Chiral quaternary ammonium salt phase transfer catalysts, methods of making and using the same

Abstract

The application provides a chiral quaternary ammonium salt phase transfer catalyst, a preparation method and application thereof, in particular, the application provides a chiral phase transfer catalyst derived from cinchona base and a synthesis method thereof, the catalyst has the following structural formula, and a preparation method of the chiral phase transfer catalyst derived from cinchona base is realized on a gram scale through condition optimization, so that the catalyst can be used in an asymmetric synthesis reaction.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to chiral quaternary ammonium salts derived from a cinchona alkaloid skeleton. Background Technology

[0002] In recent years, chiral quaternary ammonium salts have been successfully used as organic phase-transfer catalysts in asymmetric reactions, attracting widespread attention from chemists. Among them, quaternary ammonium salts of cinchonaine and binatidine skeletons have exhibited highly efficient catalytic activity in many asymmetric catalytic reactions; amino acid-derived chiral quaternary ammonium salt catalysts developed in recent years have also shown unique catalytic effects in various asymmetric addition reactions (Wang, H.; Zheng, C.; Zhao, G. Chin. J. Chem. 2019, 37, 1111-1119.). Highly efficient chiral quaternary ammonium salt catalysts derived from cinchonaine play a very important role in synthetic applications, especially in conjugate addition reactions of asymmetric reactions. Currently, the synthetic design of these highly efficient chiral quaternary ammonium salt catalysts needs to overcome their difficulties in synthesis and the numerous steps involved, especially the need to solve the problem of gram-scale synthesis, and to apply them to other asymmetric reactions, such as asymmetric alkylation, asymmetric aldol reactions, and photoreactions.

[0003]

[0004] Our research group has conducted some work on the application of cinchona bark-derived chiral phase transfer in asymmetric synthesis, mainly focusing on the following: cinchona bark catalyzes imines, causing polarity reversal, which, when reacted with electrophilic reagents, yields optically pure chiral amines. Through modification and improvement of the catalysts, this type of catalyst has potential applications in asymmetric synthesis. Currently, cinchona bark and its derived phase transfer catalysts are widely used as chiral ligands and small organic molecule catalysts in asymmetric synthesis, achieving significant progress. However, previous reports have not documented gram-scale preparations of this type of catalyst. Considering the broad application prospects of these compounds as potential chiral phase transfer catalysts in asymmetric synthesis, optimizing conditions and exploring new methods to solve synthetic problems is crucial. Summary of the Invention

[0005] The purpose of this invention is to provide a chiral quaternary ammonium salt derived from the cinchona alkaloid skeleton, its preparation method, and its application in conjugate addition reactions.

[0006] In a first aspect, the present invention provides a method for preparing a chiral phase transfer catalyst, wherein the catalyst has a structure as shown in the following formula:

[0007]

[0008] The compound of formula I has the structure shown in formula Ia or Ib:

[0009]

[0010] R 1 Selected from the following group: substituted or unsubstituted benzyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5-12 heteroaryl;

[0011] R 2 Selected from the group consisting of: substituted or unsubstituted benzyl groups, substituted or unsubstituted -CH2- (5-7 membered heteroaryl groups); wherein, the R 2 The substitution refers to the substitution of a hydrogen atom on a group by one or more R group substituents, wherein the R group substituents are selected from the group consisting of: halogens, substituted or unsubstituted phenyl groups, substituted or unsubstituted C1-C4 alkyl groups, and substituted or unsubstituted C1-C4 alkoxy groups.

[0012] R 3 Selected from the following group: H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy;

[0013] X is a halide anion;

[0014] Unless otherwise specified, the substitution refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the group consisting of: halogen, phenyl, 5-7 membered heteroaryl, C1-C4 alkyl;

[0015] The method is characterized by comprising the following steps:

[0016] (1) 9'-OH protection: Reaction of reactant of formula 1a or 1b with reactant of formula 2 yields compound of formula 3a or 3b:

[0017]

[0018] Where: R 1 R 2 X is as defined above;

[0019] (2) Reaction of 3a or 3b with R2Br yields compound Ia or Ib:

[0020]

[0021] In another preferred embodiment, step (1) includes: reacting compound 1a or 1b with R1Cl at 85-95°C for 1-5 hours in an organic solvent under a nitrogen atmosphere to prepare compound 3a or 3b.

[0022] In another preferred embodiment, step (1) is carried out in the presence of a base; preferably, the base is potassium hydroxide.

[0023] In another preferred embodiment, in step (1), the organic solvent is selected from the group consisting of toluene, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof.

[0024] In another preferred embodiment, step (2) includes: reacting compound 3a or 3b with R2Br in an organic solvent under a nitrogen atmosphere at 0-30°C for 24-72 hours to prepare compound Ia or Ib.

[0025] In another preferred embodiment, in step (2), the organic solvent is selected from the group consisting of dichloromethane, acetonitrile, or combinations thereof.

[0026] In another preferred embodiment, the molar ratio of the compound of formula 1a or 1b to the compound of formula 2 is 1:0.8-1.2.

[0027] In another preferred embodiment, the molar ratio of the compound of formula 3a or 3b to the compound of formula 4 is 1:0.8-1.2.

[0028] In another preferred embodiment, the method further includes the step of:

[0029] (i) When R 2 for At that time, the R mentioned 2 Br is prepared by the following method:

[0030]

[0031] In a nitrogen atmosphere and under palladium catalysis, compound 6 was coupled with boric acid in an organic solvent to give the multisubstituted benzyl alcohol derivative compound 8.

[0032] In another preferred embodiment, the organic solvent is selected from the group consisting of dichloromethane, toluene, 1,4-dioxane, chloroform, methanol, diethyl ether, N,N-dimethylformamide, acetonitrile, water, or combinations thereof; preferably 1,4-dioxane, water, or combinations thereof.

[0033] In another preferred embodiment, the reaction temperature is 80-100°C.

[0034] In another preferred embodiment, the reaction time is 4-8 hours.

[0035] Compound 8 reacts with triphenylphosphine, carbon tetrabromide and imidazole to give benzyl bromide derivative 9;

[0036] In another preferred embodiment, the organic solvent is selected from the group consisting of dichloromethane, toluene, 1,4-dioxane, chloroform, methanol, diethyl ether, N,N-dimethylformamide, acetonitrile, water, or combinations thereof; more preferably, the organic solvent is selected from the group consisting of dichloromethane, water, or combinations thereof.

[0037] In another preferred embodiment, the reaction temperature is -10 to 20°C.

[0038] In another preferred embodiment, the reaction time is 5-20 min.

[0039] (ii) When R 2 for At that time, the R mentioned 2 Br is prepared by the following method:

[0040]

[0041] In an organic solvent, compound 11 reacts with TBAF to give a deprotected benzyl alcohol derivative 12;

[0042] In another preferred embodiment, the organic solvent is selected from the group consisting of dichloromethane, toluene, 1,4-dioxane, chloroform, methanol, diethyl ether, N,N-dimethylformamide, acetonitrile, water, or combinations thereof; preferably tetrahydrofuran.

[0043] In another preferred embodiment, the reaction temperature is raised from zero degrees to room temperature.

[0044] In another preferred embodiment, the reaction time is 1 hour.

[0045] Compound 12 was reacted with triphenylphosphine, carbon tetrabromide and imidazole to obtain benzyl bromide derivative 13;

[0046] Wherein, R is one or more substituents located on the phenyl group selected from the following groups: H, halogen, phenyl, 5-7 membered heteroaryl, C1-C4 alkyl.

[0047] In another preferred embodiment, the organic solvent is selected from the group consisting of dichloromethane, toluene, 1,4-dioxane, chloroform, methanol, diethyl ether, N,N-dimethylformamide, acetonitrile, water, carbon tetrabromide, or combinations thereof; preferably carbon tetrabromide.

[0048] In another preferred embodiment, the reaction temperature is -10 to 30°C.

[0049] In another preferred embodiment, the reaction time is 0.1-2 hours.

[0050] In another preferred embodiment, step (i) of the method further includes:

[0051]

[0052] Compound 4 was protected with TBSCl in the presence of a base under a nitrogen atmosphere to obtain compound 5;

[0053] In another preferred embodiment, the base is triethylamine.

[0054] In another preferred embodiment, the reaction is carried out in the presence of DMAP.

[0055] In another preferred embodiment, the organic solvent is selected from the group consisting of dichloromethane, toluene, 1,4-dioxane, chloroform, methanol, diethyl ether, N,N-dimethylformamide, acetonitrile, water, or combinations thereof; preferably, the organic solvent is dichloromethane.

[0056] In another preferred embodiment, the reaction temperature is 10-40°C.

[0057] In another preferred embodiment, the reaction time is 1-5 hours.

[0058] Compound 5 was reduced in an organic solvent by sodium borohydride to give compound 6.

[0059] In another preferred embodiment, the organic solvent is selected from the group consisting of dichloromethane, toluene, 1,4-dioxane, chloroform, methanol, diethyl ether, N,N-dimethylformamide, acetonitrile, water, or combinations thereof; preferably, the organic solvent is methanol.

[0060] In another preferred embodiment, the reaction temperature is 10-40°C.

[0061] In another preferred embodiment, the reaction time is 1-5 hours.

[0062] In another preferred embodiment, step (ii) of the method further includes:

[0063]

[0064] Compound 10 was reacted with substituted or unsubstituted phenylboronic acid compounds under a nitrogen atmosphere and with palladium catalysis to prepare compound 11.

[0065] Wherein, R is one or more substituents located on the phenyl group selected from the group consisting of halogen, phenyl, 5-7 heteroaryl, and C1-C4 alkyl.

[0066] In another preferred embodiment, the method is carried out in the presence of a base, preferably sodium carbonate.

[0067] In another preferred embodiment, the organic solvent is selected from the group consisting of dichloromethane, toluene, 1,4-dioxane, chloroform, methanol, diethyl ether, N,N-dimethylformamide, acetonitrile, water, or combinations thereof; more preferably, the organic solvent is selected from the group consisting of dichloromethane, water, or combinations thereof.

[0068] In another preferred embodiment, the reaction temperature is 80-100°C.

[0069] In another preferred embodiment, the reaction time is 12-48 hours.

[0070] In another preferred embodiment, in the general formula I:

[0071] R 1 Selected from the group consisting of substituted or unsubstituted phenyl groups, or substituted or unsubstituted 5-7-membered heteroaryl groups;

[0072] R 2 Selected from the group consisting of: substituted or unsubstituted benzyl groups, substituted or unsubstituted -CH2- (5-7 membered heteroaryl groups); wherein, the R 2 The substitution refers to the substitution of a hydrogen atom on a group by one or more R group substituents, wherein the R group substituents are selected from the group consisting of: substituted or unsubstituted phenyl groups, substituted or unsubstituted C1-C4 alkoxy groups;

[0073] R 3 Selected from the following group: H, substituted or unsubstituted C1-C2 alkoxy groups;

[0074] X represents a bromide ion.

[0075] In another preferred embodiment, in the general formula I:

[0076] R 1 For substituted or unsubstituted pyrimidines;

[0077] R 2 Selected from the group consisting of substituted or unsubstituted benzyl groups; wherein, the R group... 2 The substitution refers to the substitution of a hydrogen atom on a group by one or more R group substituents, wherein the R group substituents are selected from the group consisting of: substituted or unsubstituted phenyl groups, substituted or unsubstituted C1-C4 alkoxy groups;

[0078] R 3 Selected from the following group: H, substituted or unsubstituted C1-C2 alkoxy groups.

[0079] In another preferred embodiment, the compound of formula I is a compound selected from the group consisting of, or an enantiomer thereof:

[0080]

[0081] A second aspect of the present invention provides a method for a conjugate addition reaction, the method comprising: performing an asymmetric 1,4-conjugate addition reaction of an imine with an electrophilic reagent in the presence of a chiral phase transfer catalyst of Formula I as described in the first aspect of the present invention, thereby obtaining a chiral amine.

[0082] In another preferred embodiment, the conjugate addition reaction is carried out in the following manner:

[0083]

[0084] In an organic solvent, in the presence of a catalyst as described in Formula I, the compound of Formula i and the compound of Formula ii are reacted to give the compound of Formula iii.

[0085] Ar is a substituted or unsubstituted phenyl group.

[0086] In another preferred embodiment, the conjugate addition reaction is carried out in the following manner:

[0087]

[0088] In an organic solvent, in the presence of a catalyst as described in Formula I, the compound of Formula i-1 and the compound of Formula ii-1 are reacted to give the compound of Formula iii-1.

[0089] Ar is a substituted or unsubstituted phenyl group.

[0090] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0091] The purpose of this invention is to achieve, through condition optimization, the large-scale synthesis of precursors and gram-scale synthesis of catalysts derived from cinchona alkaloids. Compared with reported methods for synthesizing chiral phase transfer catalysts, this method shortens the experimental steps, solves the problem of intermediate separation and purification, and facilitates the development and promotion of this type of phase transfer catalyst.

[0092] Chiral quaternary ammonium salts derived from the cinchona alkaloid skeleton

[0093] This invention provides a chiral quaternary ammonium salt derived from the cinchona alkaloid skeleton, which can serve as a chiral phase-transfer compound, and the compound has the structure shown in Formula I:

[0094]

[0095] Among them, R 1The commonly used one is a polysubstituted aryl benzyl bromide, which influences the interaction between the catalyst and the substrate through steric hindrance and electronic properties, while R 2 Most of the protecting groups are sterically hindered. In this invention, 4,6-dichloro-2,5-biphenylpyrimidine compounds are preferably used.

[0096] In a preferred embodiment of the present invention, each group is defined as follows:

[0097] The preferred chiral phase transfer catalysts are selected from the following compounds.

[0098]

[0099] Preparation of cinchona alkaloid-derived phase transfer catalysts

[0100] In this invention, commercially available quinine, quinine butyl, cinchonine, cinchonine butyl, and tert-butyl ((3,5-dibromo-4-(tert-butoxy)benzyl)oxy)dimethylsilane (purchased from Daicel Optically Active) are used as starting materials to prepare the cinchona alkaloid-derived phase transfer catalyst through the following reaction:

[0101] (1) Synthetic method with 9'-OH protection:

[0102]

[0103] Protection of hydroxyl groups: Compound 3 was prepared by reacting a class of compounds 1 with a 4,6-dichloro-2,5-biphenylpyrimidine compound in an organic solvent at 90°C for 2 hours under a nitrogen atmosphere.

[0104] (2)R 2 Two methods of synthesis:

[0105] Method 1:

[0106]

[0107] R 2 Synthesis Method 1: Under a nitrogen atmosphere, compound 4 was used under alkaline conditions and protected with TBSCl to obtain compound 5; compound 5 was reduced in an organic solvent by sodium borohydride to obtain compound 6; under a nitrogen atmosphere and palladium catalysis, compound 6 was coupled with boric acid in an organic solvent to prepare a multi-substituted benzyl alcohol derivative compound 8; after compound 8 reacted with triphenylphosphine, carbon tetrabromide and imidazole, benzyl bromide derivative 9 was directly obtained; subsequently, benzyl bromide reacted with a hydroxyl-protected cinchona alkaloid derivative in a solvent to obtain the corresponding phase transfer catalyst.

[0108] Method 2:

[0109]

[0110] Where: R1 R 2 X is as defined above.

[0111] R 2 Synthesis Method 2: Under a nitrogen atmosphere and with palladium catalysis, compound 10 reacts with boric acid via a Suzuki reaction to prepare compound 11. In an organic solvent, compound 11 reacts with TBAF to give a deprotected benzyl alcohol derivative 12. Compound 12 reacts with triphenylphosphine, carbon tetrabromide, and imidazole to directly give benzyl bromide derivative 9. Then, the benzyl bromide derivative reacts with a hydroxyl-protected cinchona alkaloid derivative in a solvent to obtain the corresponding phase transfer catalyst.

[0112] In the above synthesis method, the organic solvent may be one or a mixture of several of the following: dichloromethane, toluene, 1,4-dioxane, chloroform, methanol, acetonitrile, and water.

[0113] Applications of phase transfer catalysts derived from cinchona alkaloids

[0114] The cinchona alkaloid-derived phase transfer catalyst obtained in this invention can be used in a series of asymmetric catalytic reactions, such as: 1. catalytic alkylation reaction 2. catalytic cyclization reaction 3. catalytic conjugate addition reaction.

[0115] Specifically, the catalytic reaction includes: in an organic solvent, using the phase transfer catalyst described in this invention as a chiral catalyst, catalyzing the polarity reversal of an imine and its 1,4-conjugated addition reaction with an electrophilic reagent to achieve the asymmetric construction of a chiral amine, thereby obtaining a series of high-value-added chiral amine compounds.

[0116] Example 1:

[0117]

[0118] Example 2:

[0119]

[0120] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0121] Example 1: Synthesis of C-PYR compound 3-1 protected by cinchona alkaloid hydroxyl group

[0122]

[0123] In a 250 mL flask, under nitrogen atmosphere, compound Cincinnidine (compound C) (6.0 g, 20 mmol), 4,6-dichloro-2,5-biphenylpyrimidine (6.5 g, 22 mmol), toluene (160 mL), and a suitable amount of molecular sieve were added sequentially. During heating, powdered potassium hydroxide (7.8 g, 140 mmol) was added in portions to the reaction mixture. The reaction was carried out at 90 °C for 2 hours, and the reaction was monitored by thin-layer chromatography. After the reaction was complete, the molecular sieve was removed by hot filtration. After cooling to room temperature, 100 mL of water was added, and the mixture was transferred to a separatory funnel for separation. The organic layer was collected, and the aqueous layer was washed with dichloromethane (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography (eluent: dichloromethane / methanol = 10:1) to obtain the target product C-PYR compound 3, a white solid (87%, 9.7 g). 1 H NMR (500MHz, CDCl3) δ8.83(d,J=4.5Hz,1H),8.26(d,J=8.4Hz,1H),8.13(d,J=8.4Hz,1H),7.91(d,J=7.6Hz,2H),7.76(t,J=7.6Hz,1H),7.6 3(t,J=7.6Hz,1H),7.53(dq,J=14.3,7.1Hz,3H),7.42(d,J=6.8Hz,2H),7.33(dd,J=9.3,5.9Hz,2H),7.20(t,J=7.7Hz,2H),7.03(d,J=5.6Hz ,1H),5.42-5.28(m,1H),4.90(dd,J=27.9,13.6Hz,2H),3.15(dd,J=14.9,9.2Hz,1H),2.83(d,J=8.9Hz,2H),2.74(d,J=9.3Hz,1H),2.70-2 .57(m,1H),2.12(dd,J=15.3,6.9Hz,1H),1.85-1.75(m,1H),1.66(s,1H),1.58(s,1H),1.44(d,J=8.4Hz,2H),1.31(dd,J=17.9,8.9Hz,1H).

[0124] Example 2: Synthesis of cinchona bark hydroxyl-protected CD-PYR compound 3-2 (method same as 3-1, 17 mmol CD)

[0125]

[0126] White solid, 7.6 g, yield: 81%. 1H NMR (500MHz, CDCl3) δ8.84(d,J=4.5Hz,1H),8.28(d,J=8.4Hz,1H),8.17(d,J=8.3Hz,1H),7.90(d,J=7.4Hz,2H),7.79(t ,J=7.6Hz,1H),7.68(t,J=7.6Hz,1H),7.57(t,J=7.2Hz,2H),7.53-7.44(m,3H),7.35-7.28(m,2H),7.18(t,J=7.7Hz,2H ),7.03(d,J=3.5Hz,1H),5.72-5.58(m,1H),4.88(t,J=13.4Hz,2H),3.20-3.12(m,1H),3.12-2.97(m,2H),2.67-2.51(m ,2H),2.18(s,1H),1.65(d,J=2.6Hz,1H),1.54(dd,J=16.4,9.5Hz,2H),1.23(dd,J=15.1,8.2Hz,1H),1.10-0.94(m,1H);

[0127] Example 3: Synthesis of cinchona bark hydroxyl-protected QD-PYR compound 3-3 (method same as 3-1, 20 mmol QD)

[0128]

[0129] White solid, 9.6 g, yield: 83%. 1 H NMR (500MHz, CDCl3) δ8.71(d,J=4.5Hz,1H),8.04(d,J=9.5Hz,1H),8.01(d,J=7.9Hz,1H),7.60-7.48(m,4H),7.48-7.40(m, 3H),7.37(t,J=7.4Hz,1H),7.32(d,J=4.5Hz,1H),7.24(t,J=7.5Hz,2H),7.04(d,J=5.2Hz,1H),5.45-5.32(m,1H),4.95(d,J =17.0Hz,1H),4.89(d,J=10.2Hz,1H),3.90(s,3H),3.24-3.14(m,1H),2.88(s,1H),2.86(s,1H),2.84-2.74(m,1H),2.73-2 .61(m,1H),2.15(q,J=7.4Hz,1H),1.84(dd,J1=12.3Hz,J2=10.3Hz,1H),1.69(s,1H),1.51-1.41(m,2H),1.41-1.31(m,1H).

[0130] Example 4: Synthesis of Q-PYR compound 3-4 protected by cinchona alkaloid (method same as 3-1, 15 mmol Q)

[0131]

[0132] White solid, 7.5g, yield: 85%. 1 H NMR (500MHz, CDCl3) δ8.70(d,J=4.5Hz,1H),8.05(d,J=9.1Hz,1H),7.98(d,J=7.7Hz,2H),7.59-7.41(m,7H),7. 35(t,J=7.4Hz,1H),7.29(d,J=4.5Hz,1H),7.22(t,J=7.6Hz,2H),6.96(s,1H),5.72-5.62(m,1H),4.91(d,J=15. 8Hz,1H),4.87(d,J=9.5Hz,1H),3.90(s,3H),3.24-3.15(m,1H),3.14-3.06(m,1H),3.03(dd,J1=13.7Hz,J2=10. 3Hz,1H),2.68-2.54(m,2H),2.19(s,1H),1.68(s,1H),1.65-1.53(m,2H),1.35-1.24(m,1H),1.15-1.03(m,1H);

[0133] Example 5: Synthesis of benzyl bromide derivative 9:

[0134]

[0135] Step 1: Aldehyde compound 4 (2.2 g, 8.0 mmol), DMAP (0.5 eq.), and Et3N (5.0 eq.) were added to a dry 100 mL round-bottom flask. Using dichloromethane as the solvent, TBSCl (1.4 g, 9.6 mmol) was dissolved in 10 mL of dichloromethane at 0 °C and added to the reaction system through a constant-pressure dropping funnel. The mixture was allowed to rise naturally to room temperature and reacted for 3 hours until the reaction was complete. After the reaction, water was added and the mixture was transferred to a separatory funnel. The organic layer was separated, and the aqueous layer was washed with dichloromethane (3 x 30 mL). The organic layers were combined, washed several times with brine, dried over sodium sulfate, and concentrated for direct use in the next step (3.0 g, 95% yield).

[0136] Step 2: Dissolve the -TBS-protected aldehyde 5 (3.0 g) synthesized in the previous step in methanol (60 mL). Place the reaction flask in an ice bath and slowly add sodium borohydride (1.2 eq.) to the system. Allow it to rise naturally to room temperature. Detect the reaction using thin-layer chromatography. Once the starting material is completely reduced, concentrate to remove methanol, add dichloromethane, pass through a fast short column, wash with dichloromethane, and concentrate to obtain pure benzyl alcohol derivative 6 (2.9 g, 97% yield).

[0137] Step 3: In a 250 mL round-bottom flask, add a stirrer and, under a nitrogen atmosphere, add product 6 from the previous step, p-phenylboronic acid 7 (4.0 eq.), sodium carbonate (15 eq.), and lithium chloride (3 eq.) sequentially. Add 1,4-dioxane and water (2:1, 60 mL) as solvent, bubble with argon for 20 minutes, and then add tetrakis(triphenylphosphine)palladium (10 mol%). Heat to 90 °C and react at this temperature for 6 hours. After the reaction is complete, cool to room temperature, add water and stir for 10 minutes. Extract with dichloromethane (5 x 50 mL), dry and concentrate with sodium sulfate to obtain the crude product, and then perform column chromatography (petroleum ether / ethyl acetate = 6:1) to obtain pure compound 8 (2.8 g, 87% yield).

[0138] Step 4: Add a stir bar to a dry 50 mL Shrek flask, and add triphenylphosphine (3 eq.), carbon tetrabromide (3 eq.), and imidazole (3 eq.) sequentially to the reaction flask. Add 20 mL of dry dichloromethane as a solvent, and place the flask in an ice bath and stir for 10 minutes. Dissolve the benzyl alcohol (2.2 mmol, 1.0 g) from the previous step in dichloromethane and slowly add it dropwise to the reaction system. Allow the mixture to rise naturally to room temperature until the benzyl alcohol is completely consumed. Filter to remove the solid, concentrate the product, and perform column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain oily benzyl bromide product 9 (600 mg, 55% yield).

[0139] 1 H NMR (500MHz, CDCl3) δ7.60-7.53(m,4H),7.39(dd,J=10.3,4.7Hz,4H),7.35-7.28(m,4H),4.54(s,2H),0.68(d,J=2.8Hz,9H),-0.79(s,6H).

[0140] Example 6: Synthesis of benzyl bromide derivative 13a:

[0141]

[0142] Step 1:

[0143]

[0144] In a 1L three-necked round-bottom flask, a magnetic stir bar was added sequentially. Under a nitrogen atmosphere, tert-butyl((3,5-dibromo-4-(tert-butoxy)benzyl)oxy)dimethylsilane (40.5 mmol, 20.0 g), phenylboronic acid (4.0 eq.), sodium carbonate (15 eq.), and lithium chloride (3 eq.) were added. 1,4-dioxane and water (2:1, 300 mL) were used as solvents. The mixture was bubbled with argon for 45 minutes, followed by the addition of tetrakis(triphenylphosphine)palladium (10 mol%). The temperature was raised to 90°C, and the reaction was carried out at this temperature for 21 hours. After the reaction was completed, the temperature was lowered to room temperature, water was added, and the mixture was stirred for 30 minutes. The mixture was extracted with dichloromethane (5 x 100 mL), dried over sodium sulfate, and concentrated to obtain the crude product. The purified product by column chromatography (petroleum ether / ethyl acetate = 10:1) (18.8 g, 95% yield) was obtained as an oily product 11.

[0145] Under a nitrogen atmosphere and in an ice bath, TBAF (46 mmol, 46 mL 1 M in THF) was added dropwise to a solution of compound 11 dissolved in tetrahydrofuran. After the addition was complete, the reaction was allowed to proceed at room temperature for 2.5 h, and then quenched with a saturated ammonium chloride solution. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound 12 (12.1 g, 95% yield).

[0146] Step 2:

[0147]

[0148] Add a stir bar to a dry 250 mL Shrek flask, then add triphenylphosphine (3 eq.), carbon tetrabromide (3 eq.), and imidazole (3 eq.) sequentially to the reaction flask. Add 120 mL of dry dichloromethane as a solvent, and place the flask in an ice bath with stirring for 10 minutes. Dissolve the product from the previous step, benzyl alcohol (18 mmol, 6.0 g), in dichloromethane and slowly add it dropwise to the reaction system. Allow the mixture to rise naturally to room temperature until the benzyl alcohol is completely consumed. Filter to remove the solid, concentrate the product, and perform column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain an oily benzyl bromide product 9 (5.8 g, 82% yield).

[0149] 1 H NMR (500MHz, CDCl3) δ7.62-7.57(m,4H),7.40(t,J=7.5Hz,4H),7.35-7.29(m,4H),4.55(s,2H),0.59(s,10H);

[0150] Example 7: Synthesis of benzyl bromide derivative 13b: (Synthetic method is the same as 13a)

[0151]

[0152]

[0153]

[0154] Column chromatography (petroleum ether / ethyl acetate = 10:1), colorless oil, 2.8 g, 80% yield. 1 H NMR (500MHz, CDCl3) δ7.30 (s, 2H), 6.85 (s, 4H), 5.14 (s, 2H), 3.91 (d, J = 13.0Hz, 19H), 0.71 (s, 9H).

[0155] Example 8: Synthesis of chiral quaternary ammonium salt compound IA

[0156]

[0157]

[0158] A dry 50 mL round-bottom flask was stirred with a stir bar. Hydroxyl-protected C-PYR (2.0 mmol, 1.1 g) was dissolved in a mixed solvent of dichloromethane / acetonitrile (v1 / v2 = 4:1), and then the corresponding benzyl bromide (2.0 mmol, 0.8 g) was added to the reaction system. The reaction mixture was stirred at room temperature until the reaction was complete. The solvent was removed by vacuum concentration, and the crude product was purified by column chromatography to obtain the target catalyst (dichloromethane / methanol / triethylamine = 100:1:0.1-10:1:0.01).

[0159] White solid, 1.5g, yield: 79%. 1H NMR (500MHz, CDCl3) δ9.16(d,J=8.4Hz,1H),8.89(d,J=4.5Hz,1H),8.14(t,J=7.3Hz,1H),8.09(t,J=7.6Hz,1H),7.87(q,J=9.5Hz,2H ),7.85-7.77(m,2H),7.77-7.65(m,3H),7.65-7.52(m,3H),7.49-7.39(m,3H),7.34-7.28(m,1H),7.12(t,J=7.8Hz,2H),6.43(d,J=11 .7Hz,1H),5.65(t,J=11.1Hz,1H),5.13-5.00(m,2H),5.00-4.91(m,2H),4.20(d,J=11.7Hz,1H),3.38(t,J=11.3Hz,1H),3.12(dd,J=1 5.5,5.9Hz,1H),2.77(dd,J=21.2,9.7Hz,1H),2.38-2.15(m,2H),2.00-1.82(m,2H),1.82-1.65(m,1H),1.30(dt,J=14.9,7.7Hz,1H); 13 C NMR (500MHz, CDCl3) δ164.6,163.2,161.6,149.3,148.5,139.9,134.8,134.4,134.0,13 2.0,131.9,130.8,130.7,130.1,129.7,129.6,129.4,129.3,128.5,128.3,126.6,125. 2,124.6,119.0,118.6,118.5,72.5,64.8,61.7,56.1,54.9,38.4,27.4,23.4,23.1;IR( CHCl3)ν3051,2913,2193,1574,1516,1409,1352,1217,1124,1003,923,844,754,703cm -1 HRMS(ESI / [M-Br] + )Calcd.forC 42 H 38 N4OCl, m / z 649.2734, found m / z 649.2733.

[0160] Example 8: Synthesis of chiral quaternary ammonium salt compound IB (2.0 mmol)

[0161]

[0162] White solid, 1.4g, yield: 77%. 1 H NMR (500MHz, CDCl3) δ9.19(t,J=12.8Hz,1H),8.88(d,J=4.5Hz,1H),8.15(d,J=8.4Hz,1H),8.12-8.03(m,1H),7.93-7.82(m,2H) ,7.77(d,J=7.5Hz,2H),7.69(s,2H),7.59(t,J=13.4Hz,5H),7.48(s,4H),7.41(t,J=7.5Hz,6H),7.33(q,J=7.2Hz,4H),7.16(t,J =7.8Hz,2H),6.53(d,J=11.8Hz,1H),5.75-5.55(m,1H),5.17-4.99(m,3H),4.99-4.82(m,1H),4.24(d,J=11.8Hz,1H),3.40-3.2 6(m,1H),3.03-2.81(m,2H),2.38-2.13(m,2H),1.93-1.64(m,3H),1.31-1.14(m,1H),0.67(s,11H),-0.81(s,3H),-0.82(s,3H); 13 C NMR (100MHz, CDCl3) δ164.8,163.2,161.6,152.0,149.2,148.5,140.0,138.4,135.9,135.6,134.9 ,134.3,132.0,131.8,130.7,130.2,130.1,129.6,129.4,129.3,128.5,128.4,128.4,127.6,125. 3,124.6,120.0,118.8,118.7,72.9,64.7,61.2,55.9,54.6,38.2,27.3,26.1,23.3,23.0,18.3,-4 .8;IR(CHCl3)ν2950,2904,1575,1515,1463,1411,1362,1249,1215,1005,925,893,841,750,702cm -1 HRMS(ESI / [M-Br] + )Calcd.for C 60 H 60 N4O2ClSi, m / z 931.4174, found m / z 931.4161.

[0163] Example 9: Phase transfer catalysts IA and IB applied to asymmetric catalytic reactions

[0164]

[0165] At -20°C, KOH (0.3 μL, 50 wt% aq. 10 mol%) was added to a solution of imine 1A (6.2 mg, 0.025 mmol), enal 8a (4.2 μL, 0.05 mmol), and catalyst cat.a or cat.b (0.0025 mmol, 1.0 mol%) in toluene (0.25 mL). The mixture was then vigorously stirred, and the solution turned purple after a few minutes. The reaction was monitored at 10 min, 30 min, and 2 h. A 50 μL volume of the mixture was rapidly passed through a column lined with silica (5 mm thick) and washed with Et2O (0.5 mL × 3). The filtrates were combined, and the resulting pale yellow liquid was concentrated under vacuum. 19 F NMR and 1 H NMR analysis.

[0166] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing a chiral phase transfer catalyst, wherein the catalyst has the structure shown in the following formula: ； in, The compound of formula I has the structure shown in formula Ia or Ib: ； R1 is a substituted or unsubstituted pyrimidine; R2 is selected from the following group: or ; R3 is selected from the following group: H, substituted or unsubstituted C1-C4 alkoxy groups; X is a halide anion; The substitution refers to the substitution of one or more hydrogen atoms on the group by a substituent selected from the group consisting of: halogen, phenyl, 5-7 membered heteroaryl, C1-C4 alkyl; The method is characterized by comprising the following steps: (1) 9-OH protection: Reacting the starting material of formula 1a or 1b with the starting material of formula 2 to obtain the compound of formula 3a or 3b: (2) Reaction of 3a or 3b with R2Br yields compound Ia or Ib: ； The method further includes the following steps: (i) When R2 is The R2Br is prepared by the following method: In a nitrogen atmosphere and under palladium catalysis, compound 6 was coupled with boric acid in an organic solvent to give the multisubstituted benzyl alcohol derivative compound 8. Compound 8 reacts with triphenylphosphine, carbon tetrabromide and imidazole to give benzyl bromide derivative 9; (ii) When R2 is The R2Br is prepared by the following method: ； In an organic solvent, compound 11 reacts with TBAF to give a deprotected benzyl alcohol derivative 12; Compound 12 was reacted with triphenylphosphine, carbon tetrabromide and imidazole to obtain benzyl bromide derivative 13; Wherein, R is one or more substituents located on the phenyl group selected from the following groups: H, halogen, phenyl, 5-7 membered heteroaryl, C1-C4 alkyl.

2. The method as described in claim 1, characterized in that, Step (1) is carried out in the presence of a base, wherein the base is potassium hydroxide.

3. The method as described in claim 1, characterized in that, Step (1) includes: reacting compound 1a or 1b with R1Cl at 85-95°C for 1-5 hours in an organic solvent under a nitrogen atmosphere to prepare compound 3a or 3b; in step (1), the organic solvent is selected from the group consisting of toluene, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof.

4. The method as described in claim 1, characterized in that, Compound Ia or Ib is prepared by reacting compound 3a or 3b with R2Br at 0-30°C for 24-72 hours in an organic solvent under a nitrogen atmosphere; in step (2), the organic solvent is selected from the group consisting of dichloromethane, acetonitrile, or combinations thereof.

5. The method as described in claim 1, characterized in that, In step (i), the organic solvent is selected from the group consisting of dichloromethane, toluene, 1,4-dioxane, chloroform, methanol, diethyl ether, N,N-dimethylformamide, acetonitrile, water, or combinations thereof.

6. The method as described in claim 1, characterized in that, In step (ii), the organic solvent is selected from the group consisting of dichloromethane, toluene, 1,4-dioxane, chloroform, methanol, diethyl ether, N,N-dimethylformamide, acetonitrile, water, tetrahydrofuran, or combinations thereof.

7. The method as described in claim 1, characterized in that, In the method, step (i) further includes: Compound 4 was protected with TBSCl in the presence of a base under a nitrogen atmosphere to obtain compound 5; Compound 5 was reduced in an organic solvent by sodium borohydride to give compound 6.

8. The method as described in claim 1, characterized in that, In the method, step (ii) further includes: Compound 10 was reacted with substituted or unsubstituted phenylboronic acid compounds under a nitrogen atmosphere and with palladium catalysis to prepare compound 11. Wherein, R is one or more substituents located on the phenyl group selected from the group consisting of halogen, phenyl, 5-7 heteroaryl, and C1-C4 alkyl.

9. The method as described in claim 1, characterized in that, In general formula I: R1 is a substituted or unsubstituted pyrimidine; R3 is selected from the following group: H, substituted or unsubstituted C1-C2 alkoxy groups; X represents a bromide ion.

10. The method as described in claim 1, characterized in that, In general formula I: R1 is a substituted or unsubstituted pyrimidine; R3 is selected from the following group: H, substituted or unsubstituted C1-C2 alkoxy groups.

11. The method as described in claim 1, characterized in that, The compound of formula I is selected from the group consisting of compounds or their enantiomers: 。

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