.0,127.6,121.9,120.8,120.7,112.5,111.2,109.7,56.3,55.4,43.5,40.6,35.1,25.7,18.4,–4.69.IR(neat):ν _max ＝3300,2931,2855,1646,1604,1513,1488,1277,1231,1032 cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₄ H ₃₅ ⁷⁹ BrNO ₅ Si ⁺ ,524.1462；found,524.1464； C ₂₄ H ₃₅ ⁷⁹ BrNO ₅ Si ⁺ ,526.1442；found,526.1445.

Example 10 preparation of Compound 11 as R ₂₂ TBS, X is bromine, R ₁₁ For Me as an example, compound 11e was synthesized by the following route:

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the synthetic route of the compound 11e is as described above, and the synthetic operation is carried out with reference to the embodimentThe method of example 6. ¹ H NMR(400MHz, CDCl ₃ ):δ6.96(d,J＝8.4Hz,1H),6.81(d,J＝8.4Hz,1H),6.69(d,J＝8.0Hz,1H),6.60(d,J＝2.0Hz,1H),6.48(dd,J＝8.0,2.0Hz,1H),5.44(t,J＝5.8Hz,1H),3.87(s,3H),3.84(s,3H),3.75 (s,3H),3.61(s,2H),3.45(q,J＝6.6Hz,2H),2.67(t,J＝6.8Hz,2H),0.98(s,9H),0.13(s,6H). ¹³ C NMR(100MHz,CDCl ₃ ):δ169.9,152.8,150.9,146.8,143.5,132.0,127.5,126.3,120.8, 120.7,112.4,111.5,60.4,56.0,55.4,43.7,40.7,35.1,25.7,18.4,–4.7.IR(neat):ν _max ＝3055,1669, 1512,1264,1036,731cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₅ H ₃₇ ⁷⁹ BrNO ₅ Si ⁺ ,538.1619； found,538.1622；C ₂₅ H ₃₇ ⁸¹ BrNO ₅ Si ⁺ ,540.1598；found,540.1603.

Example 11 preparation of compound 12. When R in Compound 11 ₂₂ In the case of hydrogen atom, the compound 11 introduces a hydroxyl protecting group II to obtain a compound 12.

By R ₂₂ Is a hydrogen atom, X is bromine, R ₁₁ For Me, the introduced hydroxyl protecting group II is Bn, and the synthetic route of the compound 12ca is as follows:

compound 11c (830 mg,1.96mmol,1.0 equiv.) is dissolved in dry DMF (8 mL), protected by argon, and bromobenzyl (0.35 mL,2.94mmol,1.5 equiv.) is added and reacted for 1 hour at room temperature. TLC showed complete reaction of the starting material, quench with water, add ethyl acetate (10 mL), precipitate a large amount of solid, filter and wash the solid with methyl tert-butyl ether (10 mL x 2). The solid was collected and dried in vacuo to give compound 12ca (white powdery solid, 982mg, 90% yield). M.p. 151-152 ℃. ¹ H NMR(400MHz,CDCl ₃ ):δ7.45–7.43 (m,2H),7.37(t,J＝7.2Hz,2H),7.32–7.28(m,1H),6.97(d,J＝8.4Hz,1H),6.80(d,J＝8.4Hz, 1H),6.75(d,J＝8.0Hz,1H),6.66(d,J＝1.6Hz,1H),6.52(dd,J＝8.0,1.6Hz,1H),5.42(m,1H), 5.12(s,2H),3.86(s,3H),3.84(s,3H,overlapped),3.84(s,3H,overlapped),3.62(s,2H),3.45(q,J ＝6.4Hz,2H),2.68(t,J＝7.2Hz,2H). ¹³ C NMR(100MHz,CDCl ₃ ):δ170.0,153.0,149.9,146.9, 137.4,131.9,128.6,127.9,127.7,127.4,126.5,120.9,120.8,114.4,112.5,111.6,71.3,56.2,56.1,43.8,40.8,35.2.IR(neat):ν _max ＝3304,2936,1642,1592,1515,1487,1453,1266,1230,1034cm ^-1 . HRMS(m/z):[M+H] ⁺ calculated for C ₂₆ H ₂₉ ⁷⁹ BrNO ₅ ⁺ ,514.1224；found,514.1219； C ₂₆ H ₂₉ ⁸¹ BrNO ₅ ⁺ ,516.1203；found,516.1201.

Example 12 preparation of compound 12. When R in Compound 11 ₂₂ In the case of hydrogen atom, the compound 11 introduces a hydroxyl protecting group II to obtain a compound 12.

By R ₂₂ Is a hydrogen atom, X is bromine, R ₁₁ For Me, the introduced hydroxy protecting group II is PMB, and the compound 12cb is synthesized by the following synthetic route:

compound 11c (674 mg,1.60mmol,1.0 equiv.) is dissolved in dry DMF (8 mL), protected by argon, and PMBCl (0.33 mL,2.40mmol,1.5 equiv.) is added and reacted at room temperature for 3 hours. TLC showed complete reaction of the starting material, quench with water, add ethyl acetate (10 mL), precipitate a large amount of solid, filter and wash the solid with methyl tert-butyl ether (10 mL x 2). The solid was collected and dried in vacuo to give compound 12cb (788 mg, 84% yield as a white powdery solid). M.p. 144-146 ℃. ¹ H NMR(400MHz,CDCl ₃ ):δ7.36(d,J ＝8.8Hz,2H),6.97(d,J＝8.4Hz,1H),6.90(d,J＝8.4Hz,2H),6.81(d,J＝8.4Hz,1H),6.76(d,J ＝8.0Hz,1H),6.65(d,J＝1.6Hz,1H),6.53(dd,J＝8.0,1.6Hz,1H),5.40(m,1H),5.04(s,2H), 3.86(s,3H),3.84(s,3H),3.83(s,3H),3.81(s,3H),3.62(s,2H),3.45(q,J＝6.4Hz,2H),2.68(t,J ＝6.8Hz,2H). ¹³ C NMR(100MHz,CDCl ₃ ):δ170.0,159.5,153.0,150.0,147.0,131.9,129.5, 129.2,127.7,126.5,120.9,120.8,114.5,114.1,112.5,111.7,71.1,56.2,56.1,55.4,43.8,40.9,35.2.IR(neat):ν _max ＝3313,2932,1646,1591,1515,1249,1033cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₇ H ₃₁ ⁷⁹ BrNO ₆ ⁺ ,544.1329；found,544.1325；C ₂₇ H ₃₁ ⁸¹ BrNO ₆ ⁺ ,546.1309；found, 546.1306.

Example 13 preparation of compound 12. When R in Compound 11 ₂₂ In the case of hydrogen atom, the compound 11 introduces a hydroxyl protecting group II to obtain a compound 12.

By R ₂₂ Is a hydrogen atom, X is bromine, R ₁₁ For Me, the introduced hydroxyl protecting group II is Ac, and 12cc of a compound is synthesized, wherein the synthetic route is as follows:

compound 11c (1.00 g,2.36mmol,1.0 equiv.) is dissolved in dry acetonitrile (20 mL) and anhydrous potassium carbonate (651.5 mg,4.71mmol,2.0 equiv.) and acetic anhydride (0.27mL,2.83mmol,1.2 equiv.) are added sequentially under argon, and reacted at room temperature for 2 hours. TLC showed complete reaction of the starting materials, water quench reaction was added, the aqueous layer was extracted with ethyl acetate (20 mL. Times.4), the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give crude brown foamy solid. Methyl tert-butyl ether (5 mL) was added, stirred at room temperature for 20 minutes, filtered, and the solid was collected to give 12cc of compound (off-white solid, 957mg, 87% yield). M.p. 128-130 ℃. ¹ H NMR(400MHz,CDCl ₃ ):δ6.97(d,J＝8.4Hz, 1H),6.88(d,J＝8.0Hz,1H),6.83(d,J＝8.4Hz,1H),6.72(s,1H),6.66–6.61(m,1H),5.47(t,J ＝6.0Hz,,1H),3.87(s,3H),3.84(s,3H),3.78(s,3H),3.63(s,2H),3.51–3.43(m,2H),2.74(t,J ＝7.2Hz,2H),2.30(s,3H). ¹³ CNMR(100MHz,CDCl ₃ ):δ170.0,169.2,152.9,151.0,146.8, 138.3,137.7,127.5,126.4,122.7,120.8,120.7,112.8,111.6,60.5,56.1,55.9,43.7,40.6,35.5,20.7.IR(neat):ν _max ＝3290,2937,1761,1652,1597,1486,1268,1195,1031cm ^- ¹ .HRMS(m/z):[M+ H] ⁺ calculated for C ₂₁ H ₂₅ ⁷⁹ BrNO ₆ ⁺ ,466.0860；found,466.0859；C ₂₁ H ₂₅ ⁸¹ BrNO ₆ ⁺ ,468.0839；found, 468.0840.

Example 14 preparation of compound 12. When R in Compound 11 ₂₂ In the case of hydrogen atom, the compound 11 introduces a hydroxyl protecting group II to obtain a compound 12.

By R ₂₂ Is a hydrogen atom, X is bromine, R ₁₁ For Me, the introduced hydroxyl protecting group II is Bz, and the compound 12cd is synthesized by the following synthetic route:

compound 11c (1.00 g,2.36mmol,1.0 equiv.) was dissolved in dry dichloromethane (20 mL), protected by argon, cooled to 0 ℃, triethylamine (0.66 mL,4.71mmol,2.0 equiv.) and benzoyl chloride (0.33mL,2.83 mmol,1.2equiv) were added sequentially and allowed to react for 1 hour at room temperature, TLC indicated complete reaction of starting materials. The reaction was quenched with saturated aqueous ammonium chloride, the aqueous layer was extracted with dichloromethane (20 ml×4), the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether/acetone=10:1 to 2:1, v/v) to give 12cd (1.15 g, yield 92%) as a white solid. M.p. 145-147 ℃. ¹ H NMR(400MHz,CDCl ₃ )δ8.23–8.17(m,2H),7.68–7.58(m, 1H),7.54–7.47(m,2H),7.03–6.96(m,2H),6.85(d,J＝8.4Hz,1H),6.77(d,J＝1.6Hz,1H), 6.69(dd,J＝8.0,2.0Hz,1H),3.86(s,3H),3.85(s,3H),3.77(s,3H),3.65(s,2H),3.54–3.45(m, 2H),2.78(t,J＝7.2Hz,2H). ¹³ C NMR(100MHz,CDCl ₃ ):δ170.0,164.8,152.9,151.3, 146.8,138.5,137.7,133.5,130.2,129.4,128.5,127.5,126.4,122.8,120.8,120.7,112.9,111.6,60.5, 56.0,55.9,43.7,40.6,35.5.IR(neat):ν _max ＝3055,2939,1736,1665,1598,1510,1487,1264,1033, 731,704cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₆ H ₂₇ ⁷⁹ BrNO ₆ ⁺ ,528.1012；found,528.1016； C ₂₆ H ₂₇ ⁸¹ BrNO ₆ ⁺ ,530.0996；found,530.0994.

Example 15 preparation of compound 12. When R in Compound 11 ₂₂ In the case of hydrogen atom, the compound 11 introduces a hydroxyl protecting group II to obtain a compound 12.

By R ₂₂ Is a hydrogen atom, X is bromine, R ₁ For Me, the introduced hydroxy protecting group II is Piv as an example, the compound 12ce is synthesized by the following synthetic route:

Compound 11c (1.00 g,2.36mmol,1.0 equiv.) was dissolved in dry dichloromethane (20 mL), protected with argon, cooled to 0 ℃, triethylamine (0.66 mL,4.71mmol,2.0 equiv.) and pivaloyl chloride (0.35mL,2.83 mmol,1.2equiv.) were added sequentially and allowed to react for 2 hours at room temperature, TLC indicated complete reaction of starting materials. The reaction was quenched by addition of saturated aqueous ammonium chloride, the aqueous layer was extracted with dichloromethane (20 ml×4), the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether/acetone=10:1 to 6:1, v/v) to give 12ce (1.03 g, 86% yield) as a white foamy solid. ¹ H NMR(400MHz,CDCl ₃ ):δ6.96(d,J＝8.8Hz,1H),6.97–6.91(m,2H), 6.70(d,J＝1.6Hz,1H),6.63(dd,J＝8.0,2.0Hz,1H),3.87(s,3H),3.84(s,3H),3.75(s,3H),3.63 (s,2H),3.51–3.43(m,2H),2.74(t,J＝6.8Hz,2H),1.35(s,9H). ¹³ C NMR(100MHz,CDCl ₃ ):δ 176.7,170.0,152.9,151.2,146.8,138.7,137.3,127.5,126.4,122.6,120.7,120.7,112.8,111.6,60.5,56.0,55.9,43.6,40.6,39.0,35.4,27.2.IR(neat):ν _max ＝2968,1752,1683,1598,1511,1486,1268, 1114,1032cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₆ H ₂₇ ⁷⁹ BrNO ₆ ⁺ ,528.1012；found, 528.1016；C ₂₆ H ₂₇ ⁸¹ BrNO ₆ ⁺ ,530.0996；found,530.0994.

Example 16 preparation of Compound 15 (Bischler-Napieralski/asymmetric transfer hydrogenation).

By R ₂ TBDPS, X is bromine, R ₁₁ Is a hydrogen atom, R is CO ₂ Me is an example, and the synthetic route for compound 15ab is:

solid compound 11a (100.0 mg,0.154mmol,1.0 equiv.) was dissolved in dry CH ₂ Cl ₂ (1 mL) to this was added 2-fluoropyridine (27. Mu.L, 0.308mmol,2.0 equiv.) in sequence with stirring at 0deg.C, and trifluoromethanesulfonic anhydride (32. Mu.L, 0.185 mmol,1.2equiv.) and the addition was warmed to room temperature and reacted for 10 min, TLC showed complete disappearance of starting material. The reaction solution was cooled to 0℃and saturated NH was added ₄ The reaction was quenched with aqueous Cl (1 mL). Separating the organic layer from the aqueous layer by CH ₂ Cl ₂ Extraction (2 mL. Times.3), combining organic layers, washing with saturated NaCl (2 mL. Times.1), drying over anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain crude product of the compound 13a, which is used in the subsequent reaction without isolation and purification.

The crude product 13a was dissolved in dry degassed DMF (2.9 mL) and stirred at room temperature. Another reaction flask was charged with a metal catalyst (1.0 mg,0.0154mmol,0.01 equiv.), ligand (1S, 2S) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine (1.2 mg,0.0308mmol,0.02 equiv.), gas exchange, argon protection, addition of degassed dry DMF (40. Mu.L), stirring at room temperature for 30 min, adding the mixed solution to a DMF solution of Compound 13a, continuing stirring at room temperature for 10 min, then cooling to 0deg.C, and adding HCOOH/Et thereto ₃ N (5:2 complex) (55. Mu.L, 0.385mmol,2.5 equiv.) was allowed to react at room temperature for 17h. TLC detection reaction was complete. The reaction solution was cooled to 0℃and saturated NaHCO was added ₃ The reaction was quenched with water and the pH was adjusted to 9. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (1 ml×4), the organic layers were combined, washed successively with water (2 ml×1), saturated NaCl (2 ml×1), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give crude product of compound 14a, which was used in the subsequent reaction without isolation and purification.

Dissolving the above compound 14a in THF/H ₂ To a mixed solvent of O (2 ml, v/v=3:2), cooled to 0 ℃, sodium dihydrogen phosphate dihydrate (96.1 mg,0.616mmol,4.0 equiv.) was added in this order, and methyl chloroformate (0.462mmol,3.0 equiv.). The reaction was stirred at room temperature for 1 hour, and after TLC showed complete disappearance of starting material, H was added ₂ O, extracted with ethyl acetate (2 ml×3), the combined organic layers dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product purified by silica gel column chromatography (petroleum ether/acetone=7:1, v/v) to give 15ab as a white foamy solid (87 mg, three steps total yield 82%, ee=95%). HPLC conditions: OD-H column, hexane: i-PrOH=80:20, flow rate 1mL/min, column temperature 25 ℃, detection wavelength 254nm, two enantiomer retention times: t is t _major ＝8.705min，t _minor ＝6.352min。Optical rotation:[α] _D ²⁵ ＝–52.5 (c＝0.2,CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 7.77-7.70 (m, 4H), 7.46-7.33 (m, 6H), 6.72 (d, j=8.4 hz, 1H), 6.69-6.60 (m, 1H), 6.53 (s, 0.8H), 6.53 (s, 0.2H), 6.46-6.44 (m, 1H), 5.92 (s, 0.8H), 5.87 (s, 0.2H), 5.16-5.12 (m, 0.2H), 5.05-5.01 (m, 0.8H), 4.28 (dd, j=13.2, 4.8hz, 0.7H), 3.94-3.89 (m, 0.3H), 3.85-3.84 (m, 3H), 3.69 (s, 2.3H), 3.57 (d, j=6.8 hz, 1.4H), 3.22-3.15 (m, 1.2H), 5.05-5.01 (m, 0.8H), 4.28 (dd, j=13.2, 4.8hz, 0.7H), 3.94-3.89 (m, 3.3H), and (H). ¹³ C NMR(100MHz,CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 156.0,155.8,149.4,149.2,145.5,143.5,143.3,142.8, 142.7,135.54,135.47,135.4,135.35,133.5,133.4,133.3,130.9,130.7,129.75,129.68,129.64,128.5,128.3,127.65,127.62,127.60,127.53,126.8,126.6,121.6,121.5,118.8,118.4,112.5,112.1, 111.8,111.2,109.0,56.3,56.2,55.8,55.6,54.2,53.2,52.4,51.9,42.0,41.0,38.3,36.8,29.7,28.2,26.71,26.67,19.72.IR (heat): v _max ＝2928,2856,1692,1609,1488,1463,1262,1106,1033cm ^-1 ； HRMS(m/z):[M+H] ⁺ calculated for C ₃₆ H ₄₁ ⁷⁹ BrNO ₆ Si ⁺ ,690.1881；found,690.1880； C ₄₁ H ₄₅ ⁸¹ BrNO ₆ SSi ⁺ ,692.1861；found,692.1868.

Preparation of Compounds 15 from examples 17-21 (Bischler-Napieralski/asymmetric transfer hydrogenation).

the synthesis procedures of examples 17 to 21 were the same as those of example 16, and the conditions of the synthesis temperature, time, reagents and amounts thereof were as shown in the synthesis schemes. The embodiments of the groups differ only in: different ligands are used in the asymmetric hydrogenation of compound 14a from intermediate 13a during the synthesis. The results are shown in the following table:

preparation of Compounds 15 from examples 22-25 (Bischler-Napieralski/asymmetric transfer hydrogenation).

in examples 22 to 25, the synthesis procedure of the compound 15ab was the same as that of example 16, and the conditions of the synthesis temperature, time, reagents and the amounts thereof were as shown in the synthesis schemes. The embodiments of the groups differ only in: HCOOH/Et in an asymmetric hydrogenation reaction to prepare Compound 14a from intermediate 13a during the Synthesis ₃ The amount of N varies. The results are shown in the following table:

preparation of Compounds 15 from examples 26-29 (Bischler-Napieralski/asymmetric transfer hydrogenation).

in examples 26 to 29, the synthesis procedure of the compound 15ab was the same as that of example 16, and the conditions of the synthesis temperature, time, reagent and amount thereof were as shown in the synthesis route; the embodiments of the groups differ only in that. The embodiments of the groups differ only in: the amounts of metal catalyst and ligand used in the asymmetric hydrogenation reaction to prepare compound 14a from intermediate 13a during the synthesis are different. The results are shown in the following table:

preparation of Compounds 15 from examples 30-31 (Bischler-Napieralski/transfer hydrogenation).

in examples 30 to 31, the synthesis procedure of the compound 15ab was the same as that of example 16, and the conditions of the synthesis temperature, time, reagent and amount thereof were as shown in the synthesis route; the embodiments of the groups differ only in: the metal catalysts are of different kinds during the asymmetric hydrogenation of compound 14a from intermediate 13a during the synthesis. The results are shown in the following table:

preparation of Compounds 15 from examples 32-36 (Bischler-Napieralski/asymmetric transfer hydrogenation).

in examples 32 to 36, the synthesis procedure of the compound 15ab was the same as that of example 16, and the conditions of the synthesis temperature, time, reagents and the amounts thereof were as shown in the synthesis schemes. The embodiments of the groups differ only in: the asymmetric hydrogenation concentration of compound 14a during the synthesis process was different from that of intermediate 13 a. The results are shown in the following table:

example 37 preparation of Compound 15 (Bischler-Napieralski/asymmetric transfer hydrogenation).

By R ₂ TBDPS, X is bromine, R ₁₁ For example, the hydrogen atom and R as Ts, the compound 15aa is synthesized by the following synthetic route:

The solid compound 11a (10.00 g,15.42mmol,1.0 equiv.) was dissolved in dry CH ₂ Cl ₂ (100 mL) to this was added 2-fluoropyridine (2.65 mL,30.83mmol,2.0 equiv.) in sequence with stirring at 0deg.C, and trifluoromethanesulfonic anhydride (3.10 mL, 18.50mmol,1.2 equiv.) and the addition was warmed to room temperature and reacted for 10 min, TLC showed complete disappearance of starting material. The reaction solution was cooled to 0℃and saturated NH was added ₄ The reaction was quenched with aqueous Cl (100 mL). Separating the organic layer from the aqueous layer by CH ₂ Cl ₂ Extraction (100 mL ×3), combining organic layers, washing with saturated NaCl (50 mL×1), drying over anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to give crude compound 13a, which is used directly in the subsequent reaction without isolation and purification.

The crude product is treated by the method13a was dissolved in dry degassed DMF (46 mL) and stirred at room temperature. Another reaction flask was charged with metal catalyst (47.2 mg,0.077mmol, 0.005equiv.), ligand (1S, 2S) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine (56.5 mg,0.154mmol,0.01 equiv.), air-exchange, argon protection, degassed dry DMF (4 mL), stirred at room temperature for 30 min, the mixed solution was added to DMF solution of Compound 12, stirring at room temperature was continued for 10 min, and then cooled to 0deg.C, and HCOOH/Et was added thereto ₃ N (5:2 complex) (4.90 mL,33.9mmol,2.2 equiv.) was allowed to react at room temperature for 17h. TLC detection reaction was complete. The reaction solution was cooled to 0℃and saturated NaHCO was added ₃ The reaction was quenched with water and the pH was adjusted to 9. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (100 ml×4), the organic layers were combined, washed successively with water (50 ml×1) and saturated NaCl (50 ml×1), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give crude product of compound 14a, which was used in the subsequent reaction without isolation and purification.

Dissolving the above compound 14a in THF/H ₂ To a mixed solvent of O (150 ml, v/v=3:2), disodium hydrogen phosphate dodecahydrate (16.57 g,46.26mmol,3.0 equiv.) and p-toluenesulfonyl chloride (2.94 g,15.42mmol, 1.0 equiv.) were added in this order at room temperature. Stirring at room temperature for 1 hr, and adding H after TLC shows complete disappearance of the starting material ₂ O was diluted until the disodium hydrogen phosphate solid was dissolved, extracted with ethyl acetate (100 ml×3), the combined organic layers dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography over silica gel (petroleum ether/acetone=7:1, v/v) to give 15aa as a white foam (9.34 g, three steps total yield 77%, ee=96%). HPLC conditions: IC-H column, hexane: i-PrOH=70:30, flow rate 1mL/min, column temperature 25 ℃, detection wavelength 254nm, t _major ＝27.883min，t _minor ＝21.832min。Optical rotation:[α] _D ²⁵ ＝–119.5(c＝0.44,CHCl ₃ )； ¹ H NMR(400MHz,CDCl ₃ ):δ7.74–7.71(m,4H),7.47–7.33(m, 6H),7.30–7.26(m,2H),6.95(d,J＝8.0Hz,2H),6.63(d,J＝8.0Hz,1H),6.51(d,J＝10.4Hz, 1H),6.49(s,1H,overlapped),6.35(s,1H),5.83(s,1H),4.81(dd,J＝10.0,4.4Hz,1H),3.91(dd,J ＝14.4,5.6Hz,1H),3.86(s,3H),3.59(s,3H),3.49–3.42(m,1H),2.80–2.71(m,2H),2.69– 2.58(m,1H),2.43(dd,J＝16.0Hz,2.4Hz,1H),2.31(s,3H),1.12(s,9H)； ¹³ C NMR(100MHz, CDCl ₃ ):δ149.5,145.7,143.3,142.8,142.5,137.4,135.5,135.5,133.4,133.4,130.0,129.8,129.7, 128.9,127.7,127.6,127.6,127.0,125.7,122.1,118.6,112.4,111.3,109.0,56.1,55.6,55.4,42.5,38.7,26.7,26.5,21.4,19.7；IR(neat):ν _max ＝3431,2933,2857,1609,1513,1489,1442,1228,1154, 1114,1033,702cm ^-1 ；HRMS(m/z):[M+H] ⁺ calculated for C ₄₁ H ₄₅ ⁷⁹ BrNO ₆ SSi ⁺ ,786.1915；found, 786.1920；C ₄₁ H ₄₅ ⁸¹ BrNO ₆ SSi ⁺ ,788.1894；found,788.1904.

Example 38 preparation of Compound 15 (Bischler-Napieralski/asymmetric transfer hydrogenation).

By R ₂ TBDPS, X is bromine, R ₁₁ For example, compound 15ac was synthesized by the following synthetic route:

the synthetic route and reaction conditions for compound 15ac were as indicated above, and the synthesis procedure using (1 s,2 s) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine as ligand was referenced to the synthesis of 15ab (three steps 75% overall yield, ee=97% (R)). HPLC conditions: IC00C3-QG035 column, hexane: i-PrOH=80:20, flow rate 1mL/min, column temperature 25 ℃, detection wavelength 254nm, t _major ＝10.179min，t _minor ＝8.966min。Optical rotation:[α] _D ²⁵ ＝–69.0(c＝0.68,CHCl ₃ )； ¹ H NMR(400MHz,CDCl ₃ )：δ7.75–7.72(m,4H),7.43–7.22(m,9.6H),7.02–7.01(m,1.4H),6.61 –6.42(m,4H),5.87–5.76(m,1H),5.19–5.02(m,1H),4.97–4.76(m,1H),4.41(d,J＝12.4Hz, 1H),4.34–3.98(m,1H),3.82–3.81(m,3H),3.68(s,2.3H),3.59(s,0.7H),3.33–3.19(m,1H), 2.92–2.47(m,4H),1.13–1.11(m,9H)； ¹³ C NMR(100MHz,CDCl ₃ )：δ155.4,155.0,149.4, 149.2,145.57,145.55,143.5,143.4,142.8,142.7,137.1,136.1,135.53,135.49,135.5,135.4,133.44,133.40,133.3,130.8,130.7,129.73,129.70,129.65,128.5,128.4,128.3,128.2,127.8, 127.7,127.64,127.62,127.60,127.5,126.7,126.6,121.54,121.51,118.8,118.5,112.5,112.2,111.8,111.4,109.00,108.9,66.9,66.6,56.2,55.8,55.6,54.3,53.5,41.9,41.0,38.4,36.9,28.3,28.1, 26.70,26.68,19.7；IR(neat):ν _max ＝2961,2857,1688,1487,1428,1261,1100,1031,753,700cm ^-1 ； HRMS(m/z):[M+H] ⁺ calculated for C ₄₂ H ₄₅ ⁷⁹ BrNO ₆ Si ⁺ ,766.2194；found,766.2194； C ₄₂ H ₄₅ ⁸¹ BrNO ₆ Si ⁺ ,768.2174；found,768.2187.

Example 39 preparation of Compound 15 (Bischler-Napieralski/asymmetric transfer hydrogenation).

By R ₂ TBS, X is bromine, R ₁₁ Is a hydrogen atom, R is CO ₂ Me is an example, compound 15da is synthesized by the following route:

the synthetic route and reaction conditions for compound 15da are as described above, and the synthetic procedure is as described for compound 15ab of example 16, using (1 r,2 r) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine (three steps 68% overall yield, ee=97% (S)). HPLC conditions: OD-H column, hexane: i-PrOH=85:15, flow rate 0.5mL/min, column temperature 25 ℃, detection wavelength 254nm, t _major ＝15.247min，t _minor ＝18.434min。Optical rotation:[α] _D ²⁵ ＝+55.3(c＝2.0, CHCl ₃ )； ¹ H NMR(400MHz，CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 6.73-6.67 (m, 2H), 6.58-6.43 (m, 1.7H), 6.43 (s, 0.3H), 5.99-5.91 (m, 1H), 5.35-5.29 (m, 1H), 4.30-4.25 (m, 0.7H), 3.91-3.87 (m, 3.3H, overlapped), 3.76-3.77 (m, 3H), 3.64 (s, 0.8H), 3.48-3.42 (m, 0.3H), 3.35-3.28 (m, 0.7H), 3.26 (s, 2.2H), 3.24-3.07 (m, 1H), 2.98-2.84 (m, 1H), 2.81-2.65 (m, 1H), 1.00 (s, 6H), 0.9 5(s,3H),0.16–0.08(m,6H)； ¹³ C NMR(100MHz， CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 156.1,156.0,149.81,149.76,145.7, 145.6,143.4,143.1,143.0,142.8,130.79,130.76,128.6,127.2,127.0,121.80,121.75,119.6,119.1,112.1,111.9,111.8,111.3,109.3,109.2,56.3,56.2,55.6,54.9,53.6,52.5,52.1,42.3,41.1,39.0, 37.4,28.2,25.72,25.67,18.5,18.4, -4.8, -4.8, -4.7, -4.6; IR (heat): v _max ＝2930,2856,1685,1512, 1488,1260,1226,1033,755cm ^-1 ；HRMS(m/z):[M+H] ⁺ calculated for C ₂₆ H ₃₇ ⁷⁹ BrNO ₆ Si ⁺ , 566.1568；found,566.1565；C ₂₆ H ₃₇ ⁸¹ BrNO ₆ Si ⁺ ,568.1548；found,568.1545.

Example 40 preparation of Compound 15 (Bischler-Napieralski/asymmetric transfer hydrogenation).

By R ₂ TBDPS, X is bromine, R ₁₁ For Me and R as Ts, the compound 15ba is synthesized by the following synthetic route:

the solid compound 11b (30.00 g,45.27mmol,1.0 equiv.) was dissolved in dry CH ₂ Cl ₂ (300 mL) to this was added 2-fluoropyridine (7.8 mL,90.54mmol,2.0 equiv.) in this order with stirring at 0deg.C, and trifluoromethanesulfonic anhydride (9.2 mL, 54.32mmol,1.2 equiv.) and the addition was warmed to room temperature and reacted for 10 min, TLC showed complete disappearance of starting material. The reaction solution was cooled to 0℃and saturated NH was added ₄ The reaction was quenched with aqueous Cl (300 mL). Separating the organic layer from the aqueous layer by CH ₂ Cl ₂ Extraction (300 mL ×3), combining organic layers, washing with saturated NaCl (100 mL×1), drying over anhydrous magnesium sulfate, filtering, concentrating under reduced pressure to obtain crude product of yellow foamy solid 13b, which is used directly in the subsequent reaction without isolation and purification.

The crude product 13b was dissolved in dry degassed DMF (140 mL) and stirred at room temperature. Another reaction flask was filled with a metal catalyst (139 mg,0.226mmol, 0.005equiv.), and a ligand (1S, 2S) - (-) in a separate flaskAfter addition of degassed dry DMF (10 mL) under the protection of argon, stirring at room temperature for 30 min, the mixed solution was added to a DMF solution of Compound 13b, stirring was continued at room temperature for 10 min, followed by cooling to 0deg.C, and addition of HCOOH/Et thereto ₃ N (5:2 complex) (14.2mL,99.6mmol,2.2 equiv.), warmed to room temperature and reacted for 17h. TLC detection reaction was complete. The reaction solution was cooled to 0℃and saturated NaHCO was added ₃ The reaction was quenched with water and the pH was adjusted to 9. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (300 ml×3), the organic layers were combined, washed successively with water (50 ml×1) and saturated NaCl (50 ml×1), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude product of black foamy solid 14b, which was used in the subsequent reaction without isolation and purification.

Dissolving the above compound 14b in THF/H ₂ To a mixed solvent of O (300 ml, v/v=3:2), disodium hydrogen phosphate dodecahydrate (48.64 g,135.8mmol,3.0 equiv.) and p-toluenesulfonyl chloride (8.63 g,45.27mmol, 1.0 equiv.) were added in this order at room temperature. Stirring at room temperature for 1 hr, and adding H after TLC shows complete disappearance of the starting material ₂ O was diluted until the disodium hydrogen phosphate solid was dissolved, extracted with ethyl acetate (200 ml×3), the combined organic layers dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography over silica gel (petroleum ether/acetone=7:1, v/v) to give 15ba as a white foam solid (29.9 g, 84% overall three-step yield, ee=96%). HPLC conditions: AD-H column, hexane: i-PrOH=70:30, flow rate 1.0mL/min, column temperature 25 ℃, detection wavelength 254nm, t _major ＝5.585min，t _minor ＝4.769min。Optical rotation:[α] _D ²⁵ ＝– 117.9(c＝0.8,CHCl ₃ )； ¹ H NMR(400MHz,CDCl ₃ ):δ7.73–7.70(m,4H),7.46–7.28(m,8H), 6.96(d,J＝8.2Hz,2H),6.70(s,2H),6.50(s,1H),6.32(s,1H),4.89(q,J＝4.8Hz,1H),3.88– 3.87(m,1H,overlapped),3.84(s,3H),3.81(s,3H),3.58(s,3H),3.50–3.42(m,1H),2.83–2.72 (m,2H),2.56–2.48(m,1H),2.41–2.36(m,1H),2.30(s,3H),1.12(s,9H)； ¹³ C NMR(100MHz, CDCl ₃ ):δ152.2,149.5,146.2,143.3,142.6,137.6,135.5,135.44,133.38,133.3,130.0,129.74, 129.71,129.0,127.7,127.6,126.8,126.5,125.6,120.7,118.5,112.2,110.6,60.4,55.8,55.53,55.46,42.6,38.6,26.7,26.2,21.4,19.7；IR(neat):ν _max ＝2933,1513,1487,1448,1261,1155,1113,1033, 701cm ^-1 ；HRMS(m/z):[M+H] ⁺ calculated for C ₄₂ H ₄₇ ⁷⁹ BrNO ₆ SSi ⁺ ,800.2071；found,800.2066； C ₂₆ H ₃₇ ⁸¹ BrNO ₆ Si ⁺ ,802.2051；found,802.2050.

Example 41 preparation of Compound 15 (Bischler-Napieralski/asymmetric transfer hydrogenation).

By R ₂ TBDPS, X is bromine, R ₁₁ Is Me, R is CO ₂ Me is an example, compound 15bb is synthesized by the synthetic route of reference example 40 using the ligand (1R, 2R) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine.

15bb (three step yield 81%,96% ee (S)), HPLC conditions: AD-H column, hexane: i-PrOH=95:5, flow rate 0.8mL/min, column temperature 25 ℃, detection wavelength 254nm, t _major ＝8.100min，t _minor ＝10.942min。Optical rotation:[α] _D ²⁵ ＝–52.5(c＝0.2,CHCl ₃ )；Optical rotation:[α] _D ²⁵ ＝+53.6(c＝0.8,CHCl ₃ )； ¹ H NMR(400MHz,CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 7.76-7.70 (m, 4H), 7.46-7.32 (m, 6H), 6.66 (d, j=8.4 hz, 1H), 6.62-6.61 (m, 2H), 6.53 (s, 0.8H), 6.49 (s, 0.2H), 5.15-5.12 (m, 0.2H), 5.06-5.02 (m, 0.8H), 4.27 (dd, j=13.2, 4.4hz, 1H), 3.84 (s, 2.4H), 3.82 (s, 3.6H, overlapped), 3.69 (s, 2.4H), 3.56 (d, j=8.8 hz, 1.2H), 3.29-3.14 (m, 1H), 3.11 (s, 2.4H), 2.91-2.77 (m, 2.68-2.56 (m, 2.4H), 3.84 (s, 2.4H), 3.82 (s, 3.6H, overlapped); ¹³ C NMR(100 MHz，CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 155.9,155.7,152.00,149.4,149.2,146.2,143.5,143.3,135.51,135.46,135.41,135.36,133.4,133.3,130.9,130.8,129.73,129.66, 129.6,128.5,128.3,127.62,127.60,127.57,127.5,126.8,126.6,126.0,121.1,120.6,118.8,118.3,112.4,112.1,110.7,60.4,60.4,56.0,56.0,55.8,55.5,54.3,53.2,52.4,51.9,42.1,41.1,38.4,36.8, 28.20,28.15,26.71,26.68,19.7；IR(neat):ν _max ＝2932,2857,1696,1593,1513,1486,1447,1260, 1104,1032,701cm ^-1 ；HRMS(m/z):[M+H] ⁺ calculated for C ₃₇ H ₄₃ ⁷⁹ BrNO ₆ Si ⁺ ,704.2038；found, 704.2037；C ₂₆ H ₃₇ ⁸¹ BrNO ₆ Si ⁺ ,706.2017；found,706.2018.

Example 42 preparation of Compound 15 (Bischler-Napieralski/asymmetric transfer hydrogenation).

By R ₂ TBDPS, X is bromine, R ₁₁ For the case where Me and R are Cbz, the compound 15bc was synthesized, and the synthetic route was as described in reference to example 40, using (1S, 2S) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine as the ligand.

15bc (three step yield 72%,94% ee (R)), HPLC conditions: ADH0CE-EK072 column, gradient elution, 0-5.5min, hexane: i-PrOH=60:40 to 40:60;5.5-25min, hexane:i-PrOH=40:60, flow rate 1 mL/min, column temperature 40 ℃, detection wavelength 254nm, t _major ＝11.470min，t _minor ＝4.066min。Optical rotation: [α] _D ²⁵ ＝–66.3(c＝0.76,CHCl ₃ )； ¹ H NMR(400MHz,CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 7.75-7.70 (m, 4H), 7.44-7.22 (m, 9.5H), 7.04-7.02 (m, 1.5H), 6.68-6.46 (m, 4H), 5.20-5.07 (m, 1H), 5.05-4.84 (m, 1H), 4.42-3.97 (m, 2H), 3.80-3.79 (m, 3.8H), 3.67 (d, j=5.8 hz, 4.4H), 3.59 (s, 0.8H), 3.32-3.20 (m, 1H), 2.95-2.44 (m, 4H), 1.13-1.11 (m, 9H); ¹³ C NMR(100MHz,CDCl ₃ due to the amide rotamase phenomenon, certain signals occur in pairs): delta 155.3,155.0,152.04, 151.99,149.4,149.2,146.3,146.2,143.44,143.37 ,137.1,136.4,135.51,135.49,135.44,135.40,133.4,133.3,130.79,130.76,129.73,129.66,128.5,128.4,128.3,128.2,127.7,127.64,127.59, 127.54,127.45,126.8,126.6,126.0,121.1,120.1,118.7,118.5,112.4,112.2,110.72,110.68,66.71,66.65,60.4,60.3,56.0,55.7,55.6,54.2,53.6,41.9,41.1,38.4,37.0,28.3,28.0,26.9,26.7,26.7, 19.7；IR(neat):ν _max ＝2932,2857,1697,1593,1513,1486,1427,1261,1102,1034,700cm ^-1 ； HRMS(m/z):[M+H] ⁺ calculated for C ₄₃ H ₄₇ ⁷⁹ BrNO ₆ Si ⁺ ,780.2351；found,780.2355； C ₄₃ H ₄₇ ⁸¹ BrNO ₆ Si ⁺ ,782.2330；found,782.2340.

Example 43 preparation of Compound 15 (Bischler-Napieralski/asymmetric transfer hydrogenation).

By R ₂ TBS, X is bromine, R ₁₁ For Me and R as Ts, the compound 15ea is synthesized by the following synthetic route:

the compound 15ea is prepared by taking 11e as a starting material, passing through intermediate 13e and 14e and then introducing Cbz protecting groups. The synthesis procedure was identical to 15 aa. The reaction conditions and the amounts of reagents from 11e to 15ea are as indicated above. 15ea using (1S, 2S) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine as ligand in 69% three steps yield, 96% ee (S). HPLC conditions: IC00C3-QG035 column, hexane: i-PrOH=60:40, flow rate 1mL/min, column temperature 25 ℃, detection wavelength 254nm, t _major ＝16.703min，t _minor ＝13.134min。Optical rotation:[α] _D ²⁵ ＝–111.8(c＝0.6,CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 7.44 (d, j=8.0 Hz, 2H), 7.03 (d, j=8.0 Hz, 2H), 6.82 (d, j=8.4 Hz, 1H), 6.74 (d, j=8.4 Hz, 1H), 6.46 (s, 1H), 6.40 (s, 1H), 5.16-5.12 (m, 1H), 3.89-3.87 (m, 1H, overlapped), 3.85 (s, 3H), 3.83 (s, 3H), 3.72 (s, 3H), 3.62-3.55 (m, 1H), 3.15-3.06 (m, 2H), 2.70-2.50 (m, 2H), 2.31 (s, 3H), 0.96 (s, 9H), 0.10 (s, 6H)). ¹³ C NMR(100MHz,CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 152.3, 149.9,146.4,143.1,142.7,137.4,130.1,129.2,127.8,127.0,126.7,126.1,120.8,119.2,111.9,110.8,60.4,55.9,55.8,55.5,43.0,39.2,26.5,25.7,21.4,18.4, -4.66, -4.73.IR (heat): v _max ＝2931, 2857,1511,1487,1259,1156,1092,1033,801cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₃₂ H ₄₃ ⁷⁹ BrNO ₆ SSi ⁺ ,676.1758；found,676.1752；C ₃₂ H ₄₃ ⁷⁹ BrNO ₆ SSi ⁺ ,678.1738；found,678.1735.

Preparation of Compounds No. 15 from examples 44-50 (Bischler-Napieralski/transfer hydrogenation).

By R ₂ Is hydroxy protecting group II, X is bromine, R ₁₁ For Me or PMB, R is a secondary amine protecting group, the compound 15 is synthesized by the following synthetic route:

example 44 is a compound of R ₂ TBDPS, X is bromine, R ₁₁ For PMB and R as COOMe, compound 15ad was synthesized using (1R, 2R) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine as the ligand, and the total yield of three steps was 80%, ee=86% (S). HPLC conditions: IC-H column, hexane: i-PrOH=85:15, flow rate 0.8mL/min, column temperature 25 ℃, detection wavelength 254 nm, t _major ＝21.438min，t _minor ＝24.448min。Optical rotation:[α] _D ²⁵ ＝+49.9(c＝0.68,CHCl ₃ )； ¹ H NMR(400MHz,CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 7.77-7.69 (m, 4H), 7.53-7.31 (m, 8H), 6.97-6.90 (m, 2H), 6.74-6.45 (m, 4H), 5.17-5.03 (m, 1H), 4.91-4.90 (m, 2H), 4.30-4.12 (m, 1H), 3.85-3.80 (m, 6.2H), 3.67-3.56 (m, 3.6H), 3.21-3.14 (m, 1H), 3.11 (s, 2H), 2.97-2.77 (m, 2H), 2.68-2.40 (m, 2H), 1.14-1.11 (m, 9H). ¹³ C NMR(100MHz,CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 159.6,159.4,156.0,155.8,152.2,149.4,149.2,145.2,145.1,143.5,143.3,135.53,135.48,135.44,135.39,133.5,133.3,131.0,130.8,130.3,130.2, 129.72,129.65,129.4,128.5,128.4,127.64,127.61,127.5,126.9,126.6,126.0,121.6,121.1,118.8,118.4,113.7,113.6,112.4,112.1,110.7,74.4,74.2,56.1,56.0,55.7,55.6,55.32,55.28,54.3,53.2, 52.4,52.0,42.2,41.1,38.4,36.9,28.22,28.15,26.74,26.71,19.7.IR(neat):ν _max ＝2932,2858, 1697,1612,1592,1513,1484,1447,1260,1106,1032,752,702cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₄₄ H ₄₉ ⁷⁹ BrNO ₇ Si ⁺ ,810.2456；found,810.2450；C ₄₄ H ₄₉ ⁸¹ BrNO ₇ Si ⁺ ,812.2436；found, 812.2441.

Example 45 is R ₂ Bn, X is bromine, R ₁₁ For the case where Me and R are COOMe, compound 15ca was synthesized using (1R, 2R) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine as the ligand, and the total three steps yield was 82%, ee=96% (S). HPLC conditions: IC-H column, hexane: i-PrOH=60:40, flow rate 1.0mL/min, column temperature 25 ℃, detection wavelength 254 nm, t _major ＝18.441min，t _minor ＝14.962min。Optical rotation:[α] _D ²⁵ ＝+75.3(c＝0.68,CHCl ₃ ). ¹ H NMR(400MHz，CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 7.46-7.28 (m, 5H), 6.79-6.70 (m, 2.8H), 6.61 (d, j=12.4 hz, 1H), 6.37 (s, 0.2H), 5.31-5.23 (m, 1H), 5.14 (s, 1.5H), 4.32 (dd, j=13.2, 4.2hz, 0.5H), 4.34-4.30 (m, 0.7H), 3.96-3.91 (m, 0.3H), 3.88-3.82 (m, 9H), 3.63 (s, 0.7H), 3.45-3.38 (m, 0.3H), 3.28 (td, j=12.8, 4.0hz, 0.8H), 3.21 (s, 2H), 3.13-3.04 (m, 1.2H), 2.92-2.76 (m, 2.3H), 3.88-3.82 (m, 9H), 3.63 (s, 1.61 (m, 1H). ¹³ C NMR(100MHz，CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 155.91,155.87,152.14,148.5,148.4,146.4,146.3,146.2, 137.2,137.1,130.8,130.7,128.6,128.5,128.3,128.2,127.9,127.8,127.2,127.1,126.8,126.7,126.3,126.2,121.3,120.6,113.2,112.9,111.8,111.6,110.9,110.8,71.4,71.1,60.5,60.4,56.1,56.02,55.98,54.7,53.5,52.5,52.1,42.3,41.2,38.7,37.0,28.2,28.1.IR (coat)):ν _max ＝2929,1695, 1594,1515,1486,1448,1256,1101,1032cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₈ H ₃₁ BrNO ₆ ⁺ ,556.1329；found,556.1326；C ₄₄ H ₄₉ ⁸¹ BrNO ₇ Si ⁺ ,558.1309；found,558.1310.

Example 46 is described as R ₂ Is PMB, X is bromine, R ₁₁ For the case where Me and R are COOMe, compound 15cb was synthesized using (1R, 2R) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine as the ligand, and the total yield of three steps was 68%, ee=96% (S). HPLC conditions: IC-H column, hexane: i-PrOH=60:40, flow rate 1mL/min, column temperature 25 ℃, detection wavelength 254nm, t _major ＝30.306min，t _minor ＝24.274min。Optical rotation:[α] _D ²⁵ ＝+66.3(c＝0.48,CHCl ₃ ). ¹ H NMR(400MHz，CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 7.38 (d, j=8.8 Hz, 1.5H), 7.30 (d, j=8.4 Hz, 0.5H), 6.92-6.86 (m, 2H), 6.78-6.71 (m, 2.8H), 6.62-6.59 (m, 1H), 6.38 (s, 0.2H), 5.33-5.25 (m, 1H), 5.05 (s, 1.5H), 4.85 (q, j=12.0 Hz, 0.5H), 4.32 (dd, j=13.2, 5.6Hz, 0.7H), 3.98-3.91 (m, 0.3H), 3.88-3.80 (m, 12H), 3.63 (s, 0.7H), 3.45-3.38 (m, 0.2H), 3.32-3.25 (m, 0.8H, folded), 3.22 (m, 3.32-3.2H), 3.1.1H, 2.1.8H), 3.1.1-2H (m, 2.1.8H). ¹³ C NMR(100MHz，CDCl ₃ Due to the amide rotamase phenomenon, certain signals occur in pairs): delta 159.34,159.28,155.92,155.88,152.2,148.6,148.4,146.5,146.3,146.2,130.9,130.7,129.2, 129.1,129.0,128.9,128.3,128.2,126.7,126.6,126.3,126.2,121.3,120.6,114.0,113.9,113.3,113.0,111.8,111.5,110.9,110.8,71.1,70.9,60.5,60.4,56.1,56.0,55.96,55.3,55.2,54.7,53.5, 52.5,52.1,42.3,41.2,38.7,37.0,28.2,28.1.IR (heat): v _max ＝3013,2935,1690,1613,1486,1451, 1243,1102,748cm ^- ¹ .HRMS(m/z):[M+H] ⁺ calculated for C ₂₉ H ₃₃ ⁷⁹ BrNO ₇ ⁺ ,586.1435；found, 586.1434；C ₂₉ H ₃₃ ⁸¹ BrNO ₇ ⁺ ,588.1414；found,588.1420.

Example 47 is R ₂ Is Ac, X is bromine, R ₁₁ For the case of Me, R as Ts, 15cc of compound was synthesized using (1R, 2R) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine as ligand, 84% of total three steps, ee=94% (S) (measured after Ac removal). HPLC conditions: IC-H column, hexane: i-PrOH=85:15, flow rate 1.5mL/min, column temperature 25 ℃, detection wavelength 254nm, t _major ＝34.567min，t _minor ＝44.746min。Optical rotation:[α] _D ²⁵ ＝+87.4(c＝ 0.88,CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ ):δ7.40(d,J＝8.4Hz,2H),7.05(d,J＝8.0Hz,2H), 6.80–6.69(m,2H),6.67(s,1H),6.55(s,1H),5.18(dd,J＝8.0,6.0Hz,1H),3.92(m,1H),3.82(s, 3H),3.81(s,3H),3.76(s,3H),3.50–3.62(m,1H),3.14–3.05(m,2H),2.73–2.85(m,1H),2.53 –2.64(m,1H),2.33(s,3H),2.28(s,3H). ¹³ C NMR(100MHz,CDCl ₃ ):δ168.8,152.3,149.8, 146.3,142.9,137.9,137.1,131.7,129.7,129.2,128.0,127.0,126.7,121.2,120.7,112.3,110.9,60.4,55.9,55.8,55.3,42.9,38.7,27.1,21.4,20.6.IR(neat):ν _max ＝2962,1763,1596,1511,1488, 1261,1155,1032cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₈ H ₃₁ ⁷⁹ BrNO ₇ S ⁺ ,604.0999；found, 604.1004；C ₂₈ H ₃₁ ⁸¹ BrNO ₇ S ⁺ ,606.0979；found,606.0984.

Example 48 is in R ₂ Bz, X is bromine, R ₁₁ For the case where Me and R are Ts groups, compound 15cd was synthesized using (1R, 2R) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine as the ligand, the total yield of three steps was 84%, and ee=94% (S). HPLC conditions: AD-H column, hexane: i-PrOH=80:20, flow rate 1.0mL/min, column temperature 25 ℃, detection wavelength 254nm, t _major ＝15.023min，t _minor ＝18.524min。Optical rotation:[α] _D ²⁵ ＝+120.5(c＝0.64,CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ ):δ8.21–8.15(m,2H),7.67–7.60(m,1H),7.54–7.40(m,4H),7.10– 7.03(m,2H),,6.79(d,J＝9.2Hz,1H),6.77(s,1H,overlap),6.73(d,J＝8.4Hz,1H),6.61(s,1H), 5.21(t,J＝7.6Hz,1H),4.04–3.89(m,1H),3.83(s,3H),3.81(s,3H),3.75(s,3H),3.66–3.54(m, 1H),3.19–3.07(m,2H),2.88–2.76(m,1H),2.68–2.59(m,1H),2.34(s,3H). ¹³ C NMR(100 MHz,CDCl ₃ ):δ164.6,152.4,150.1,146.3,143.0,138.2,137.2,133.5,131.8,130.2,129.8,129.3, 129.3,128.5,128.1,127.1,126.8,121.4,120.7,112.5,110.9,60.4,55.9,55.9,55.4,42.9,38.8,27.2,21.4.IR(neat):ν _max ＝1738,1511,1487,1450,1261,1213,1154,1025,811,729cm ^-1 .HRMS (m/z):[M+H] ⁺ calculated for C ₃₃ H ₃₃ ⁷⁹ BrNO ₇ S ⁺ ,666.1156；found,666.1151；C ₃₃ H ₃₃ ⁸¹ BrNO ₇ S ⁺ , 668.1135；found,668.1135.

Example 49 is in R ₂ Is Piv, X is bromine, R ₁₁ For the case of Me and R as Ts, compound 15ce was synthesized using (1R, 2R) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine as ligand, with a total three step yield of 82%, ee=95% (S). HPLC conditions: IC00C3-QG035, H ₂ O: meOH=10:90, flow rate 1mL/min, column temperature 25 ℃, detection wavelength 254nm, t _major ＝16.37min，t _minor ＝18.44min。Optical rotation:[α] _D ²⁵ ＝+104.3(c＝0.6,CHCl ₃ ). ¹ H NMR (400MHz,CDCl ₃ ):δ7.45–7.41(m,2H),7.06(d,J＝8.0Hz,2H),6.78–6.69(m,2H),6.54(s, 1H),6.53(s,1H),5.18(t,J＝7.2Hz,1H),3.95–3.87(m,1H),3.86(s,3H),3.83(s,3H),3.73(s, 3H),3.62–3.52(m,1H),3.11(d,J＝7.6Hz,2H),2.81–2.70(m,1H),2.64–2.54(m,1H),2.33(s,3H),1.33(s,9H). ¹³ C NMR(100MHz,CDCl ₃ ):δ176.5,152.3,150.0,146.3,143.0,138.3,137.3, 131.3,129.8,129.3,127.8,127.0,126.8,121.2,120.8,112.3,110.9,60.4,55.9,55.9,55.3,42.9,39.0,38.8,27.2,27.1,21.4.IR(neat):ν _max ＝1751,1511,1486,1449,1272,1154,1097,1030,749 cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₃₁ H ₃₇ ⁷⁹ BrNO ₇ S ⁺ ,646.1469；found,646.1469； C ₃₁ H ₃₇ ⁸¹ BrNO ₇ S ⁺ ,648.1448；found,648.1457.

Implementation of the embodimentsExample 50 preparation of compound 17 (preparation of intramolecular oxidation dearomatization of Heck coupling reaction substrate). When R in Compound 15 ₁₁ In the case of a hydrogen atom, the compound 15 is introduced with a hydroxy protecting group I (PMB) and then the compound 17 is prepared.

By R ₂ TBDPS, X is bromine, R ₁₁ For example, the compound 17aab is synthesized by taking a hydrogen atom and R as Ts as an example, and the synthetic route is as follows:

compound 15aa (10.00 g,12.71mmol,1.0 equiv.), potassium carbonate (5.27 g,38.13mmol,3.0 equiv.) and TBAI (469 mg,1.27mmol,0.1 equiv.) are placed in a reaction flask, purged with argon, and dry DMF (180 mL) is added. PMBCl (3.45 mL,25.42mmol,2.0 equiv.) was added thereto with stirring at room temperature. After reaction at room temperature for about 6 hours, TLC showed complete disappearance of starting material, dimethylamine (1.30 mL,25.42mmol,2.0 equiv.) was added to the reaction solution, stirred at room temperature for 2 hours, and then saturated NH was added ₄ The reaction was quenched with Cl solution (100 mL), extracted with ethyl acetate (100 mL. Times.4), and the organic layers combined, washed sequentially with water (100 mL. Times.1), saturated sodium chloride solution (100 mL. Times.2). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and dried. The crude product was purified by column chromatography on silica gel (petroleum ether/dichloromethane/acetone=100:100:1, v/v, containing 0.5% aqueous ammonia; column packed after silica gel treatment with petroleum ether containing 0.5% aqueous ammonia) to give 16aab as a white foamy solid (9.9 g, 86% yield). Compound 16aab data: optical rotation [ alpha ]] _D ²⁵ ＝–77.6(c＝1.32,CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ ):δ7.77–7.70(m,4H),7.49(d,J＝8.6Hz,2H),7.43–7.25(m,9H), 6.96(d,J＝8.0Hz,2H),6.93(d,J＝8.8Hz,2H),6.70(s,1H),6.52(s,1H),6.31(s,1H),4.93– 4.90(m,1H,overlapped),4.90(s,3H),3.87–3.85(m,1H),3.83(s,3H,overlapped),3.82(s,3H,overlapped),3.57(s,3H),3.48–3.41(m,1H),2.79–2.76(m,2H),2.56–2.48(m,1H),2.40– 2.35(m,1H),2.28(s,3H),1.12(s,9H). ¹³ C NMR(100MHz,CDCl ₃ ):δ159.4,152.5,149.5,145.1, 143.3,142.6,137.6,135.49,135.47,134.8,133.4,133.4,130.2,130.1,129.7,129.71,129.69,129.1,127.73,127.68,127.58,127.56,126.9,126.5,125.6,121.2,118.6,113.6,112.2,110.7,74.2,55.9, 55.53,55.48,55.3,42.8,38.7,26.7,26.2,21.4,19.7.IR(neat):ν _max ＝2932,1513,1485,1463,1428, 1248,1155,1033,749cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₄₉ H ₅₃ ⁷⁹ BrNO ₇ SSi ⁺ ,906.2490；found,906.2494；C ₄₉ H ₅₃ ⁸¹ BrNO ₇ SSi ⁺ ,908.2469；found,908.2481.

Compound 16aab (9.00 g,9.92mmol,1.0 equiv.) was dissolved in CH ₃ CN/H ₂ O-mixed solvent (210 mL, v/v=20:1), KF (1.15 g,19.84mmol,2.0 equiv.) was added thereto at room temperature, and the reaction was heated to 50℃for about 3 hours, and TLC showed complete disappearance of starting material. Cooling to 0deg.C, adding saturated NaHCO ₃ The reaction was quenched with aqueous solution (100 mL) and the mixture was distilled under reduced pressure to remove CH ₃ CN, the residue was extracted with ethyl acetate (100 mL. Times.3), the organic layers were combined, washed with saturated aqueous sodium chloride (100 mL. Times.2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether/acetone=4:1, v/v, 0.5% aqueous ammonia; column packed after silica gel treatment with petroleum ether containing 0.5% aqueous ammonia) to give 17aab as a white foamy solid (6.04 g, 91% yield).

Compound 17aab data: optical rotation [ alpha ]] _D ²⁵ ＝–103.2(c＝0.6,CHCl ₃ ). ¹ H NMR(400MHz, CDCl ₃ ):δ7.48(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,2H),7.03(d,J＝8.0Hz,2H),6.92–6.90 (m,2H),6.82(d,J＝8.4Hz,1H),6.74(d,J＝8.4Hz,1H),6.64(s,1H),6.45(s,1H),5.46(s,1H), 5.12(dd,J＝9.6,4.8Hz,1H),4.92(s,2H),3.93–3.88(m,1H),3.85(s,2H),3.82(s,3H,overlapped),3.82(s,3H,overlapped),3.61–3.53(m,1H),3.17(dd,J＝14.0,4.8Hz,1H),3.05(dd, J＝14.0,9.6Hz,1H),2.80–2.71(m,1H),2.57–2.51(m,1H),2.30(s,3H). ¹³ C NMR(100MHz, CDCl ₃ ):δ159.6,152.7,145.8,145.4,143.9,143.0,137.3,130.3,129.3,128.8,127.2,126.8,124.8, 121.5,113.8,112.9,110.9,74.4,56.0,55.4,43.1,39.2,26.9,21.6.IR(neat):ν _max ＝1596,1512, 1484,1462,1441,1245,1151,1029,748cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₃₃ H ₃₅ ⁷⁹ BrNO ₇ S ⁺ ,668.1312；found,668.1313；C ₃₃ H ₃₅ ⁸¹ BrNO ₇ S ⁺ ,670.1292；found,670.1298.

Example 51 preparation of compound 17 (preparation of intramolecular oxidation dearomatization of Heck coupling reaction substrate). When R in Compound 15 ₁₁ In the case of a hydrogen atom, the compound 15 is introduced with a hydroxyl protecting group I (Bn) and then the compound 17 is prepared.

By R ₂ TBDPS, X is bromine, R ₁₁ For the example of a hydrogen atom with R as Ts, compound 17aaa was synthesized, synthetic route was referred to in example 48. Compound 17aaa data: ¹ H NMR(400MHz，CDCl ₃ ):δ7.57(d,J＝7.2Hz,2H),7.41 –7.37(m,4H),7.34–7.31(m,1H),7.03(d,J＝8.0Hz,2H),6.84(d,J＝8.4Hz,1H),6.75(d,J＝ 8.4Hz,1H),6.65(s,1H),6.45(s,1H),5.47(s,1H),5.13(dd,J＝9.6,4.8Hz,1H),4.98(s,2H),3.94–3.89(m,1H),3.85(s,3H),3.82(s,3H),3.61–3.54(m,1H),3.17(dd,J＝14.0,5.2Hz,1H), 3.05(dd,J＝14.0,9.6Hz,1H),2.79–2.71(m,1H),2.57–2.51(m,1H),2.30(s,3H). ¹³ C NMR (100MHz,CDCl ₃ ):δ152.7,145.8,145.3,143.9,143.0,137.6,137.3,130.3,129.3,128.7,128.5, 128.4,128.0,127.2,126.8,124.8,121.4,112.9,111.0,110.8,74.6,56.0,43.1,39.2,26.9,21.6.IR (neat):ν _max ＝1511,1484,1454,1271,1150,1028,750cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₃₂ H ₃₃ BrNO ₆ S ⁺ ,638.1206；found,638.1211；C ₃₃ H ₃₅ ⁸¹ BrNO ₇ S ⁺ ,640.1186；found,640.1196.

example 52 preparation of compound 17 (preparation of intramolecular oxidation dearomatization of Heck coupling reaction substrate). When R in Compound 15 ₁₁ In the case of hydroxy protecting group I, compound 15 is prepared directly as compound 17.

By R ₂ Is Ac, X is bromine, R ₁₁ For Me and R as Ts, the compound 17aac is synthesized by the following synthetic route:

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compound (S) -15cc (1.00 g,1.65mmol,1.0 equiv.) is dissolved in MeOH (10 mL) to which K is added at room temperature ₂ CO ₃ (0.57 g,4.13mmol,2.5 equiv.) the reaction was stirred for about 0.5 h and TLC showed complete disappearance of starting material. Cooled to 0deg.C, quenched with water, extracted with ethyl acetate (20 mL. Times.3), the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether/acetone=6:1, v/v,) to give (S) -17aac as a white foamy solid (854 mg, 92% yield). Optical rotation [ alpha ] ] _D ²⁵ ＝+83.7(c＝0.84,CHCl ₃ ). ¹ H NMR(400 MHz,CDCl ₃ ):δ7.39(d,J＝8.0Hz,2H),7.02(d,J＝8.0Hz,2H),6.83(d,J＝8.4Hz,1H),6.73(d, J＝8.8Hz,1H),6.66(s,1H),6.45(s,1H),5.48(s,1H),5.12(dd,J＝10.0,4.8Hz,1H),3.94–3.89 (m,1H),3.86(s,3H),3.82(s,6H),3.61–3.54(m,1H),3.16(dd,J＝14.0,4.8Hz,1H),3.04(dd,J ＝14.0,9.6Hz,1H),2.79–2.70(m,1H),2.57–2.51(m,1H),2.32(s,3H). ¹³ C NMR(100MHz, CDCl ₃ )δ152.5,146.5,145.8,144.0,143.0,137.4,130.2,129.3,128.8,127.2,126.7,124.8,121.0, 112.9,111.0,56.0,43.0,39.2,26.9,21.6.IR(neat):ν _max ＝3428,1512,1487,1449,1265,1149, 1031cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₆ H ₂₉ ⁷⁹ BrNO ₆ S ⁺ ,562.0893；found,562.0893； C ₃₃ H ₃₅ ⁸¹ BrNO ₇ S ⁺ ,564.0873；found,564.0873.

Example 53 preparation of compound 17 (preparation of intramolecular oxidation dearomatization of Heck coupling reaction substrate). When R in Compound 15 ₁₁ In the case of hydroxy protecting group I, compound 15 is prepared directly as compound 17.

By R ₂ TBDPS, X is bromine, R ₁₁ For Me and R as Ts, the compound 17aac is synthesized by the following synthetic route:

compound (R) -15ba (10.00 g,12.49mmol,1.0 equiv.) was dissolved in CH ₃ CN/H ₂ O-mixed solvent (210 mL, v/v=20:1), KF (1.45 g,24.97mmol,2.0 equiv.) was added thereto at room temperature, and the reaction was heated to 50℃for about 3 hours, and TLC showed complete disappearance of starting material. Cooling to 0deg.C, adding saturated NaHCO ₃ The reaction was quenched with aqueous solution (100 mL) and the mixture was distilled under reduced pressure to remove CH ₃ CN, the residue was extracted with ethyl acetate (100 mL. Times.3), the organic layers were combined, washed with saturated aqueous sodium chloride (100 mL. Times.2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether/acetone=4:1, v/v,) to give (R) -17aac as a white foamy solid (6.67 g, 95% yield). Optical rotation [ alpha ]] _D ²⁵ ＝–96.9(c＝0.8,CHCl ₃ ).

Example 54 preparation of Compound 18 (intramolecular oxidative dearomatization Heck reaction).

X is bromine, R ₁ For Me and R as Ts, the synthetic compound 18aac is synthesized by the following synthetic route:

Compound 17aac (200 mg,0.356mmol,1.0 equiv.), palladium chloride (6.3mg,0.0356mmol,0.1 equiv), phosphine ligand (16.8 mg,0.0356mmol,0.1 equiv.) and potassium carbonate (147 mg,1.067mmol,3.0 equiv.) were placed in a reaction vessel, purged with argon, and degassed dry DMF (4 ml, c=0.1 mol/L) was added thereto, and reacted in an oil bath at 80 ℃ for 12 hours. TLC monitored the starting material, the reaction solution was cooled to room temperature, quenched with water (4 mL) at 0deg.C, extracted with ethyl acetate (5 mL. Times.3), the organic layers combined and washed successively with water (10 mL. Times.1), saturated sodium chloride solution (10 mL. Times.1). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether/dichloromethane)Alkane/acetone=15:15:1, v/v) to afford 18aac as an off-white foam solid (27 mg, 16% yield). 18aac data: optical rotation [ alpha ]] _D ²⁵ ＝+4.5(c＝0.4,CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ ):δ7.66 (d,J＝8.4Hz,2H),7.27(d,J＝4.0Hz,2H),7.16(s,1H),6.84–6.77(m,2H),6.22(s,1H),4.95(d, J＝3.6Hz,1H),3.92(s,3H),3.86(s,3H),3.74(s,3H),3.73-3.68(m,1H),3.28(dd,J＝17.6,4.8 Hz,1H),3.20(dd,J＝17.6,1.6Hz,1H),3.04–2.96(m,1H),2.41(s,3H),2.22–2.19(m,1H), 1.40–1.26(m,1H). ¹³ C NMR(100MHz,CDCl ₃ ):δ180.8,157.9,152.2,151.3,147.4,143.9, 137.2,130.3,130.0,127.8,127.1,124.0,122.4,120.0,112.3,56.0,55.0,43.6,40.3,39.0,21.7.IR(neat):ν _max ＝2936,1674,1649,1616,1483,1280,1213,1159cm ^- ¹ .HRMS(m/z):[M+H] ⁺ calculated for C ₂₆ H ₂₈ NO ₆ S ⁺ ,482.1632；found,482.1636.

Examples 55-58 preparation of Compound 18 (intramolecular oxidative dearomatization of Heck reaction solvent screening).

the synthesis procedure of the compound 18aac in examples 55 to 58 is the same as that of example 54, and the conditions of the synthetic reagents and the amounts thereof and the like are shown in the synthesis route; the embodiments of the groups differ only in: different solvents and temperatures were used in the reaction to prepare compound 18aac from compound 17 aac. The results are shown in the following table:

Group of	Solvent(s)	Temperature T (. Degree. C.)	Yield%
				Example 55	toluene	110	19％
Example 56	dimethylbezene	125	55％
				Example 57	PhOMe	125	62％
Example 58	DMF	125	67％

Preparation of Compounds 18 from examples 59-62 (intramolecular Oxidation dearomatization Heck reaction temperature Screen)

the synthesis procedure of the compound 18aac in examples 59 to 62 is the same as that in example 58, and the conditions of the synthetic reagents and the amounts thereof and the like are as shown in the synthesis route; the only differences from embodiment 58 are that the only differences between the various sets of embodiments are: different reaction temperatures were used in the reaction to prepare compound 18aac from compound 17 aac.

Group of	Temperature (. Degree. C.)	Yield%
			Example 59	100	11％
Example 60	125	61％
			Example 61	135	68％
Example 62	145	69％

Examples 63-67 preparation of Compound 18 (screening of base for intramolecular Oxidation dearomatization of Heck reaction).

the synthesis procedure of the compound 18aac in examples 63 to 67 is the same as that of example 62, and the synthetic reagents, the amounts thereof, the reaction temperature and the like are all shown in the synthesis route; the embodiments of the groups differ only in: different bases were used in the reaction to prepare compound 18aac from compound 17 aac. The results are shown in the following table:

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Examples 68-69 preparation of Compound 18 (intramolecular oxidative dearomatization Heck reaction catalyst and ligand equivalent number screening).

the synthesis procedure of the compound 18aac in examples 68 to 69 is the same as that of example 62, and the synthetic reagents, the amounts thereof, the reaction temperature and the like are all as shown in the synthesis route; the embodiments of the groups differ only in: the equivalent weights of palladium chloride and ligand used in the reaction to prepare compound 18aac from compound 17aac are different. The results are shown in the following table:

group of	PdCl ₂ Dosage (mol%)	Ligand dosage (mol%)	Yield%
				Example 68	7.5％	7.5％	57％
Example 69	5％	5％	51％

Examples 70-74 preparation of Compound 18 (concentration screening of intramolecular oxidative dearomatization Heck reaction).

the synthesis procedure of the compound 18aac in examples 70 to 74 is the same as that of example 62, and the synthetic reagents, the amounts thereof, the reaction temperature and the like are all shown in the synthesis route; the embodiments of the groups differ only in: the reaction concentration in the preparation of compound 18aac from compound 17aac was varied. The results are shown in the following table:

group of	Reaction concentration c (mol/L)	Yield%
			Example 70	0.6	40％
Example 71	0.4	40％
			Example 72	0.2	51％
Example 73	0.075	72％
			Example 74	0.05	67％

Example 75 preparation of Compound 18 (preferred concentration application for intramolecular oxidative dearomatization of Heck reaction)

In example 73, the synthesis procedure of the compound 18aac was the same as in example 67, and the synthetic reagents, the amounts thereof, the reaction temperature and the like were as shown in the synthetic route; the only difference from example 67 is that: the reaction concentration in the preparation of compound 18aac from compound 17aac was varied. The results are shown in the following table:

group of	Reaction concentration c (mol/L)	Yield%
			Example 75	0.075	73％

Preparation of Compounds 18 from examples 76-87 (intramolecular oxidative dearomatization of Heck reaction ligand screening).

the synthesis steps of the compounds 18aac in the examples 76 to 87 are the same as those in the example 75, the alkali is potassium phosphate, and other synthetic reagents, the dosage and the reaction temperature and other conditions are shown in the synthesis route; the embodiments of the groups differ only in: the ligands used in the reaction to prepare compound 18aac from compound 17aac are different. The results are shown in the following table:

examples 88-97 preparation of Compound 18 (screening of the molar ratio of the amount of the metal catalyst and ligand used in the oxidation dearomatization of Heck reaction).

the synthesis procedure of the compound 18aac in examples 88 to 97 is the same as that of example 75, and the synthetic reagents, the dosage thereof, the reaction temperature and other conditions are shown in the synthesis route; the embodiments of the groups differ only in: the palladium chloride and ligand amounts in the reaction to prepare compound 18aac from compound 17aac are different. The results are shown in the following table:

group of	PdCl ₂ Dosage (mol%)	Ligand dosage (mol%)	Yield%
				Example 88	10％	20％	76％
Example 89	10％	30％	82％
				Example 90	10％	40％	80％
Example 91	10％	50％	79％
				Implementation of the embodimentsExample 92	7.5％	22.5％	74％
Example 93	7.5％	15％	71％
				Example 94	5％	15％	73％
Example 95	5％	10％	67％
				Example 96	2.5％	7.5％	51％
Example 97	2.5％	5％	46％

Examples 98-100 preparation of compound 18. (selection of the preferred ligand to metal catalyst dosage ratio for intramolecular oxidative dearomatization Heck reaction).

the synthesis steps of the compounds 18aac in examples 98-100 are the same as those in example 81, and the synthetic reagents, the dosage, the reaction temperature and other conditions are shown in the synthesis route; the embodiments of the groups differ only in: the palladium chloride and ligand amounts in the reaction to prepare compound 18aac from compound 17aac are different. The results are shown in the following table:

Group of	PdCl ₂ Dosage (mol%)	Ligand dosage (mol%)	Yield%
				Example 98	5％	15％	72％
Example 99	7.5％	22.5％	73％
				Example 100	10％	30％	79％

Examples 101-102 preparation of Compound 18 (molecular oxidative dearomatization of Heck reaction, preferably ligand to metal catalyst dosage ratio screening).

the synthesis procedure of the compound 18aac in examples 101 to 102 is the same as that of example 83, and the synthetic reagents, the dosage thereof, the reaction temperature and other conditions are shown in the synthesis route; the embodiments of the groups differ only in: the amount of ligand used in the reaction to prepare compound 18aac from compound 17aac varies. The results are shown in the following table:

group of	PdCl ₂ Dosage (mol%)	Ligand dosage (mol%)	Yield%
				Example 101	10％	20％	74％
Example 102	10％	30％	80％

Examples 103-104 preparation of Compound 18 (molecular oxidative dearomatization of Heck reaction, preferably ligand to metal catalyst dosage ratio screening).

the synthesis procedure of the compound 18aac in examples 103 to 104 is the same as that of example 84, and the synthetic reagents, the amounts thereof, the reaction temperature and the like are all as shown in the synthesis route; the embodiments of the groups differ only in: the amount of ligand used in the reaction to prepare compound 18aac from compound 17aac varies. The results are shown in the following table:

Group of	PdCl ₂ Dosage (mol%)	Ligand dosage (mol%)	Yield%
				Example 103	10％	20％	75％
Example 104	10％	30％	81％

Examples 105-106 preparation of Compound 18 (preferred ratio of intramolecular oxidative dearomatization of Heck reaction ligand to amount of metal catalyst used).

the synthesis procedure of the compound 18aac in examples 105 to 106 is the same as that of example 89, and the synthetic reagents, the amounts thereof, the reaction temperature and the like are all shown in the synthesis routes; the embodiments of the groups differ only in: the ligands used in the reaction to prepare compound 18aac from compound 17aac are different. The results are shown in the following table:

example 107 purification of Compound 18aac

The product (R) -18aac of examples 54-106 above was recrystallized from ethanol in 80% yield with an ee value of the product increased to 99.9% (R), M.p.:162-164 ℃ Optical rotation: [ alpha ]] _D ²⁵ ＝+11.9(c＝0.52,CHCl ₃ ) HPLC conditions: AD-H column, hexane: i-PrOH=60:40, flow rate 1mL/min, column temperature 25 ℃, detection wavelength 254nm, t _major ＝16.632 min，t _minor ＝9.754min。

The (S) -18aac is recrystallized by isopropanol, the recrystallization yield is 93 percent, the ee value of the product is improved to 99.9 (S), M.p. 162-164 ℃ Optical rotation is shown in [ alpha ]] _D ²⁵ ＝–11.3(c＝0.68,CHCl ₃ ) HPLC conditions: AD-H column, hexane: i-PrOH=60:40, flow rate 1mL/min, column temperature 25 ℃, detection wavelength 254nm, t _major ＝9.888min，t _minor ＝16.453 min。

Example 108 preparation of compound 18.

X is bromine, R ₁ For PMB and R as Ts, the compound 18aab is synthesized by the following synthetic route:

the compound 17aab (4.00 g,5.98mmol,1.0 equiv.), palladium chloride (106 mg,0.598mmol,0.1 equiv.), phosphine ligand (847 mg,1.794mmol,0.3 equiv.) and potassium phosphate (3.81 g,17.94mmol,3.0 equiv.) were placed in a reaction vessel, purged with air, under argon, degassed dry DMF (80 ml, c=0.075 mol/L) was added thereto, and reacted in an oil bath at 145 ℃ for 40min. TLC monitored the starting material, cooled the reaction to room temperature, quenched with water (40 mL) at 0 ℃, extracted with ethyl acetate (60 ml×3), combined with the organic layers, washed sequentially with water (50 ml×1), saturated sodium chloride solution (50 mL ×1). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether/dichloromethane/acetone=15:15:1, v/v) to give 18aab (2.07 g, yield 72%) as an off-white foam solid. 18aab data: optical rotation [ alpha ]] _D ²⁵ ＝+57.1(c＝0.8,CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ ):δ7.65(d,J＝8.0 Hz,2H),7.37(d,J＝8.4Hz,2H),7.26(d,J＝8.4Hz,2H),7.20(s,1H),6.92–6.79(m,4H),6.17 (s,1H),5.26(d,J＝11.2Hz,1H),4.94–4.92(m,2H),3.88(s,3H),3.82(s,3H),3.69(dd,J＝13.6, 3.6Hz,1H),3.40(s,3H),3.31–3.19(m,2H),3.06-2.99(m,1H),2.40(s,3H),2.14(d,J＝12.8 Hz,1H),1.33–1.25(m,1H). ¹³ C NMR(100MHz,CDCl ₃ ):δ180.8,159.6,157.7,152.0,151.2, 146.3,143.9,137.2,130.3,130.0,129.5,129.1,128.0,127.1,124.0,122.4,120.3,114.1,112.4,74.2,56.0,55.4,54.9,43.6,40.3,39.2,21.6.IR(neat):ν _max ＝1673,1648,1613,1513,1480,1277, 1248,1215,1202,1157,718cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₃₃ H ₃₄ NO ₇ S ⁺ ,588.2050；found,588.2051.

Examples 109-110 preparation of compound 18.

X is bromine, R ₁ For PMB and R as Ts, the synthetic compound 18aab is synthesized according to the synthetic route：

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The synthesis procedure of the compound 18aab in examples 109-110 is the same as that of example 108, and the synthetic reagents, the amounts thereof, the reaction temperature and the like are all as shown in the synthesis route; the embodiments of the groups differ only in: the ligands used in the reaction to prepare compound 18aac from compound 17aac are different. The results are shown in the following table:

Example 111 preparation of compound 18.

X is bromine, R ₁ Taking Bn and R as Ts as examples, the compound 18aaa is synthesized by the following synthetic route:

the synthesis procedure of 18aab was the same as that of example 83, and the synthetic reagents, the amounts thereof, the reaction temperature, and the like were as shown in the synthesis schemes. ¹ H NMR(400MHz,CDCl ₃ ):δ7.65(d,J＝8.4Hz,2H),7.46-7.45(m,2H),7.41–7.32 (m,3H),7.25(d,J＝8.0Hz,2H),7.15(s,1H),6.88–6.81(m,2H),6.18(s,1H),5.30(s,1H, overlapped),5.28(d,J＝12.4Hz,1H,overlapped),5.07(d,J＝11.6Hz,1H),4.93(d,J＝3.6Hz,1H),3.87(s,3H),3.69(dd,J＝14.0,4.0Hz,1H),3.34(s,3H),3.28–3.20(m,1H),3.07–3.00(m, 1H),2.40(s,3H),2.16(d,J＝12.4Hz,1H),1.31(dd,J＝13.2,5.2Hz,1H). ¹³ C NMR(100MHz, CDCl ₃ ):δ180.8,157.7,152.1,151.3,146.2,143.9,137.5,137.2,130.4,123.0,128.8,128.2,128.1, 127.3,127.1,124.2,122.5,120.1,112.5,74.3,56.0,54.9,43.7,40.3,39.2,21.7.IR(neat):ν _max ＝ 1673,1647,1615,1480,1433,1278,1215,1158,747cm ^-1 .IR(neat):ν _max ＝1673,1647,1615, 1480,1433,1278,1215,1158,747cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₃₂ H ₃₂ NO ₆ S ⁺ , 558.1945；found,558.1940.

EXAMPLE 112 preparation of Compound 19

By R ₁ For PMB and R as Ts, compound 19 is synthesized by the following synthetic route:

compound 18aab (100.0 mg,0.170mmol,1.0 equiv.) was dissolved in CH ₂ Cl ₂ (4 mL), cooled to-40 ℃, trifluoroacetic acid (65 uL,0.851mmol,5.0 equiv.) was added, and after 17 hours of reaction, the reaction was continued at 0℃for 7 hours, with TLC indicating complete disappearance of starting material. Saturated NaHCO is added at 0 DEG C ₃ The reaction was quenched with aqueous (2 mL) and quenched with CH ₂ Cl ₂ Extraction (5 ml×3), combining the organic layers, drying over anhydrous magnesium sulfate, filtration, concentration, purification of the resulting crude product by silica gel column chromatography (petroleum ether/acetone=3:1, v/v) afforded 19 (56.0 mg, 70% yield) as a white foam. Optical rotation [ alpha ]] _D ²⁵ ＝+13.8(c＝1.44,CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ ):δ7.67(d,J＝8.2Hz,2H),7.45(s,1H), 7.28(s,1H),6.76(d,J＝8.4Hz,1H),6.60(d,J＝8.4Hz,1H),6.23(d,J＝15.6Hz,2H),4.96(d,J ＝3.3Hz,1H),3.89(s,3H),3.74–3.71(m,1H,overlapped),3.71(s,3H),3.30–3.18(m,2H),3.03 (td,J＝13.2,3.2Hz,1H),2.41(s,3H),2.41–2.36(m,1H,overlapped),1.31(td,J＝12.8,4.8Hz, 1H). ¹³ C NMR(100MHz,CDCl ₃ ):δ180.9,157.8,151.3,145.7,143.9,143.5,137.3,129.9,128.2, 127.1,122.5,119.7,110.0,56.4,55.0,43.4,40.5,38.9,37.6,21.7.IR(neat):ν _max ＝3350,2929, 1670,1640,1484,1219,1158,1054cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₅ H ₂₆ NO ₆ S ⁺ , 468.1475；found,468.1477.

EXAMPLE 113 preparation of Compound 19

compound 18aab (200.0 mg,0.34mmol,1.0 equiv.) was dissolved in DMF (3.5 mL) and hydrobromic acid (48% aqueous solution, 0.7 mL) was added dropwise thereto at room temperature and the addition was then allowed to react at 45℃for 20 hours. The reaction was then cooled to room temperature and hydrobromic acid (48% aqueous solution, 0.3 mL) was added, and the mixture was then allowed to react at 45℃for 15 hours. The reaction was cooled to room temperature again and hydrobromic acid (48% aqueous solution, 0.3 mL) was added, and the reaction was continued at 45 ℃ for 5 hours, with TLC indicating complete disappearance of starting material. Saturated NaHCO is added at 0 DEG C ₃ The aqueous solution was extracted with ethyl acetate (8 ml×3) until no more gas was produced, the organic layers were combined, washed with water (5 ml×1) and saturated sodium chloride (5 ml×1) in this order, the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether/acetone=4:1, v/v) to give a white foamy solid 19 (137 mg, yield 86%). The hydrogen spectrum data is the same as in example 112.

EXAMPLE 114 preparation of Compound 19

By R ₁ For Me and R as Ts, the compound 19 is synthesized by the following synthetic route:

compound 18aac (100.0 mg,0.208mmol,1.0 equiv.) is dissolved in dry N, N-dimethylacetamide (DMAc, 7 mL), sodium hydrosulfide (68% -72% purity, 66.4mg,0.83mmol,4.0 equiv.) is added and reacted at 125℃for 1 hour, TLC showing complete disappearance of starting material. Cooled to 0deg.C, quenched with 0.5M aqueous HCl, extracted with ethyl acetate (5 mL. Times.4), combined with organic layers, followed by water (5 mL. Times.2) and saturated NaHCO ₃ Aqueous solution (5 mL. Times.1) and saturated aqueous NaCl solution (5 mL. Times.1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether/acetone=4:1, v/v) to give 19 (69.0 mg, yield 71%) as a white solid. The hydrogen spectrum data is the same as in example 112.

Example 115 preparation of Compound 19

By R ₁ For Me and R as Ts, a combinationThe synthetic route of the compound 19 is as follows:

compound 18aac (100 mg,0.208mmol,1.0 equiv.) and cesium carbonate (102 mg,0.312mmol,1.5 equiv.) were charged into a reaction tube, evacuated, and protected with argon. To this was added dry degassed dimethyl sulfoxide (DMSO, 2 mL), thiophenol (29.0 μl,0.281mmol,1.35 equiv.) and reacted for 1 hour in an oil bath at 150 ℃ with TLC showing complete disappearance of starting material. Cooled to room temperature, quenched with water, the layers separated, the aqueous layer extracted with ethyl acetate (3 mL. Times.5), the organic layers combined and washed sequentially with water (5 mL. Times.2), saturated sodium chloride solution (5 mL. Times.1). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether/dichloromethane/acetone=15:15:1 to 10:10:1, v/v) to give 19 (83 mg, yield 85%) as a white solid. The hydrogen spectrum data is the same as in example 112.

Example 116 preparation of Compound 19

compound 18aac (100 mg,0.208mmol,1.0 equiv.) and potassium carbonate (43 mg,0.312mmol,1.5 equiv.) were charged into a reaction tube, and the gas was vented under argon. To this was added dry degassed dimethyl sulfoxide (DMSO, 4 mL), thiophenol (32.0 μl,0.312mmol,1.5 equiv.) and reacted in an oil bath at 150 ℃ for 1.5 hours, TLC showed complete disappearance of starting material. Cooled to room temperature, quenched with water, the layers separated, the aqueous layer extracted with ethyl acetate (3 mL. Times.5), the organic layers combined and washed sequentially with water (5 mL. Times.2), saturated sodium chloride solution (5 mL. Times.1). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether/dichloromethane/acetone=15:15:1 to 10:10:1, v/v) to give 19 (77 mg, yield 79%) as a white solid. The hydrogen spectrum data is the same as in example 112.

EXAMPLE 117 preparation of intermediate I

Taking R as Ts as an example, compound 21 (i.e., intermediate I) is synthesized by the following synthetic route:

compound 19 (510.0 mg,1.09mmol,1.0 equiv.) was dissolved in CH ₂ Cl ₂ Mixed solution of MeOH (v/v=1:1, 10 mL), cooled to 0 ℃, and NaBH was slowly added ₄ (82.5 mg,2.18mmol,2.0 equiv.) the reaction was then warmed to room temperature and TLC after about 15min detected complete disappearance of starting material. The reaction solution was cooled to 0 ℃, quenched with water to separate an organic layer, the aqueous layer was extracted with dichloromethane (10 ml×3), the organic layers were combined, washed with saturated NaCl solution (10 ml×1), dried over anhydrous magnesium sulfate, filtered, and concentrated to give a crude product of the white foam-like compound 20, which was directly subjected to the next reaction without purification.

Under the protection of argon, the crude product of the compound 20 is placed in a reaction bottle, the gas is pumped, the protection of the argon is carried out, N-dimethylformamide dimethyl acetal (2.5 mL) is added, the reaction is carried out for about 40 minutes after heating to 60 ℃, and TLC monitoring shows that the reaction of the raw materials is complete. The solvent was removed by suction under reduced pressure, and the crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, v/v=5:1 to 3.5:1) to give 21 as a white foam (418 mg, two-step yield 85%). Optical rotation [ alpha ] ] _D ²⁵ ＝–117.8(c＝0.72, CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ ):δ7.73(d,J＝8.0,2H),7.30(d,J＝8.0Hz,2H),6.64(d,J＝ 8.0Hz,1H),6.51(d,J＝8.0Hz,1H),5.60(d,J＝6.4Hz,1H),5.19(s,1H),4.98(dd,J＝13.6,6.4 Hz,2H),3.82(s,3H),3.74(dd,J＝12.0,5.2Hz,1H),3.59(s,3H),3.26(td,J＝13.2,3.6Hz,1H), 3.00(dd,J＝18.2,6.8Hz,1H),2.89(d,J＝18.0Hz,1H),2.44(s,3H),1.95(td,J＝12.8,5.4Hz, 1H),1.74–1.70(m,1H). ¹³ C NMR(100MHz,CDCl ₃ ):δ153.0,144.8,143.4,143.1,137.3,132.1, 129.7,129.0,127.4,126.1,119.5,113.2,112.5,95.4,88.6,56.4,55.0,54.4,45.9,38.9,37.1,36.0,21.6.IR(neat):ν _max ＝2922,1603,1502,1234,1155,725cm ^-1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₅ H ₂₆ NO ₅ S ⁺ ,452.1526；found,452.1519.

EXAMPLE 118 preparation of Compound 22

Taking R as Ts as an example, compound 22 is synthesized by the following synthetic route:

compound 21 (500 mg,1.11mol,1.0 equiv.) is placed in a round bottom flask and toluene (7.5 mL) and butenone (2.5 mL) are added in sequence and reacted with heating at 80 ℃. After 16 hours, TLC detection reaction was complete. The reaction solution was dried under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether/acetone=4:1, v/v) to give 22 (532 mg, yield 92%) as a white foam. [ alpha ]] _D ²⁵ ＝–171.6(c＝0.93,CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ ):δ7.70(d,J＝8.4Hz,2H), 7.34(d,J＝8.0Hz,2H),6.59(d,J＝8.4Hz,1H),6.39(d,J＝8.0Hz,1H),5.94(d,J＝8.8Hz,1H), 5.50(d,J＝9.2Hz,1H),4.56(d,J＝0.8Hz,1H),4.53(d,J＝7.2Hz,1H),3.82–3.72(m,4H), 3.58(s,3H),2.99–2.88(m,2H),2.77(dd,J＝19.2,7.2Hz,1H),2.63(dd,J＝12.8,9.2Hz,1H), 2.52–2.42(m,4H),2.14(s,3H),2.02(td,J＝12.8,5.6Hz,1H),1.96–1.89(m,1H),1.51(dd,J＝ 12.8,6.4Hz,1H). ¹³ C NMR(100MHz,CDCl ₃ ):δ208.1,148.1,143.6,142.2,136.9,134.0,132.6, 130.0,127.0,126.9,126.0,119.6,114.0,95.2,81.1,56.6,53.7,53.6,50.3,47.7,42.6,37.8,32.8,30.8,30.1,29.6,21.6.IR(neat):ν _max ＝2942,1711,1450,1159,1094,746cm ^–1 .HRMS(m/z):[M +Na] ⁺ calculated for C ₂₉ H ₃₁ NNaO ₆ S ⁺ ,544.1764；found,544.1772.

EXAMPLE 119 preparation of Compound 23

Taking R as Ts as an example, compound 23 is synthesized by the following synthetic route:

compound 22 (479 mg,0.918 mm)ol,1.0 equiv.) was placed in a round bottom flask, methanol (30 mL), acetic acid (105. Mu.L, 1.84mmol,2.0 equiv.) and 10% palladium on carbon (144 mg,30% w/w) were added in this order, air was vented, and the mixture was hydrogenated at room temperature (5 atm.) for 20 hours. After completion of the TLC detection reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3:1, v/v) to give 23 as a white foam (443 mg, yield 92%). [ alpha ]] _D ²⁵ ＝–93.9(c＝0.57,CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ ):δ7.66(d,J＝8.0Hz, 2H),7.31(d,J＝8.0Hz,2H),6.67(d,J＝8.4Hz,1H),6.43(d,J＝8.0Hz,1H),4.46(s,1H),4.05 (d,J＝6.8Hz,1H),3.85(s,3H),3.69(dd,J＝12.8,5.6Hz,1H),3.41(s,3H),3.03(dd,J＝10.8, 6.4Hz,1H),2.83(td,J＝12.8,3.6Hz,1H),2.61(dd,J＝18.8,7.2Hz,1H),2.45(s,3H),2.43– 2.36(m,1H),2.35–2.27(m,1H),2.25(s,3H),2.09(td,J＝12.8,6.0Hz,1H),1.88(dd,J＝13.2, 6.0Hz,1H),1.74(dd,J＝13.2,2.8Hz,1H),1.59–1.46(m,2H),1.38(td,J＝12.4,6.0Hz,1H), 0.69–0.57(m,1H). ¹³ C NMR(100MHz,CDCl ₃ ):δ210.0,146.9,143.4,142.2,137.0,131.0, 129.9,127.0,126.4,119.4,114.4,94.5,56.7,54.8,52.3,49.2,46.0,37.5,35.4,34.3,33.8,29.8,29.8,27.80,21.6,17.1.IR(neat):ν _max ＝2968,1260,1089,1013,749cm ^–1 .HRMS(m/z):[M+ Na] ⁺ calculated for C ₂₉ H ₃₃ NNaO ₆ S ⁺ ,546.1921；found,546.1914.

EXAMPLE 120 preparation of Compound 24

Taking R as Ts as an example, a compound 24 is synthesized, and the synthetic route is as follows:

compound 23 (212 mg,0.405mmol,1.0 equiv.) was placed in a round bottom flask, purged with argon, dry toluene (12 mL) was added, and propyl magnesium chloride (2.0M in diethyl ether, 0.61mL,1.21mmol,3.0 equiv.) was added dropwise with stirring at 50 ℃ and reacted for about 30 minutes, and the complete disappearance of starting material was detected by TLC. The reaction solution was cooled to 0℃and quenched by the addition of a saturated ammonium chloride solution The layers were separated, the aqueous layer was extracted with EtOAc (10 ml×4), the organic layers were combined, washed with saturated aqueous NaCl (10 ml×1), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4:1 to 3:1, v/v) to give compound 24 (152 mg, yield 66%) as a white foam. [ alpha ]] _D ²⁰ ＝–72.5(c＝0.8,CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ ):δ7.69(d,J＝8.4Hz,2H),7.33(d,J＝8.0 Hz,2H),6.69(d,J＝8.4Hz,1H),6.44(d,J＝8.4Hz,1H),4.98(s,1H),4.39(s,1H),4.01(d,J＝ 6.8Hz,1H),3.86(s,3H),3.65(dd,J＝12.8,5.6Hz,1H),3.53(s,3H),2.87(td,J＝12.4,3.6Hz, 1H),2.60(dd,J＝18.8,6.8Hz,1H),2.50–2.35(m,5H),2.01(td,J＝13.2,5.6Hz,1H),1.92– 1.71(m,4H),1.58–1.45(m,1H),1.45–1.29(m,6H),1.25–1.05(m,2H),0.96(t,J＝6.4Hz, 3H),0.75–0.62(m,1H). ¹³ C NMR(100MHz,CDCl ₃ ):δ147.1,143.5,142.0,136.9,130.9,129.8, 127.2,126.6,119.4,114.6,96.6,80.0,75.5,56.8,54.8,52.8,46.4,45.6,43.7,37.5,35.8,34.7,31.1,29.9,29.0,23.4,21.6,17.6,16.0,14.8.IR(neat):ν _max ＝3474,2960,1452,1262,1158,1086,752 cm ^–1 .HRMS(m/z):[M+Na] ⁺ calculated for C ₃₂ H ₄₁ NNaO ₆ S ⁺ ,590.2547；found,590.2551.

Example 121 preparation of Compound 26

Taking R as Ts as an example, compound 26 is synthesized by the following synthetic route:

compound 24 (114 mg,0.201mmol,1.0 equiv.) is placed in a reaction flask, purged with argon, dry tetrahydrofuran (7.0 mL) is added, cooled to 0 ℃, lithium aluminum hydride (1M tetrahydrofuran solution, 1.0mL,1.00mmol, 5.0 equiv.) is added, and after addition, the reaction is completed by TLC detection after about 18 hours, indicating complete reaction of starting materials. Cooled to 0 ℃, isopropanol (80 mu L) is added, stirred for 5 minutes, water (46 mu L) is added, stirred for 5 minutes, then 15 percent sodium hydroxide aqueous solution (46 mu L) and water (138 mu L) are added in turn, the reaction solution is warmed to room temperature and stirred continuouslyMix for 30 minutes. The resulting mixture was filtered through celite and the filter cake was washed with a dichloromethane/methanol mixture (CH ₂ Cl ₂ Meoh=10/1, v/v) and the filtrate was concentrated under reduced pressure to give crude compound 25. The reaction mixture was used in the next reaction without isolation and purification.

The above crude product 25 was dissolved in methanol (7.0 mL), paraformaldehyde (108 mg,1.20mmol,6.0 equiv.) was added, stirred at room temperature for 3 hours, cooled to 0 ℃, sodium borohydride (60.8 mg,1.61mmol,8.0 equiv.) was added, and then the reaction mixture was allowed to warm to room temperature for 10 minutes, and TLC monitoring showed complete reaction. The reaction solution was cooled to 0 ℃, quenched with saturated aqueous ammonium chloride solution, extracted with dichloromethane (5 ml×1), separated, the aqueous layer was pH-adjusted with 15% sodium hydroxide solution=10, extracted with dichloromethane (5 ml×4), the combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate v/v=6:1 to 4:1 gradient elution, containing 0.5% aqueous ammonia) to give 6 (67.2 mg, two-step yield 78%) as a white solid. [ alpha ]] _D ²⁰ ＝–105.9(c＝0.56,CHCl ₃ ).Melting point:176.3–178.0℃. ¹ H NMR(400MHz,CDCl ₃ ):δ6.71(d,J＝8.0Hz,1H),6.57(d,J＝8.4Hz,1H),5.10(s,1H),4.40 (s,1H),3.88(s,3H),3.54(s,3H),3.12(d,J＝18.4Hz,1H),2.79–2.69(m,1H),2.64(d,J＝6.0 Hz,1H),2.43(dd,J＝12.0,5.2Hz,1H),2.34–2.18(m,5H),1.99(td,J＝12.8,5.6Hz,1H),1.91(t, J＝10.0Hz,1H),1.84–1.75(m,2H),1.69–1.62(m,1H),1.58–1.29(m,7H),1.12–0.99(m, 2H),0.93(t,J＝6.8Hz,3H),0.82–0.70(m,1H). ¹³ C NMR(100MHz,CDCl ₃ ):δ147.0,141.6, 132.5,128.8,119.0,114.1,97.0,80.3,75.7,61.3,56.9,52.7,46.1,45.8,45.1,43.9,43.6,36.0,35.5,31.8,29.8,23.3,21.9,17.9,15.9,14.8.IR(neat):ν _max ＝3482,2960,2928,1447,1259,1084,1012, 799,754cm ^–1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₆ H ₃₈ NO ₄ ⁺ ,428.2795；found,428.2790.

EXAMPLE 122 preparation of dihydroetorphine

Sodium ethoxide (39.8 mg,0.585mmol,10.0 equiv.) is placed in a reaction flask, vented, argon shielded, degassed dry dimethyl sulfoxide (1.0 mL) added, tertiary dodecyl mercaptan (138 μl,0.585mmol,10.0 equiv.) added and stirred in an oil bath preheated to 150 ℃ for about 5 minutes until the solids dissolve. To this was added a solution of compound 26 (25.0mg,0.058 mmol,1.0equiv) in dry dimethyl sulfoxide (1.0 mL) and after about 4 hours of reaction at 150 ℃, the starting material disappeared completely. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate (2 ml×1), layered, aqueous layer ph=10 with aqueous ammonia, extracted with ethyl acetate (2 ml×4), and the organic layers were combined and washed sequentially with water (2 ml×2), saturated sodium chloride solution (2 ml×1). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography over silica gel (petroleum ether/ethyl acetate v/v=3:1 to 1.5:1 gradient elution, containing 0.5% aqueous ammonia) to give dihydroetorphine as a white foamy solid (20.6 mg, yield 85%). [ alpha ] ] _D ²⁰ ＝–70.9(c＝0.37,CHCl ₃ ). ¹ H NMR(400MHz,CDCl ₃ ):δ6.69(d,J＝8.4 Hz,1H),6.53(d,J＝7.8Hz,1H),5.09(s,1H),4.42(s,1H),3.52(s,3H),3.10(d,J＝18.6Hz,1H), 2.78–2.68(m,1H),2.65(d,J＝6.6Hz,1H),2.44(dd,J＝11.4,4.8Hz,1H),2.33–2.24(m,4H), 2.20(dd,J＝18.0,6.0Hz,1H),2.00(td,J＝12.6,5.4Hz,1H),1.91(t,J＝10.2Hz,1H),1.82– 1.72(m,2H),1.66(d,J＝13.2Hz,1H),1.57–1.39(m,3H),1.37–1.28(m,4H),1.12–0.99(m, 2H),0.92(t,J＝7.2Hz,3H),0.79–0.70(m,1H). ¹³ C NMR(100MHz,CDCl ₃ ):δ145.5,137.2, 132.1,128.3,119.5,116.4,97.4,80.4,75.8,61.3,52.7,46.5,45.7,45.2,43.9,43.5,36.0,35.4,31.8,29.7,23.3,22.0,17.9,15.9,14.8.IR(neat):ν _max ＝3419,3161,2959,2926,1454,1280,1158,1084, 751cm ^–1 .HRMS(m/z):[M+H] ⁺ calculated for C ₂₅ H ₃₆ NO ₄ ⁺ ,414.2639；found,414.2643.

The foregoing is merely a preferred embodiment of the invention, and it is to be understood that the invention is not limited to the form disclosed herein but is not to be construed as excluding other embodiments, but is capable of numerous other combinations, modifications and environments and is capable of modifications within the scope of the inventive concept, either as taught or as a matter of routine skill or knowledge in the relevant art. And that modifications and variations which do not depart from the spirit and scope of the invention are intended to be within the scope of the appended claims.

Claims

1. The synthesis method of the dihydro etorphine is characterized by comprising the following steps of:

A)

providing a compound 17, wherein the compound 17 is subjected to intramolecular oxidation to remove an aromatic Heck reaction to generate a compound 18; the intramolecular oxidation dearomatization Heck reaction is carried out in the presence of a reaction reagent and alkali, wherein the reaction reagent is a ligand II and a transition metal catalyst II;

the transition metal catalyst II is PdCl ₂ ；

The ligand II is selected from One of the following;

B)

C)

the compound 19 undergoes a reduction reaction to produce a compound 20;

D)

cyclizing the compound 20 to generate an intermediate I;

E)

F)

G)

H)

I)

the compound 25 undergoes reductive amine methylation to produce a compound 26;

J)

the compound 26 is subjected to selective removal of methyl on benzene ring for reaction to obtain the dihydro etorphine;

in the above reaction, X is a halogen atom, R ₁ Is hydroxyl protecting group I, R is secondary amine protectionA base.

2. The method for synthesizing dihydroetorphine according to claim 1, wherein the hydroxyl protecting group i is one selected from the group consisting of p-methoxybenzyl, benzyl, acetyl, benzyloxycarbonyl, methoxymethylene, methyl, triisopropylsilyl, triethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl.

3. The method for synthesizing dihydroetorphine according to claim 1, wherein the secondary amine protecting group R is selected from one of benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, methyl formate, t-butoxycarbonyl, benzyl, benzyloxycarbonyl, trifluorosulfonyl, methanesulfonyl and trimethylbenzenesulfonyl.

4. A process for the synthesis of dihydroetorphine according to any one of claims 1 to 3, characterized in that in step E) the Diels-Alder reaction solvent is selected from one of toluene, isopropanol, ethanol; the temperature of the Diels-Alder reaction is 50-110 ℃.

5. A process for the synthesis of dihydroetorphine according to any one of claims 1 to 3, characterized in that in step F) the catalyst of the catalytic hydrogenation reaction is selected from one of palladium on carbon and palladium hydroxide; the reaction solvent for the catalytic hydrogenation reaction is one or more selected from methanol, ethanol, dichloromethane, dichloroethane, ethyl acetate, isopropanol, tertiary butanol, formic acid, acetic acid and water; the hydrogen pressure of the catalytic hydrogenation reaction is 1-25 atm; the temperature of the catalytic hydrogenation reaction is 0-80 ℃.

6. The method for synthesizing dihydroetorphine according to claim 5, wherein in step F), the catalyst for the catalytic hydrogenation reaction is palladium on carbon; the molar ratio of the compound 22 to the catalyst is 1:0.05-0.3; the reaction solvent of the catalytic hydrogenation reaction is selected from methanol and acetic acid; the hydrogen pressure of the catalytic hydrogenation reaction is 5-10atm; the temperature of the catalytic hydrogenation reaction is 10-40 ℃.

7. A method of synthesis of dihydroetorphine according to any one of claims 1 to 3, wherein in step G) the propyl grignard reagent is propyl magnesium chloride or propyl magnesium bromide; the reaction solvent of the addition reaction is selected from one of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, methyl tertiary butyl ether, dioxane and toluene; the reaction temperature of the addition reaction is-20 to 110 ℃.

8. A process for the synthesis of dihydroetorphine according to claim 3, characterized in that in step H) when the secondary amine protecting group is selected from the group consisting of p-toluenesulfonyl:

the reactant for removing the secondary amine protecting group R is one of red aluminum, lithium aluminum hydride, magnesium powder and sodium-naphthalene; the reaction solvent for removing the secondary amine protecting group R is selected from one of tetrahydrofuran, ethylene glycol dimethyl ether and toluene; the reaction temperature for removing the secondary amine protecting group R is 25-80 ℃.

9. A process for the synthesis of dihydroetorphine according to claim 8, characterized in that in step H) when the secondary amine protecting group is selected from the group consisting of p-toluenesulfonyl:

the reaction reagent for removing the secondary amine protecting group R is lithium aluminum hydride, and the molar ratio of the compound 24 to the reaction reagent is 1:3-6; the reaction solvent is tetrahydrofuran; the reaction temperature is 40-70 ℃.

10. A method of synthesizing dihydroetorphine according to any one of claims 1 to 3, characterized in that in step I) the reagent of the reductive amine methylation reaction is selected from one of paraformaldehyde sodium borohydride in combination with aqueous formaldehyde sodium borohydride in combination; the reaction solvent for the reductive amine methylation reaction is selected from one of methanol, ethanol, tetrahydrofuran and acetic acid; the reaction temperature of the reductive amine methylation reaction is 0-60 ℃.

11. The method for synthesizing dihydroetorphine according to claim 10, wherein in step I), the reaction reagent of the reductive amine methylation reaction is sodium borohydride combined with paraformaldehyde, and the molar ratio of the compound 25 to the reaction reagent is 1:2-5; the reaction solvent of the reductive amine methylation reaction is methanol; the reaction temperature of the reductive amine methylation reaction is 10-40 ℃.

12. A process according to any one of claims 1 to 3, wherein in step J) the removal reagent for the selective removal of methyl groups is selected from one of boron tribromide, sodium hydrosulphide, sodium sulphide, sodium ethanethiolate, thiophenol, sodium p-toluenesulphide, t-dodecyl mercaptan, potassium fluoride, sodium ethoxide, tetrabutylammonium fluoride, acetic acid, trifluoroacetic acid, hydrobromic acid, trimethyliodosilane, aluminium trichloride, cerium trichloride, ceric ammonium nitrate, camphorsulphonic acid, p-toluene sulphonic acid, phosphorus oxychloride, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone and hydrochloric acid; the reaction solvent for the selective methyl removal reaction is one or two selected from dimethyl sulfoxide, N-dimethylacetamide, azomethylpyrrolidone, methanol, N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane and acetic acid.

13. The method for synthesizing dihydroetorphine according to claim 12, wherein in step J), the removing reagent for the selective methyl removing reaction is sodium ethoxide and tert-dodecyl mercaptan, or thiophenol; the reaction solvent for the selective methyl removal reaction is dimethyl sulfoxide.