Phosphite ligand, chiral quaternary carbon nitrile derivative, and preparation method and application of chiral quaternary carbon nitrile derivative

Abstract

The invention relates to the technical field of organic synthetic chemistry, in particular to a phosphite ligand, a chiral quaternary carbon nitrile derivative, a preparation method and application. The structural formula of the phosphite ligand is shown in the specification, and the phosphite ligand introduces a 7, 7 '-site substituent on a binaphthol skeleton with only 3, 3'-site substituent traditionally. The structural modification can effectively change the dihedral angle of a binaphthol skeleton and enhance the overall rigidity of the binaphthol skeleton, thereby providing good space support for coordination of a ligand and a metal center and weak interaction between substituents. The phosphite ligand and a zero-valent nickel catalyst form a catalytic system to catalyze the asymmetric hydrocyanation reaction of polysubstituted olefin and hydrocyanic acid equivalent, so that the chiral quaternary carbon nitrile derivative is successfully prepared, the problems of high reaction temperature and low enantioselectivity in the prior art are solved, and the chiral quaternary carbon nitrile derivative has excellent practical value and popularization prospect.

Description

Technical Field

[0001] This invention relates to the field of organic synthetic chemistry, specifically to a phosphite ligand, a chiral quaternary carbide derivative, its preparation method, and its application. Background Technology

[0002] Chiral quaternary carbamates are a crucial class of structural units, possessing not only biocompatibility and metabolic stability, facilitating interactions between drug molecules and receptors, but also enhancing toxicological properties. They hold significant research value in pharmaceutical research and are widely found in natural products, drugs such as the COVID-19 antiviral drug remdesivir, and other biologically active molecules. Furthermore, chiral quaternary carbamates can be efficiently and conveniently converted into corresponding quaternary carbon chiral carbonyl compounds, quaternary carbon chiral amines, and quaternary carbon chiral nitrogen heterocycles, thus serving as important intermediates in organic synthesis. Therefore, developing efficient and stereoselective asymmetric synthetic methodologies for constructing chiral quaternary carbamates undoubtedly holds significant scientific importance and promising application prospects.

[0003] Asymmetric hydrocyanation of olefins is undoubtedly one of the most efficient and atom-economical methods for constructing open-chain chiral quaternary carbapenems. In 2020, Professor Fang Xianjie reported the hydrocyanation of 1,1-disubstituted styrene catalyzed by nickel and phosphite ligands to construct chiral quaternary carbapenem derivatives. However, this reaction requires a high temperature of 120°C and suffers from low enantioselectivity. The root cause is that the traditional binaphthol ligand skeleton is substituted only at the 3,3′ position, resulting in high ligand flexibility and continuous conformational drift of the chiral environment at the metal center during the catalytic cycle, leading to a decline in enantiomeric recognition ability. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a phosphite ligand, a chiral quaternary carbapenem derivative, its preparation method, and its applications. This invention provides a novel phosphite ligand with aryl substitutions at the 3,3' and 7,7' positions. Using this phosphite ligand and a zero-valent nickel catalyst as a catalytic system, it is applied to the asymmetric hydrocyanation reaction of polysubstituted alkenes with hydrogen cyanide equivalents. Under low-temperature conditions, it achieves efficient and highly enantioselective preparation of chiral quaternary carbapenem derivatives, thus overcoming the problems of high reaction temperature and low enantioselectivity in existing technologies. Compared to the traditional binaphthol skeleton with only a 3,3'-substituent, the phosphite ligand of this invention has an additional 7,7'-substituent. Through steric hindrance and electronic effects, it effectively alters the dihedral angle of the binaphthol skeleton, increasing its overall rigidity and providing good steric support for the coordination of the metal center and the weak interactions between substituents. Meanwhile, by utilizing non-covalent interactions, including C–H···π, π···π stacking and C–H···F interaction, the conformation of the ligand framework is precisely controlled, thereby crucially shaping the chiral environment around the nickel-ligand complexation center. This ensures that the chiral environment remains precise even at low temperatures, effectively overcoming the problems of high reaction temperature and low enantioselectivity in existing technologies.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The first object of the present invention is to provide a phosphite ligand having the structure shown in Formula II: .

[0006] Among them, R 1 R 5 R 8 and R 12 The radicals are independently selected from halogen, hydroxyl, mercapto, nitro, cyano, amino, C1-C8 alkyl, substituted or unsubstituted aryl, -CXOR, -CXR, -CXH, -XCXR, -CXSR, -CXNH2, -OP(OR)(OR'), OPRR', PRR', P(X)RR', P(X)(OR)(OR'), SOR or S(O)2R; wherein R and R' are independently selected from hydrogen, C1-C8 alkyl, C6-C 10 The aryl group or a 5- to 10-membered heteroaryl group; X is selected from oxygen or sulfur; the substituent of the substituted aryl group is selected from at least one of -OCF3, C1-C4 alkyl, and C1-C4 alkoxy. Wherein, R... 1 and R 12 For 3,3'-substituents, R 5 and R 8 The 33 is a 7,7'-position substituent.

[0007] R 2 R 3R 4 R 6 R 7 R 9 R 10 R 11 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 and R 24 The groups are individually selected from hydrogen, halogen, hydroxyl, mercapto, cyano, amino, or optionally from the following substituted groups: C1-C8 alkyl, C6-C6 alkyl, C7-C8 alkyl, C8-C8 alkyl, C9-C ... 10 The aryl, 5-10 nucleotide heteroaryl, silyl, -CXOR, -CXR, -CXH, -XCXR, -CXSR, -CXNH2, -OP(OR)(OR'), OPRR', PRR', P(X)RR', P(X)(OR)(OR'), SOR or S(O)2R; wherein R and R' are independently selected from C1-C8 alkyl, C6-C 10 The aryl group or a 5- to 10-membered heteroaryl group; X is selected from oxygen or sulfur.

[0008] The substituents of the aforementioned substituted groups are selected from amino groups, C1-C8 alkyl groups, and C6-C8 alkyl groups. 10 Aryl or heteroaryl compounds of 5 to 10 yuan; Preferred, or R 1 R 2 R 3 R 4 R 5 and R 6 Any two adjacent carbon atoms and their bonded carbon atoms together form a carbon atom selected from C6~C6. 10 aryl, 5-10 membered heteroaryl, C5-C8 cycloalkyl or 5-10 membered heterocyclic; or R 7 R 8 R 9 R 10 R 11 and R 12 Any two adjacent carbon atoms and their bonded carbon atoms together form a carbon atom selected from C6~C6. 10 aryl, 5-10 membered heteroaryl, C5-C8 cycloalkyl or 5-10 membered heterocyclic; or R 6 and R 12 The carbon atoms bonded to it together form a group selected from C6~C6. 10aryl, 5-10 membered heteroaryl, C5-C8 cycloalkyl or 5-10 membered heterocyclic; or R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 and R 24 Any two adjacent carbon atoms and their bonded carbon atoms together form a carbon atom selected from C6~C6. 10 aryl, 5-10 membered heteroaryl, C5-C8 cycloalkyl or 5-10 membered heterocyclic; or R 5 and R 8 Substituents are selected from R 5 -CX-R 8 R 5 -SR 8 R 5 -NX-R 8 R 5 -OR 8 Connected or not connected; or R 17 and R 20 Substituents are selected from R 17 -CX-R 20 R 17 -SR 20 R 17 -NX-R 20 R 17 -OR 20 Connected or not connected.

[0009] Wherein, the cycloalkyl or heterocyclic group is a saturated or partially unsaturated carbocyclic or heterocyclic group, and when the cycloalkyl or heterocyclic group is fused with an unsaturated or aromatic ring, it is partially unsaturated. Alkyl, R, X, amino, aryl, heteroaryl, cycloalkyl, or heterocyclic group may optionally be substituted by one or more substituents selected from hydrogen, halogen, hydroxyl, amino, C1-C8 alkyl, or 5- to 10-membered aryl.

[0010] Preferred, R 1 R 5 R 8 R 12 Each group is independently selected from Cl, Br, I, nitro, cyano, substituted or unsubstituted aryl groups.

[0011] Preferred, R 1 R 5 R 8 R12 Each aryl group is independently selected from substituted or unsubstituted aryl groups, and the substituent of the substituted aryl group is -OCF3.

[0012] Preferred, R 2 R 3 R 4 R 6 R 7 R 9 R 10 R 11 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 and R 24 Each is independently selected from hydrogen.

[0013] Preferably, the phosphite ligand is In this invention, Ar 1 Ar 2 "in "" indicates the macromolecular skeleton to which it is connected.

[0014] A second objective of this invention is to provide a method for preparing the above-mentioned phosphite ligand, comprising the following steps: S1. A multiaxially chiral (S)-7,7'-dibromo-[1,1'-binaphthyl]-2,2'-diol, denoted as (S)-A, and a first organoboronide, with SPhos as the ligand, are added to a sealed tube. Under a nitrogen atmosphere, in the presence of a palladium catalyst, toluene, and K3PO4, a Suzuki coupling reaction is carried out at 100°C for 16-24 h to obtain a 7,7'-substituted binaphthyl diol skeleton, denoted as (S)-B. The palladium catalyst is Pd(dba)2; the molar ratio of Pd(dba)2 to (S)-A is 0.02-0.2:1, the molar ratio of K3PO4 to (S)-A is 4-6:1, and the molar ratio of SPhos to (…) is… S The molar ratio of (S)-A is 0.02 to 0.2:1, and the molar ratio of the first organoboronide to (S)-A is 4 to 6:1; 15 mL of toluene is added for every 1 mmol of (S)-A. More preferably, the reaction time is 18 h.

[0015] S2. Under an ice bath at 0°C, (S)-B, a dry stir bar, and tetrahydrofuran solution were added to a three-necked flask. NaH was slowly added under nitrogen protection, and the reaction was stirred at room temperature for 2-3 hours. The flask was then placed back into an ice bath at 0°C, and chloromethyl ether was slowly added dropwise, reacting at room temperature for 2-3 hours. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction. The flask was extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a hydroxyl-protected intermediate, denoted as (S)-C. The molar ratio of NaH to (S)-B was 3-5:1, the molar ratio of chloromethyl ether to (S)-B was 3-5:1, and 20 mL of tetrahydrofuran was added for every 1 mmol of (S)-B.

[0016] S3. Add (S)-C, a dry stir bar, and tetrahydrofuran solution to a three-necked flask. Place the flask in a low-temperature stirrer under nitrogen protection. Then, add alkyl lithium dropwise to the system using a constant-pressure funnel. Stir at -78°C for 2-3 hours, then remove the flask and stir at room temperature for 2-3 hours. Next, place the three-necked flask back in the -78°C stirrer and add iodine granules in batches to the reaction solution. React at room temperature for 12-16 hours. After the reaction is complete, quench with saturated ammonium chloride solution, extract three times with ethyl acetate, collect the organic phase solution, dry it with anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography to obtain the 3,3'-iodinated intermediate, denoted as (S)-D. The molar ratio of alkyllithium to (S)-C is 3~5:1, and the alkyllithium is preferably n-BuLi with a concentration of 2.5 mol / L, stored in n-hexane; the molar ratio of iodine granules to (S)-C is 3~5:1, and 20 mL of tetrahydrofuran is added for every 1 mmol of (S)-C.

[0017] S4. In a sealed tube, add (S)-D, zero-valent palladium catalyst, K3PO4, SPhos, a second organoboride, a dry stir bar, and toluene. React under nitrogen at 100°C for 16-24 hours. After purification by silica gel column chromatography, obtain a hydroxyl-protected 3,3'- and 7,7'-substituted binaphthol skeleton, denoted as (S)-E. The palladium catalyst is Pd(dba)2; the molar ratio of Pd(dba)2 to (S)-D is 0.02-0.2:1, the molar ratio of K3PO4 to (S)-D is 4-6:1, the molar ratio of SPhos to (S)-D is 0.02-0.2:1, the molar ratio of the second organoboride to (S)-D is 4-6:1, and 15 mL of toluene is added for every 1 mmol of (S)-D.

[0018] S5. In a reflux flask, (S)-E was dissolved in a mixed solvent of dichloromethane and methanol, and 2 mol / L dilute hydrochloric acid and a stir bar were added. The mixture was refluxed for 4-5 hours. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, and the organic phase solution was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a hydroxyl-protected 3,3'- and 7,7'-substituted binaphthol skeleton, denoted as (S)-F. The volume ratio of dichloromethane to methanol in the mixed solvent was 1:1, and 15 mL of the mixed solvent was added for every 1 mmol of (S)-E.

[0019] S6. Add (S)-F, DMAP, Et3N, and a phosphoryl chloride compound to a sealed tube, then add 4 mL of tetrahydrofuran. Tighten the cap and reflux at 60°C for 10–16 h in an oil bath. After the reaction, evaporate the solvent to dryness and purify by silica gel column chromatography to obtain the phosphite ligand, denoted as II. The molar ratio of DMAP to (S)-F is 0.1–0.4:1, the molar ratio of Et3N to (S)-F is 4–8:1, and the molar ratio of the phosphoryl chloride compound to (S)-F is 3–6:1. Add 4 mL of tetrahydrofuran for every 0.3 mmol of (S)-F.

[0020] The first organoboride may be the same as or different from the second organoboride.

[0021] Preferably, the phosphoryl chloride compound is selected from diphenylphosphine chloride or ( S )-1,1′-binaphthyl-2,2′-dimethylphosphoryl chloride.

[0022] Preferably, the first organoboride and the second organoboride are independently selected from boric acid, borate esters, boric acid derivatives or borate ester derivatives.

[0023] A third objective of this invention is to provide a method for preparing chiral quaternary carbamate derivatives, comprising the following steps: Using polysubstituted olefins and hydrogen cyanide equivalents as raw materials, and phosphite ligands and zero-valent nickel catalysts as catalytic systems, the polysubstituted olefins, phosphite ligands, hydrogen cyanide equivalents, and zero-valent nickel catalysts are dissolved together in a solvent. The carbon-carbon double bonds of the polysubstituted olefins undergo an asymmetric hydrocyanation reaction with the cyano carbon atoms of the hydrogen cyanide equivalents. After the reaction is completed, the chiral quaternary carbamate derivative is obtained by separation and purification.

[0024] The reaction formula is: .

[0025] The polysubstituted olefin is selected from 1,1-disubstituted olefins or trisubstituted olefins, and has the structure shown in formula (I): .

[0026] Wherein, R' is selected from C1~C8 alkyl groups, C6~C6 alkyl groups, and C6~C6 alkyl groups. 10 The aryl group, C4 heterocyclic aryl group; R'' and R''' are independently selected from hydrogen, substituted or unsubstituted groups of the following group: C1~C8 alkyl, C6~C 10 Aryl, hydroxyl, cyano, amide, -CXOR, -CXR, -CXH, -XCXR, -CXSR, -CXNH2, silyl or siloxane.

[0027] The conditions for the asymmetric hydrocyanation reaction are: stirring at 30℃~50℃ for 36h~72h.

[0028] Preferably, the hydrogen cyanide equivalent is selected from at least one of hydrogen cyanide gas, hydrogen cyanide solution, acetone cyanohydrin, and butanone cyanohydrin.

[0029] Preferably, the molar ratio of the phosphite ligand to the zero-valent nickel catalyst is 1:0.1 to 30, more preferably 1:1 to 10; and even more preferably 1:1 to 2.

[0030] Preferably, the molar ratio of zero-valent nickel catalyst to polysubstituted olefin is 0.01~1:1, more preferably 0.02~0.2:1; and even more preferably 0.05~0.1:1.

[0031] Preferably, the molar ratio of the polysubstituted olefin to the hydrogen cyanide equivalent is 1:1 to 10; more preferably, the molar ratio of the polysubstituted olefin to the hydrogen cyanide equivalent is 1:2 to 6.

[0032] Preferably, the hydrogen cyanide equivalent is selected from at least one of hydrogen cyanide gas, hydrogen cyanide solution, acetone cyanohydrin, and butanone cyanohydrin.

[0033] Preferably, the zero-valent nickel catalyst is selected from bis(1,5-cyclooctadiene) nickel or tri(trans-1,2-bis(4-tert-butylphenyl)ethylene) nickel (0).

[0034] Preferably, the solvent is selected from halogenated hydrocarbons, aromatic hydrocarbons, ethers, or esters, wherein the halogenated hydrocarbons are selected from dichloromethane or trichloromethane; the aromatic hydrocarbons are selected from toluene, ethylbenzene, or cumene; the ethers are selected from diethyl ether, cyclopentyl methyl ether, or tetrahydrofuran; and the esters are selected from ethyl acetate or isopropyl acetate.

[0035] Preferably, the separation and purification process involves cooling the reaction solution to room temperature after the reaction is completed, then adding a saturated ammonium chloride solution for quenching; next, performing multiple extractions with ethyl acetate, and combining the organic phases obtained from each extraction; the combined organic phases are then dried sequentially with anhydrous MgSO4 and filtered; next, the solvent is removed by rotary evaporation under reduced pressure to obtain the crude product; subsequently, using petroleum ether and ethyl acetate as developing solvents, thin-layer chromatography is performed, and based on the results of the thin-layer chromatography analysis, column chromatography is used to separate the chiral quaternary carbamate derivative.

[0036] A fourth object of the present invention is to provide a chiral quaternary carbide derivative prepared using the above-mentioned phosphite ligand, wherein the chiral quaternary carbide derivative is selected from... , , , or .

[0037] A fifth objective of this invention is to provide the application of the above-mentioned chiral quaternary carbamate derivatives in the preparation of pharmaceuticals or pharmaceutical intermediates, wherein the above-mentioned chiral quaternary carbamate derivatives are used to prepare... , , or It is a pharmaceutical intermediate. It is a drug.

[0038] Preferably, adopt preparation ,use preparation ,use preparation ,use preparation and adoption preparation .

[0039] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention provides a novel phosphite ligand, which, together with a zero-valent nickel catalyst, forms a catalytic system for the asymmetric hydrocyanation reaction of polysubstituted alkenes with hydrogen cyanide equivalents. This enables the efficient and highly enantioselective preparation of chiral quaternary carbamate derivatives, thereby overcoming the problems of high reaction temperature and low enantioselectivity in existing technologies.

[0040] Compared to the traditional binaphthol skeleton with only a 3,3'-substituent, the phosphite ligand of this invention features a newly added 7,7'-substituent. Through steric hindrance and electronic effects, this effectively alters the dihedral angle of the binaphthol skeleton, increasing its overall rigidity and providing excellent steric support for the coordination of the metal center and the weak interactions between substituents. Simultaneously, this rigid structure can lock the conformation of the metal center, reducing the conformational freedom of the phosphite ligand and the zero-valent nickel catalyst, ensuring the chiral environment remains precise even at low temperatures. Furthermore, the newly added 7,7'-substituent can enhance weak interactions. The 7,7'-aryl substituent, through CH···π stacking (such as the π-π interaction between the benzene ring and the substrate aryl group) and CH···F hydrogen bonding (such as the hydrogen bond between the F of the trifluoromethoxy group and the H of the substrate), pre-organizes the substrate to a specific orientation, lowering the activation energy and eliminating the need for high temperatures.

[0041] 2. The present invention also provides a method for preparing phosphite ligands. The method has mild reaction conditions and the obtained phosphite ligands have excellent stability and are not sensitive to air, water vapor and temperature.

[0042] 3. This invention uses readily available and easily prepared polysubstituted olefins as starting materials and employs a catalytic system constructed from chiral phosphite ligands and zero-valent nickel catalysts to catalyze the asymmetric hydrocyanation reaction of polysubstituted olefins. It has the significant advantages of high atom economy, mild and easily controllable reaction conditions, good compatibility with various substrates, and a simple and clear reaction system.

[0043] 4. The chiral quaternary carbamate derivatives prepared in this invention exhibit excellent biocompatibility and metabolic stability. This characteristic not only greatly promotes efficient and precise interactions between drug molecules and receptors but also significantly improves the toxicological properties of the molecules, providing a safer and more effective option for drug development. These chiral quaternary carbamate derivatives can be used to construct cyano-substituted quaternary carbon chiral centers, and these structural units have important applications in the synthesis of drugs and their key intermediates. In particular, the chiral quaternary carbamate derivatives of this invention can serve as key synthetic intermediates for the preparation of drugs such as… (R)-the serotonin antagonist Drugs and (+)-sporochnol A, (+)-epilaurene, HCV polymerase inhibitor and (R)-ammoglutethimide It is an intermediate that can significantly reduce the preparation process and steps of these drugs, and has extremely high application value and broad development prospects in the field of drug preparation. Attached Figure Description

[0044] Figure 1 The photon spectrum of phosphite ligand II in Example 1 is shown.

[0045] Figure 2 The image shows the fluorine spectrum of phosphite ligand II from Example 1.

[0046] Figure 3 Phosphorus spectrum of phosphite ligand II in Example 1 Figure 4 The hydrogen spectrum of compound III-1 from Application Example 1.

[0047] Figure 5 The HPLC chromatogram of compound III-1 from Application Example 1 is shown, where a is the racemic mixture and b is III-1.

[0048] Figure 6 The hydrogen spectrum of compound III-2 in Application Example 2.

[0049] Figure 7 The HPLC chromatogram of compound III-2 from Application Example 2 is shown, where a is the racemic mixture and b is III-2.

[0050] Figure 8 The hydrogen spectrum of compound III-2a from Application Example 2 is shown.

[0051] Figure 9 The HPLC chromatogram of compound III-2a from Application Example 2 is shown, where a is the racemic mixture and b is III-2a.

[0052] Figure 10 The hydrogen spectrum of compound III-3 in Application Example 3.

[0053] Figure 11 The HPLC chromatogram of compound III-3 from Application Example 3 is shown, where a is the racemic mixture and b is III-3.

[0054] Figure 12 The hydrogen spectrum of compound III-3a obtained in Example 3 is shown.

[0055] Figure 13 The hydrogen spectrum of compound III-4 in Application Example 4.

[0056] Figure 14 The HPLC chromatogram of compound III-4 from Application Example 4 is shown, where a is the racemic mixture and b is III-4.

[0057] Figure 15 The hydrogen spectrum of compound III-4a from Application Example 4 is shown.

[0058] Figure 16 The HPLC chromatogram of compound III-4a from Application Example 4 is shown, where a is the racemic mixture and b is III-4a.

[0059] Figure 17 For the application of compound 4 ( R ) -the serotonin antagonist Hydrogen spectrum of drug molecules.

[0060] Figure 18 For the application of compound 4 ( R ) -the serotonin antagonist HPLC chromatogram of drug molecules, where a is the racemic mixture and b is the compound ( R ) -the serotonin antagonist Drug molecules.

[0061] Figure 19 The hydrogen spectrum of compound III-5 from Application Example 5.

[0062] Figure 20 The HPLC chromatogram of compound III-5 from Application Example 5 is shown, where a is the racemic mixture and b is III-5. Detailed Implementation

[0063] The technical solution of the present invention will be clearly and completely described below with reference to the data in the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0064] It should be noted that the technical terms used in this invention are for the purpose of describing specific embodiments only and are not intended to limit the scope of protection of this invention. Unless otherwise specified, all raw materials, reagents, instruments and equipment used in the following embodiments of this invention can be purchased commercially or prepared by existing methods. Among them, chloromethyl methyl ether is denoted as MOMCl; pyridinium chlorochromate is denoted as PCC; tetrahydrofuran is denoted as THF; dichloromethane is denoted as DCM; and 4-dimethylaminopyridine is denoted as DMAP.

[0065] To enable those skilled in the art to more clearly understand the technical solution of the present invention, the following will provide a detailed description in conjunction with specific embodiments: Example 1 A method for preparing a phosphite ligand includes the following steps: S1. Add 1.0 mmol of (S)-A, 2 mol% of Pd(dba)2, 4.0 mmol of K3PO4, 4 mol% of SPhos, 4.0 mmol of 4-trifluoromethoxyphenylboronic acid and 15 mL of toluene solvent to a sealed tube containing a dry stir bar. React at 100 °C for 18 h under nitrogen. After purification by silica gel column chromatography, a 7,7'-substituted binaphthol skeleton is obtained, denoted as (S)-B.

[0066] S2. Under 0°C ice bath conditions, 1.0 mmol of (S)-B, a dry stir bar, and 20 mL of tetrahydrofuran solution were added to a three-necked flask. Under nitrogen protection, 4.0 mmol of NaH was then slowly added. The reaction was then moved to room temperature and stirred for 2 h. The flask was then placed in a 0°C ice bath, and 3.0 mmol of chloromethyl ether was slowly added dropwise. The reaction was allowed to proceed for another 2 h at room temperature. After the reaction was complete, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phase solution was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a hydroxyl-protected intermediate, denoted as (S)-C.

[0067] S3. Under nitrogen protection, 1.0 mmol of (S)-C and 20 mL of tetrahydrofuran were added to a three-necked flask equipped with a dry stir bar. The reaction system was placed in a -78°C low-temperature stirrer, and 4.0 mmol of n-butyllithium was slowly added dropwise to the reaction solution using a constant pressure funnel. The mixture was stirred at -78°C for 2 h. The reaction system was then raised to room temperature and stirred for another 2 h. The reaction flask was then cooled to -78°C, and 4.0 mmol of iodine granules were added in portions. The reaction solution was then gradually restored to room temperature and reacted for 12 h. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a hydroxyl-protected 3,3'- and 7,7'-substituted binaphthol skeleton, denoted as (S)-D.

[0068] S4. Add 1.0 mmol of (S)-D, 2 mol% of Pd(dba)2, 4.0 mmol of K3PO4, 4 mol% of SPhos, 4.0 mmol of 4-trifluoromethoxyphenylboronic acid and 15 mL of toluene solvent to a sealed tube containing a dry stir bar. React at 100 °C for 16 h under nitrogen atmosphere. After purification by silica gel column chromatography, obtain the 3,3'- and 7,7'-substituted skeleton (S)-E.

[0069] S5. In a reflux flask, 1.0 mmol of (S)-E was dissolved in a mixed solvent of 15 mL of dichloromethane and methanol, and 5 mL of 6 mol / L dilute hydrochloric acid and a stir bar were added. The mixture was refluxed for 4 h. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phase solution was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a 3,3'- and 7,7'-substituted binaphthol skeleton, denoted as (S)-F. The volume ratio of dichloromethane to methanol was 1:1.

[0070] S6. Add 0.3 mmol of (S)-F, 0.06 mmol of DMAP, 2.4 mmol of Et3N, and 1.5 mmol of (S)-F to the sealing tube. SAfter adding 4 mL of tetrahydrofuran, the mixture was sealed and refluxed in an oil bath at 60 °C for 16 h. After the reaction was completed, the solvent in the system was evaporated to dryness and then purified by silica gel column chromatography to obtain phosphite ligand II-1, which was a white solid.

[0071] The reaction formula is: .

[0072] In this invention, Ar 1 Ar 2 "in "" indicates the macromolecular skeleton to which it is connected.

[0073] The structural characterization of the obtained II-1 is as follows Figure 1 , Figure 2 and Figure 3 As shown, the specific data is as follows: 1 H NMR (400MHz, CDCl3) δ 8.12 (s, 2H), 7.96 (d, J =8.5Hz, 2H), 7.82 (d, J =8.2Hz, 2H), 7.77(d, J =8.9Hz, 2H), 7.66-7.58(m, 8H), 7.49-7.33(m, 12H), 7.25(s, 2H), 7.18(dd, J =11.6, 3.1Hz, 12H), 7.07(d, J =8.8Hz, 2H), 6.75 (d, J =8.8Hz, 2H), 5.97 (d, J =8.8Hz, 2H). 31 PNMR(162MHz, CDCl3) δ 145.45. 19 F NMR (376MHz, CDCl3) δ -57.50, -57.81. 13C NMR (100MHz, CDCl3) δ 149.21, 148.88, 147.57, 147.46, 146.76, 139.73, 138.85, 136.42, 134.28, 132.6 4, 132.38, 131.52, 131.42, 131.03, 130.75, 130.23, 130.16, 129.54, 129.06, 128 .97, 128.38, 128.32, 127.00, 126.91, 126.30, 126.14, 125.75, 125.14, 124.97, 124.23, 123.93, 122.48, 122.00, 121.86, 121.46, 121.31, 120.71, 119.44, 119.30. Due to the splitting of fluorine and phosphorus, coupled interpretation is difficult; the carbon spectra are listed according to the actual peak numbers. [α] 25 D =+71.0(c=0.5, CHCl3). HRMS-ESI(m / z):[M+Na] + calcd for C 88 H 48 F 12 O 10 P2Na, 1577.2423; found 1577.2443.

[0074] Example 2 A method for preparing a phosphite ligand includes the following steps: S1. Add 1.0 mmol of (S)-A, 20 mol% of Pd(dba)2, 6.0 mmol of K3PO4, 2 mol% of SPhos, 6.0 mmol of 4-trifluoromethoxyphenylboronic acid and 15 mL of toluene solvent to a sealed tube containing a dry stir bar. React at 100 °C for 16 h under nitrogen. After purification by silica gel column chromatography, a 7,7'-substituted binaphthol skeleton is obtained, denoted as (S)-B.

[0075] S2. Under 0°C ice bath conditions, 1.0 mmol of (S)-B, a dry stir bar, and 20 mL of tetrahydrofuran solution were added to a three-necked flask. Under nitrogen protection, 3.0 mmol of NaH was then slowly added. The reaction was then moved to room temperature and stirred for 2 h. The flask was then placed in an ice bath at 0°C, and 4.0 mmol of chloromethyl methyl ether was slowly added dropwise. The reaction was allowed to proceed for another 2 h at room temperature. After the reaction was complete, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phase solution was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a hydroxyl-protected intermediate, denoted as (S)-C.

[0076] S3. Under nitrogen protection, 1.0 mmol of (S)-C and 20 mL of tetrahydrofuran were added to a three-necked flask equipped with a dry stir bar. The reaction system was placed in a -78°C low-temperature stirrer, and 3.0 mmol of n-butyllithium was slowly added dropwise to the reaction solution using a constant pressure funnel. The mixture was stirred at -78°C for 2 h. The reaction system was then raised to room temperature and stirred for another 2 h. The reaction flask was then cooled to -78°C, and 3.0 mmol of iodine granules were added in portions. The reaction solution was then gradually restored to room temperature and reacted for 12 h. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a hydroxyl-protected 3,3'- and 7,7'-substituted binaphthol skeleton, denoted as (S)-D.

[0077] S4. Add 1.0 mmol of (S)-D, 20 mol% of Pd(dba)2, 4.0 mmol of K3PO4, 2 mol% of SPhos, 6.0 mmol of 4-trifluoromethoxyphenylboronic acid and 15 mL of toluene solvent to a sealed tube containing a dry stir bar. React at 100 °C for 16 h under nitrogen atmosphere. After purification by silica gel column chromatography, obtain the 3,3'- and 7,7'-substituted skeleton (S)-E.

[0078] S5. In a reflux flask, 1.0 mmol of (S)-E was dissolved in a mixed solvent of 15 mL of dichloromethane and methanol, and 5 mL of 6 mol / L dilute hydrochloric acid and a stir bar were added. The mixture was refluxed for 4 h. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phase solution was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a 3,3'- and 7,7'-substituted binaphthol skeleton, denoted as (S)-F. The volume ratio of dichloromethane to methanol was 1:1.

[0079] S6. Add 0.3 mmol of (S)-F, 0.12 mmol of DMAP, 1.2 mmol of Et3N, and 0.9 mmol of (S)-F to the sealing tube. S After adding 4 mL of tetrahydrofuran, the mixture was sealed and refluxed in an oil bath at 60 °C for 16 h. After the reaction was completed, the solvent in the system was evaporated to dryness and then purified by silica gel column chromatography to obtain phosphite ligand II as a white solid.

[0080] Example 3 A method for preparing a phosphite ligand includes the following steps: S1. Add 1.0 mmol of (S)-A, 2 mol% of Pd(dba)2, 4.0 mmol of K3PO4, 20 mol% of SPhos, 4.0 mmol of 4-trifluoromethoxyphenylboronic acid and 15 mL of toluene solvent to a sealed tube containing a dry stir bar. React at 100 °C for 24 h under nitrogen. After purification by silica gel column chromatography, a 7,7'-substituted binaphthol skeleton is obtained, denoted as (S)-B.

[0081] S2. Under 0°C ice bath conditions, 1.0 mmol of (S)-B, a dry stir bar, and 20 mL of tetrahydrofuran solution were added to a three-necked flask. Under nitrogen protection, 5.0 mmol of NaH was then slowly added. The reaction was then moved to room temperature and stirred for 3 h. The flask was then placed in an ice bath at 0°C, and 5.0 mmol of chloromethyl ether was slowly added dropwise, reacting at room temperature for another 3 h. After the reaction was complete, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic phase solution was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a hydroxyl-protected intermediate, denoted as (S)-C.

[0082] S3. Under nitrogen protection, 1.0 mmol of (S)-C and 20 mL of tetrahydrofuran were added to a three-necked flask equipped with a dry stir bar. The reaction system was placed in a -78°C low-temperature stirrer, and 5.0 mmol of n-butyllithium was slowly added dropwise to the reaction solution using a constant pressure funnel. The mixture was stirred at -78°C for 3 h. The reaction system was then raised to room temperature and stirred for another 3 h. The reaction flask was then cooled to -78°C, and 5.0 mmol of iodine granules were added in portions. The reaction solution was then gradually restored to room temperature and reacted for 16 h. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a hydroxyl-protected 3,3'- and 7,7'-substituted binaphthol skeleton, denoted as (S)-D.

[0083] S4. Add 1.0 mmol of (S)-D, 2 mol% of Pd(dba)2, 4.0 mmol of K3PO4, 20 mol% of SPhos, 4.0 mmol of 4-trifluoromethoxyphenylboronic acid and 15 mL of toluene solvent to a sealed tube containing a dry stir bar. React at 100 °C for 24 h under nitrogen. After purification by silica gel column chromatography, obtain the 3,3'- and 7,7'-substituted skeleton (S)-E.

[0084] S5. In a reflux flask, 1.0 mmol of (S)-E was dissolved in a mixed solvent of 15 mL of dichloromethane and methanol, and 5 mL of 6 mol / L dilute hydrochloric acid and a stir bar were added. The mixture was refluxed for 5 h. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phase solution was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a 3,3'- and 7,7'-substituted binaphthol skeleton, denoted as (S)-F. The volume ratio of dichloromethane to methanol was 1:1.

[0085] S6. Add 0.3 mmol of (S)-F, 0.03 mmol of DMAP, 1.8 mmol of Et3N, and 1.8 mmol of (S)-F to the sealing tube. S After adding 4 mL of tetrahydrofuran, the mixture was sealed and refluxed in an oil bath at 60 °C for 10 h. After the reaction was completed, the solvent in the system was evaporated to dryness and then purified by silica gel column chromatography to obtain phosphite ligand II, which was a white solid.

[0086] The following is an example of Embodiment 1 of the present invention. Using phosphite ligands, chiral quaternary carbamate derivatives were prepared, as detailed in Application Examples 1 to 5: Application Example 1 A method for preparing a chiral quaternary carbide derivative involves reacting tris(trans-1,2-bis(4-tert-butylphenyl)ethylene)nickel (0) with a ligand of formula II-1 to catalyze the asymmetric hydrocyanation of an olefin of formula I-1, yielding (R)-2-(4-methoxyphenyl)-2,6-dimethylhept-5-enene nitrile of formula III-1. This compound is (+). -sporochnol A The key intermediate includes the following steps: Reaction formula: .

[0087] S1. Preparation of III-1 from I-1: In a molar ratio of 0.1:0.1:1:3, 10 mol% of the ligand of formula II-1, 10 mol% of tris(trans-1,2-bis(4-tert-butylphenyl)ethylene)nickel (0), 0.2 mmol of the olefin of formula I-1, and 0.6 mmol of acetone cyanohydrin were added to a reaction flask. Under a nitrogen atmosphere, using a mixed solution of 0.3 mL cyclopentyl methyl ether and 0.2 mL toluene as a solvent, the reaction was stirred at 30 °C for 36 minutes. h; After the reaction was complete, stirring was stopped, and the mixture was cooled to room temperature. 3 mL of saturated ammonium chloride solution was added, followed by extraction with ethyl acetate three times. The combined organic phases were dried over anhydrous MgSO4, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The product was purified by column chromatography with petroleum ether / ethyl acetate to obtain a colorless oily product, a chiral quaternary carbide derivative, namely (R)-2-(4-methoxyphenyl)-2,6-dimethylhept-5-enonitrile of formula III-1, with a yield of 32.0 mg and a yield of 66%.

[0088] S2. Referring to the English literature titled "Enantioselective synthesis of nitriles containing aquaternary carbon center by Michael reactions of silyl ketene imines with 1-acrylpyrazoles" and "Enantioselective construction of quaternary stereogenic centers from tertiary boronic esters: methodology and applications," preparation (+) was performed using III-1. -sporochnol A .

[0089] The structural characterization of the obtained III-1 is as follows Figure 4 and Figure 5 As shown, the specific data is as follows: 1 H NMR (400MHz, CDCl3) δ 7.37-7.32(m, 2H), 6.94-6.87(m, 2H), 5.07-4.96(m, 1H), 3.81(s, 3H), 2.1 8-2.04 (m, 1H), 1.97-1.84 (m, 3H), 1.68 (s, 3H), 1.65 (s, 3H), 1.52 (s, 3H). 13C NMR (100MHz, CDCl3) δ 159.0, 133.0, 132.3, 126.7, 123.7, 122.5, 114.2, 55.4, 42.2, 41.8, 28.1, 25.7, 24.4, 17.7. Optical rotation [α] 25 D =17.0(c=0.5, CHCl3). HRMS-ESI(m / z):[M+Na] + calcd for C 16 H 21 NONa, 266.1515; found 266.1514. HPLC (Daicel Chiralpak AD-H, V 正己烷 :V 异丙醇 =98:2, flow rate 0.5 mL / min, 254 nm): t R1 (major) = 13.9 min, t R2 (minor) = 15.7 min, 87% ee .

[0090] Application Example 2 A method for preparing a chiral quaternary carbide derivative involves asymmetric hydrocyanation of a ligand of formula II-1 with an olefin of formula I-2 to prepare (R)-5-hydroxy-2-methyl-2-(p-tolyl)pentanilonitrile of formula III-2. Compound III-2 is then further oxidized in one step to obtain compound III-2a, which is (+). - epilaurene The key intermediate includes the following steps: The reaction formula is: .

[0091] S1. Preparation of III-2 from I-2: 10 mol% of the ligand of formula II-1, 10 mol% of tris(trans-1,2-bis(4-tert-butylphenyl)ethylene)nickel (0), 0.2 mmol of the olefin of formula I-2, and 0.6 mmol of acetone cyanohydrin were added to a reaction flask at a molar ratio of 0.1:0.1:1:3. The reaction was carried out under a nitrogen atmosphere with a mixed solution of 0.3 mL cyclopentyl methyl ether and 0.2 mL toluene as the solvent, and stirred at 30 °C for 60 h. After the reaction was completed, stirring was stopped, and the mixture was cooled to room temperature. 3 mL of saturated ammonium chloride solution was added, followed by extraction with ethyl acetate three times. The combined organic phases were dried with anhydrous MgSO4, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The product was purified by column chromatography with petroleum ether / ethyl acetate to obtain a colorless oily liquid product, a chiral quaternary carbide derivative, namely (R)-5-hydroxy-2-methyl-2-(p-tolyl)pentanilonitrile of formula III-2, with a yield of 27.2 mg and a yield of 67%.

[0092] The structural characterization data of III-2 obtained are shown below: 1 H NMR (400MHz, CDCl3) δ 7.33-7.31(m, 2H), 7.20-7.18(m, 2H), 3.61(t, J=6.2Hz, 2H), 2.35(s, 3H), 2.02-1.98(m, 2H), 1.71(s, 4H), 1.54-1.45(m, 2H). 13 C NMR (100MHz, CDCl3) δ 137.7, 137.1, 129.7, 125.4, 123.7, 62.3, 42.1, 38.6, 28.9, 28.1, 21.1. HRMS-ESI(m / z):[M+Na] + calcd for C 13 H 17 NONa, 226.1202; found 226.1199. Optical rotation [α] 25 D =-21.9(c=1.0, CHCl3). HPLC (Daicel Chiralpak OJ-H, V 正己烷 :V 异丙醇 =80:20, flow rate 0.7 mL / min, 254 nm): t R1 (major) = 9.8 min, t R2 (minor) = 10.7 min, 88% ee .

[0093] S2. Preparation of III-2a from III-2: 0.4 mmol of pyridinium chlorochromate, 0.2 mmol of (R)-5-hydroxy-2-methyl-2-(p-tolyl)pentanonitrile of III-2, a magnetic stir bar, and 4.0 mL of dichloromethane were added to a single-necked flask. After reacting at room temperature for 4 h, the reaction was detected by TLC. Saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic phases were combined, dried over anhydrous MgSO4, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The product was purified by column chromatography with petroleum ether / ethyl acetate to obtain 29.7 mg of a colorless liquid product of III-2a, with a yield of 74%.

[0094] The structural characterization results of III-2a obtained are as follows Figure 8 and Figure 9 As shown, the specific data is as follows: 1 H NMR (400MHz, CDCl3) δ 9.69 (s, 1H), 7.31 (d, J =8.3Hz, 2H), 7.21-7.19(m, 2H), 2.76-2.60(m, 1H), 2.38-2.32(m, 4H), 2.27-2.15(m, 2H), 1.73(s, 3H). 13 C NMR (100MHz, CDCl3) δ 200.1, 138.2, 136.1, 129.9, 125.4, 123.0, 41.7, 40.4, 34.0, 28.2, 21.1. HRMS-ESI(m / z):[M+Na] + calcd for C 13 H 15 NONa, 224.1046; found 224.1047. Optical rotation [α] 25 D =-18.5(c=1.0, CHCl3). HPLC (Daicel Chiralpak OJ-H, V 正己烷 :V 异丙醇 =98:2, flow rate 0.5 mL / min, 254 nm): t R1 (minor) = 28.6 min, t R2 (major) = 30.8 min, 86% ee .

[0095] S3. Referring to the English literature entitled "Enantioselective synthesis of nitriles containing aquaternary carbon center by Michael reactions of silyl ketene imines with 1-acrylpyrazoles" and "Asymmetric construction of quaternary carbons from chiralmalonates: Total syntheses of (+)-epilaurene and (−)-Isolaurene", (+)- epilaurene .

[0096] Application Example 3 A method for preparing a chiral quaternary carbide derivative involves the asymmetric hydrocyanation of an olefin of formula I-3 with a ligand of formula II-1 to prepare (R)-2,5-dimethyl-2-phenylhexanenitrile. Compound III-3 is then subjected to a one-step cyanohydrolysis to yield compound III-3a. This compound is... HCV polymerase inhibitor The key intermediate includes the following steps: The reaction formula is: .

[0097] S1. Preparation of III-3 from I-3: 10 mol% of formula II-1 ligand, 10 mol% of tris(trans-1,2-bis(4-tert-butylphenyl)ethylene)nickel (0), 0.2 mmol of the olefin of formula I-3, and 0.6 mmol of acetone cyanohydrin were added to a reaction flask at a molar ratio of 0.1:0.1:1:3. The reaction was carried out under a nitrogen atmosphere with a mixed solution of 0.3 mL cyclopentyl methyl ether and 0.2 mL toluene as the solvent, and stirred at 30 °C for 60 h. After the reaction was completed, stirring was stopped, and the mixture was cooled to room temperature. 3 mL of saturated ammonium chloride solution was added, followed by extraction with ethyl acetate three times. The combined organic phases were dried with anhydrous MgSO4, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The product was purified by column chromatography with petroleum ether / ethyl acetate to obtain a colorless oily liquid product, namely (R)-2,5-dimethyl-2-phenylhexanenitrile of formula III-3, with a yield of 20.9 mg and a yield of 52%.

[0098] The structural characterization results of III-3 obtained are as follows Figure 10 and Figure 11 As shown, the specific data is as follows: 1H NMR (400MHz, CDCl3) δ 7.46-7.35(m, 4H), 7.35-7.28(m, 1H), 1.95-1.86(m, 2H), 1.71(s, 3H), 1.56-1.46(m, 1H), 1.40-1.32(m, 1H), 1.16-1.06(m, 1H), 0.86(dd, J =9.7, 6.6 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 140.6, 129.0, 127.8, 125.5, 123.7, 42.7, 40.2, 34.4, 28.1, 28.0, 22.54, 22.47. [α] 25 D =-11.9(c=1.0, CHCl3). HRMS-ESI(m / z):[M+Na] + calcdfor C 14 H 19 NNa, 224.1410; found 224.1411. HPLC (Daicel Chiralpak IG, V 正己烷 :V 异丙醇 =95:5, flow rate 0.3 mL / min, 254 nm): t R1 (major) = 15.3 min, t R2 (minor) = 16.6 min, 84% ee .

[0099] S2. Preparation of III-3a from III-3: 0.8 mmol KOH, 0.2 mmol III-3, a magnetic stir bar, 4.0 mL ethylene glycol and 1.0 mL water were added to a single-necked flask. The mixture was then reacted at 100 °C for 10 h. The reaction was monitored by TLC. After adding saturated ammonium chloride solution, ethyl acetate was added for extraction. The organic phases were combined, dried with anhydrous MgSO4, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The product was purified by column chromatography with petroleum ether / ethyl acetate to obtain a yellow oily liquid product III-3a, 86%, 37.8 mg.

[0100] The structural characterization results of III-3a obtained are as follows Figure 12 As shown, the specific data is as follows: 1 H NMR (400MHz, CDCl3) δ 7.39-7.32 (m, 4H), 7.27-7.25 (m, 1H), 2.11-1.89 (m, 2H), 1.69-1.44 (m, 4H), 1.16-1.01 (m, 2H), 0.87 (dd,J= 8.3, 6.7 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 182.2, 143.3, 128.5, 127.0, 126.3, 50.1, 36.9, 33.7, 28.7, 22.7, 22.6, 22.5. HRMS-ESI(m / z):[M–H] + calcd for C 14 H 19 O2, 219.1391; found 219.1385.

[0101] S3. Referring to the English literature titled "Inhibitors of hepatitis C virus polymerase: Synthesis and biological characterization of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines", preparation was carried out using III-3a. HCV polymerase inhibitor .

[0102] Application Example 4 A method for preparing a chiral quaternary carbide derivative involves asymmetric hydrocyanation of an olefin of formula I-4 with a ligand of formula II-1 to prepare (R)-4-hydroxy-2-methyl-2-phenylbutyronitrile, i.e., compound III-4. After oxidation of the hydroxyl group in compound III-4, it reacts with ammonia to obtain compound III-4a. Compound III-4a then reacts with a phenyl Grignard reagent to prepare (R)-4-hydroxy-2-methyl-2-phenylbutyronitrile, i.e., compound III-4. R ) -the serotonin antagonist Drug molecules, including the following steps: The reaction formula is: .

[0103] S1. Preparation of III-4 from I-4: 10 mol% of the ligand of formula II-1, 10 mol% of tris(trans-1,2-bis(4-tert-butylphenyl)ethylene)nickel (0), 0.2 mmol of the olefin of formula I-4, and 0.6 mmol of acetone cyanohydrin were added to a reaction flask at a molar ratio of 0.1:0.1:1:3. The reaction was carried out under a nitrogen atmosphere with a mixed solution of 0.3 mL cyclopentyl methyl ether and 0.2 mL toluene as the solvent, and stirred at 30 °C for 72 h. After the reaction was completed, stirring was stopped, and the mixture was cooled to room temperature. 3 mL of saturated ammonium chloride solution was added, followed by extraction with ethyl acetate three times. The combined organic phases were dried with anhydrous MgSO4, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The product was purified by column chromatography with petroleum ether / ethyl acetate to obtain a colorless oily liquid product, namely (R)-4-hydroxy-2-methyl-2-phenylbutyronitrile of formula III-4, with a yield of 20.7 mg and a yield of 59%.

[0104] The structural characterization results of III-4 obtained are as follows Figure 13 and Figure 14 As shown, the specific data is as follows: 1 H NMR (400MHz, CDCl3) δ 7.48-7.33 (m, 5H), 3.81-3.74 (m, 1H), 3.68-3.62 (m, 1H), 2.37-2.13 (m, 2H), 1.77 (s, 3H). 13 C NMR (100MHz, CDCl3) δ 139.8, 129.2, 128.1, 125.5, 123.4, 59.7, 44.2, 40.5, 28.4. HRMS-ESI(m / z):[M+Na] + calcd for C 11 H 13 NONa, 198.0889; found 198.0888. Optical rotation [α] 25 D =-16.6(c=1.0, CHCl3). HPLC (Daicel ChiralpakOD-H, V 正己烷 :V 异丙醇 =80:20, flow rate 0.6 mL / min, 260 nm): t R1 (minor) = 9.2 min, t R2 (major) = 10.1 min, 92% ee .

[0105] S2. Preparation of III-4a from III-4: 0.2 mmol of compound III-4 was added to a 15 mL sealed tube, along with a stir bar, 0.4 mmol of PCC, 0.1 g of diatomaceous earth, and 4 mL of dichloromethane solvent. The tube was then sealed tightly and reacted at room temperature for 4 h. After the reaction, the mixture was filtered through diatomaceous earth, washed three times with dichloromethane solvent, and the filtrate was collected and concentrated under reduced pressure without further purification. The crude product was collected and dissolved in a 15 mL sealed tube with DCE. Under nitrogen protection, 0.24 mmol of 1-(2-methoxyphenyl)piperazine was added, and the mixture was stirred at room temperature for 30 min. Then, 0.4 mmol of sodium triacetoxyborohydride was added, and the mixture was reacted at room temperature for 12 h. After the reaction, the mixture was quenched with saturated sodium bicarbonate solution, extracted three times with dichloromethane, and the organic phase solution was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product III-4a was obtained in two steps by column chromatography with a total yield of 75%, 52.3 mg, as a colorless oily liquid.

[0106] The structural characterization results of III-4a obtained are as follows Figure 15 and Figure 16 As shown, the specific data is as follows: 1 H NMR (400MHz, CDCl3) δ 7.53-7.27(m, 5H), 7.07-6.78(m, 4H), 3.84(s, 3H), 3.06(br, 4H), 2.74-2.47(m, 5H), 2.39-2.32(m, 1H), 2.24-2.11(m, 2H), 1.76(s, 3H). 13 C NMR (100MHz, CDCl3) δ 152.3, 141.3, 139.9, 129.1, 127.9, 125.5, 123.3, 123.1, 121.1, 118.3, 111.3, 55.5, 54.7, 53.6, 50.6, 41.2, 38.8, 28.4. HPLC (Daicel Chiralpak OD-H, V 正己烷 :V 异丙醇 =95:5, flow rate 0.5 mL / min, 254 nm): t R1 (minor) = 26.3 min, t R2 (major) = 27.2 min, 91% ee .

[0107] S3, prepared from III-4a ( R ) -the serotonin antagonistUnder a nitrogen atmosphere and in an ice bath at 0°C, 0.1 mmol of III-4a, a dry stir bar, and 3 mL of toluene were added to a 15 mL sealed tube. Then, 0.3 mL of a 1 mol / L tetrahydrofuran solution of phenyl magnesium bromide was added, the tube was sealed tightly, and the mixture was placed in an oil bath at 110°C for 12 h. After the reaction, the mixture was cooled to room temperature, quenched with 2 mL of water, and then 6 mL of a mixture of acetic acid, tetrahydrofuran, and water in a volume ratio of 4:1:1 was added. The mixture was stirred at room temperature for 4 h. The reaction solution was then extracted three times with ethyl acetate, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solution was purified by column chromatography in two steps to obtain ( ) in 96% overall yield. R ) -the serotonin antagonist 41.1 mg, a colorless oily liquid.

[0108] The result ( R ) -the serotonin antagonist The characterization results are as follows Figure 17 and Figure 18 As shown: 1 H NMR (400MHz, CDCl3) δ 7.46-7.44(m, 2H), 7.38-7.32(m, 5H), 7.29-7.27(m, 1H), 7.23-7.19(m, 2H), 7.01-6.95(m, 1H), 6.92-6.89(m, 2H), 6.83(d, J=7.9 Hz, 1H), 3.83 (s, 3H), 3.00 (br, 4H), 2.53 (br, 4H), 2.44-2.23 (m, 4H), 1.62 (s, 3H). HPLC (Daicel Chiralpak OD-H, V 正己烷 :V 异丙醇 =95:5, flow rate 0.5 mL / min, 254 nm): t R1 (major) = 16.7 min, t R2 (minor) = 18.8 min, 91% ee .

[0109] Application Example 5 A method for preparing a chiral quaternary carbide derivative involves asymmetric hydrocyanation of tris(trans-1,2-bis(4-tert-butylphenyl)ethylene)nickel (0) with a ligand of formula II-1 catalyzing an olefin of formula I-5 to prepare (R)-4-hydroxy-2-ethyl-2-phenylbutyronitrile of formula III-5. This compound is a pharmaceutical molecule. R ) -aminoglutethimide The key intermediate includes the following steps: The reaction formula is: .

[0110] S1. Preparation of III-5 from I-5: 10 mol% of the ligand of formula II-1, 10 mol% of tris(trans-1,2-bis(4-tert-butylphenyl)ethylene)nickel (0), 0.2 mmol of the olefin of formula I-5 and 0.6 mmol of acetone cyanohydrin were added to a reaction flask at a molar ratio of 0.1:0.1:1:3. The reaction was carried out under a nitrogen atmosphere with 0.5 mL of toluene as solvent at 50 °C for 60 h. After the reaction was completed, stirring was stopped, and the mixture was cooled to room temperature. 3 mL of saturated ammonium chloride solution was added, followed by extraction with ethyl acetate three times. The combined organic phases were dried with anhydrous MgSO4, filtered, and the solvent was removed by rotary evaporation under reduced pressure. The product was purified by column chromatography with petroleum ether / ethyl acetate to obtain a colorless oily liquid product of formula III-5, 15.4 mg, 38%.

[0111] The structural characterization results of III-5 obtained are as follows Figure 19 and Figure 20 As shown, the specific data is as follows: 1 H NMR (400MHz, CDCl3) δ 7.51-7.26 (m, 5H), 3.60 (t, J =6.2Hz, 2H), 2.12-1.91(m, 4H), 1.70(tdd, J =11.0, 9.1, 5.5Hz, 1H), 1.42-1.32(m, 1H), 0.91(t, J =7.4Hz, 3H). HRMS-ESI(m / z):[M+Na] + calcd for C 13 H 17 NONa, 226.1202; found 226.1198. Optical rotation [α] 25 D =-12.8(c=0.5, CH3OH). HPLC (Daicel Chiralpak OD-H, V 正己烷 :V 异丙醇 =96:4, flow rate 0.6 mL / min, 214 nm): t R1 (minor) = 29.7 min, t R2 (major) = 31.1 min, 84% ee .

[0112] S2. Referring to the English literature titled "Chemo-enzymatic synthesis of (R)-(+)-aminoglutethimide by kinetic resolution of (±)-4-cyano-4-phenyl-1-hexanol", preparation was carried out using III-5. (R)-aminoglutethimide .

[0113] It should be noted that when numerical ranges are involved in this invention, it should be understood that both endpoints of each numerical range and any value between the two endpoints can be selected. Since the steps and methods used are the same as in the embodiments, preferred embodiments are described in this invention to avoid redundancy. Although preferred embodiments of the invention have been described, those skilled in the art, once they understand the basic inventive concept, can make other changes and modifications to these embodiments.

Claims

1. A phosphite ligand, characterized in that, The structural formula of the phosphite ligand is: ; Among them, R 1 R 5 R 8 and R 12 The radicals are independently selected from halogen, hydroxyl, mercapto, nitro, cyano, amino, C1-C8 alkyl, substituted or unsubstituted aryl, -CXOR, -CXR, -CXH, -XCXR, -CXSR, -CXNH2, -OP(OR)(OR'), OPRR', PRR', P(X)RR', P(X)(OR)(OR'), SOR or S(O)2R; wherein R and R' are independently selected from hydrogen, C1-C8 alkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl; X is selected from oxygen or sulfur; The substituents of the substituted aryl group are selected from at least one of -OCF3, C1~C4 alkyl, and C1~C4 alkoxy groups; R 2 R 3 R 4 R 6 R 7 R 9 R 10 R 11 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 and R 24 Each is independently selected from hydrogen, halogen, hydroxyl, mercapto, cyano, or amino.

2. The phosphite ligand according to claim 1, characterized in that, R 1 R 5 R 8 R 12 Each group is independently selected from Cl, Br, I, nitro, cyano, substituted or unsubstituted aryl groups.

3. The phosphite ligand according to claim 2, characterized in that, R 1 R 5 R 8 R 12 Each aryl group is independently selected from substituted or unsubstituted aryl groups, and the substituent of the substituted aryl group is -OCF3.

4. The phosphite ligand according to claim 1, characterized in that, R 2 R 3 R 4 R 6 R 7 R 9 R 10 R 11 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 and R 24 Each is independently selected from hydrogen.

5. A method for preparing the phosphite ligand according to any one of claims 1 to 4, characterized in that, Includes the following steps: Using multiaxial chiral (S)-7,7'-dibromo-[1,1'-binaphthyl]-2,2'-diol and the first organoboronide as raw materials, and SPhos as ligand, a Suzuki coupling reaction was carried out in the liquid phase in the presence of a catalyst and a base to obtain a 7,7'-substituted binaphthyl diol skeleton. Using a 7,7'-substituted binaphthol skeleton and chloromethyl methyl ether as raw materials, a hydroxyl protection reaction was carried out in the liquid phase under alkaline conditions to obtain a hydroxyl-protected intermediate. Using a hydroxyl-protected intermediate as a raw material, in the liquid phase, the hydroxyl-protected intermediate first undergoes a lithium-hydrogen exchange reaction with alkyllithium, and then undergoes a 3,3'-iodination reaction with iodine to obtain a 3,3'-iodinated intermediate; Using 3,3'-iodinated intermediates and second organoboronides as raw materials, and SPhos as ligand, a Suzuki coupling reaction was carried out in the liquid phase in the presence of a catalyst and a base to obtain a hydroxyl-protected 3,3'- and 7,7'-substituted binaphthol skeleton. The hydroxyl-protected 3,3'- and 7,7'-substituted binaphthol skeleton was subjected to a deprotection reaction to obtain the 3,3'- and 7,7'-substituted binaphthol skeleton. Under alkaline conditions, the 3,3'- and 7,7'--substituted binaphthol skeleton undergoes a substitution reaction with phosphoryl chloride compounds to yield phosphite ligands; The first organoboride may be the same as or different from the second organoboride.

6. A method for preparing a chiral quaternary carbamate derivative based on the phosphite ligand of claim 1, characterized in that, Includes the following steps: Using polysubstituted olefins and hydrogen cyanide equivalents as raw materials, and phosphite ligands and zero-valent nickel catalysts as catalytic systems, the polysubstituted olefins, phosphite ligands, hydrogen cyanide equivalents, and zero-valent nickel catalysts were dissolved together in a solvent. The carbon-carbon double bonds of the polysubstituted olefins underwent an asymmetric hydrocyanation reaction with the cyano carbon atoms of the hydrogen cyanide equivalents. The conditions for the asymmetric hydrocyanation reaction were: stirring at 30℃~50℃ for 36h~72h. After separation and purification, chiral quaternary carbamate derivatives were obtained. The reaction formula is: ; The polysubstituted olefin is selected from 1,1-disubstituted or trisubstituted olefins and has the structure shown in formula (I): ; Wherein, R' is selected from C1~C8 alkyl, C6~C 10 The aryl group is a C1-C8 heterocyclic aryl group; R'' and R''' are each independently selected from hydrogen, substituted or unsubstituted groups, wherein the substituted or unsubstituted groups are selected from C1-C8 alkyl groups, C6-C8 heterocyclic aryl groups, and C4-C6 heterocyclic aryl groups. 10 Aryl, hydroxyl, cyano, amide, -CXOR, -CXR, -CXH, -XCXR, -CXSR, -CXNH2, silyl or siloxane.

7. The method for preparing the chiral quaternary carbide derivative according to claim 6, characterized in that, The molar ratio of the polysubstituted olefin, phosphite ligand, and hydrocyanic acid equivalent is 1:0.05~0.2:1~10.

8. The method for preparing the chiral quaternary carbide derivative according to claim 6, characterized in that, The molar ratio of phosphite ligand to zero-valent nickel catalyst is 1:0.1~30.

9. A chiral quaternary carbide derivative, characterized in that, The chiral quaternary carbamate derivative is prepared by the method according to any one of claims 6 to 8, wherein the chiral quaternary carbamate derivative is selected from... , , , or .

10. The use of the chiral quaternary carbamate derivative of claim 9 in the preparation of a drug or pharmaceutical intermediate, characterized in that, , , or It is a pharmaceutical intermediate. It is a drug.

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