阅读说明：本技术 一种棉酚、其衍生物的制备方法及其中间体 (Preparation method and intermediate of gossypol and derivative thereof ) 是由 汤文军 杨贺 于 2019-04-30 设计创作，主要内容包括：本发明公开了一种棉酚、其衍生物的制备方法及其中间体。本发明的制备方法包括如下步骤：在溶剂中,在碱、钯催化剂和手性配体的作用下,将化合物6和双硼试剂进行如下所示的偶联反应得到化合物(+)-7即可；所述的手性配体结构如式L1所示。本发明的制备方法简洁,操作简单,适用于工业化生产。<Image he="416" wi="700" file="DDA0002047842250000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a preparation method and an intermediate of gossypol and derivatives thereof. The preparation method comprises the following steps: in a solvent, under the action of alkali, a palladium catalyst and a chiral ligand, carrying out coupling reaction on a compound 6 and a diboron reagent as shown in the specification to obtain a compound (+) -7; the chiral ligand structure is shown as a formula L1. The preparation method is simple, simple to operate and suitable for industrial production.)

1. A process for the preparation of compound (+) -7 comprising the steps of: in a solvent, under the action of alkali, a palladium catalyst and a chiral ligand, carrying out coupling reaction on a compound 6 and a diboron reagent as shown in the specification to obtain a compound (+) -7; the chiral ligand is

Wherein R is C₁～C₄Alkyl group of (A) or (B),

2. The method according to claim 1, wherein the reaction mixture,

In R, the C₁～C₄The alkyl group of (a) is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;

and/or said n is 0, 1,2, 3, 4 or 5, preferably 0, 1,2 or 3;

and/or R is

3. The production method according to claim 1 or 2,

the solvent is an organic solvent or a mixed solvent of the organic solvent and water; the organic solvent is preferably one or more of aromatic hydrocarbon solvents, ether solvents and halogenated hydrocarbon solvents; the aromatic hydrocarbon solvent is preferably toluene; the ether solvent is preferably tetrahydrofuran; the halogenated hydrocarbon solvent is preferably 1, 2-dichloroethane;

and/or the volume mol ratio of the solvent to the compound 6 is 1L/mol to 15L/mol, preferably 2L/mol to 10L/mol;

and/or, the alkali is inorganic alkali; the inorganic base is preferably one or more of hydroxide, phosphate and carbonate of alkali metal; the hydroxide of the alkali metal is preferably sodium hydroxide and/or potassium hydroxide; the alkali metal phosphate is preferably potassium phosphate and/or sodium phosphate, more preferably potassium phosphate; the carbonate of the alkali metal is preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate;

And/or the molar ratio of the alkali to the compound 6 is 1.0-6.0;

and/or, the palladium catalyst is Pd (OAc)₂、Pd(dba)₂And Pd₂(dba)₃One or more of;

and/or the molar ratio of the palladium catalyst to the compound 6 is 0.01-1;

and/or the molar ratio of the chiral ligand to the compound 6 is 0.01-1;

and/or, the diboron reagent is

and/or the molar ratio of the diboron reagent to the compound 6 is 0.5-0.8;

and/or the reaction temperature of the coupling reaction is 50-100 ℃, preferably 60-70 ℃.

4. The method of any one of claims 1 to 3, further comprising the steps of: in a solvent, under the action of an inorganic base, the compound 5 and an alkylating reagent RX are subjected to the following reaction to obtain a compound 6:

wherein X is Br, Cl or I; r is as defined in claim 1 or 2;

in the method for producing compound 6, the solvent is preferably a nitrile solvent and/or an amide solvent; the nitrile solvent is preferably acetonitrile or propionitrile; the amide solvent is preferably N, N-dimethylformamide or N, N-dimethylacetamide;

In the preparation method of the compound 6, the volume molar ratio of the organic solvent to the compound 5 is preferably 1L/mol to 20L/mol, more preferably 5L/mol to 10L/mol;

in the preparation method of the compound 6, the inorganic base is preferably one or more of alkali metal carbonate, alkali metal hydroxide, alkali metal phosphate and alkali metal hydride; the carbonate of the alkali metal is preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate, and more preferably potassium carbonate; the hydroxide of the alkali metal is preferably sodium hydroxide and/or potassium hydroxide; the alkali metal phosphate is preferably sodium phosphate and/or potassium phosphate; the hydride of the alkali metal is preferably sodium hydride and/or potassium hydride;

in the preparation method of the compound 6, the molar ratio of the inorganic base to the compound 5 is preferably 1.0-2.0;

in the preparation method of the compound 6, the molar ratio of the alkylating agent RX to the compound 5 is preferably 1.0-5.0, and preferably 1.0-1.5;

in the method for producing compound 6, the reaction temperature in the reaction is preferably 10 to 100 ℃, more preferably 20 to 80 ℃.

5. The method of claim 4, further comprising the steps of: in a solvent, in the presence of an initiator, a brominating agent and an oxidizing agent, carrying out the following reaction on a compound 4 to obtain a compound 5; the oxidant is N-methylmorpholine-N-oxide;

Wherein R is¹Is composed of

In the method for producing the compound 5, the solvent is preferably a nitrile solvent or a haloalkane solvent; the nitrile solvent is preferably acetonitrile and/or propionitrile; the acetonitrile is preferably ultra-dry acetonitrile; the halogenated alkane solvent is preferably carbon tetrachloride;

in the preparation method of the compound 5, the volume molar ratio of the solvent to the compound 4 is preferably 1L/mol-15L/mol, and more preferably 2L/mol-5L/mol;

in the preparation method of the compound 5, the initiator is preferably AIBN and/or dibenzoyl peroxide;

and/or in the preparation method of the compound 5, the molar ratio of the initiator to the compound 4 is preferably 0.05-0.2;

in the preparation method of the compound 5, the brominating reagent is preferably N-bromosuccinimide or dibromohydantoin;

in the preparation method of the compound 5, the molar ratio of the brominating agent to the compound 4 is preferably 1:1-1.5: 1;

in the preparation method of the compound 5, the molar ratio of the oxidant to the compound 4 is preferably 2:1-10: 1;

in the preparation method of the compound 5, the reaction temperature is preferably 60 ℃ to 90 ℃.

6. The method of claim 5, further comprising the steps of: (a) in a solvent, the compound 3 and a reducing agent are subjected to the following reaction to obtain a compound 3 a; (b) reacting the compound 3a obtained in step (a) with an acylating agent R ¹Y is reacted as shown below to obtain a compound 4;

wherein R is¹As defined in claim 5; y is Cl or Br;

in step (a), the solvent is preferably a halogenated alkane solvent; the halogenated alkane solvent is preferably one or more of dichloromethane, chloroform and 1, 2-dichloroethane;

in the step (a), the volume mol ratio of the solvent to the compound 3 is preferably 1L/mol to 10L/mol, and more preferably 1L/mol to 5L/mol;

in step (a), the reducing agent is preferably a combination of boron trifluoride diethyl etherate and triethylsilane; in the composition, the molar ratio of boron trifluoride diethyl etherate to triethylsilane is preferably 1: 1-1: 10;

in the step (a), the molar ratio of the triethylsilane to the compound 3 is preferably 1.0-10.0;

in step (a), the reaction temperature of the reaction is preferably room temperature;

preferably, step (a) is carried out directly after completion of the reaction without post-treatment;

in step (b), the solvent and the amount are preferably the same as those in step (a);

in step (b), the acylating agent R¹The mol ratio of X to the compound 3 is preferably 1.0-10.0;

in step (b), the acylating agent R ¹The temperature of the addition of X is preferably-5 ℃ to 5 ℃;

in step (b), the reaction temperature of the reaction is preferably room temperature.

7. The method of claim 6, further comprising the steps of: in a solvent, the compound 1 and the compound 2 are subjected to the following reaction to obtain a compound 3;

in the preparation method of the compound 3, the solvent is preferably a halogenated alkane solvent and/or an ether solvent; the halogenated alkane solvent is preferably dichloromethane or 1, 2-dichloroethane; the ether solvent is preferably tetrahydrofuran and/or 1, 4-dioxane;

in the preparation method of the compound 3, the volume mol ratio of the solvent to the compound 1 is preferably 0.5L/mol to 15L/mol, and more preferably 0.5L/mol to 10L/mol;

in the preparation method of the compound 3, the molar ratio of the compound 2 to the compound 1 is preferably 1.5-3;

in the method for producing the compound 3, the reaction temperature of the reaction is preferably 0 ℃ to 50 ℃, more preferably 15 ℃ to 30 ℃.

8. A process for the preparation of compound (+) -8 comprising the steps of: subjecting a compound (+) -7 produced by the production method according to any one of claims 1-7 to a catalytic hydrogenation reaction in a solvent under the action of hydrogen, a palladium catalyst and an acid to obtain a compound (+) -8;

Wherein R is as defined in claim 1 or 2;

in the preparation method of the compound (+) -8, the solvent is preferably one or more of an ether solvent, an alcohol solvent and an ester solvent; the ether solvent is preferably tetrahydrofuran; the ester solvent is preferably ethyl acetate; the alcohol solvent is preferably ethanol or methanol;

in the preparation method of the compound (+) -8, the volume molar ratio of the solvent to the compound (+) -7 is preferably 1L/mol-20L/mol, more preferably 5L/mol-10L/mol;

in the preparation method of the compound (+) -8, the pressure of the hydrogen is preferably 1-50 atm, and more preferably 1-10 atm;

in the preparation of compound (+) -8, the palladium catalyst is preferably a Pd catalyst attached to any support, more preferably Pd/C, Pd (OH)₂C and PdCl₂Most preferably 15% by weight of Pd (OH)₂/C；

In the preparation method of the compound (+) -8, the mass ratio of the palladium catalyst to the compound (+) -7 is preferably 1: 1-1: 20;

in the preparation of compound (+) -8, the acid is preferably one or more of acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and hydrochloric acid;

In the preparation method of the compound (+) -8, the volume ratio of the acid to the solvent is preferably 1: 1-1: 20, more preferably 1: 5-1: 10;

in the process for the preparation of compound (+) -8, the reaction temperature of the reaction is preferably from 15 ℃ to 70 ℃, more preferably from 20 ℃ to 30 ℃.

9. A process for the preparation of compound (+) -9 comprising the steps of: in a solvent, under the action of alkali, the compound (+) -8 prepared by the preparation method of claim 8 and trifluoromethanesulfonic anhydride are reacted as shown in the following;

in the preparation method of the compound (+) -9, the solvent is preferably a halogenated alkane solvent and/or an ether solvent; the halogenated alkane solvent is preferably dichloromethane or 1, 2-dichloroethane; the ether solvent is preferably tetrahydrofuran and/or diethyl ether;

in the preparation method of the compound (+) -9, the volume molar ratio of the solvent to the compound (+) -8 is preferably 1L/mol to 20L/mol, and more preferably 10L/mol to 20L/mol;

in the process for the preparation of compound (+) -9, the base is preferably one or more of triethylamine, diisopropylethylamine, pyridine, 2, 6-lutidine, 4-dimethylaminopyridine, 2, 6-di-tert-butylpyridine, sodium hydride and potassium carbonate, more preferably triethylamine;

In the preparation method of the compound (+) -9, the molar ratio of the alkali to the compound (+) -8 is preferably 1-6: 1;

in the preparation method of the compound (+) -9, the molar ratio of the trifluoromethanesulfonic anhydride to the compound (+) -8 is preferably 1-6: 1.

10. A process for the preparation of compound (+) -10 comprising the steps of: in a solvent, under the action of alkali, a palladium catalyst and a phosphine ligand, carrying out a coupling reaction between a compound (+) -9 prepared by the preparation method as claimed in claim 9 and isopropylboronic acid to obtain a compound (+) -10; the phosphine ligand is

in the preparation method of the compound (+) -10, the solvent is preferably one or more of aromatic hydrocarbon solvents, amide solvents, halogenated hydrocarbon solvents and sulfone solvents; the aromatic hydrocarbon solvent is preferably toluene; the amide solvent is preferably N, N-dimethylformamide; the halogenated hydrocarbon solvent is preferably 1, 2-dichloroethane; the sulfone solvent is preferably dimethyl sulfoxide;

in the preparation method of the compound (+) -10, the volume molar ratio of the solvent to the compound (+) -9 is preferably 10L/mol to 30L/mol, more preferably 15L/mol to 25L/mol;

In the preparation of compound (+) -10, the base is preferably an inorganic base; the inorganic base is preferably one or more of hydroxide, phosphate and carbonate of alkali metal; the alkali metal hydroxide is preferably strong sodium oxide and/or potassium hydroxide, the alkali metal phosphate is preferably potassium phosphate and/or sodium phosphate, more preferably potassium phosphate, the alkali metal carbonate is preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate, and when the alkali is potassium phosphate, the potassium phosphate can be a hydrate thereof;

in the preparation method of the compound (+) -10, the molar ratio of the alkali to the compound (+) -10 is preferably 1.0-6.0;

in the preparation method of the compound (+) -10, the palladium catalyst is preferably Pd (OAc)₂、Pd(dba)₂、Pd₂(dba)₃And [ Pd (cinnamyl) Cl]₂One or more of;

in the preparation method of the compound (+) -10, the molar ratio of the palladium catalyst to the compound (+) -9 is preferably 0.001-0.1;

in the preparation method of the compound (+) -10, the molar ratio of the phosphine ligand to the compound (+) -9 is preferably 0.001-0.2;

in the preparation method of the compound (+) -10, the molar ratio of the isopropylboronic acid to the compound (+) -9 is preferably 2.0-9.0;

In the process for the preparation of compound (+) -10, the reaction temperature of the reaction is preferably 80 ℃ to 150 ℃, more preferably 80 ℃ to 90 ℃.

11. A process for the preparation of compound (+) -11 comprising the steps of: reacting a compound (+) -10 produced by the production method according to claim 10 in a solvent under the action of boron tribromide to obtain a compound (+) -11;

in the preparation method of the compound (+) -11, the solvent is preferably a halogenated alkane solvent and/or an ether solvent; the halogenated alkane solvent is preferably dichloromethane or 1, 2-dichloroethane; the ether solvent is preferably tetrahydrofuran and/or diethyl ether;

in the preparation method of the compound (+) -11, the volume molar ratio of the solvent to the compound (+) -10 is preferably 10L/mol-30L/mol, more preferably 10L/mol-25L/mol;

in the preparation method of the compound (+) -11, the molar ratio of the boron tribromide to the compound (+) -10 is preferably 2-18;

in the process for the preparation of compound (+) -11, the reaction temperature of the reaction is preferably-78 ℃ to 20 ℃, more preferably-20 ℃ to 0 ℃.

12. A method for preparing (+) -gossypol is characterized by comprising the following steps: in a solvent, under the action of Lewis acid, carrying out the reaction of a compound (+) -11 prepared by the preparation method of claim 11 and 1, 1-dichloromethyl ether to obtain (+) -gossypol;

In the (+) -gossypol preparation method, the solvent is preferably a halogenated alkane solvent and/or an ether solvent; the halogenated alkane solvent is preferably dichloromethane or 1, 2-dichloroethane; the ether solvent is preferably tetrahydrofuran and/or diethyl ether;

in the (+) -gossypol preparation method, the volume molar ratio of the solvent to the compound (+) -11 is preferably 5L/mol-30L/mol, more preferably 10L/mol-25L/mol;

in the (+) -gossypol production process, the Lewis acid is preferably titanium tetrachloride or tin tetrachloride;

in the (+) -gossypol preparation method, the molar ratio of the Lewis acid to the compound (+) -11 is preferably 1-8;

in the (+) -gossypol preparation method, the molar ratio of the 1, 1-dichloromethyl ether to the compound (+) -11 is preferably 2-10;

in the (+) -gossypol preparation method, the reaction temperature of the reaction is preferably-78-20 ℃, and more preferably-20-0 ℃.

13. A process for the preparation of compound (-) -7 comprising the steps of: in a solvent, under the action of alkali, a palladium catalyst and a chiral ligand, carrying out a coupling reaction between a compound 6 and a diboron reagent as shown in the specification to obtain a compound (-) -7;

The chiral ligand is

wherein R is as defined in claim 1 or 2.

14. A process for the preparation of the compound (-) -8, comprising the steps of: carrying out catalytic hydrogenation reaction on the (-) -7 compound prepared by the preparation method of any one of claims 1-7 in a solvent under the action of hydrogen and a palladium catalyst to obtain a (-) -8 compound; the reaction method under the same conditions as those in the production method according to claim 8;

wherein R is as defined in claim 1 or 2.

15. A process for the preparation of the compound (-) -9, comprising the steps of: in a solvent, under the action of a base, carrying out the reaction of the compound (-) -8 prepared according to the claim 14 and trifluoromethanesulfonic anhydride as shown in the following; the reaction method under the same conditions as the production method according to claim 9;

16. a process for the preparation of the compound (-) -10, comprising the steps of: in solutionIn the preparation, under the action of alkali, a palladium catalyst and a phosphine ligand, a compound (-) -9 prepared according to claim 15 and isopropylboronic acid are subjected to coupling reaction as shown in the specification to obtain a compound (-) -10; the phosphine ligand is

17. a process for the preparation of the compound (-) -11, comprising the steps of: in a solvent, under the action of boron tribromide, carrying out the reaction of the compound (-) -10 prepared according to claim 16 to obtain a compound (-) -11; the reaction method under the same conditions as those in the production method according to claim 11;

18. a preparation method of (-) -gossypol is characterized by comprising the following steps: reacting (-) -11, prepared according to claim 17, with 1, 1-dichloromethyl methyl ether in a solvent under the action of a lewis acid to obtain (-) -gossypol; the reaction method under the same conditions as those in the production method according to claim 12;

19. the preparation method of the compound (+/-) -8 is characterized by comprising the following steps: in a solvent, under the action of alkali, a palladium catalyst and a ligand, carrying out coupling reaction on a compound 3a and a diboron reagent as shown in the specification to obtain a compound (+/-) -8; the reaction method except the ligand is the same as the method for preparing the compound (+) -7 of any one of claims 1-3;

20. A method for preparing (+/-) -gossypol is characterized by comprising the following steps: in a solvent, carrying out the reaction shown as the following on the compound (+/-) -8 prepared by the preparation method of claim 19; the conditions in the method of the reaction are the same as those in the production method of any one of claims 9 to 12;

21. compounds 3,3a,4a,5,6, (+) -7, (-) -7, (+) -8, (-) -8, (±) -8, (+) -9, (-) -9, (±) -9:

wherein R is as defined in claim 1 or 2.

22. A process for the preparation of compound 4, wherein the reaction is carried out under the conditions as defined in claim 6;

Technical Field

The invention relates to a preparation method of gossypol and derivatives thereof and intermediates thereof.

Background

Gossypol (gossypol) is a natural product of polyphenol hydroxy dinaphthalene aldehyde. This compound was first isolated from cottonseed oil by two scientists, Longmore and Marchlewski, at the end of the 19 th century (j.chem.ind. (London)1886,5, 200-206; j.prakt.chem.,1899,60, 84-94). Gossypol is found mainly in the roots, stems, leaves and seeds of cotton, and is present in the highest amount in the cottonseed kernels. Gossypol was first used as a male contraceptive in china (chinese. med. j. (Engl.)1978,4, 417-. With the intensive research on the biological activity, it is found that gossypol and the derivatives thereof have various biological activities, including antiparasitic, anticancer, antiviral and anti-infectious activities (Future Med. chem.,2017,9, 1243-.

The presence of the ortho-tetra-substituted biaryl structure in gossypol provides a certain energy barrier for rotation along the carbon-carbon bond of the binaphthyl group, and thus the molecule has axial chirality. Gossypol isolated from cotton is often a mixture of the two enantiomers (+) - (S) -gossypol and (-) - (R) -gossypol. The ratio of the two gossypol enantiomers also differs in different cotton species or in different parts of cotton. There is also some difference in biological activity between (+) -gossypol, (-) -gossypol and mixtures thereof, for example, the racemate of gossypol has an anti-fertility activity, whereas (+) -gossypol is not found (Ann. Rev. Pharmacol. Toxicol.,1984,24, 329) -360; int. J. Androl. supplement 1982,5, 53-70); (-) -gossypol or cottonseed oil containing a high proportion of (-) -gossypol has the activity of inhibiting the proliferation of mammary gland fat cells, thereby having the potential of resisting breast cancer and preventing obesity (Anticancer Res.,2013,33, 949-one 956); additional studies have shown that (-) -gossypol can interfere with pro-angiogenic factor release from cancer cells at the mRNA and protein levels, and thus inhibit tumor angiogenesis (mol. cancer ther.,2011,10, 795-. Due to the differences in biological activity of the two gossypol enantiomers, it is important to develop methods that yield a single gossypol enantiomer of high optical purity.

The currently reported and commonly used method for obtaining a single gossypol enantiomer of high optical purity is chemical resolution. The method generates corresponding Schiff base by the action of a cotton phenol racemate and a chiral resolution reagent (usually chiral amino acid), then obtains a single stereoisomer by a high performance liquid chromatography or recrystallization method, and obtains a single cotton phenol enantiomer with high optical purity by removing the resolution reagent. The limitation of this approach is the use of equivalent chiral resolving reagents, which undoubtedly increases the cost of the overall process; meanwhile, the acquisition of the gossypol racemate is a restriction factor of the scale of the method. In comparison, it is more promising to use cheap and easily available raw materials to obtain a single gossypol enantiomer with high optical purity by a chemical preparation method. So far, only one example of the asymmetric preparation method to obtain a single gossypol enantiomer with high optical purity has been reported, namely asymmetric complete preparation of gossypol by using Ullmann coupling reaction involving chiral prosthetic group substrates as a key step in Meyers project group (chem.Commun, 1997,16, 1573-1574; Tetrahedron 1998,54, 10493-10511). The use of chiral auxiliary groups increases the cost of production; meanwhile, the introduction and removal of the chiral auxiliary group also make the preparation route not concise and practical. Therefore, the development of a simple and high-efficiency chemical preparation method for obtaining the single gossypol enantiomer with high optical purity is of great significance. Meanwhile, the research on the chemical preparation of gossypol has mainly focused on the preparation of gossypol racemates (Future Med. chem.,2017,9, 1243-. However, the steps for preparing the gossypol racemate reported at present are relatively complicated, and a short preparation route which is easy to industrialize needs to be developed urgently.

Disclosure of Invention

The invention provides a preparation method of gossypol and derivatives thereof and an intermediate thereof, aiming at the defects of high cost, complicated preparation steps and the like of the preparation method of gossypol and derivatives thereof in the prior art. The preparation method provided by the invention can obtain the single gossypol enantiomer with high optical purity by only 10 steps from cheap and easily-obtained raw materials, and compared with the currently reported preparation method (20 steps of reaction), the preparation method disclosed by the invention is simpler and more efficient. Meanwhile, the invention also provides a short method for chemically preparing the gossypol racemate. Compared with the chemical preparation method (14 steps) of the gossypol racemate reported at present, the preparation route of the gossypol racemate provided by the invention is simpler and more efficient, and has practicability. The preparation method is simple, is easy to operate and is suitable for industrial production.

The invention provides a preparation method of a compound (+) -7, which comprises the following steps: in a solvent, under the action of alkali, a palladium catalyst and a chiral ligand, carrying out coupling reaction on a compound 6 and a diboron reagent as shown in the specification to obtain a compound (+) -7; the chiral ligand is

Wherein R is C₁～C₄Alkyl group of (A) or (B),n is 0 to 5.

In R, the C₁～C₄The alkyl group of (a) is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group.

Said n may be 0, 1,2, 3, 4 or 5, preferably 0, 1,2 or 3.

R is preferably

More preferably

The solvent may be a conventional solvent in the art for performing such a reaction, and is preferably an organic solvent or a mixed solvent of an organic solvent and water. The organic solvent is preferably one or more of aromatic hydrocarbon solvents, ether solvents and halogenated hydrocarbon solvents. The aromatic hydrocarbon solvent is preferably toluene. The ether solvent is preferably tetrahydrofuran. The halogenated hydrocarbon solvent is preferably 1, 2-dichloroethane. The amount of the solvent to be used is not particularly limited as long as it does not affect the reaction, and is preferably 1L/mol to 15L/mol, more preferably 2L/mol to 10L/mol, for example, 7.84L/mol, in terms of the volume mol ratio to the compound 6.

The base may be conventional bases used in the art to carry out such reactions, preferably inorganic bases. The inorganic base is preferably one or more of hydroxides, phosphates and carbonates of alkali metals. The hydroxide of the alkali metal is preferably sodium hydroxide and/or potassium hydroxide. The alkali metal phosphate is preferably potassium phosphate and/or sodium phosphate, more preferably potassium phosphate. The carbonate of the alkali metal is preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate. The amount of the base may be an amount conventionally used in carrying out such a reaction in the art, and is preferably 1.0 to 6.0, for example, 3.0 in terms of a molar ratio to the compound 6.

The palladium catalyst may be a conventional palladium catalyst in the art for carrying out such reactions, preferably Pd (OAc)₂、Pd(dba)₂And Pd₂(dba)₃More preferably Pd₂(dba)₃. The palladium catalyst can be used in an amount conventionally used for carrying out such a reaction, and is preferably used in a molar ratio of 0.01 to 1, for example, 0.05, to the compound 6.

The chiral ligand can be used in an amount which is conventional in the art for carrying out such a reaction, and is preferably used in a molar ratio of 0.01 to 1, for example, 0.1, to the compound 6.

The bisboron reagent may be a conventional bisboron reagent used in the art to carry out such reactions, and is preferably one that is conventional in the art And more preferably one or more ofThe amount of the diboron reagent can be conventional in the art, and preferably the molar ratio of the diboron reagent to the compound 6 is 0.5-0.8, for example, 0.6.

The reaction temperature of the coupling reaction may be a temperature conventional in the art for carrying out such reactions, preferably from 50 ℃ to 100 ℃, more preferably from 60 ℃ to 70 ℃, for example: at 60 ℃.

The preferred compound (+) -7 is prepared by a process comprising the steps of: mixing the compound 6, a diboron reagent, alkali, a solvent, the palladium catalyst and a chiral ligand, deoxidizing, and carrying out the reaction. More preferably the following steps: and mixing the compound 6, a bisboron reagent and alkali, deoxidizing, and mixing with a solvent, the palladium catalyst and a chiral ligand in sequence. The mixing is preferably carried out under gas protection.

The progress of the coupling reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC, or NMR), typically with the disappearance of compound 6 as the end point of the reaction. The reaction time is preferably 10 to 20 hours, for example, 15 hours.

The reaction may also include a post-treatment, which may be conventional for such reactions, and the present invention preferably comprises the steps of: after the reaction is finished, cooling to room temperature, adding water, extracting by using an organic solvent, combining organic phases, drying, concentrating, and purifying by column chromatography to obtain a compound (+) -7.

The preparation method of the compound (+) -7 can further comprise the following steps: in a solvent, under the action of an inorganic base, the compound 5 and an alkylating reagent RX are subjected to the following reaction to obtain a compound 6:

wherein X is Br, Cl or I; r is as defined above.

Said X is preferably Br.

In the preparation method of the compound 6, the reaction can be performed according to the conventional method of the reaction in the field, and the invention is particularly preferably as follows;

in the production method of compound 6, the solvent is preferably a nitrile solvent and/or an amide solvent. The nitrile solvent is preferably acetonitrile or propionitrile. The amide solvent is preferably N, N-dimethylformamide or N, N-dimethylacetamide. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected. It is preferably from 1L/mol to 20L/mol, more preferably from 5L/mol to 10L/mol, for example 1.2L/mol, in comparison with the volume mol of the compound 5.

In the preparation method of the compound 6, the inorganic base is preferably one or more of an alkali metal carbonate, an alkali metal hydroxide, an alkali metal phosphate and an alkali metal hydride. The carbonate of the alkali metal is preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate, and more preferably potassium carbonate. The hydroxide of the alkali metal is preferably sodium hydroxide and/or potassium hydroxide. The alkali metal phosphate is preferably sodium phosphate and/or potassium phosphate. The alkali metal hydride is preferably sodium hydride and/or potassium hydride. The inorganic base may be used in an amount conventionally used in the art for carrying out such a reaction, and preferably, it is used in a molar ratio of 1.0 to 2.0, for example, 1.2, to the compound 5.

In the preparation method of the compound 6, the molar ratio of the alkylating agent RX to the compound 5 is preferably 1.0 to 5.0, more preferably 1.0 to 1.5, for example, 1.4.

In the preparation method of compound 6, the reaction temperature of the reaction may be a temperature conventional in the art for performing such a reaction, preferably 10 to 100 ℃, more preferably 20 to 80 ℃, for example: at 60 ℃.

In the preparation of compound 6, the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), and the end point of the reaction is generally determined when compound 5 disappears. The reaction time is preferably 5 to 20 hours, more preferably 6 to 8 hours, for example, 15 hours.

In the preparation method of compound 6, the reaction may further include a post-treatment, and the post-treatment method may be a conventional post-treatment method for such a reaction, and the present invention preferably comprises the steps of: after the reaction is finished, adding water and an organic solvent, layering, extracting the water phase by using the organic solvent, combining the organic phases, drying, concentrating, and purifying by column chromatography to obtain the compound 6.

The preparation method of the compound 6 can further comprise the following steps: in a solvent, in the presence of an initiator, a brominating agent and an oxidizing agent, carrying out the following reaction on a compound 4 to obtain a compound 5; the oxidant is N-methylmorpholine-N-oxide;

wherein R is¹Is composed of

In the preparation method of the compound 5, the reaction can be performed according to the conventional method of the reaction in the field, and the invention particularly preferably comprises the following steps:

in the method for producing compound 5, the solvent is preferably a nitrile solvent or a haloalkane solvent. The nitrile solvent is preferably acetonitrile and/or propionitrile. The acetonitrile is preferably ultra-dry acetonitrile. The halogenated alkane solvent is preferably carbon tetrachloride. The volume molar ratio of the solvent to the compound 4 is preferably 1L/mol to 10L/mol, more preferably 1L/mol to 5L/mol, for example, 1.2L/mol.

In the process for the preparation of compound 5, the initiator is preferably AIBN and/or dibenzoyl peroxide, e.g., AIBN. The molar ratio of the initiator to the compound 4 is preferably 0.05 to 0.2, for example, 0.1.

In the preparation method of the compound 5, the brominating reagent is preferably N-bromosuccinimide or dibromohydantoin. The molar ratio of the brominating agent to the compound 4 is preferably 1:1-1.5:1, more preferably 1.06: 1.

In the preparation method of the compound 5, the oxidant is preferably N-methylmorpholine-N-oxide.

In the preparation method of the compound 5, the molar ratio of the oxidizing agent to the compound 4 is preferably 2:1 to 10:1, for example, 4: 1.

In the process for producing compound 5, the reaction temperature is preferably 60 ℃ to 90 ℃, for example, 80 ℃.

The preferred preparation method of compound 5 comprises the following steps: AIBN is added into a solution formed by the compound 4, a brominating agent and a solvent, and bromination is carried out at the reaction temperature until the compound 4 disappears. Then adding oxidant to carry out oxidation reaction until the product of bromination reaction disappears.

In the preparation of compound 5, the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), and the end point of the reaction is generally determined when compound 4 disappears. The reaction time is preferably 15 to 25 hours, for example, 20 hours.

In the preparation method of the compound 5, the reaction may further include a post-treatment, and the post-treatment method may be a conventional post-treatment method for such a reaction, and the present invention preferably comprises the steps of: after completion of the reaction, dilute hydrochloric acid (e.g., 3N hydrochloric acid solution) and an organic solvent are added, the layers are separated, the aqueous phase is extracted with an organic solvent, the organic phases are combined, dried, and concentrated to give compound 5.

The preparation method of the compound 5 can further comprise the following steps: (a) in a solvent, the compound 3 and a reducing agent are subjected to the following reaction to obtain a compound 3 a; (b) the reaction of step (a) does not require any work-up, and is reacted with an acylating agent R¹Reacting Y to obtain a compound 4;

wherein R is¹As defined above; y is Cl or Br.

In the preparation method of the compound 4, the reaction can be performed according to the conventional method of the reaction in the field, and the invention particularly preferably comprises the following steps:

in step (a), the solvent is preferably a haloalkane solvent. The haloalkane solvent is preferably one or more of dichloromethane, chloroform and 1, 2-dichloroethane, more preferably dichloromethane, for example, dried dichloromethane. The volume molar ratio of the solvent to the compound 3 is preferably 1L/mol to 10L/mol, more preferably 1L/mol to 5L/mol, for example, 1.6L/mol.

In step (a), the reducing agent is preferably a combination of boron trifluoride diethyl etherate and triethylsilane. In the composition, the molar ratio of boron trifluoride diethyl etherate to triethylsilane is preferably 1:1 to 1:10, for example, 1: 1. The molar ratio of the triethylsilane to the compound 3 is preferably 1.0-10.0, for example, 2.0.

In step (a), the reaction temperature of the reaction is preferably room temperature.

In step (a), the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and the end point of the reaction is generally determined when compound 3 disappears. The reaction time is preferably 5 to 20 hours, for example, 15 hours.

In step (b), the solvent and the amount are preferably the same as in step (a).

In step (b), the acylating agent R¹The molar ratio of X to the compound 3 is preferably 1.0 to 10.0, for example, 2.0.

In step (b), the acylating agent R¹The temperature of addition of X is preferably from-5 ℃ to 5 ℃, for example, 0 ℃.

In step (b), the reaction temperature of the reaction is preferably room temperature.

In step (b), the progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC or NMR), and the end point of the reaction is generally determined when the compound 3a disappears. The reaction time is preferably 5 to 20 hours, for example, 6 hours.

In step (b), the reaction may further comprise a post-treatment, and the post-treatment may be a conventional post-treatment for such a reaction, and the present invention preferably comprises the steps of: after the reaction is finished, adding water, layering, extracting a water phase by using an organic solvent, combining organic phases, drying, concentrating, and purifying by column chromatography to obtain a compound 4.

The preferred preparation method of compound 4 comprises the following steps: reacting the compound 3 with a reducing agent until the compound 3 disappears to obtain a reaction solution, and reacting the reaction solution with an acylating reagent R¹And mixing Y to obtain a compound 4. The mixing is preferably carried out with acylating agent R¹Y is added to the reaction solution. The temperature of said addition is preferably between-5 ℃ and 5 ℃, for example 0 ℃.

The preparation method of the compound 4 further comprises the following steps: in a solvent, the compound 1 and the compound 2 are subjected to the following reaction to obtain a compound 3;

in the preparation method of the compound 3, the reaction can be performed according to the conventional method of the reaction in the field, and the invention particularly preferably comprises the following steps:

in the preparation method of the compound 3, the solvent is preferably a halogenated alkane solvent and/or an ether solvent. The halogenated alkane solvent is preferably dichloromethane or 1, 2-dichloroethane. The ether solvent is preferably tetrahydrofuran and/or 1, 4-dioxane. The volume molar ratio of the solvent to the compound 1 is preferably 0.5L/mol to 15L/mol, more preferably 0.5L/mol to 10L/mol, for example, 0.9L/mol.

In the preparation method of the compound 3, the molar ratio of the compound 2 to the compound 1 is preferably 1.5-3, for example, 2.0.

In the method for producing compound 3, the reaction temperature of the reaction is preferably 0 ℃ to 50 ℃, more preferably 15 ℃ to 30 ℃, for example, room temperature.

In the preparation of compound 3, the progress of the reaction can be monitored by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and the end point of the reaction is generally determined when compound 1 disappears. The reaction time is preferably 10 to 20 hours, for example, 20 hours.

In the preparation method of the compound 3, the reaction may further include a post-treatment, and the post-treatment method may be a conventional post-treatment method for such a reaction, and the present invention preferably comprises the steps of: after the reaction is finished, adding glacial acetic acid, stirring, concentrating under reduced pressure, and purifying by column chromatography to obtain a compound 3.

The invention also provides a preparation method of the compound (+) -8, which comprises the following steps: in a solvent, under the action of hydrogen, a palladium catalyst and acid, carrying out catalytic hydrogenation reaction on the compound (+) -7 as shown in the specification to obtain a compound (+) -8;

wherein R is as defined above;

In the preparation of compound (+) -8, compound (+) -7d is prepared as described above.

In the preparation of compound (+) -8, said reaction can be referred to the conventional methods of this type of reaction in the art, and the present invention particularly preferably comprises the following:

in the preparation method of the compound (+) -8, the solvent is preferably one or more of an ether solvent, an alcohol solvent and an ester solvent. The ether solvent is preferably tetrahydrofuran. The ester solvent is preferably ethyl acetate. The alcohol solvent is preferably ethanol or methanol. The molar ratio of the solvent to the compound (+) -7 is preferably 1L/mol to 20L/mol, more preferably 5L/mol to 10L/mol, e.g. 10L/mol.

In the method for preparing the compound (+) -8, the pressure of the hydrogen gas is preferably 1 to 50atm, more preferably 1 to 10atm, for example, 1 atm.

In the preparation of compound (+) -8, the palladium catalyst can be any supported Pd catalyst, preferably Pd/C, Pd (OH)₂C and PdCl₂More preferably 15% by mass of Pd (OH)₂and/C. The mass ratio of the catalyst to the compound (+) -7 is preferably 1:1 to 1:20, for example, 1: 4.9.

In the process for the preparation of compound (+) -8, the acid is preferably one or more of acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and various concentrations of hydrochloric acid, more preferably acetic acid. The volume ratio of the acid to the solvent is preferably 1: 1-1: 20, and more preferably 1: 5-1: 10.

In the process for the preparation of compound (+) -8, the reaction temperature of the reaction is preferably from 15 ℃ to 70 ℃, more preferably from 20 ℃ to 30 ℃.

In the preparation of compound (+) -8, the progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC or NMR), and the end point of the reaction is generally determined as the disappearance of compound (+) -7. The reaction time is preferably 24 to 36 hours, for example, 48 hours.

In the preparation of compound (+) -8, the reaction may further comprise a work-up which may be a conventional work-up for such reactions, the present invention preferably comprises the steps of: after the reaction is finished, filtering, concentrating the filtrate, and purifying by column chromatography to obtain a compound (+) -8.

The invention also provides a preparation method of the compound (+) -9, which comprises the following steps: in a solvent, under the action of alkali, a compound (+) -8 and trifluoromethanesulfonic anhydride are subjected to a reaction shown in the following formula;

In the preparation of compound (+) -9, compound (+) -8 is prepared as described above.

In the preparation of compound (+) -9, said reaction can be referred to the conventional methods of this type of reaction in the art, and the present invention particularly preferably comprises the following:

the solvent is preferably a halogenated alkane solvent and/or an ether solvent. The haloalkane solvent is preferably dichloromethane or 1, 2-dichloroethane. The ether solvent is preferably tetrahydrofuran and/or diethyl ether. The molar ratio of the solvent to the compound (+) -8 is preferably 1L/mol to 20L/mol, more preferably 10L/mol to 20L/mol, for example 15.7L/mol.

The base is preferably one or more of triethylamine, diisopropylethylamine, pyridine, 2, 6-lutidine, 4-dimethylaminopyridine, 2, 6-di-tert-butylpyridine, sodium hydride and potassium carbonate, preferably triethylamine. The molar ratio of the base to compound (+) -8 is preferably 1-6: 1, e.g., 3: 1.

the molar ratio of the trifluoromethanesulfonic anhydride to the compound (+) -8 is preferably 1-6: 1, e.g., 2.5: 1.

the preferred compound (+) -9 is prepared by a process comprising the steps of: the compound (+) -8 and the base are added dropwise to a solution of the compound with the solvent at-5 ℃ to react at this temperature for 1 to 2 hours, and then the reaction is carried out at room temperature.

In the preparation of compound (+) -9, the progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC, or NMR), typically with the disappearance of compound (+) -8 as the end point of the reaction. The reaction time is preferably 6 to 15 hours, for example, 11 hours.

In the process for the preparation of compound (+) -9, said reaction may also comprise a work-up which may be a conventional work-up for such reactions, the invention preferably comprises the following steps: after the reaction is finished, quenching the reaction, extracting the water phase by using an organic solvent, combining the organic phases, drying, concentrating the organic phase, and purifying by column chromatography to obtain a compound (+) -9.

A process for the preparation of compound (+) -10 comprising the steps of: in a solvent, under the action of alkali, a palladium catalyst and a phosphine ligand, carrying out a coupling reaction shown as the following on a compound (+) -9 and isopropylboronic acid to obtain a compound (+) -10; the phosphine ligand isOne or more of the enantiomers;

in the preparation of compound (+) -10, compound (+) -9 is prepared as described above.

In the preparation of compound (+) -10, said reaction can be referred to the conventional methods of this type of reaction in the art, and the present invention particularly preferably comprises the following:

In the preparation method of the compound (+) -10, the solvent is preferably one or more of aromatic hydrocarbon solvents, amide solvents, halogenated hydrocarbon solvents and sulfone solvents. The aromatic hydrocarbon solvent is preferably toluene. The amide solvent is preferably N, N-dimethylformamide. The halogenated hydrocarbon solvent is preferably 1, 2-dichloroethane. The sulfone solvent is preferably dimethyl sulfoxide. The volume molar ratio of the solvent to the compound (+) -9 is preferably 10L/mol to 30L/mol, more preferably 15L/mol to 25L/mol, for example 20L/mol.

In the preparation of compound (+) -10, the base is preferably an inorganic base. The inorganic base is preferably one or more of hydroxides, phosphates and carbonates of alkali metals. The alkali metal hydroxide is preferably strong sodium oxide and/or potassium hydroxide. The alkali metal phosphate is preferably potassium phosphate and/or sodium phosphate, more preferably potassium phosphate. The carbonate of the alkali metal is preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate. When the base is potassium phosphate, the potassium phosphate may be a hydrate thereof. The amount of base may be that conventionally used in the art for such reactions, and preferably is in a molar ratio of 1.0 to 6.0, e.g., 6.0, to compound (+) -10.

In the preparation method of the compound (+) -10, the palladium catalyst is preferably Pd (OAc)₂、Pd(dba)₂、Pd₂(dba)₃And [ Pd (cinnamyl) Cl]₂More preferably Pd₂(dba)₃. The molar ratio of the palladium catalyst to the compound (+) -9 is 0.001-0.1, for example, 0.02.

In the preparation method of the compound (+) -10, the molar ratio of the phosphine ligand to the compound (+) -9 is 0.001-0.2, for example, 0.04.

In the preparation method of the compound (+) -10, the molar ratio of the isopropylboronic acid to the compound (+) -9 is 2.0-9.0, for example, 6.0.

In the process for the preparation of compound (+) -10, the reaction temperature of said reaction may be the temperature conventional in the art for carrying out such reactions, preferably from 80 ℃ to 150 ℃, more preferably from 80 ℃ to 90 ℃, for example: 80 ℃.

Among the processes for the preparation of compound (+) -10, the preferred process for the preparation of compound (+) -10 comprises the steps of: and (2) mixing a compound (+) -9, isopropylboronic acid, alkali, a solvent, the palladium catalyst and a phosphine ligand, deoxidizing, and carrying out the reaction. More preferably the following steps: and (2) mixing the compound (+) -9, isopropyl boric acid and alkali, deoxidizing, and mixing with a solvent, the palladium catalyst and a phosphine ligand in sequence. The mixing is preferably carried out under gas protection.

In the preparation of compound (+) -10, the progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC or NMR), and the end point of the reaction is generally determined as the disappearance of compound (+) -9. The reaction time is preferably 10 to 20 hours, for example, 15 hours.

In the preparation of compound (+) -10, the reaction may further comprise a work-up which may be a conventional work-up for such reactions, the present invention preferably comprises the steps of: after the reaction is finished, cooling to room temperature, adding water, extracting by using an organic solvent, combining organic phases, drying, concentrating, and purifying by column chromatography to obtain a compound (+) -10.

The invention also provides a preparation method of the compound (+) -11, which comprises the following steps: in a solvent, under the action of boron tribromide, carrying out the following reaction on a compound (+) -10 to obtain a compound (+) -11;

in the preparation of compound (+) -11, compound (+) -10 is prepared as described above.

In the preparation of compound (+) -11, said reaction can be referred to the conventional methods of this type of reaction in the art, and the present invention particularly preferably comprises the following:

in the preparation method of the compound (+) -11, the solvent is preferably a halogenated alkane solvent and/or an ether solvent. The haloalkane solvent is preferably dichloromethane or 1, 2-dichloroethane. The ether solvent is preferably tetrahydrofuran and/or diethyl ether. The solvent is preferably present in a molar ratio of 10L/mol to 30L/mol, more preferably 10L/mol to 25L/mol, e.g. 25L/mol, to the compound (+) -10.

In the preparation method of the compound (+) -11, the molar ratio of the boron tribromide to the compound (+) -10 is preferably 2-18, for example, 6.

Among the processes for the preparation of compound (+) -11, the preferred process for the preparation of compound (+) -11 comprises the steps of: and (2) dropwise adding boron tribromide into a solution formed by the compound (+) -10 and a solvent at the temperature of-78 ℃, maintaining the temperature, stirring for 1 hour, and then carrying out the reaction at the temperature of-78-20 ℃. The temperature rise is preferably slow.

In the process for the preparation of compound (+) -11, the reaction temperature of the reaction may be the temperature conventional in the art for carrying out such reactions, preferably-78 ℃ to 20 ℃, more preferably-20 ℃ to 0 ℃, for example: -10 ℃.

In the preparation of compound (+) -11, the progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC or NMR), and the end point of the reaction is generally determined as the disappearance of compound (+) -10. The reaction time is preferably 5 to 12 hours, for example, 8 hours.

In the preparation of compound (+) -11, the reaction may further comprise a work-up which may be a conventional work-up for such reactions, the present invention preferably comprises the steps of: after the reaction is finished, quenching the reaction by using an alcohol solvent, stirring, concentrating under reduced pressure, and purifying by column chromatography to obtain a compound (+) -11. The alcohol solvent is preferably one or more of methanol, ethanol and propanol.

The invention also provides a preparation method of (+) -gossypol, which comprises the following steps: in a solvent, under the action of Lewis acid, a compound (+) -11 and 1, 1-dichloromethyl ether are reacted as follows to obtain (+) -gossypol;

in the preparation of (+) -gossypol, compound (+) -11 is prepared as described above.

In the preparation of (+) -gossypol, said reaction can be referred to the conventional methods of this type of reaction in the art, and the present invention particularly preferably comprises the following:

in the method for preparing (+) -gossypol, the solvent is preferably a halogenated alkane solvent and/or an ether solvent. The haloalkane solvent is preferably dichloromethane or 1, 2-dichloroethane. The ether solvent is preferably tetrahydrofuran and/or diethyl ether. The volume molar ratio of the solvent to the compound (+) -11 is preferably 5L/mol to 30L/mol, more preferably 10L/mol to 25L/mol, for example 25L/mol.

In the process for the preparation of (+) -gossypol, the Lewis acid is preferably titanium tetrachloride or tin tetrachloride, e.g. titanium tetrachloride. The molar ratio of the Lewis acid to the compound (+) -11 is preferably 1-8, for example, 1.0.

In the preparation method of (+) -gossypol, the molar ratio of the 1, 1-dichloromethyl ether to the compound (+) -11 is preferably 2-10: 1, e.g., 4.0.

In the (+) -gossypol production process, the reaction temperature of the reaction is preferably-78 ℃ to 20 ℃, more preferably-20 ℃ to 0 ℃, for example: 0 ℃ or room temperature.

In the process for the preparation of (+) -gossypol, the reaction is preferably carried out under a gas blanket. The gas is preferably nitrogen.

In the preparation of (+) -gossypol, the progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC or NMR), and the end point of the reaction is generally determined as the disappearance of compound (+) -11. The reaction time is preferably 1 to 20 hours, for example, 5 hours.

In the process for the preparation of (+) -gossypol, said reaction may also comprise a post-treatment, which may be a conventional post-treatment for such reactions, the present invention preferably comprises the following steps: after the reaction is finished, quenching the reaction by using a dilute hydrochloric acid solution, extracting by using an organic solvent after stirring, combining organic phases, concentrating under reduced pressure, and purifying by column chromatography to obtain (+) -gossypol.

The invention provides a preparation method of a compound (-) -7, which comprises the following steps: in a solvent, under the action of alkali, a palladium catalyst and a chiral ligand, carrying out a coupling reaction between a compound 6 and a diboron reagent as shown in the specification to obtain a compound (-) -7; the chiral ligand is

The reaction method is the same as the method for producing the compound (+) -7 as described above except for the ligand;

wherein R is as defined above.

In the preparation of compound (-) -7, compound 6 is prepared as described above.

The invention also provides a preparation method of the compound (-) -8, which comprises the following steps: in a solvent, under the action of hydrogen and a palladium catalyst, carrying out catalytic hydrogenation reaction on a compound (-) -7 as shown in the specification to obtain a compound (-) -8; the conditions in the process of the reaction are the same as those in the process for the preparation of the compound (+) -8 described above; the compound (-) -7 is prepared as described above;

wherein R is as defined above.

The invention also provides a preparation method of the compound (-) -9, which comprises the following steps: in a solvent, under the action of alkali, the compound (-) -8 prepared as described above and trifluoromethanesulfonic anhydride are reacted as shown below; the conditions in the process of the reaction are the same as those in the process for the preparation of the compound (+) -9 described above; the compound (-) -8 is prepared as described above.

A process for the preparation of compound (-) -10 comprising the steps of: in a solvent, under the action of alkali, a palladium catalyst and a phosphine ligand, carrying out a coupling reaction between a compound (-) -9 and isopropylboronic acid as shown in the specification to obtain a compound (-) -10; the phosphine ligand is One or more of the enantiomers; the conditions in the process of the reaction are the same as those in the process for the preparation of the compound (+) -10 described above; the compound (-) -9 is prepared as described above;

the invention also provides a preparation method of the compound (-) -11, which comprises the following steps: in a solvent, under the action of boron tribromide, carrying out the following reaction on a compound (-) -10 to obtain a compound (-) -11; the conditions in the process of the reaction are the same as those in the process for the preparation of the compound (+) -11 described above; the compound (-) -10 is prepared as described above;

the invention also provides a preparation method of (-) -gossypol, which comprises the following steps: in a solvent, under the action of Lewis acid, carrying out the following reaction on a compound (-) -11 and 1, 1-dichloromethyl ether to obtain (-) -gossypol; the conditions in the process of the reaction are the same as in the process of the preparation of (+) -gossypol as described above; the compound (-) -11 is prepared as described above;

the invention also provides a preparation method of the compound (+/-) -8, which comprises the following steps: in a solvent, under the action of alkali, a palladium catalyst and a ligand, carrying out coupling reaction on a compound 3a and a diboron reagent as shown in the specification to obtain a compound (+/-) -8; the reaction method is the same as the method for producing the compound (+) -7 as described above except for the ligand;

The ligand is preferably

The invention also provides a preparation method of the compound (+/-) -9, which comprises the following steps: in a solvent, under the action of alkali, the compound (+/-) -8 and trifluoromethanesulfonic anhydride are subjected to the following reaction; the conditions in the process of the reaction are the same as those in the process for the preparation of the compound (+) -9 described above; the preparation method of the compound (+/-) -8 is the same as that described above;

the invention also provides a preparation method of the compound (+/-) -10, which comprises the following steps: in a solvent, under the action of alkali, a palladium catalyst and a phosphine ligand, carrying out coupling reaction on a compound (+/-) -9 and isopropylboronic acid as shown in the specification to obtain a compound (+/-) -10; the phosphine ligand isOne or more of the enantiomers; the conditions in the process of the reaction are the same as those in the process for the preparation of the compound (+) -10 described above; the preparation method of the compound (+/-) -9 is the same as that described above;

the invention also provides a preparation method of the compound (+/-) -11, which comprises the following steps: in a solvent, under the action of boron tribromide, carrying out the following reaction on a compound (+/-) -10 to obtain a compound (+/-) -11; the conditions in the process of the reaction are the same as those in the process for the preparation of the compound (+) -11 described above; the preparation method of the compound (+/-) -10 is the same as that described above;

The invention also provides a preparation method of the (+/-) -gossypol, which comprises the following steps: in a solvent, under the action of Lewis acid, carrying out the following reaction on a compound (+/-) -11 and 1, 1-dichloromethyl ether to obtain (+/-) -gossypol; the conditions in the process of the reaction are the same as in the process of the preparation of (+) -gossypol as described above; the preparation method of the compound (+/-) -11 is the same as that described above;

the invention provides a compound 3,3a,4a,5,6, (+) -7, (-) -7, (+) -8, (-) -8, (+ -) -9, (+ -) -9, and a structural formula as follows:

wherein R is as defined above.

Based on the disclosure, the invention also provides a preparation method of each of the compounds 3,3a,4, 5 and 6, wherein each preparation method is as described above.

The preferred method of making (+) -gossypol comprises the steps of:

the preferred preparation method of (-) -gossypol comprises the following steps:

the preferred method for preparing (±) -gossypol comprises the steps of:

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

In the present invention, the operation is carried out at room temperature unless otherwise specified. The room temperature is 0-35 ℃, preferably 20-30 ℃.

In the present invention, compound 1 can be prepared according to the methods described in Eur.J.org.chem.,2000, 1313-1317; compound 2 can be prepared according to the references angelw.chem.int.ed., 2015,54, 3792; ligands L3 and L4 can be prepared as described in the references angelw. chem. int.ed.,2015,54, 3792; org.biomol.chem.2017,15, 9903-.

The positive progress effects of the invention are as follows: the invention provides a method for preparing a single gossypol enantiomer with high optical purity by high-efficiency and high-enantioselectivity chemistry. The initial raw materials are cheap and easy to obtain, the preparation steps are short and efficient, and only 10 steps are needed from the initial raw materials to obtain the single gossypol enantiomer with high optical purity. Compared with the reported preparation method (20 steps of reaction) of a single gossypol enantiomer, the preparation method provided by the invention is simpler and more efficient. Meanwhile, the invention also provides a short method for chemically preparing the gossypol racemate. Compared with the chemical preparation method (14 steps) of the gossypol racemate reported at present, the preparation route of the gossypol racemate provided by the invention is simpler and more efficient, and has practicability. The preparation method is simple, is easy to operate and is suitable for industrial production.

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.