CN109912663B

CN109912663B - Oxygen-linked cyclopentadiene rhodium complex, preparation method, intermediate and application thereof

Info

Publication number: CN109912663B
Application number: CN201910164735.0A
Authority: CN
Inventors: 游书力; 王少博; 顾庆
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2019-03-05
Filing date: 2019-03-05
Publication date: 2021-06-08
Anticipated expiration: 2039-03-05
Also published as: CN109912663A

Abstract

The invention discloses an oxygen-linked cyclopentadiene rhodium complex, and a preparation method, an intermediate and application thereof. The structure of the rhodium complex is shown as the formula (R)_a) -Rh-K or formula (S)_a) -Rh-K. The rhodium complex of the invention shows higher yield and enantioselectivity in the catalytic Heck coupling reaction.

Description

Oxygen-linked cyclopentadiene rhodium complex, preparation method, intermediate and application thereof

Technical Field

The invention relates to an oxygen-linked cyclopentadiene rhodium complex, a preparation method, an intermediate and application thereof.

Background

The C-H bond functionalization reaction catalyzed by pentamethylcyclopentadiene metal (such as rhodium) complex can efficiently construct carbon-carbon bond and carbon heterobond, and is widely applied to chemical synthesis. However, until the last few years, there have been major breakthroughs in the asymmetric C-H bond functionalization reactions catalyzed by these complexes, in particular with rhodium and iridium. Ward and Rovis group succeeded in synthesizing biotinylated [ Cp Rh (III) 2012]The complex can be successfully applied to asymmetric C-H bond functionalization reaction [ T.K.hyster, L ] by combining the complex with streptavidin.

T.R.Ward,T.Rovis,Science 2012,338,500-503]. However, the synthesis of the catalyst is complex, and the reaction application range is not ideal. At approximately the same time, the Cramer group successfully bound the tartaric acid derivative backbone to cyclopentadiene, synthesizing a series of C2-symmetric cyclopentadiene ligands and applying them to the synthesis of rhodium complexes. The rhodium complex can efficiently and highly enantioselectively catalyze the hydroarylation reaction of the benzohydroxamic acid derivatives [ B.Ye, N.Cramer, Science 2012,338, 504-]. Subsequently, the panel in turn applied the binaphthyl backbone to the synthesis of C2-symmetric cyclopentadienyl ligands, and theyThe corresponding rhodium complex has wider application value in the reaction of the asymmetric C-H bond functionalization [ (a) Ye, B ]; cramer, n.j.am.chem.soc.2013,135,636, (b) Ye, b.; donets, p.a.; cramer, n.angelw.chem., int.ed.2014,53,507.(c) Ye, b.; cramer, n.angelw.chem., int.ed.2014,53,7896.(d) Zheng, j.; you, s. -l.angelw.chem., int.ed.2014,53,13244.(e) Ye, b.; cramer, n.synlett 2015,26,1490-1495 (f) Zheng, j.; wang, S. -B.; zheng, c.; you, S. -L.J.am.chem.Soc.2015,137,4880.]. Moreover, such cyclopentadienyl ligands have a wide variety of uses in other metal complexes [ (a) Song, g.; o, w.w.n.; hou, z.j.am.chem.soc.2014,136,12209.(b) Dieckmann, m.; jang, y. -s.; the amount of the Cramer compound is,N.Angew.Chem.Int.Ed.2015,54,12149.(c)Kossler, D；Cramer,N.J.Am.Chem.Soc.2015,137,12478.]. In 2016, the Youli group designed and synthesized a series of cyclopentadiene ligands based on a spiro chiral framework, which acted with metal rhodium to form rhodium complexes and showed very good catalytic effects in asymmetric C-H bond activation reactions [ (a) Zheng, J.; cui, w. -j.; zheng, c.; you, S. -L.J.am.chem.Soc.2016,138,5242.(b) Zheng, J.; wang, S. -B.; zheng, c.; you, s. -l.angelw.chem.int.ed.2017, 56,4540.(c) Li, t.; zhou, c.; yan, x.; wang, j.angelw.chem.int.ed.2018, 57,4048.]. In recent years, there are also few reports on the synthesis of novel chiral cyclopentadiene frameworks or the post-modification of existing frameworks in (a) Jia, z. -j.; merten, c.; gontla, R.; daniliuc, c.g.; antoinchick, a.p.; waldmann, h.angelw.chem.int.ed.2017, 56,2429.(b) Wang, s. -g.; park, s.h.; cramer, n.angelw.chem.int.ed.2018, 57,5459.(c) Sun, y.; cramer, n.chem.sci.,2018,9,2981.]. However, the backbone of the current cyclopentadienyl ligands is still relatively rare overall.

Disclosure of Invention

The invention aims to solve the technical problem of providing an oxygen-linked cyclopentadiene rhodium complex, and a preparation method, an intermediate and application thereof. The cyclopentadiene ligand in the rhodium complex has a brand-new oxygen bridge structure. The rhodium complex of the invention shows higher yield and enantioselectivity in the catalytic Heck coupling reaction.

The invention provides a compound of formula(R_a) -Rh-K or formula (S)_a) -Rh-K:

wherein R is¹And R^1aEach independently is H, C₁-C₈Alkyl (e.g. methyl), substituted or unsubstituted C₃-C₈Cycloalkyl, or substituted or unsubstituted C₆-C₁₂Aryl (e.g., phenyl);

R²and R^2aEach independently is H, C₁-C₈Alkyl (e.g. methyl or ethyl), substituted or unsubstituted C₃-C₈Cycloalkyl, or substituted or unsubstituted C₆-C₁₂Aryl (e.g., phenyl);

R³and R^3aEach independently is H, C₁-C₈Alkyl radical, C₁-C₈Alkoxy (e.g. methoxy or ethoxy), substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₆-C₁₂Aryl (e.g. phenyl), substituted or unsubstituted C₆-C₁₂Aryloxy (e.g. phenoxy), or substituted or unsubstituted-O- (C)₁-C₃Alkyl group) - (C₆-C₁₂Aryl) (e.g., benzyloxy);

said substituted C₃-C₈Cycloalkyl, substituted C₆-C₁₂Aryl, substituted C₆-C₁₂Aryloxy and substituted-O- (C)₁-C₃Alkyl group) - (C₆-C₁₂Aryl) means substituted by one or more C₁-C₈Alkyl groups are substituted.

At R¹、R²、R³、R^1a、R^2aAnd R^3aIn (b), the C₁-C₈The alkyl groups may each independently be C₁-C₄Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical, and also methyl or ethyl radicals.

At R¹、R²、R³、R^1a、R^2aAnd R^3aIn (b), the C₃-C₈The cycloalkyl groups may each independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

At R¹、R²、R³、R^1a、R^2aAnd R^3aIn (b), the C₆-C₁₂Aryl, substituted or unsubstituted C₆-C₁₂C in aryloxy₆-C₁₂Aryl and-O- (C)₁-C₃Alkyl group) - (C₆-C₁₂C in aryl)₆-C₁₂Aryl groups may each independently be phenyl or naphthyl, for example phenyl.

At R³And R^3aIn (b), the C₁-C₈The alkoxy groups may each independently be C₁-C₄Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

In some embodiments of the invention, the compound is represented by formula (R)_a) In the compounds represented by-Rh-K, R¹Is C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, or substituted or unsubstituted C₆-C₁₂Aryl, preferably C₁-C₈An alkyl group.

In some embodiments of the invention, the compound is represented by formula (S)_a) In the compounds represented by-Rh-K, R^1aIs C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, or substituted or unsubstituted C₆-C₁₂Aryl, preferably C₁-C₈An alkyl group.

In the formula (R)_a) In the compounds represented by-Rh-K, R²Preferably H or C₁-C₈An alkyl group.

In the formula (S)_a) In the compounds represented by-Rh-K, R^2aPreferably H or C₁-C₈An alkyl group.

In the formula(R_a) In the compounds represented by-Rh-K, R³Preferably C₁-C₈An alkoxy group.

In the formula (S)_a) In the compounds represented by-Rh-K, R^3aPreferably C₁-C₈An alkoxy group.

In some embodiments of the invention, the compound is represented by formula (R)_a) In the compounds represented by-Rh-K, R¹Is C₁-C₈An alkyl group;

R²is H or C₁-C₈An alkyl group;

R³is C₁-C₈An alkoxy group.

In some embodiments of the invention, the compound is represented by formula (S)_a) In the compounds represented by-Rh-K, R^1aIs C₁-C₈An alkyl group;

R^2ais H or C₁-C₈An alkyl group;

R^3ais C₁-C₈An alkoxy group.

In some embodiments of the invention, the compound is represented by formula (R)_a) The compounds of-Rh-K are

In some embodiments of the invention, the formula is (S)_a) The compounds of-Rh-K are

The invention also provides a compound as described above as formula (R)_a) A method for preparing a compound represented by-Rh-K, comprising the steps of: in an organic solvent, the phenylacetic acid methyl ester compound is mixed with [ Rh (cod) Cl]₂The following coordination reaction is carried out in the presence of a base to obtain a compound represented by the formula (R)_a) A compound represented by-Rh-K; the methyl phenylacetate compound is shown as a formula (R)_a) A compound of formula (R) I-C_a)-A compound of I-D or a mixture of both; wherein R is¹、R²And R³The definition of (a) is as described above,&represents chirality of carbon atoms in R configuration, S configuration or a mixture of the two; # denotes that the chirality of the carbon atom is R configuration, S configuration, or a mixture of both;

the conditions for the coordination reaction may be conventional in the art for such reactions, and the following conditions are preferred in the present invention.

In the coordination reaction, the organic solvent may be an aromatic hydrocarbon solvent, such as toluene. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected. For example, the molar concentration of the methyl phenylacetate compound in the organic solvent can be 0.01-1 mol/L.

In the coordination reaction, the [ Rh (cod) Cl ] is]₂The molar ratio to the methyl phenylacetate compound may be from 0.4 to 1:1, for example from 0.5 to 0.7: 1.

In the coordination reaction, the base may be an alkali metal hydroxide, such as potassium hydroxide. The base may be used in an amount conventional to such reactions in the art, for example the molar ratio of the base to the methyl phenylacetate compound may be from 1 to 5:1, for example from 2 to 4: 1.

The reaction temperature of the coordination reaction may be 20 to 100 deg.C (e.g., 60 to 80 deg.C).

The operation of the coordination reaction may be conventional in the art for such reactions. The progress of the coordination reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, GC, or NMR), and is generally determined as the end point of the reaction when the methyl phenylacetate compound is no longer reacted.

As shown in formula (R)_a) The preparation method of the compound represented by-Rh-K can further comprise the following steps: in an organic solvent, the cyclopentadiene compound and methyl benzoylformate react in n-butyl lithium and diethylCarrying out addition reaction as shown in the specification in the presence of aluminum chloride to obtain a product; the cyclopentadiene compound is shown as a formula (R)_a) A compound represented by formula (I-A), formula (R)_a) -a compound represented by I-B or a mixture of both;

when the cyclopentadiene compound is shown as the formula (R)_a) When the compound is a compound shown as the formula (R)_a) -a compound of formula I-C;

when the cyclopentadiene compound is shown as the formula (R)_a) When the compound is a compound shown as the formula (I-B), the product is shown as the formula (R)_a) -a compound of formula I-D;

when the cyclopentadiene compound is shown as the formula (R)_a) A compound represented by the formula (I-A) and a compound represented by the formula (R)_a) When the compound shown as the formula I-B is a mixture, the product is shown as the formula (R)_a) A compound represented by the formula (I-C) and a compound represented by the formula (R)_a) -a mixture of compounds represented by I-D;

the conditions for the addition reaction may be conventional in the art for such reactions, and the following conditions are preferred in the present invention.

In the addition reaction, the organic solvent may be an ether solvent, such as tetrahydrofuran. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected. For example, the molar concentration of the cyclopentadiene compound in the organic solvent may be 0.01 to 1 mol/L.

In the addition reaction, the molar ratio of the methyl benzoylformate to the cyclopentadiene compound can be 1-2:1, for example 1.5-1.8: 1.

In the addition reaction, the molar ratio of the n-butyllithium to the cyclopentadiene compound may be 1.1 to 2:1, for example, 1.5 to 1.8: 1.

In the addition reaction, the molar ratio of the diethyl aluminum chloride to the cyclopentadiene compound may be 1.1 to 2:1, for example, 1.5 to 1.8: 1.

The reaction temperature of the addition reaction may be from-30 ℃ to-10 ℃ (e.g., -15 ℃ to-10 ℃).

The operation of the addition reaction can be the conventional operation of the reaction in the field, for example, after the cyclopentadiene compound is reacted with n-butyl lithium, diethyl aluminum chloride is added, after a period of reaction, methyl benzoylformate is added, and the reaction is continued.

The progress of the addition reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, GC, or NMR), and is generally determined as the end point of the reaction when the cyclopentadiene compound is no longer reacted.

The invention also provides a compound as described above as formula (S)_a) A process for the preparation of the compound represented by the formula (R) only by reacting a compound represented by the formula (R) as described above_a) The reactant in the preparation method of the compound shown as-Rh-K is replaced by dinaphthalene with chiral axis of S_aThe corresponding compound of the configuration is sufficient.

The invention also provides a compound shown as the formula I-A or I-B,

wherein R is¹、R²And R³Is as defined above;

indicates that the axial chirality of binaphthyl is R_aConfiguration or S_aConfiguration;&indicates that the chirality of the carbon atom is R configuration, S configuration or the mixture of the two.

In some embodiments of the invention, the compound of formula I-A is

In some embodiments of the invention, the compound of formula I-B is

The invention also provides a preparation method of the compound shown as the formula I-A or I-B, which comprises the following steps: in an organic solvent, carrying out a reduction reaction shown as the following on a compound shown as a formula II in the presence of lithium aluminum hydride to obtain a compound shown as a formula I-A and/or I-B; wherein R is¹、R²、R³A, b, and&is as defined above;

the conditions for the reduction reaction may be conventional in the art, and the following conditions are preferred in the present invention.

The reduction is preferably carried out under a gas (e.g. argon) blanket.

In the reduction reaction, the organic solvent may be an ether solvent, such as tetrahydrofuran. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected. For example, the molar concentration of the compound shown in the formula II in the organic solvent can be 0.01-1 mol/L.

In the reduction reaction, the molar ratio of the lithium aluminum hydride to the compound shown in the formula II can be 5-20:1 (for example, 8-12: 1).

The reduction is preferably carried out in the presence of a Lewis acid. The lewis acid may be a lewis acid conventional to such reactions in the art, such as aluminum trichloride. The amount of Lewis acid may be any amount conventionally used in such reactions in the art, for example the molar ratio of the Lewis acid to the compound of formula II may be from 1 to 10:1 (e.g., from 4 to 6: 1).

The reaction temperature of the reduction reaction may be 10 to 70 deg.C (e.g., 30 to 50 deg.C).

The progress of the reduction reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, GC, or NMR), and is generally determined as the end point of the reaction when the compound of formula II is no longer reacted.

The preparation method of the compound shown in the formula I-A or I-B can further comprise a preparation method of a compound shown in the formula II, and the preparation method of the compound shown in the formula II is method 1 or method 2:

the method 1 comprises the following steps: in an organic solvent, carrying out coupling reaction on a compound shown as a formula III and an organic zinc reagent or an organic boron reagent in the presence of a palladium catalyst to obtain a compound shown as a formula II; wherein the organic zinc reagent is Zn (R)²)₂Or ZnR²Y, Y is chlorine, bromine or iodine (e.g. chlorine); the organic boron reagent is R²B(OH)₂；R¹、R²、R³A, b, and&is as defined above;

the method 2 comprises the following steps: in an organic solvent, carrying out an elimination reaction shown in the following formula on a compound shown in a formula III-2 in the presence of tert-butyl alcohol alkali metal salt and water to obtain a compound shown in a formula II; wherein R is²Is hydrogen; r¹、R³A, b, and&is as defined above;

in the method 1, the conditions of the coupling reaction may be conventional in the art, and the following conditions are preferred in the present invention.

In the method 1, the coupling reaction is preferably performed under a gas (e.g., argon) shield.

In the method 1, in the coupling reaction, the organic solvent may be an ether solvent, such as dioxane. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected. For example, the molar concentration of the compound shown in the formula III in the organic solvent can be 0.01-1 mol/L.

In some embodiments of the invention, the method 1 is performed when R is²When the compound is alkyl, an organic zinc reagent is adopted to react with the compound shown in the formula III. In one embodiment of the invention, the organozinc reagent is ZnMe₂. In one embodiment of the invention, the organozinc reagent is ZnEtCl.

In some embodiments of the invention, the method 1 is performed when R is²In the case of aryl, an organoboron reagent is used to react with the compound shown in formula III. In one embodiment of the invention, the organoboron reagent is PhB (OH)₂。

In the method 1, in the coupling reaction, the organic zinc reagent can be added to the reaction system in the form of a commercially available solution, for example, an n-hexane solution of the organic zinc reagent.

In the method 1, in the coupling reaction, the molar ratio of the organic zinc reagent to the compound shown in the formula III can be 2-8:1 (for example, 4-6: 1).

In the method 1, the molar ratio of the organoboron reagent to the compound represented by the formula III in the coupling reaction may be 2 to 8:1 (for example, 4 to 6: 1).

In the method 1, in the coupling reaction, the palladium catalyst may be a palladium catalyst conventional in the art, such as tetrakis (triphenylphosphine) palladium. The amount of the palladium catalyst may be that conventionally used in such reactions in the art, for example the molar ratio of the palladium catalyst to the compound of formula III may be 0.02 to 0.3:1 (e.g. 0.05 to 0.1: 1).

In the method 1, the reaction temperature of the coupling reaction may be 25 to 100 ℃ (e.g., 70 ℃ to 90 ℃).

In the method 1, the progress of the coupling reaction can be monitored by conventional testing methods in the art (such as TLC, HPLC, GC or NMR), and the reaction end point is generally determined when the compound represented by the formula III is no longer reacted.

In the method 2, the conditions of the elimination reaction can be conventional in the art, and the following conditions are preferred in the present invention.

In the method 2, the elimination reaction is preferably performed under a gas (e.g., argon) shield.

In the method 2, in the elimination reaction, the organic solvent may be a sulfone solvent, such as dimethyl sulfoxide. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected. For example, the molar concentration of the compound shown in the formula III-2 in the organic solvent can be 0.01-1 mol/L.

In the method 2, in the elimination reaction, the alkali metal salt of t-butanol may be sodium t-butoxide and/or potassium t-butoxide. In one embodiment of the present invention, the alkali metal salt of tert-butanol is potassium tert-butoxide. The alkali metal tert-butoxide may be used in amounts customary in the art for such reactions, for example the molar ratio of the alkali metal tert-butoxide to the compound of formula III-2 may be from 2.2 to 3.2:1 (e.g. from 3 to 3.2: 1).

In the elimination reaction in the method 2, the amount of water used may be an amount conventionally used in such reactions in the art, for example, the molar ratio of the water to the compound represented by the formula III-2 may be 10 to 100:1 (e.g., 30 to 40: 1).

In the method 2, the reaction temperature of the elimination reaction may be 25 to 100 ℃ (e.g., 60 ℃ to 80 ℃).

In the method 2, the progress of the elimination reaction can be monitored by a conventional test method in the art (such as TLC, HPLC, GC or NMR), and the reaction end point is generally determined when the compound represented by the formula III-2 is not reacted any more.

The method isThe method 1 can further comprise the following steps: in an organic solvent, mixing a compound shown as IV and R¹Carrying out addition reaction on MgX as shown in the specification to obtain a compound shown in a formula III; wherein X is chlorine, bromine or iodine, R¹、R³A, b, and&is as defined above;

in the method 1, the conditions of the addition reaction can be conventional in the art, and the following conditions are preferred in the present invention.

In the method 1, the addition reaction is preferably performed under a gas (e.g., argon) shield.

In the method 1, in the addition reaction, the organic solvent may be an ether solvent, such as diethyl ether.

In the method 1, the amount of the organic solvent used in the addition reaction is not particularly limited as long as the reaction is not affected. For example, the molar concentration of the compound shown in the formula IV in the organic solvent can be 0.01-1 mol/L.

In the method 1, the addition reaction is carried out with the addition of R¹The molar ratio of MgX to the compound of formula IV may be 1-2:1 (e.g., 1.5-2: 1).

In the method 1, the reaction temperature of the addition reaction may be-30 ℃ to 5 ℃ (e.g., -20 ℃ to 0 ℃).

In the method 1, the progress of the addition reaction can be monitored by conventional testing methods in the art (such as TLC, HPLC, GC or NMR), and the end point of the reaction is generally determined when the compound represented by the formula IV is no longer reacted.

The method 1 may further include the following steps: in an organic solvent, carrying out iodination reaction on a compound shown as a formula V and iodine in the presence of alkali to obtain a compound shown as a formula IV; wherein R is³Definition of (a) and (b)As described above;

in the method 1, the condition of the iodination reaction can be a conventional condition of the reaction in the field, and the following condition is preferred in the invention.

In the method 1, the iodination reaction is preferably performed under a gas (e.g., argon) shield.

In the method 1, in the iodination reaction, the organic solvent may be a mixed solvent of a nitrile solvent (e.g., acetonitrile) and a chlorinated hydrocarbon solvent (e.g., dichloromethane). In the mixed solvent, the volume ratio of the nitrile solvent to the chlorohydrocarbon solvent can be 0.8-1.2: 1. In one embodiment of the present invention, the organic solvent is a mixed solvent of acetonitrile and dichloromethane. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected. For example, the molar concentration of the compound shown in the formula V in the organic solvent can be 0.01-1 mol/L.

In the method 1, in the iodination reaction, the molar ratio of the iodine to the compound represented by the formula V can be 1-6:1 (e.g., 3-5: 1).

In the method 1, in the iodination reaction, the base may be an inorganic base, such as an alkali metal bicarbonate (e.g., sodium bicarbonate and/or potassium bicarbonate). The base may be added to the reaction system in the form of an aqueous solution. When the base is added to the reaction system in the form of an aqueous solution, the volume ratio of the aqueous solution to the organic solvent may be 1:10 to 30. In one embodiment of the invention, the base is sodium bicarbonate. In one embodiment of the present invention, the base is sodium bicarbonate, and the aqueous solution of sodium bicarbonate is added to the reaction system.

In the method 1, the reaction temperature of the iodination reaction may be 0 to 50 ℃ (e.g., 10 to 30 ℃).

In the method 1, the iodination reaction is preferably carried out in the absence of light.

In the method 1, the progress of the iodination reaction can be monitored by conventional testing methods in the art (such as TLC, HPLC, GC or NMR), and the end point of the reaction is generally determined when the compound represented by the formula V is no longer reacted.

The method 2 may further include the following steps: in an organic solvent, a compound shown as V and R¹MgX is subjected to addition reaction as shown in the specification to obtain a compound shown in a formula III-2; wherein X is chlorine, bromine or iodine, R¹、R³A, b, and&is as defined above;

in the method 2, the conditions of the addition reaction can be conventional in the field, and the following conditions are preferred in the invention.

In the method 2, the addition reaction is preferably performed under a gas (e.g., argon) shield.

In the method 2, in the addition reaction, the organic solvent may be an ether solvent, such as diethyl ether.

In the method 2, in the addition reaction, the amount of the organic solvent used may not be particularly limited as long as the reaction is not affected. For example, the molar concentration of the compound shown in the formula V in the organic solvent can be 0.01-1 mol/L.

In the method 2, the addition reaction is carried out with the addition of R¹The molar ratio of MgX to the compound shown as V may be from 1 to 2:1 (e.g., from 1.5 to 2: 1).

In the method 2, the reaction temperature of the addition reaction may be-30 ℃ to 5 ℃ (e.g., -20 ℃ to 0 ℃).

In the method 2, the progress of the addition reaction can be monitored by conventional testing methods in the art (such as TLC, HPLC, GC or NMR), and the end point of the reaction is generally determined when the compound represented by the formula V is no longer reacted.

The method 1 or the method 2 can further comprise the following steps: in an organic solvent, carrying out cyclization reaction on a compound shown as a formula VI and a cobalt carbonyl reagent in a carbon monoxide atmosphere to obtain a compound shown as a formula V;

wherein R is³And are as defined above.

The conditions for the ring-closure reaction may be conventional in the art, and the following conditions are preferred in the present invention.

The cyclization reaction is preferably carried out under a gas (e.g., argon) blanket.

In the cyclization reaction, the organic solvent may be an aromatic hydrocarbon solvent, such as toluene. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected. For example, the molar concentration of the compound shown in the formula VI in the organic solvent can be 0.01-1 mol/L.

In the cyclization reaction, the cobalt carbonyl reagent can be BrCCo₃(CO)₉. The molar ratio of the cobalt carbonyl reagent to the compound of formula VI can be from 0.05 to 0.2:1 (e.g., from 0.1 to 0.2: 1).

In the cyclization reaction, the pressure of the carbon monoxide may be 10 to 30atm (e.g., 20 to 30 atm).

The reaction temperature of the cyclization reaction may be from 50 ℃ to 130 ℃ (e.g., from 90 ℃ to 120 ℃).

The progress of the ring closure reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, GC or NMR), and is generally determined as the end point of the reaction when the compound of formula VI is no longer reacted.

The method 1 or the method 2 can further comprise the following steps: reacting a compound shown as a formula VII with tert-butyl lithium in an organic solvent, and then reacting with trimethylchlorosilane in the presence of hexamethylphosphoric triamide to obtain a compound shown as a formula VI;

wherein R is³And are as defined above.

In the above-mentioned preparation method of the compound represented by the formula VI, each reaction condition may be a conventional condition of the same type of reaction in the art, and the following conditions are preferred in the present invention.

In the above-mentioned process for preparing the compound represented by the formula VI, each reaction is preferably carried out under a gas (e.g., argon) shield.

In the above method for preparing the compound represented by the formula VI, the organic solvent may be an ether solvent, such as tetrahydrofuran. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected. For example, the molar concentration of the compound shown in the formula VII in the organic solvent can be 0.01-1 mol/L.

In the reaction of the compound shown in the formula VII and the tert-butyl lithium, the molar ratio of the tert-butyl lithium to the compound shown in the formula VII can be 3-5:1 (such as 4-5: 1). The t-butyllithium may be added to the reaction system in the form of a commercially available solution, for example, a hexane solution of t-butyllithium, a pentane solution of t-butyllithium.

In the reaction of the compound shown as the formula VII and tert-butyl lithium, the reaction temperature can be-90 to-60 ℃, such as-80 to-70 ℃.

The reaction of the compound shown as the formula VII and tert-butyl lithium is directly carried out with trimethylchlorosilane in the presence of hexamethylphosphoric triamide without post-treatment. In one embodiment of the invention, the reaction of the compound of formula VII with tert-butyllithium is carried out after 30 minutes to 3 hours (e.g. 30 minutes to 1 hour) and without work-up is reacted directly with trimethylchlorosilane in the presence of hexamethylphosphoric triamide.

The molar ratio of trimethylchlorosilane to the compound of formula VII may be 3-5:1 (e.g., 4-5: 1).

The molar ratio of hexamethylphosphoric triamide to the compound of formula VII may be 3-5:1 (e.g. 4-5: 1).

In the reaction of the trimethylchlorosilane, the reaction temperature can be 10-30 ℃.

In the preparation method of the compound shown in the formula VI, the reaction operation can be the conventional operation of the same type of reaction in the field, for example: under the protection of gas, reacting the compound shown as the formula VII and tert-butyl lithium at-90 to-60 ℃ (for example at-80 to-70 ℃) for 30 minutes to 3 hours (for example, 30 minutes to 1 hour), adding trimethylchlorosilane and hexamethyl phosphoric triamide, and naturally heating to 10-30 ℃ for reaction.

In the above-described process for the preparation of the compound of formula VI, the progress of the reaction can be monitored by conventional methods of art (e.g., TLC, HPLC, GC or NMR).

The method 1 or the method 2 can further comprise the following steps: in an organic solvent, carrying out substitution reaction on a compound shown as a formula VIII and trichloroethylene in the presence of sodium hydride as shown in the specification to obtain a compound shown as a formula VII;

wherein R is³And are as defined above.

The conditions for the substitution reaction may be conventional in the art, and the following conditions are preferred in the present invention.

The substitution reaction is preferably carried out under a gas (e.g., argon) blanket.

In the substitution reaction, the organic solvent may be a sulfone solvent, such as dimethyl sulfoxide. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected. For example, the molar concentration of the compound shown in the formula VIII in the organic solvent can be 0.01-1 mol/L.

In the substitution reaction, the molar ratio of the trichloroethylene to the compound shown in the formula VIII can be 2-8:1 (such as 4-6:1, and further such as 5: 1).

In the substitution reaction, the molar ratio of the sodium hydride to the compound shown in the formula VIII can be 3-5:1 (such as 4-5: 1).

The substitution reaction may be carried out at a temperature of from 20 ℃ to 100 ℃ (e.g., from 50 ℃ to 70 ℃).

The operation of the substitution reaction may be conventional in the art for such reactions, for example: the compound shown as the formula VIII firstly reacts with sodium hydride, and then reacts with trichloroethylene. In one embodiment of the invention, the compound shown as the formula VIII reacts with sodium hydride at the temperature of 0-30 ℃ for 30 minutes to 2 hours, and then trichloroethylene is directly added for reaction.

The progress of the substitution reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, GC, or NMR), and is generally determined as the end point of the reaction when the compound of formula VIII is no longer reacted.

The compound shown as the formula I-A, the compound shown as the formula I-B or the mixture of the compound shown as the formula I-A and the compound shown as the formula I-B, which are prepared by the preparation method of the compound shown as the formula I-A or the formula I-B, can be used for preparing the compound shown as the formula (R)_a) -Rh-K or formula (S)_a) -Rh-K.

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

wherein R is¹、R²、R³A, b, and&is as defined above.

The invention also provides a preparation method of the compound shown in the formula II, and each reaction condition is as described in the preparation method of the compound shown in the formula I-A or I-B.

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

wherein R is¹、R³A, b, and&is as defined above.

The invention also provides a preparation method of the compound shown in the formula III, and each reaction condition is as described in the preparation method of the compound shown in the formula I-A or I-B.

The invention also provides a compound shown as the formula III-2:

wherein R is¹、R³A, b, and&is as defined above.

The invention also provides a preparation method of the compound shown in the formula III-2, and each reaction condition is as described in the preparation method of the compound shown in the formula I-A or I-B.

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

wherein R is³And are as defined above.

The invention also provides a preparation method of the compound shown in the formula IV, and each reaction condition is as described in the preparation method of the compound shown in the formula I-A or I-B.

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

wherein R is³And are as defined above.

The invention also provides a preparation method of the compound shown in the formula V, and each reaction condition is as described in the preparation method of the compound shown in the formula I-A or I-B.

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

wherein R is³And are as defined above.

The invention also provides a preparation method of the compound shown in the formula VI, and each reaction condition is as described in the preparation method of the compound shown in the formula I-A or I-B.

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

wherein R is³And are as defined above.

The invention also provides a preparation method of the compound shown in the formula VII, and each reaction condition is as described in the preparation method of the compound shown in the formula I-A or I-B.

The invention also provides a compound as described above as formula (R)_a) -Rh-K or formula (S)_a) Application of a compound represented by-Rh-K as a catalyst in preparation of a compound P by performing a coupling reaction of a compound A and a compound B as shown in the specification; wherein, # denotes the axial chirality of compound P, as in formula (R)_a) When a compound represented by-Rh-K is used as a catalyst, @ denotes S_aConfiguration; when the formula is (S)_a) When a compound represented by-Rh-K is used as a catalyst, @ denotes R_aConfiguration;

the invention also provides a preparation method of the compound P, which comprises the following steps: in an organic solvent, compound A and compound B are reacted as shown in the formula (R)_a) -Rh-K or formula (S)_a) Under the catalysis of a compound represented by-Rh-K, carrying out coupling reaction shown as the following in the presence of benzoyl peroxide, copper acetate and silver carbonate to obtain a compound P;

@ denotes axial chirality of compound P, as in formula (R)_a) When a compound represented by-Rh-K is used as a catalyst, @ denotes S_aConfiguration; when the formula is (S)_a) When a compound represented by-Rh-K is used as a catalyst, @ denotes R_aConfiguration;

in the preparation method of the compound P, the conditions of the coupling reaction can be conventional in the field, and the following conditions are preferred in the invention.

In the preparation method of the compound P, the coupling reaction is preferably performed under the protection of a gas (e.g., nitrogen or argon).

In the preparation method of the compound P, the organic solvent may be an alcohol solvent, such as methanol, in the coupling reaction. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected. For example, the molar concentration of the compound A in the organic solvent may be 0.01 to 1 mol/L.

In the preparation method of the compound P, the molar ratio of the compound B to the compound a in the coupling reaction may be 1-2:1 (e.g., 1.2-1.4: 1).

In the preparation method of the compound P, in the coupling reaction, the molar ratio of the benzoyl peroxide to the compound A can be 0.01-0.5:1 (such as 0.05-0.1: 1).

In the preparation method of the compound P, the molar ratio of the copper acetate to the compound A in the coupling reaction can be 0.02-1.0:1 (such as 0.2-0.4: 1).

In the preparation method of the compound P, the molar ratio of the silver carbonate to the compound a in the coupling reaction may be 1.0-2.0:1 (e.g., 1.0-1.2: 1).

In the preparation method of the compound P, the coupling reaction is carried out in a formula shown in the specification (R)_a) -Rh-K or formula (S)_a) The molar ratio of the compound "represented by-Rh-K to the compound A may be 0.01 to 0.5:1 (e.g., 0.05 to 0.1: 1).

In the preparation method of the compound P, the reaction temperature of the coupling reaction can be 15-80 ℃ (such as 25-45 ℃).

In the preparation method of the compound P, the progress of the coupling reaction can be monitored by a conventional test method in the field (such as TLC, HPLC, GC or NMR), and the end point of the reaction is generally determined when the compound A is not reacted any more.

In the present invention, R is used_aAnd S_a(subscript a represents axis) chirality to distinguish it from the configuration of the chiral carbon atoms (R and S).

In the present invention, the term "alkyl" refers to a saturated, straight or branched chain, monovalent hydrocarbon radical having the specified number of carbon atoms, such as C₁-C₁₀Alkyl refers to alkyl groups having 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).

In the present invention, the term "alkoxy" refers to an alkyl group (alkyl as defined herein) attached to the rest of the molecule through an oxygen bridge.

In the present invention, the term "cycloalkyl" refers to a saturated monovalent cyclic hydrocarbon group having the specified number of ring carbon atoms, and the cycloalkyl group may be monocyclic or polycyclic (e.g., bicyclic and tricyclic), may be a fused, spiro and bridged ring structure. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.

In the present invention, the term "aryl" refers to any stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocycle of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthryl, or acenaphthenyl (acenaphthyl). It will be understood that where the aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, the attachment is through an aromatic ring.

In the present invention, the term "substituted" or "substituent" means that one or more hydrogen atoms are replaced by the specified group. When the position of substitution is not indicated, the substitution may be at any position, but formation of a stable or chemically feasible chemical is permissible.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and R in each case has the independent option that two R's may be the same or different. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the rhodium complex of the invention shows higher yield and enantioselectivity in the catalytic Heck coupling reaction.

Detailed Description

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

Example 1: compound (R)_a) -synthesis of K1:

step 1

Synthesis of (Ra) -VII-1: under the protection of argon, a 250mL three-necked bottle is dried and added with (R)_a) -VIII-1(17.32g,50mmol) and DMSO (200mL) were dissolved with stirring at room temperature, NaH (8.0g,4.0equiv, 60%) was added to the system, and after completion of the addition, the reaction was carried out at room temperature for 30 minutes, and then chlorotrifluoroethylene (5.0equiv) was added to the system, and after completion of the addition, the reaction was carried out at 60 ℃. TLC monitored the reaction until the starting material disappeared. After the reaction is finished, stopping heating, cooling to room temperature, and saturating NH₄Quenching reaction by Cl solution, extracting by ethyl acetate, washing by saturated sodium chloride solution, and anhydrous Na₂SO₄The organic phase was dried and the solvent removed under reduced pressure on a rotary evaporator and the residue was chromatographed on a silica gel column (PE/EtOAc. 5/1) to give the corresponding compound.

White foam, 80% yield.¹H NMR(400MHz,CDCl₃)δ7.81(d,J＝8.0Hz,2H),7.47-7.38(m,2H),7.36(s,2H),7.21-7.11(m,4H),5.18(s,2H),4.04(s,6H)；¹³CNMR(100MHz,CDCl₃) δ 151.1,141.13,141.1,132.0,128.1,126.6,126.4,126.2,124.9,124.3,108.1,95.6, 56.1; IR (film) < v >_max(cm^-1) 3104,1666,1629,1596,1503,1460,1425,1391,1363,1328,1294,1271,1243,1196,1164,1151,1119,1075,1015,983,938,902,865,831,773,744,730,636,619; calculated value of elemental analysis C₂₆H₁₈Cl₄O₄(536.23) C, 58.24; h,3.38, found C, 58.11; h,3.53.[ alpha ]]_D ²⁹-22.0(c ═ 0.20, chloroform).

Step 2

Synthesis of (Ra) -VI-1: a100 mL single-neck bottle was dried under argon and compound (R) was added_a) VII-1(2.68g,5mmol) and THF (50mL) were stirred to make the system white and turbid, and placed under a dry cold acetone bath, a dry ice acetone bath and added dropwise to the system^tBuLi (17.3mL,1.3M in hexane,4.5equiv), after the addition of dry ice, was reacted for 1 hour in an acetone bath, and then added to the systemTMSCl (1.7mL,4.0equiv) and HMPA (3.4mL,4.0equiv) were added dropwise, and the system was naturally warmed to room temperature to react. During this time TLC monitored the reaction until the starting material disappeared. After the reaction is finished, water is added for quenching the reaction, ethyl acetate is used for extraction, saturated sodium chloride solution is used for washing, and anhydrous Na₂SO₄The organic phase is dried and the solvent is removed under reduced pressure on a rotary evaporator and the residue is chromatographed on a silica gel column (PE/DCM ═ 40/1) to give the corresponding product.

White foam, 81% yield.¹H NMR(400MHz,CDCl₃)δ7.82(d,J＝8.0Hz,2H),7.47-7.42(m,2H),7.40(s,2H),7.22-7.14(m,4H),4.09(s,6H),-0.13(s,18H)；¹³C NMR(100MHz,CDCl₃) δ 149.4,143.2,132.0,128.0,126.7,126.4,126.0,124.7,122.3,108.8,105.4,56.0,37.3, 0.1; IR (film) < v >_max(cm^-1) 2958,2897,2178,1622,1597,1504,1461,1425,1393,1328,1295,1244,1198,1179,1145,1095,1011,974,928,834,748,696,635; calculated value of elemental analysis C₃₂H₃₄O₄Si₂(538.78) C, 71.34; h,6.36, found C, 71.41; h,6.34.[ alpha ]]_D ²⁹-24.5(c ═ 0.20, chloroform).

Step 3

(R_a) -synthesis of V-1: adding (R) into the high-pressure reaction kettle in sequence_a)-VI-1(1.346g,2.5mmol,1.0equiv)，BrCCo₃(CO)₉(130.2mg,0.25mmol,0.1equiv) and toluene (30mL), replacing CO gas for 3 times, finally charging CO (20atm) into the autoclave, reacting at 100 ℃ for 4 hours, cooling to room temperature after the reaction is completed, removing toluene by rotary evaporator under reduced pressure, and separating the residue by silica gel column chromatography (PE/DCE: 30/1) to obtain the corresponding product.

Yellow foam, 78% yield.¹H NMR(400MHz,CDCl₃)δ7.82(d,J＝8.0Hz,2H),7.44(t,J＝7.2Hz,2H),7.32(s,2H),7.29(d,J＝7.2Hz,2H),7.20(t,J＝7.6Hz,2H),4.01(s,6H),0.28(s,18H)；¹³C NMR(100MHz,CDCl₃) δ 203.8,172.7,151.8,142.1,132.4,126.9,126.7,126.6,126.4,126.1,124.4,114.6,107.8,55.3, -0.5; IR (film) < v >_max(cm^-1) 2954,2898,1681,1621,1592,1569,1505,1456,1425,1344,1298,1279,1242,1192,1160,1122,1081,1014,988,941,908,831,782,745,733,694,617; calculated value of elemental analysis C₃₃H₃₄O₅Si₂(566.79) C, 69.93; h,6.05. found C, 69.93; h,6.24.[ alpha ]]_D ²⁹(c ═ 0.20, chloroform).

Step 4

(R_a) Synthesis of IV-1: under the protection of argon, a 50mL single-neck bottle is filled with (R)_a) V-1(992mg,1.75mmol,1.0equiv), acetonitrile (17mL,0.1M), dichloromethane (17mL,0.1M), saturated NaHCO₃The aqueous solution (1.7mL,1.0M) was dissolved with stirring at room temperature, and I was added with stirring₂(1.77g,6.99mmol,4.0equiv), after the addition, the reaction was carried out at room temperature with exclusion of light. TLC monitored the reaction until the starting material disappeared. After the reaction is completed, Na is added₂S₂O₃Quenching the reaction with aqueous solution, extracting with DCM, washing with saturated sodium chloride solution, and adding anhydrous Na₂SO₄The organic phase was dried and the solvent was removed under reduced pressure on a rotary evaporator and the residue was chromatographed on a silica gel column (PE/DCM ═ 5/1) to give the corresponding product.

Red solid, 91% yield, m.p. ═ 207 ℃ decomposition.¹H NMR(400MHz,CDCl₃)δ7.86(d,J＝8.4Hz,2H),7.52-7.45(m,2H),7.39(s,2H),7.27(d,J＝8.4Hz,2H),7.24-7.18(m,2H),4.05(s,6H)；¹³C NMR(100MHz,CDCl₃) δ 183.5,168.8,150.7,141.4,132.7,127.1,126.9,126.5,126.5,125.3,124.8,108.2,66.6, 55.8; IR (film) < v >_max(cm^-1) 3052,2960,2932,2862,2828,2093,1715,1620,1577,1504,1457,1421,1342,1288,1245,1197,1165,1122,1080,1013,978,938,917,891,860,827,781,768,744,734,677,666,637,619; element classificationAnalysis of calculated value C₂₇H₁₆I₂O₅(674.22) C, 48.10; h,2.39, found C, 48.13; h,2.37.[ alpha ]]_D ²⁰300.0(c 0.10, chloroform).

Step 5

(R_a) -synthesis of III-1: under argon, a 50mL single-neck flask was charged with compound (R)_a) IV-1(451.7mg,0.67mmol,1.0equiv) and Et₂O (12mL), placing the system in an ice salt bath, dropwise adding MeMgI (0.33mL,1.0mmol,1.5equiv,3.0M) under the ice salt bath, placing the system in the ice salt bath for reaction for 1 hour after the addition is finished, and monitoring the reaction by TLC until the raw materials disappear and saturated NH disappears₄Quenching reaction with Cl aqueous solution, extracting with ethyl acetate, washing with saturated sodium chloride solution, and adding anhydrous Na₂SO₄The organic phase is dried and the solvent is removed under reduced pressure on a rotary evaporator and the residue is chromatographed on a silica gel column (PE/DCM ═ 4/1) to give the corresponding compound.

Light yellow foam, 94% yield.¹H NMR(400MHz,CDCl₃)δ7.83(d,J＝8.0Hz,2H),7.49-7.40(m,2H),7.35(d,J＝2.2Hz,2H),7.25(d,J＝11.2Hz,2H),7.19(d,J＝6.4Hz,2H),4.03(s,6H),1.87(s,1H),1.31(s,3H)；¹³C NMR(100MHz,CDCl₃) δ 153.4,153.1,151.13,151.0,141.9,141.6,132.4,126.85,126.8,126.5,126.47,126.4,126.3,126.1,124.4,108.0,107.9,87.0,86.9,77.5,77.2,55.5, 25.5; IR (film) < v >_max(cm^-1) 3671,2972,2902,2118,1618,1584,1503,1454,1423,1342,1304,1242,1192,1151,1103,1077,1017,974,939,908,865,832,785,727,681,635; HRMS (ESI) calculated value C₂₈H₂₁I₂O5[M+H]⁺690.9473; measured value 690.9470]_D ²⁶＝+260.7(c＝0.20,CH₂Cl₂)。

Step 6

(R_a) Synthesis of II-1: a50 mL single-neck bottle was dried under argon and added sequentially (R)_a)-III-1(849mg,1.23mmol,1.0equiv)，Pd(PPh₃)₄(71.2mg,0.062mmol,5mol％)，ZnMe₂(6.2mL,1.0M in hexane,5.0equiv) and dioxane (15mL), and after the addition, the system was placed in an oil bath at 80 ℃ for reaction. The reaction was monitored by TCL until disappearance of starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, washing with saturated aqueous sodium chloride solution, and adding anhydrous Na₂SO₄The organic phase is dried and the solvent is removed under reduced pressure on a rotary evaporator and the residue is chromatographed on a silica gel column (PE/DCM ═ 4/1) to give the corresponding compound.

Light yellow foam, 84% yield.¹H NMR(400MHz,CDCl₃)δ7.80(d,J＝7.6Hz,2H),7.43-7.37(m,2H),7.32(s,2H),7.23-7.18(m,2H),7.17-7.11(m,2H),4.01(s,3H),3.99(s,3H),1.91(s,3H),1.90(s,3H),1.25(s,3H),1.17(s,1H)；¹³C NMR(100MHz,CDCl₃) δ 151.8,151.7,144.5,144.4,143.1,143.0,132.1,127.3,127.2,126.8,126.6,126.5,126.4,125.9,124.9,124.8,124.2,107.8,107.7,77.4,77.2,55.8,55.7,21.0,6.7, 6.6; IR (film) < v >_max(cm^-1) 2967,2933,2906,2851,2830,1649,1621,1596,1503,1457,1424,1381,1327,1243,1194,1163,1109,1077,1019,983,944,899,864,832,775,732,690,637,616; HRMS (ESI) calculated value C₃₀H₂₇O₅[M+H]⁺467.1853; measured value 467.1850]_D ¹⁹+173.4(c ═ 0.20, dichloromethane).

Step 7

(R_a) -I-1 and (R)_a) -synthesis of I' -1: a50 mL single-neck flask was dried under argon and THF (10mL), LiAlH was added₄(557.7mg,14.7mmol,10.0equiv), stirring in an ice-water bath, and adding AlCl₃(979.7mg,7.35mmol,5.0equiv), smoking yellow smoke, stirring in ice water bath until no smoke is produced, heating to room temperature, and adding dropwise (R) at room temperature_a) Solution of II-1(685.8mg,1.47mmol,1.0equiv) in THF (10mL) was added and the reaction was completed at 40 ℃. TLC monitored the reaction until the starting material disappeared. Carefully adding dropwise water in ice water bath to quench the reaction, adding aqueous NaOH solution (1.5mL,2.0M,2.0equiv), stirringFor 10 min, ethyl acetate extraction, washing with saturated aqueous sodium chloride solution, anhydrous Na₂SO₄The organic phase is dried and the solvent is removed under reduced pressure on a rotary evaporator and the residue is chromatographed on a silica gel column (PE/DCM ═ 4/1) to give the corresponding compound. LCMS has two peaks of the same molecular weight.

White solid, 68% yield. m.p. 138-.¹H NMR(400MHz,C₆D₆)δ7.68(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.52(d,J＝8.4Hz,2H),7.27(dd,J＝16.8,8.4Hz,2H),7.03(d,J＝5.6Hz,2H),7.01-6.93(m,2H),3.42(s,3H),3.40(s,3H),3.36(t,J＝7.6Hz,1H),2.20(s,3H),1.73(s,3H),1.25(d,J＝7.6Hz,3H)；¹³C NMR(100MHz,C₆D₆) δ 152.0,151.9,144.9,144.5,144.0,140.7,132.5,132.4,129.7,128.51,128.5,128.0,127.6,127.2,127.2,126.0,124.6,124.6,108.7,108.4,55.2,45.1,12.8,11.2, 9.9; IR (film) < v >_max(cm^-1) 2956,2923,2865,1660,1619,1597,1503,1458,1425,1385,1342,1289,1244,1216,1194,1163,1113,1020,993,949,892,863,831,775,746,680,636,620; HRMS (ESI) calculated value C₃₀H₂₇O₄[M+H]⁺451.1904; measured value 451.1902]_D ²³+128.1(c 0.20, chloroform).

Step 8

(R_a) Synthesis of Rh-K1: dry 25mL reaction tube, add (R)_a) -I-1 and (R)_a) -I' -1(144.2mg,0.32mmol,1.0equiv), THF (3mL,0.1M), dissolved with stirring, placed in a cryosaline bath (-15 ℃) and added dropwise under the cryosaline bathⁿBuLi (0.2mL,0.48mmol,1.5equiv,2.4M in hexane), was reacted for 30 minutes in an ice salt bath, and Et was added dropwise to the system₂AlCl (0.24mL,0.48mmol,1.5equiv,2.0M in THF), was maintained at-15 deg.C after addition and the reaction was continued for 30 minutes, followed by addition of methyl benzoylformate (78.8mg,0.48mmol,1.5equiv) dropwise to the system and continued under ice-salt bath. TLC monitored the reaction until the starting material disappeared. Adding water to quench the reaction, extracting with ethyl acetate, washing with saturated aqueous solution of sodium chlorideAnhydrous Na₂SO₄Drying and spin-drying through a silica gel column (PE/EtOAc ═ 50/1) gave the corresponding compound (containing a portion of methyl benzoylformate).

Another dry reaction tube is taken, the mixture obtained in the previous step is added under Ar, and [ Rh (cod) Cl]₂(94.7mg,0.19mmol,0.6equiv), KOH (53.8mg,0.96mmol,3.0equiv) and toluene (3mL,0.1M), and reacted at 70 ℃ for 10 to 15 minutes. Stopping reaction, cooling to room temperature, performing rotary evaporator to remove toluene under reduced pressure, and collecting the residue as neutral Al₂O₃Column separation (toluene) to obtain the target compound.

Yellow foam, 37% yield.¹H NMR(400MHz,C₆D₆)δ7.77(d,J＝8.0Hz,1H),7.62(d,J＝8.0Hz,1H),7.37(d,J＝8.4Hz,1H),7.30-7.21(m,4H),6.95(s,1H),6.94-6.85(m,2H),3.69(s,3H),3.50(t,J＝8.0Hz,2H),3.41(s,3H),3.09(t,J＝8.0Hz,2H),2.46(s,3H),2.33-2.18(m,2H),2.13-2.02(m,2H),2.03-1.90(m,4H),1.86(s,3H),1.75(s,3H)；¹³C NMR(100MHz,C₆D₆)δ152.4,151.8,146.4,145.3,132.5,132.3,128.6,128.4,127.2,127.13,127.1,127.0,126.1,126.0,125.0(d,J_Rh-C＝4.6Hz),124.6,124.5,117.2(d,J_Rh-C＝3.8Hz),108.3,108.1,86.7(d,J_Rh-C＝3.6Hz),85.8(d,J_Rh-C＝4.6Hz),85.3(d,J_Rh-C＝3.8Hz),71.1(d,J_Rh-C＝13.7Hz),70.6(d,J_Rh-C13.7Hz),55.3,55.0,33.1,32.8,9.3,9.1, 7.1; IR (film) < v >_max(cm^-1) 2918,2858,2820,1620,1597,1501,1458,1424,1377,1341,1325,1242,1210,1194,1163,1151,1112,1080,1053,1021,950,896,862,829,812,774,745,693,663,633,618; HRMS (MALDI-FT DHB) Calculation C₃₈H₃₇O₄Rh[M]⁺660.1741; measured value 660.1763]_D ²⁴-324.8(c ═ 0.20, dichloromethane).

Example 2

Prepared according to the method of example 1. Yellow foam, final yield 62%.¹H NMR(400MHz,C₆D₆)δ7.87(d,J＝8.8Hz,1H),7.80(d,J＝8.8Hz,1H),7.74(d,J＝8.0Hz,1H),7.62(t,J＝7.6Hz,2H),7.38(t,J＝7.6Hz,2H),7.32(d,J＝8.8Hz,1H),7.15-7.10(m,2H),6.96-6.87(M,2H),3.39(t,J＝8.0Hz,2H),2.95(t,J＝8.0Hz,2H),2.46-2.32(m,2H),2.19(s,3H),2.12-1.99(m,4H),1.85-1.73(m,2H),1.63(s,6H)；¹³C NMR(100MHz,C₆D₆)δ155.0,153.9,133.8,133.6,131.9,131.8,131.1,131.0,128.6,128.5,128.4,127.2,127.1,127.06,126.9,126.3(d,J_Rh-C＝4.4Hz),125.6,125.5,125.4(d,J_Rh-C＝4.5Hz),124.0,122.2,117.7(d,J_Rh-C＝3.8Hz),87.3(d,J_Rh-C＝4.6Hz),84.5(d,J_Rh-C＝4.0Hz),71.3(d,J_Rh-C＝13.8Hz),70.6(d,J_Rh-C13.8Hz),34.0,32.0,9.2,8.6, 7.4; IR (film) < v >_max(cm^-1) 3055,2986,2960,2926,2907,2864,2817,1618,1588,1504,1456,1427,1380,1362,1324,1218,1151,1071,1050,1026,997,975,939,891,867,836,818,754,737,665,629; HRMS (MALDI-FT DHB) Calculation C₃₆H₃₃O₂Rh[M]⁺600.1530; measured value 600.1545]_D ²⁸-121.2(c ═ 0.20, dichloromethane).

Example 3

Prepared according to the method of example 1. Yellow foam, final yield 37%. HRMS (MALDI-FT DHB) Calculation C₄₀H₄₁O₄Rh[M]⁺688.2060; measured value 688.2062]_D ²⁴-330.8(c ═ 0.20, dichloromethane).

Example 4

Prepared according to the method of example 1. Yellow foam, and the final yield was 39%. HRMS (MALDI-FT DHB) Calculation C₄₈H₄₁O₄Rh[M]⁺784.2060; measured value 784.2061]_D ²⁴-340.8(c ═ 0.20, dichloromethane).

Example 5

Prepared according to the method of example 1. Yellow foam, final yield 35%. HRMS (MALDI-FT DHB) Calculation C₅₀H₄₅O₄Rh[M]⁺812.2373; measured value 812.2376]_D ²⁴-335.8(c ═ 0.20, dichloromethane).

Example 6

Prepared according to the method of example 1. Yellow foam, 31% yield in the last step. HRMS (MALDI-FT DHB) Calculation C₄₈H₄₁O₂Rh[M]⁺752.2162; measured value 752.2163]_D ²⁴-331.8(c ═ 0.20, dichloromethane).

Example 7

A process according to example 1, wherein in step 6 ZnMe is reacted₂The substitution was EtZnCl. Yellow foam, final yield 37%. HRMS (MALDI-FT DHB) Calculation C₄₀H₄₁O₄Rh[M]⁺688.2060; measured value 688.2065]_D ²⁴-315.8(c 0.20, dichloromethane).

Example 8

A process according to example 1, wherein in step 6 ZnMe is reacted₂Replacement by PhB (OH)₂. Yellow foam, and the final yield was 33%. HRMS (MALDI-FT DHB) Calculation C₄₈H₄₁O₄Rh[M]⁺784.2060; measured value 784.2063]_D ²⁴-355.8(c 0.20, dichloromethane).

Example 9

The method of example 1 was followed, wherein MeMgI was replaced with PhMgBr in step 5. Yellow foam, 31% yield in the last step. HRMS (MALDI-FT DHB) Calculation C₄₃H₃₉O₄Rh[M]⁺722.1903; measured value 722.1905]_D ²⁴-332.8(c 0.20, dichloromethane).

Example 10

Step 1

(R_a) Preparation of III-2: the procedure as in step 5 of example 1, mixing (R)_a) Replacement of-IV-1 by (R)_a) -V-1. Yield 85%. HRMS (MALDI-FT DHB) Calculations C₃₄H₃₈O₅Si₂，[M]⁺582.2258; found 582.2253.

Step 2

(R_a) Preparation of II-2: under argon, a 50mL single-neck flask was charged with compound (R)_a) III-2(512mg,1.0mmol,1.0equiv), DMSO (11.4mL), and H was added with stirring at room temperature₂O(0.6mL)，^tBuOK (359mg,3.2mmol,3.2equiv), placing the system in oil bath at 70 ℃ for reaction after the addition is finished, monitoring the reaction by TLC until the raw materials disappear, cooling the system to room temperature, extracting with ethyl acetate/water, washing with saturated sodium chloride solution, and removing anhydrous Na₂SO₄The organic phase was dried and the solvent was removed under reduced pressure on a rotary evaporator and the residue was chromatographed on a silica gel column (PE/EtOAc. 5/1) to give the corresponding compound. Yield 80%. HRMS (MALDI-FTDHB) calculated value C₂₈H₂₂O₅，[M]⁺438.1467; found 438.1464.

Step 3

(R_a) Preparation of I-2: the procedure as in step 7 of example 1, mixing (R)_a) -II-1 is replaced by (R)_a) -II-2. Yield 75%. HRMS (MALDI-FT DHB) Calculations C₂₈H₂₂O₄，[M]⁺422.1518; found 422.1516.

Step 4

Prepared according to the method of step 8 of example 1. Will (R)_a)-I-1，(R_a) -I' 1 is replaced by (R)_a) -I-2. Yellow bubble, 32% yield. HRMS (MALDI-FT DHB) Calculation C₃₆H₃₃O₄Rh[M]⁺632.1434; measured value 632.1436]_D ²⁴-341.4(c 0.20, dichloromethane).

Example 11

The synthesis according to example 10, wherein MeMgI is replaced by PhMgCl in step 1. Yellow foam, 31% yield in the last step. HRMS (MALDI-FT DHB) Calculation C₄₁H₃₅O₄Rh[M]⁺694.1590; measured value 694.1593]_D ²⁴-331.2(c ═ 0.20, dichloromethane).

Example 12

By using (S)_a) -VIII-1 substitution (R)_a) VIII-1 Synthesis of (S) according to example 1_a) -K1, yellow foam, final yield 36%. HRMS (MALDI-FT DHB) Calculation C₃₈H₃₇O₄Rh[M]⁺660.1741; measured value 660.1763]_D ²⁴325.8(c 0.20, dichloromethane).

Effect example 1 (references angelw. chem. int.ed.2014,53,13244. j.am. chem. soc.2016,138,5242)

General reaction operation: the catalyst (0.01mmol) and benzoyl peroxide (2.4mg,0.01mmol) were dissolved in methanol (0.5mL) under nitrogen and reacted at room temperature for 30 min. Then, A (0.2mmol), B (0.24mmol), copper acetate (7.3mg,0.04mmol) and Ag were added in this order₂CO₃(55.2mg,0.2mmol) and methanol (0.5mL) at 25 ℃. After completion of the TLC tracing reaction, it was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure, and purified by column chromatography (petroleum ether/acetone-30/1). The ee value of product P was determined by HPLC.

Catalyst (R)_a) Results of Rh-K1: yield 95%.¹H NMR(400MHz,CDCl₃) δ 8.94(d, J ═ 4.8Hz,1H),8.11-8.04(m,2H),8.01-7.73(m,5H),7.67-7.52(m,5H),7.42-7.32(m,4H),7.24(s,1H),7.21-7.13(m,1H),7.13-6.93(m,3H),6.77(d, J ═ 16.4Hz, 1H). HPLC conditions: chiral column Daicel Chiralcel AD-H (0.46 cm. times.25 cm), n-hexane/isopropanol 90/10(V/V), flow rate 1.0mL/min, detection wavelength 254nm, t (minor) 20.96min, t (major) 46.04min],96:4er；[α]_D ²²+560.1(c 0.22, chloroform).

TABLE 1 results of the experiment

Claims

1. As shown in formula (R)_a) -Rh-K or formula (S)_a) -Rh-K:

wherein R is¹And R^1aEach independently is H, C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, or substituted or unsubstituted C₆-C₁₂An aryl group;

R²and R^2aEach independently is H, C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, or substituted or unsubstituted C₆-C₁₂An aryl group;

R³and R^3aEach independently is H, C₁-C₈Alkyl radical, C₁-C₈Alkoxy, substituted or unsubstituted C₃-C₈Cycloalkyl, substituted or unsubstituted C₆-C₁₂Aryl, substituted or unsubstituted C₆-C₁₂Aryloxy, or substituted or unsubstituted-O- (C)₁-C₃Alkyl group) - (C₆-C₁₂Aryl groups);

2. The compound of claim 1, wherein: at R¹、R²、R³、R^1a、R^2aAnd R^3aIn (b), the C₁-C₈Alkyl is independently C₁-C₄An alkyl group;

and/or, at R¹、R²、R³、R^1a、R^2aAnd R^3aIn (b), the C₃-C₈Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

and/or, at R¹、R²、R³、R^1a、R^2aAnd R^3aIn (b), the C₆-C₁₂Aryl, substituted or unsubstituted C₆-C₁₂C in aryloxy₆-C₁₂Aryl and-O- (C)₁-C₃Alkyl group) - (C₆-C₁₂C in aryl)₆-C₁₂Each aryl is independently phenyl or naphthyl;

and/or, at R³And R^3aIn (b), the C₁-C₈Alkoxy is independently C₁-C₄An alkoxy group.

3. The compound of claim 1, wherein: at R¹、R²、R³、R^1a、R^2aAnd R^3aIn (b), the C₁-C₈Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;

and/or, at R¹、R²、R³、R^1a、R^2aAnd R^3aIn (b), the C₆-C₁₂Aryl, substituted or unsubstituted C₆-C₁₂C in aryloxy₆-C₁₂Aryl and-O- (C)₁-C₃Alkyl group) - (C₆-C₁₂C in aryl)₆-C₁₂Each aryl group is independently phenyl;

and/or, at R³And R^3aIn (b), the C₁-C₈Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

4. The compound of claim 1, wherein: at R¹、R²、R³、R^1a、R^2aAnd R^3aIn (b), the C₁-C₈Alkyl is independently methyl or ethyl.

5. The compound of claim 1, wherein: r¹Is C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, or substituted or unsubstituted C₆-C₁₂An aryl group;

and/or, R^1aIs C₁-C₈Alkyl, substituted or unsubstituted C₃-C₈Cycloalkyl, or substituted or unsubstituted C₆-C₁₂An aryl group;

and/or, R²Is H or C₁-C₈An alkyl group;

and/or, R^2aIs H or C₁-C₈An alkyl group;

and/or, R³Is C₁-C₈An alkoxy group;

and/or, R^3aIs C₁-C₈An alkoxy group.

6. The compound of claim 1, wherein: r¹Is C₁-C₈An alkyl group;

and/or, R^1aIs C₁-C₈An alkyl group.

7. The compound of claim 1, wherein: as shown in formula (R)_a) The compounds of-Rh-K are

And/or, said formula is (S)_a) The compounds of-Rh-K are

8. A compound represented by formula I-A or I-B,

wherein R is¹、R²And R³As defined in any one of claims 1 to 7;

9. The compound of claim 8, having formula I-a or I-B, wherein: the compound shown as the formula I-A is

And/or the compound shown as the formula I-B is

10. A process for the preparation of a compound of formula I-a or I-B as claimed in claim 8 or 9, comprising the steps of: in an organic solvent, carrying out a reduction reaction shown as the following on a compound shown as a formula II in the presence of lithium aluminum hydride to obtain a compound shown as a formula I-A and/or I-B; wherein R is¹、R²、R³A, b, and&as defined in claim 8;

11. the method of claim 10, wherein: the reduction reaction is carried out under the protection of gas;

and/or, in the reduction reaction, the organic solvent is an ether solvent;

and/or the molar ratio of the lithium aluminum hydride to the compound shown in the formula II is 5-20: 1;

and/or, the reduction reaction is carried out in the presence of a lewis acid;

and/or the reaction temperature of the reduction reaction is 10-70 ℃.

12. The method of claim 10, wherein: in the reduction reaction, the organic solvent is tetrahydrofuran;

and/or the molar ratio of the lithium aluminum hydride to the compound shown in the formula II is 8-12: 1;

and/or the reduction reaction is carried out in the presence of Lewis acid, wherein the Lewis acid is aluminum trichloride;

and/or the reaction temperature of the reduction reaction is 30-50 ℃.

13. The method of claim 10, wherein: the reduction reaction is carried out in the presence of Lewis acid; the molar ratio of the Lewis acid to the compound shown as the formula II is 1-10: 1.

14. The method of claim 10, wherein: the reduction reaction is carried out in the presence of Lewis acid; the molar ratio of the Lewis acid to the compound shown as the formula II is 4-6: 1.

15. The method of claim 10, wherein: the preparation method of the compound shown in the formula II is method 1 or method 2:

the method 1 comprises the following steps: in an organic solvent, reacting a compound shown as a formula III withCarrying out coupling reaction as shown in the specification on an organic zinc reagent or an organic boron reagent in the presence of a palladium catalyst to obtain a compound as shown in a formula II; wherein the organic zinc reagent is Zn (R)²)₂Or ZnR²Y and Y are chlorine, bromine or iodine; the organic boron reagent is R²B(OH)₂；

The method 2 comprises the following steps: in an organic solvent, carrying out an elimination reaction shown in the following formula on a compound shown in a formula III-2 in the presence of tert-butyl alcohol alkali metal salt and water to obtain a compound shown in a formula II; wherein, in the method 2, R²Is hydrogen;

16. the method of claim 15, wherein: in the method 1, the preparation method of the compound shown as the formula III comprises the following steps: in an organic solvent, mixing a compound shown as IV and R¹Carrying out addition reaction on MgX as shown in the specification to obtain a compound shown in a formula III; wherein X is chlorine, bromine or iodine;

17. the method of claim 16, wherein: in the method 1, the preparation method of the compound shown as IV comprises the following steps: in an organic solvent, carrying out iodination reaction on a compound shown as a formula V and iodine in the presence of alkali to obtain a compound shown as a formula IV;

18. the method of claim 15, wherein: in the method 2, the preparation method of the compound shown as the formula III-2 comprises the following steps: in an organic solvent, a compound shown as V and R¹MgX is subjected to addition reaction as shown in the specification to obtain a compound shown in a formula III-2; wherein X is chlorine, bromine or iodine;

19. the method of claim 17 or 18, wherein: in the method 1 or the method 2, the preparation method of the compound shown as the formula V comprises the following steps: in an organic solvent, carrying out cyclization reaction on a compound shown as a formula VI and a cobalt carbonyl reagent in a carbon monoxide atmosphere to obtain a compound shown as a formula V;

20. the method of claim 19, wherein: in the method 1 or the method 2, the preparation method of the compound shown as the formula VI comprises the following steps: reacting a compound shown as a formula VII with tert-butyl lithium in an organic solvent, and then reacting with trimethylchlorosilane in the presence of hexamethylphosphoric triamide to obtain a compound shown as a formula VI;

21. the method of claim 20, wherein: in the method 1 or the method 2, the preparation method of the compound shown as the formula VII comprises the following steps: in an organic solvent, carrying out substitution reaction on a compound shown as a formula VIII and trichloroethylene in the presence of sodium hydride as shown in the specification to obtain a compound shown as a formula VII;

22. the method of claim 15, wherein: in the method 1, the coupling reaction is carried out under the protection of gas;

and/or, in the method 1, in the coupling reaction, the organic solvent is an ether solvent;

and/or, in the method 1, when R is²When the compound is alkyl, an organic zinc reagent is adopted to react with the compound shown in the formula III;

and/or, in the method 1, when R is²When the aryl is aryl, reacting an organic boron reagent with a compound shown as a formula III;

and/or, in the method 1, in the coupling reaction, the molar ratio of the organic zinc reagent to the compound shown in the formula III is 2-8: 1;

and/or, in the method 1, in the coupling reaction, the molar ratio of the organoboron reagent to the compound shown in the formula III is 2-8: 1;

and/or, in the method 1, in the coupling reaction, the palladium catalyst is tetrakis (triphenylphosphine) palladium;

and/or, in the method 1, in the coupling reaction, the molar ratio of the palladium catalyst to the compound shown in the formula III is 0.02-0.3: 1;

and/or, in the method 1, the reaction temperature of the coupling reaction is 25-100 ℃; and/or, in the method 2, the elimination reaction is carried out under the protection of gas;

and/or in the method 2, in the elimination reaction, the organic solvent is a sulfone solvent;

and/or, in the method 2, in the elimination reaction, the tert-butyl alcohol alkali metal salt is sodium tert-butoxide and/or potassium tert-butoxide;

and/or, in the method 2, in the elimination reaction, the molar ratio of the tert-butanol alkali metal salt to the compound shown in the formula III-2 is 2.2-3.2: 1;

and/or, in the method 2, in the elimination reaction, the molar ratio of the water to the compound shown in the formula III-2 is 10-100: 1;

and/or, in the method 2, the reaction temperature of the elimination reaction is 25-100 ℃.

23. The method of claim 15, wherein: in the method 1, in the coupling reaction, the organic solvent is dioxane;

and/or, in the method 1, in the coupling reaction, the molar ratio of the organic zinc reagent to the compound shown in the formula III is 4-6: 1;

and/or, in the method 1, in the coupling reaction, the molar ratio of the organoboron reagent to the compound shown in the formula III is 4-6: 1;

and/or, in the method 1, in the coupling reaction, the molar ratio of the palladium catalyst to the compound shown in the formula III is 0.05-0.1: 1;

and/or, in the method 1, the reaction temperature of the coupling reaction is 70-90 ℃;

and/or, in the method 2, in the elimination reaction, the organic solvent is dimethyl sulfoxide;

and/or, in the method 2, in the elimination reaction, the molar ratio of the tert-butanol alkali metal salt to the compound shown in the formula III-2 is 3-3.2: 1;

and/or, in the method 2, in the elimination reaction, the molar ratio of the water to the compound shown in the formula III-2 is 30-40: 1;

and/or, in the method 2, the reaction temperature of the elimination reaction is 60-80 ℃.

24. The method of claim 16, wherein: in the method 1, the addition reaction is carried out under the protection of gas;

and/or, in the method 1, in the addition reaction, the organic solvent is an ether solvent;

and/or, in the method 1, in the addition reaction, the R¹The molar ratio of MgX to the compound shown as IV is 1-2: 1;

and/or, in the method 1, the reaction temperature of the addition reaction is-30 ℃ to 5 ℃.

25. The method of claim 16, wherein: in the method 1, in the addition reaction, the organic solvent is diethyl ether;

and/or, in the method 1, in the addition reaction, the R¹The molar ratio of MgX to the compound shown as IV is 1.5-2: 1;

and/or, in the method 1, the reaction temperature of the addition reaction is-20 ℃ to 0 ℃.

26. The method of claim 17, wherein: in the method 1, the iodination reaction is carried out under the protection of gas;

and/or, in the method 1, in the iodination reaction, the organic solvent is a mixed solvent of a nitrile solvent and a chlorinated hydrocarbon solvent;

and/or in the method 1, in the iodination reaction, the molar ratio of the iodine to the compound shown in the formula V is 1-6: 1;

and/or, in the method 1, in the iodination reaction, the base is an inorganic base;

and/or, in the method 1, the reaction temperature of the iodination reaction is 0-50 ℃.

27. The method of claim 17, wherein: in the iodination reaction, the organic solvent is a mixed solvent of a nitrile solvent and a chlorohydrocarbon solvent; wherein the volume ratio of the nitrile solvent to the chlorohydrocarbon solvent is 0.8-1.2: 1;

in the method 1, in the iodination reaction, the molar ratio of iodine to the compound shown in the formula V is 3-5: 1;

and/or, in the method 1, in the iodination reaction, the base is an alkali metal bicarbonate;

and/or, in the method 1, the reaction temperature of the iodination reaction is 10-30 ℃.

28. The method of claim 17, wherein: in the method 1, in the iodination reaction, the alkali is sodium bicarbonate and/or potassium bicarbonate.

29. The method of claim 18, wherein: in the method 2, the addition reaction is carried out under the protection of gas;

and/or, in the method 2, in the addition reaction, the organic solvent is an ether solvent;

and/or, in the method 2, in the addition reaction, the R¹The molar ratio of MgX to the compound shown as V is 1-2: 1;

and/or, in the method 2, the reaction temperature of the addition reaction is-30 ℃ to 5 ℃.

30. The method of claim 18, wherein: in the method 2, in the addition reaction, the organic solvent is diethyl ether;

and/or, in the method 2, in the addition reaction, the R¹The molar ratio of MgX to the compound shown as V is 1.5-2: 1;

and/or, in the method 2, the reaction temperature of the addition reaction is-20 ℃ to 0 ℃.

31. The method of claim 19, wherein: in the method 1 or the method 2, the cyclization reaction is carried out under the protection of gas;

and/or, in the method 1 or the method 2, in the cyclization reaction, the organic solvent is an aromatic hydrocarbon solvent;

and/or, in the method 1 or the method 2, in the cyclization reaction, the cobalt carbonyl reagent is BrCCo in the cyclization reaction₃(CO)₉；

And/or, in the method 1 or the method 2, in the cyclization reaction, the molar ratio of the cobalt carbonyl reagent to the compound shown in the formula VI is 0.05-0.2: 1;

and/or, in the method 1 or the method 2, the pressure of the carbon monoxide in the cyclization reaction is 10-30 atm;

and/or, in the method 1 or the method 2, the reaction temperature of the cyclization reaction is 50-130 ℃.

32. The method of claim 19, wherein: in the method 1 or 2, in the cyclization reaction, the organic solvent is toluene;

and/or, in the method 1 or the method 2, in the cyclization reaction, the molar ratio of the cobalt carbonyl reagent to the compound shown in the formula VI is 0.1-0.2: 1;

and/or, in the method 1 or the method 2, the pressure of the carbon monoxide in the cyclization reaction is 20-30 atm;

and/or, in the method 1 or the method 2, the reaction temperature of the cyclization reaction is 90-120 ℃.

33. The method of claim 20, wherein: in the method 1 or the method 2, in the preparation method of the compound shown in the formula VI, the organic solvent is an ether solvent;

and/or in the method 1 or the method 2, in the preparation method of the compound shown in the formula VI, the molar ratio of tert-butyl lithium to the compound shown in the formula VII is 3-5: 1;

and/or in the method 1 or the method 2, in the preparation method of the compound shown in the formula VI, the molar ratio of the trimethylchlorosilane to the compound shown in the formula VII is 3-5: 1;

and/or in the method 1 or the method 2, in the preparation method of the compound shown in the formula VI, the molar ratio of hexamethylphosphoric triamide to the compound shown in the formula VII is 3-5: 1.

34. The method of claim 20, wherein: in the method 1 or the method 2, in the preparation method of the compound shown in the formula VI, the organic solvent is tetrahydrofuran;

and/or in the method 1 or the method 2, in the preparation method of the compound shown in the formula VI, the molar ratio of tert-butyl lithium to the compound shown in the formula VII is 4-5: 1;

and/or in the method 1 or the method 2, in the preparation method of the compound shown in the formula VI, the molar ratio of the trimethylchlorosilane to the compound shown in the formula VII is 4-5: 1;

and/or in the method 1 or the method 2, in the preparation method of the compound shown in the formula VI, the molar ratio of hexamethylphosphoric triamide to the compound shown in the formula VII is 4-5: 1.

35. The method of claim 21, wherein: in the method 1 or the method 2, the substitution reaction is carried out under the protection of gas;

and/or in the method 1 or the method 2, in the substitution reaction, the organic solvent is a sulfone solvent;

and/or, in the method 1 or the method 2, in the substitution reaction, the molar ratio of the trichloroethylene to the compound shown in the formula VIII is 2-8: 1;

and/or, in the method 1 or the method 2, in the substitution reaction, the molar ratio of the sodium hydride to the compound shown in the formula VIII is 3-5: 1;

and/or, in the method 1 or the method 2, the reaction temperature of the substitution reaction is 20-100 ℃.

36. The method of claim 21, wherein: in the method 1 or 2, in the substitution reaction, the organic solvent is dimethyl sulfoxide;

and/or, in the method 1 or the method 2, in the substitution reaction, the molar ratio of the trichloroethylene to the compound shown in the formula VIII is 4-6: 1;

and/or, in the method 1 or the method 2, in the substitution reaction, the molar ratio of the sodium hydride to the compound shown in the formula VIII is 4-5: 1;

and/or, in the method 1 or the method 2, the reaction temperature of the substitution reaction is 50-70 ℃.