Synthesis method of procyanidine B3

Abstract

The invention provides a synthesis method of procyanidine B3. Specifically, the invention provides a preparation method of a compound 6, which comprises the following steps: in a solvent, under the action of a catalyst, a compound 4 and a compound 5 are subjected to a condensation reaction to obtain the compound 6, the catalyst is (R) 3SiOTf, and R is independently C1-4 alkyl or phenyl. The preparation method provided by the invention is low in cost, simple and convenient to operate and good in industrial application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a synthetic method of procyanidin B3. BACKGROUND

[0002] Procyanidin B3, CAS No. 23567-23-9, molecular formula: C30H26O12, molecular weight: 578.52, structural formula as follows:

[0003]

[0004] Procyanidin B3 has antioxidant effect and various biological activities, such as neuroprotection, anti-inflammatory, antitumor, antibacterial, antiviral, hypoglycemic, etc., and has high application value in the field of medicine.

[0005] At present, the method for preparing procyanidin B3 is mainly to extract it from plants and then purify it by using modern separation technology. Due to the complex stereostructure of oligomeric procyanidins and the low relative content of procyanidin B3, the cost of obtaining procyanidin B3 by using extraction and purification is high. The method of organic synthesis can realize the small-scale synthesis of procyanidin B3, but the synthesis process is complex, involving multiple reaction steps such as phenolic hydroxyl protection, C4 activation, 3-hydroxyl protection, C8 blocking, condensation, deprotection, etc. Among them, compared with other protecting groups, benzyl is the main choice of protecting groups due to its stability and mild deprotection conditions.

[0006] In "Synthetic studies of proanthocyanidins. Part 2: Stereoselective gram-scale synthesis of procyanidin-B3, DOI: 10.1016 / s0040-4020(02)00936-5", a synthetic route of procyanidin B3 is disclosed as follows, wherein the condensation reaction, hydrolysis reaction and hydrogenolysis reaction all need to use column chromatography for purification:

[0007]

[0008] "Synthesis of Procyanidin B3 and Its Anti-inflammatory Activity. The Effect of 4-Alkoxy Group of Catechin Electrophile in the Yb(OTf)3-Catalyzed Condensation with Catechin Nucleophile, DOI: 10.1021 / jo1009382" discloses a synthesis route two of procyanidin B3 as follows, wherein the condensation reaction, the hydrolysis reaction and the hydrogenolysis reaction all need to use column chromatography for purification:

[0009]

[0010] The above prior art needs multi-step column chromatography purification, the cost of large-scale synthesis is high, and the condensation reaction process has defects. Specifically, the condensation strategy represented by route one needs a large excess of raw materials to reduce the production of polymers, and the atomic utilization rate is low; the equimolar condensation strategy represented by route two also cannot avoid column chromatography purification, and relies on rare earth metals as catalysts.

[0011] The condensation reaction plays an important role in the synthesis of oligomeric procyanidins, and the conditions of the condensation reaction determine the yield, the degree of polymerization and the diastereomeric ratio of the product, and also determine the selection of the condensation reaction raw materials, thereby affecting the entire synthesis route. Therefore, for the condensation reaction, if appropriate protecting groups, leaving groups and blocking groups are selected to construct the condensation reaction raw materials, and appropriate condensation reaction conditions are used to make the raw materials react completely, the atomic utilization rate, the yield and the stereoselectivity of the reaction can be improved, column chromatography purification can be avoided, the cost of large-scale synthesis can be reduced, and the industrialization of procyanidin B3 is very important. SUMMARY

[0012] The technical problem to be solved by the present application is to overcome the defects of large raw material loss and complex operation of the existing procyanidin B3 synthesis method. To this end, the present application provides a synthesis method of procyanidin B3. The synthesis method of procyanidin B3 provided by the present application has high yield, low cost, high atomic utilization rate, simple operation and good industrial application prospect.

[0013] The present application solves the above technical problems through the following scheme.

[0014] The present application provides a compound 6 or a compound 4;

[0015]

[0016] The present invention provides a method for preparing compound 6, which includes the following steps: in a solvent, under the action of a catalyst, compound 4 and compound 5 are subjected to a condensation reaction to obtain compound 6;

[0017]

[0018] The catalyst is (R)3SiOTf, where each R is independently C. 1-4 Alkyl or phenyl.

[0019] In one embodiment, the solvent in the condensation reaction is selected from one or more of haloalkane solvents, ether solvents, and aromatic hydrocarbon solvents, preferably haloalkane solvents.

[0020] In one embodiment, the condensation reaction is carried out by a chloro-C1-C4 alkane solvent, preferably selected from one or more of dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, and chloroform, such as dichloromethane.

[0021] In one embodiment, the ether solvent in the condensation reaction is selected from one or more of 1,4-dioxane, tetrahydrofuran, diethyl ether, and methyl tert-butyl ether.

[0022] In one embodiment, the aromatic hydrocarbon solvent in the condensation reaction is selected from one or more of toluene, xylene, and ethylbenzene.

[0023] In one embodiment, the solvent in the condensation reaction is selected from one or more of dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, 1,4-dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, toluene, xylene, and ethylbenzene, for example, dichloromethane.

[0024] In one scheme, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, such as methyl.

[0025] In one embodiment, the chlorinated C 1-4 C in alkanes 1-4 The alkanes are methane, ethane, n-propane, or isopropane, such as chloromethane.

[0026] In one embodiment, the catalyst in the condensation reaction is selected from one or more of trimethyl trifluoromethanesulfonate (TMSOTf), tert-butyl dimethyl trifluoromethanesulfonate (TBSOTf), triethyl trifluoromethanesulfonate (TESOTf), triisopropyl trifluoromethanesulfonate (TIPSOTf), and tert-butyl diphenyl trifluoromethanesulfonate (TBDPSOTf), for example, trimethyl trifluoromethanesulfonate (TMSOTf).

[0027] In one embodiment, the molar volume of compound 4 to the solvent in the condensation reaction is 0.02 to 0.4 mol / L, for example 0.04 mol / L.

[0028] In one embodiment, the molar ratio of compound 4 to compound 5 in the condensation reaction is 1 : 0.8-1 : 1.5, for example 1 : 1.

[0029] In one embodiment, the molar ratio of compound 4 to the catalyst in the condensation reaction is 1 : 0.01-1 : 2, for example 1 : 1.

[0030] In one embodiment, the condensation reaction is carried out at -80°C to -40°C, preferably at -80°C to -60°C, for example at -50°C, -70°C or -60°C.

[0031] The progress of the condensation reaction is monitored by conventional methods for such reactions in the art, for example HPLC, TLC, etc. Preferably, the reaction is terminated when compound 5 or 4 is completely converted or compound 6 is no longer formed. The reaction time can be 5 min to 6 h, for example 30 min.

[0032] In one embodiment, the condensation reaction is carried out using the solvent (for example dichloromethane), the catalyst (for example trimethylsilyl triflate (TMSOTf)), compound 4 and compound 5 as starting materials.

[0033] In one embodiment, the condensation reaction comprises the following work-up steps: after the reaction is completed, quenching (for example with saturated aqueous sodium bicarbonate solution), washing (for example with aqueous sodium chloride solution), separation, concentration (for example under vacuum), and preferably, after concentration, the subsequent reaction (i.e. the subsequent hydrolysis reaction) is carried out directly.

[0034] In one embodiment, after concentration, the work-up step comprises purification, for example chromatography on silica gel (preferably, in the chromatography, the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3 : 1), to obtain compound 6.

[0035] In one embodiment, the method for preparing compound 6 comprises the following step: condensation of compound 4 and compound 5 in the presence of a catalyst at -80 to -60°C in a chlorinated C1-C4 alkane solvent to obtain compound 6; the catalyst is trimethylsilyl triflate.

[0036] In one embodiment, the condensation reaction comprises the following steps: at -80°C to -60°C, in a chlorinated C1-C4 alkane solvent, under the action of trimethylsilyl trifluoromethanesulfonate, compound 4 and compound 5 undergo a condensation reaction to obtain compound 6. After the reaction is completed, the mixture is quenched, washed, separated, and concentrated; preferably, the concentrated mixture is directly used for subsequent reactions.

[0037] In one embodiment, the method for preparing compound 6 further comprises the steps described in embodiment 1 or embodiment 2:

[0038] Scheme 1 includes the following steps: in a solvent, in the presence of a base, and under the action of a catalyst, compound 2 undergoes an acetylation reaction with an acylation reagent to obtain compound 4;

[0039]

[0040] Scheme 2 includes the following steps: in a solvent, compound 3 undergoes a bromination reaction with a brominating reagent to obtain compound 4;

[0041]

[0042] In Scheme 1, the solvent is a conventional solvent for this type of reaction in the art, preferably a haloalkane solvent.

[0043] In Scheme 1, the haloalkane solvent may be a chlorinated C1-C4 alkane solvent, preferably selected from one or more of dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane and chloroform, such as dichloromethane.

[0044] In Scheme 1, the chlorinated C 1-4 C in alkanes 1-4 Alkanes can be methane, ethane, n-propane, or isopropane, such as chloromethane.

[0045] In Scheme 1, the catalyst in the acetylation reaction is a conventional catalyst for such reactions in the art, such as 4-dimethylaminopyridine (DMAP).

[0046] In Scheme 1, the base used in the acetylation reaction is a base commonly used in this type of reaction in the art, preferably an organic base, such as triethylamine.

[0047] In Scheme 1, the acylation reagent is a conventional acylation reagent for this type of reaction in the art, such as acetic anhydride.

[0048] In Scheme 1, the molar volume of compound 2 and solvent is conventional for such reactions in the art, preferably 0.02 to 0.4 mol / L, for example 0.07 mol / L.

[0049] The molar ratio of compound 2 to the catalyst in Scheme 1 is conventional in the art for such reactions, preferably 1 :0.01 to 1 :0.2, for example 1 :0.05.

[0050] The molar ratio of compound 2 to the base in Scheme 1 is conventional in the art for such reactions, preferably 1 :1 to 1 :5, for example 1 :2.5 or 1 :2.4.

[0051] The molar ratio of compound 2 to the acylating agent in Scheme 1 is conventional in the art for such reactions, preferably 1 :0.8 to 1 :3, for example 1 :1.2 or 1 :1.1.

[0052] The acetylation reaction in Scheme 1 is carried out at a temperature conventional in the art for such reactions, for example 0 °C to 50 °C, for example the acylating agent is added at 5-10 °C, and the acetylation reaction is carried out at 0 °C to 50 °C, for example 25 °C.

[0053] The progress of the acetylation reaction in Scheme 1 is monitored using conventional methods for such reactions in the art, for example HPLC, TLC, and the like. Preferably, the reaction is terminated when compound 2 is completely converted or compound 4 is no longer formed. The reaction time can be 1-12 h, for example 3 h.

[0054] The acetylation reaction in Scheme 1 can be carried out from the starting materials, i.e. the solvent (e.g. dichloromethane), the catalyst (e.g. 4-dimethylaminopyridine), the base (e.g. triethylamine), compound 2 and the acylating agent (e.g. acetic anhydride).

[0055] Preferably, in Scheme 1, the acetylation reaction is carried out by adding the catalyst, the base and the acylating agent to a mixture of compound 2 and the solvent.

[0056] The acetylation reaction in Scheme 1 can comprise the following work-up steps: after the reaction is completed, washing (e.g. with water), adjusting the pH (e.g. to a pH of 6 in the aqueous phase, preferably using 10% aqueous hydrochloric acid), partitioning, washing (e.g. with saturated aqueous sodium chloride), drying (e.g. over anhydrous sodium sulfate); preferably, the subsequent reaction (i.e. the subsequent condensation reaction) is carried out directly after drying.

[0057] In the work-up steps in Scheme 1, preferably, compound 4 is obtained after drying and concentration (e.g. under vacuum).

[0058] In Scheme 1, the acetylation reaction preferably includes the following steps: at 0°C to 50°C, in the presence of the base in the chlorinated C1-C4 alkane solvent, under the action of 4-dimethylaminopyridine, compound 2 and the acylation reagent undergo an acetylation reaction to obtain compound 4. After the reaction is completed, the mixture is washed, pH is adjusted, separated, washed again, and dried. Preferably, subsequent reactions are carried out directly after drying.

[0059] In Scheme 2, the solvent is a conventional solvent for such reactions in the art, preferably selected from one or more of nitrile solvents, haloalkane solvents, ether solvents, nitrogen-containing compound solvents, ketone solvents and ester solvents, for example, haloalkane solvents.

[0060] In Scheme 2, the nitrile solvent can be acetonitrile.

[0061] In Scheme 2, the haloalkane solvent may be a chlorinated C1-C4 alkane solvent, preferably selected from one or more of dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, chloroform and carbon tetrachloride, such as dichloromethane.

[0062] In Scheme 2, the chlorinated C 1-4 C in alkanes 1-4 Alkanes can be methane, ethane, n-propane, or isopropane, such as chloromethane.

[0063] In Scheme 2, the ether solvent may be selected from one or more of 1,4-dioxane, tetrahydrofuran, diethyl ether, and methyl tert-butyl ether.

[0064] In Scheme 2, the nitrogen-containing compound solvent may be N,N-dimethylformamide.

[0065] In Scheme 2, the ketone solvent may be acetone.

[0066] In Scheme 2, the ester solvent may be ethyl acetate.

[0067] In Scheme 2, the solvent may be selected from one or more of acetonitrile, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, 1,4-dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, N,N-dimethylformamide, acetone, toluene, xylene, and ethylbenzene, for example, the solvent may be dichloromethane.

[0068] In the Scheme 2, the bromination reagent is a conventional bromination reagent for such reaction in the art, preferably selected from bromine, N-bromosuccinimide (NBS), N-bromophthalimide (NBP), 1,3,5-tribromo-1,3,5-thiazinan-2,4,6-trione (TBCA), N-bromoacetamide (NBA), 2-bromo-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (NBSac) and dibromoisocyanuric acid urine one or more of the acids (DBI), for example the brominating agent is N-bromosuccinimide (NBS).

[0069] In the Scheme 2, the bromination reaction can be carried out in a protective gas, which is a conventional protective gas for such reaction in the art, for example, nitrogen.

[0070] In the Scheme 2, the molar volume of the compound 3 to the solvent is conventional for such reaction in the art, preferably 0.02 to 0.4 mol / L, for example, 0.135 mol / L.

[0071] In the Scheme 2, the molar ratio of the compound 3 to the bromination reagent is conventional for such reaction in the art, preferably 1:0.8 to 1:2, for example, 1:1.03.

[0072] In the Scheme 2, the bromination reaction is carried out at a conventional temperature for such reaction in the art, preferably 0 °C to 50 °C, for example, 25 °C.

[0073] In the Scheme 2, the progress of the bromination reaction is detected by a conventional monitoring method for such reaction in the art, for example, HPLC, TLC, etc. Preferably, the reaction end point is that the compound 3 is completely converted or the compound 4 is no longer generated. The reaction time can be 1-12 h, for example, 3 h.

[0074] In the Scheme 2, the raw materials for the bromination reaction can be the solvent (for example, dichloromethane), the compound 3 and the bromination reagent (for example, N-bromosuccinimide).

[0075] In the Scheme 2, the bromination reaction can comprise the following post-treatment steps: after the reaction is completed, washing (for example, washing with aqueous sodium thiosulfate), liquid separation, drying (for example, drying with anhydrous sodium sulfate); preferably, after drying, the subsequent reaction (i.e., the subsequent condensation reaction) is directly carried out.

[0076] In the Scheme 2, in the post-treatment step, preferably, after liquid separation, concentration (for example, vacuum concentration) and purification, for example, silica gel chromatography purification (preferably, in the chromatography purification, the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1), to obtain the compound 4.

[0077] In Scheme 2, the bromination reaction may include the following steps: at 0°C to 50°C, compound 3 and the brominating reagent undergo a bromination reaction in the chlorinated C1-C4 alkane solvent to obtain compound 4. After the reaction is completed, the mixture is washed, separated, and dried; preferably, subsequent reactions are carried out directly after drying.

[0078] In one embodiment, the preparation method of compound 6 further includes the following steps: in a solvent, compound 1 undergoes a bromination reaction A with a brominating reagent to obtain compound 2;

[0079]

[0080] In the bromination reaction A, the solvent is a conventional solvent for such reactions in the art, preferably selected from one or more of nitrile solvents, haloalkane solvents, ether solvents, nitrogen-containing compound solvents, ketone solvents and ester solvents, for example, haloalkane solvents.

[0081] In the bromination reaction A, the nitrile solvent may be acetonitrile.

[0082] In the bromination reaction A, the haloalkane solvent may be a chlorinated C1-C4 alkane solvent, preferably selected from one or more of dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride, such as dichloromethane.

[0083] In the bromination reaction A, the chlorinated C 1-4 C in alkanes 1-4 Alkanes can be methane, ethane, n-propane, or isopropane, such as chloromethane.

[0084] In the bromination reaction A, the ether solvent may be selected from one or more of 1,4-dioxane, tetrahydrofuran, diethyl ether, and methyl tert-butyl ether.

[0085] In the bromination reaction A, the nitrogen-containing compound solvent can be N,N-dimethylformamide.

[0086] In the bromination reaction A, the ketone solvent may be acetone.

[0087] In the bromination reaction A, the ester solvent may be ethyl acetate.

[0088] In the bromination reaction A, the solvent may be selected from one or more of acetonitrile, dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, 1,4-dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, N,N-dimethylformamide, acetone, toluene, xylene, and ethylbenzene, for example, the solvent may be dichloromethane.

[0089] In the bromination reaction A, the bromination reagent is one or more selected from the group consisting of bromine, N-bromosuccinimide (NBS), N-bromophthalimide (NBP), 1,3,5-tribromo-1,3,5-thiazinan-2,4,6-trione (TBCA), N-bromoacetamide (NBA), 2-bromo-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (NBSac) and dibromoisocyanuric acid (DBI), for example the bromination reagent is N-bromosuccinimide (NBS).

[0090] In the bromination reaction A, the bromination reaction A can be carried out in a protective gas, which is a protective gas conventional for such reactions in the art, for example nitrogen.

[0091] In the bromination reaction A, the molar volume of compound 1 to the solvent is conventional for such reactions in the art, for example 0.02 to 0.4 mol / L, for example 0.135 mol / L.

[0092] In the bromination reaction A, the molar ratio of compound 1 to the bromination reagent is conventional for such reactions in the art, preferably 1:0.8 to 1:2, for example 1:1.03.

[0093] In the bromination reaction A, the bromination reaction A is carried out at a temperature conventional for such reactions in the art, for example 0 °C to 50 °C, for example 25 °C.

[0094] In the bromination reaction A, the progress of the bromination reaction is detected using a method of monitoring conventional for such reactions in the art, for example HPLC, TLC, etc. Preferably, the reaction endpoint is taken as the complete conversion of compound 1 or the non-formation of compound 2. The reaction time can be 1-12 h, for example 3 h.

[0095] In the bromination reaction A, the starting materials of the bromination reaction A can be the solvent (for example dichloromethane), the bromination reagent (for example N-bromosuccinimide (NBS)) and compound 1. compounds 1 and the brominating agent (for example N-bromosuccinimide). one, for example methanol.

[0096] In the bromination reaction A, the bromination reaction A can comprise the following work-up steps: after the reaction is completed, washing (for example washing with aqueous sodium thiosulfate), liquid separation, drying (for example drying with anhydrous sodium sulfate); preferably, after drying, the subsequent reaction (i.e. the subsequent acetylation reaction) is carried out directly.

[0097] In the work-up steps of the bromination reaction A, after liquid separation, concentration (for example vacuum concentration) and purification, for example silica gel chromatography purification (preferably, in the chromatography purification, the mobile phase is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1), compound 2 is obtained.

[0098] The bromination reaction A may include the following steps: at 0°C to 50°C, compound 1 and the brominating reagent undergo a bromination reaction in the chlorinated C1-C4 alkane solvent to obtain compound 2. After the reaction is completed, the mixture is washed, separated, and dried; preferably, the subsequent reaction is carried out directly after drying.

[0099] In one embodiment, the preparation method of compound 6 further includes the following steps: in a solvent, in the presence of a base, and under the action of a catalyst, compound 1 undergoes an acetylation reaction A with an acylation reagent to obtain compound 3;

[0100]

[0101] In the acetylation reaction A, the solvent is a conventional solvent for such reactions in the art, preferably a haloalkane solvent.

[0102] In the acetylation reaction A, the haloalkane solvent may be a chlorinated C1-C4 alkane solvent, preferably selected from one or more of dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane and chloroform, such as dichloromethane.

[0103] In the acetylation reaction A, the chlorinated C 1-4 C in alkanes 1-4 Alkanes can be methane, ethane, n-propane, or isopropane, such as chloromethane.

[0104] In the acetylation reaction A, the catalyst is a conventional catalyst for such reactions in the art, such as 4-dimethylaminopyridine (DMAP).

[0105] In the acetylation reaction A, the base is a base commonly used in this type of reaction in the art, preferably an organic base, such as triethylamine.

[0106] In the acetylation reaction A, the acylation reagent is a conventional acylation reagent for such reactions in the art, such as acetic anhydride.

[0107] In the acetylation reaction A, the molar volume of compound 1 and the solvent is conventional for such reactions in the art, for example, 0.02 to 0.4 mol / L, such as 0.07 mol / L or 0.27 mol / L.

[0108] In the acetylation reaction A, the molar ratio of compound 1 to the catalyst is conventional for such reactions in the art, preferably 1:0.01 to 1:0.2, for example 1:0.05.

[0109] In the acetylation reaction A, the molar ratio of compound 1 to the base is conventional for such reactions in the art, preferably 1:1 to 1:5, for example 1:2.5 or 1:2.4.

[0110] The molar ratio of compound 1 to acylating reagent in the acetylation reaction A is conventional in the art for such reactions, preferably 1 :0.8 to 1 :3, for example 1 :1.2 or 1 :1.1.

[0111] The acetylation reaction A is carried out at a temperature conventional in the art for such reactions, for example 0°C to 50°C, for example 5-10°C, preferably the acylating reagent is added at 0°C to 50°C, for example 25°C, and the acetylation reaction is carried out at 0°C to 50°C, for example 25°C.

[0112] The progress of the acetylation reaction A is monitored using conventional methods for such reactions in the art, for example HPLC, TLC, etc. Preferably the reaction is terminated when compound 1 is completely converted or compound 3 is no longer formed. The reaction time can be 1-12h, for example 3h.

[0113] The starting materials for the acetylation reaction A can be the solvent (for example dichloromethane), the catalyst (for example 4-dimethylaminopyridine), the base (for example triethylamine), compound 1 and the acylating reagent (for example acetic anhydride) in the acetylation reaction A.

[0114] Preferably, the acylating reagent, the base and the catalyst are added to the mixture of compound 1 and the solvent in the acetylation reaction A.

[0115] The acetylation reaction A can comprise the following work-up steps: after the reaction is completed, washing (for example washing with water), adjusting the pH (for example adjusting the pH of the aqueous phase to 6, preferably using 10% hydrochloric acid aqueous solution), separating the phases, washing (for example washing with saturated aqueous sodium chloride), drying (for example drying over anhydrous sodium sulfate); preferably the subsequent reaction (i.e. the subsequent bromination reaction) is carried out directly after drying.

[0116] In the acetylation reaction A, preferably after drying, compound 3 is obtained by concentrating (for example concentrating under vacuum) in the work-up steps.

[0117] The acetylation reaction A can comprise the following steps: at 0°C to 50°C, in the presence of a base, in the presence of 4-dimethylaminopyridine, compound 1 and the acylating reagent are subjected to an acetylation reaction in a chlorinated C1-C4 alkane solvent to obtain compound 3, after the reaction is completed, washing, adjusting the pH, separating the phases, washing, drying; preferably the subsequent reaction is carried out directly after drying.

[0118] The present application provides a method for preparing compound 8, which comprises the following steps:

[0119] (1) obtaining compound 6 according to the method for preparing compound 6 described above

[0120]

[0121] (2) hydrolysis reaction of compound 6 in a solvent in the presence of a base to obtain compound 7;

[0122]

[0123] The base is MOH, and M is an alkali metal.

[0124] (3) hydrogenolysis reaction of compound 7 in a solvent in the presence of a base under the action of a catalyst to obtain compound 8;

[0125]

[0126] The solvent is a mixed solvent of an ether solvent and an alcohol solvent, and the base is an inorganic base.

[0127] In an embodiment, in the hydrolysis reaction, the solvent is selected from one or more of a nitrile solvent, an ether solvent, an alcohol solvent, an aromatic hydrocarbon solvent, and water, and is preferably a mixed solvent of an ether solvent and an alcohol solvent.

[0128] In an embodiment, in the hydrolysis reaction, the nitrile solvent is acetonitrile.

[0129] In an embodiment, in the hydrolysis reaction, the ether solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, diethyl ether, and methyl tert-butyl ether, and is preferably tetrahydrofuran.

[0130] In an embodiment, in the hydrolysis reaction, the alcohol solvent is selected from one or more of methanol, ethanol, and isopropanol, and is preferably methanol.

[0131] In an embodiment, in the hydrolysis reaction, the aromatic hydrocarbon solvent is selected from one or more of toluene, xylene, and ethylbenzene.

[0132] In an embodiment, in the hydrolysis reaction, the solvent is selected from one or more of acetonitrile, 1,4-dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, toluene, xylene, ethylbenzene, methanol, ethanol, isopropanol, and water, and is preferably a mixed solvent of tetrahydrofuran and methanol, and more preferably a mixed solvent of tetrahydrofuran and methanol in a volume ratio of 2:3 (volume of tetrahydrofuran: volume of methanol).

[0133] In an embodiment, in the hydrolysis reaction, the base is MOH, and M is an alkali metal, and the alkali metal is preferably Na, K, or Li (the base is selected from one or more of lithium hydroxide, sodium hydroxide, and potassium hydroxide), and more preferably the base is NaOH.

[0134] In an embodiment, in the hydrolysis reaction, the molar volume of compound 6 to the solvent is 0.02 to 0.14 mol / L, and more preferably 0.07 mol / L.

[0135] In one embodiment, the molar ratio of compound 6 to base in the hydrolysis reaction is 1 : 1 to 1 : 10, such as 1 : 2, 1 : 3, 1 : 4, or 1 : 5.

[0136] In one embodiment, the hydrolysis reaction is carried out at 40-80 °C, such as 62 °C, preferably at reflux temperature when the solvent is a mixture of tetrahydrofuran and methanol.

[0137] The progress of the hydrolysis reaction is monitored by conventional methods for monitoring such reactions in the art, such as HPLC, TLC, and the like. The reaction is preferably terminated when compound 6 is completely converted or compound 7 is no longer formed. The reaction time can be 0.5 h to 24 h, such as 4 h.

[0138] In one embodiment, the hydrolysis reaction comprises the following work-up steps: after the reaction is completed, the mixture is concentrated (e.g., under vacuum), an ester solvent (e.g., ethyl acetate) is added, the mixture is washed (e.g., with saturated aqueous sodium chloride), the mixture is separated, and the mixture is concentrated (e.g., under vacuum); preferably, the second concentration is directly followed by a subsequent reaction (i.e., a subsequent hydrogenolysis reaction).

[0139] In one embodiment, the hydrolysis reaction comprises the following work-up steps: after the reaction is completed, the mixture is concentrated (e.g., under vacuum), an ester solvent (e.g., ethyl acetate) is added, the mixture is washed (e.g., with saturated aqueous sodium chloride), the mixture is separated, and the mixture is concentrated (e.g., under vacuum); preferably, the second concentration is directly followed by a subsequent reaction (i.e., a subsequent hydrogenolysis reaction).

[0140] In one embodiment, the hydrolysis reaction comprises the following work-up steps: after the reaction is completed, the mixture is concentrated (e.g., under vacuum), an ester solvent (e.g., ethyl acetate) is added, the mixture is washed (e.g., with saturated aqueous sodium chloride), the mixture is separated, and the mixture is concentrated (e.g., under vacuum); preferably, the second concentration is directly followed by a subsequent reaction (i.e., a subsequent hydrogenolysis reaction).

[0141] In one embodiment, the hydrolysis reaction comprises the following steps: compound 6 is subjected to a hydrolysis reaction in the presence of a base, MOH, wherein M is an alkali metal, in a mixture of an ether solvent and an alcohol solvent to obtain compound 7, the mixture is concentrated after the reaction is completed, an ester solvent is added, the mixture is washed, the mixture is separated, and the mixture is concentrated; preferably, the second concentration is directly followed by a subsequent reaction.

[0142] In one embodiment, the hydrogenolysis reaction is carried out in an ether solvent.

[0143] In one embodiment, the ether solvent in the hydrogenolysis reaction is selected from one or more of 1,4-dioxane, tetrahydrofuran, diethyl ether, and methyl tert-butyl ether, such as tetrahydrofuran.

[0144] In one embodiment, the alcohol solvent in the hydrogenolysis reaction is selected from one or more of methanol, ethanol, and isopropanol. In one aspect, the purification in the work-up step of the hydrogenolysis reaction is chromatographic purification, preferably chromatographic purification on a silica gel column.

[0145] In some embodiments, the solvent in the hydrogenolysis reaction is a mixture of tetrahydrofuran and methanol, preferably a mixture of tetrahydrofuran and methanol in a volume ratio of 1 :2 (volume of tetrahydrofuran: volume of methanol).

[0146] In some embodiments, the base in the hydrogenolysis reaction is an inorganic base, such as an alkali salt, wherein the anion is hydroxide, carbonate or bicarbonate, and the alkali is preferably Na, K or Li. For example, the base is sodium bicarbonate.

[0147] In some embodiments, the catalyst in the hydrogenolysis reaction is palladium hydroxide on carbon, preferably 20% palladium hydroxide on carbon (e.g., the palladium hydroxide on carbon contains 62.5% water).

[0148] In some embodiments, the hydrogenolysis reaction is the reaction of compound 7 with hydrogen (preferably in a hydrogen environment), and the hydrogen pressure is preferably 15 psi to 150 psi, such as 15 psi.

[0149] In some embodiments, the molar volume of compound 7 to the solvent in the hydrogenolysis reaction is 0.02 to 0.24 mol / L, such as 0.36 / 7.5 mol / L.

[0150] In some embodiments, the molar ratio of compound 7 to the base in the hydrogenolysis reaction is 1 :2 to 1 :3.5, such as 1 :3.

[0151] In some embodiments, the mass ratio of compound 7 to the catalyst in the hydrogenolysis reaction is 20: 1 to 1 : 1, such as 5: 1.

[0152] In some embodiments, the hydrogenolysis reaction is carried out at a temperature of 0 °C to 50 °C, preferably at 20 °C.

[0153] In some embodiments, the progress of the hydrogenolysis reaction can be monitored by conventional methods for monitoring such reactions in the art, such as HPLC, TLC, etc. Preferably, the reaction endpoint is the complete conversion of compound 7 or the absence of the formation of compound 8. The reaction time can be 1 h to 24 h, such as 6 h.

[0154] In some embodiments, the starting materials for the hydrogenolysis reaction are the solvent (e.g., a mixture of tetrahydrofuran and methanol), hydrogen, the base (e.g., sodium bicarbonate), the catalyst (e.g., palladium hydroxide on carbon), and compound 7.

[0155] In one embodiment, the hydrogenolysis reaction comprises a post-treatment step of adjusting the pH to 5 to 7 (e.g., adjusting the pH to 6, e.g., using acetic acid or ascorbic acid) after the reaction is completed, and purifying to obtain compound 8. Preferably, the hydrogenolysis reaction comprises a post-treatment step of adjusting the pH to 5 to 7 (e.g., using acetic acid or ascorbic acid) after the reaction is completed (preferably, purging with nitrogen), filtering (e.g., using a 0.45 μιη microporous filter), concentrating (e.g., vacuum concentration), purifying (e.g., using an ODS column), and drying (e.g., vacuum concentration and / or lyophilization) to obtain compound 8.

[0156] In one embodiment, the post-treatment step of the hydrogenolysis reaction comprises adjusting the pH to 5 to 7, preferably using an acid to adjust the pH, and the acid can be selected from one or more of hydrochloric acid, formic acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, ascorbic acid, citric acid, and salicylic acid, e.g., acetic acid or ascorbic acid, and further preferably, the molar ratio of compound 7 to the acid is 1 :0.8 to 1 :10, e.g., 1 :2.1.

[0157] In one aspect, the purification in the work-up step of the hydrogenolysis reaction is chromatographic purification, preferably chromatographic purification on a silica gel column. Synthesis of pyran-3-ol (2) In one embodiment, the filler used in the chromatographic purification is selected from one or more of silica gel, octadecylsilane-bonded silica gel (ODS), HW-40 gel resin, NKA-9 macroporous resin, YDKH-9 macroporous resin, ADS-7 macroporous resin, and ADS-21 macroporous resin, e.g., octadecylsilane-bonded silica gel (ODS).

[0158] In one embodiment, the post-treatment step of the hydrogenolysis reaction comprises using a mixture of dichloromethane, methanol, and water as the eluent in the chromatographic purification when the filler is silica gel, and the volume ratio of dichloromethane, methanol, and water can be (10-2): 1 :0.1, or using a mixture of methanol and water as the eluent when the filler is octadecylsilane-bonded silica gel (ODS), HW-40 gel resin, NKA-9 macroporous resin, YDKH-9 macroporous resin, ADS-7 macroporous resin, or ADS-21 macroporous resin, and the volume ratio of methanol and water can be 1 :19 to 1 :0.05, e.g., 1 :4.

[0159] In one embodiment, the hydrogenolysis reaction comprises the following steps: adding the inorganic base and the catalyst to a mixture of compound 7, the ether solvent, and the alcohol solvent, and performing the hydrogenolysis reaction under a hydrogen atmosphere (e.g., purging with nitrogen first and then purging with hydrogen) at 15 psi to 150 psi; adjusting the pH (e.g., using acetic acid), filtering (e.g., using a 0.45 μιη microporous filter), concentrating (e.g., vacuum concentration), purifying (e.g., chromatographic purification using an ODS column with a mixture of water and methanol as the eluent at a volume ratio of 4:1), and drying (e.g., concentration and / or lyophilization) to obtain compound 8 after the reaction is completed.

[0160] In one aspect, the method of preparing compound 8 comprises the following steps:

[0161] Step (1): preparing compound 2 or 3 according to the following Scheme 3 or Scheme 4;

[0162] Scheme 3 comprises the following step: bromination reaction A of compound 1 with a bromination reagent in a solvent to obtain compound 2;

[0163]

[0164] Scheme 4 comprises the following step: acetylation reaction A of compound 1 with an acetylation reagent in a solvent in the presence of a base and under the action of a catalyst to obtain compound 3;

[0165]

[0166] (2) preparing compound 4 according to the following Scheme 1 or 2;

[0167] Scheme 1 comprises the following step: acetylation reaction of compound 2 with an acetylation reagent in a solvent in the presence of a base and under the action of a catalyst to obtain compound 4;

[0168]

[0169] Scheme 2 comprises the following step: bromination reaction of compound 3 with a bromination reagent in a solvent to obtain compound 4;

[0170]

[0171] (3) condensation reaction of compound 4 and compound 5 in a solvent and under the action of a catalyst to obtain compound 6;

[0172]

[0173] The catalyst is (R)3SiOTf, and each R is independently C 1-4 alkyl or phenyl;

[0174] (4) hydrolysis reaction of compound 6 in a solvent in the presence of a base to obtain compound 7;

[0175]

[0176] The base is MOH, and M is an alkali metal;

[0177] (5) hydrogenolysis reaction of compound 7 in a solvent in the presence of a base and under the action of a catalyst to obtain compound 8;

[0178]

[0179] The solvent is a mixed solvent of an ether solvent and an alcohol solvent, and the base is an inorganic base.

[0180] The conditions and operations of the bromination reaction A, the acetylation reaction A, the acetylation reaction, the bromination reaction, the condensation reaction, the hydrolysis reaction, and the hydrogenolysis reaction are each independently as described in any one of the schemes of the present application.

[0181] The present application provides a preparation method of compound 7, comprising the following steps: in a solvent, in the presence of a base, compound 6 is subjected to a hydrolysis reaction to obtain compound 7.

[0182]

[0183] The base is MOH, and M is an alkali metal.

[0184] The solvent, the base, the compound 6, the hydrolysis reaction operation, and the conditions can be as described in any one of the technical solutions of the present application.

[0185] Preferably, the preparation method of compound 7 further comprises the preparation method of compound 6 described above.

[0186] The present application provides a preparation method of compound 8, comprising the following steps: in a solvent, in the presence of a base, under the action of a catalyst, compound 7 is subjected to a hydrogenolysis reaction to obtain compound 8.

[0187]

[0188] The solvent is a mixed solvent of an ether solvent and an alcohol solvent, and the base is an inorganic base.

[0189] The solvent, the inorganic base, the compound 7, and the hydrogenolysis reaction conditions and operations can be as described in any one of the technical solutions of the present application.

[0190] Preferably, the preparation method of compound 8 further comprises the preparation method of compound 7 described above.

[0191] The present application provides a preparation method of compound 4, comprising the steps described in scheme 1 or scheme 2:

[0192] Scheme 1 comprises the following steps: in a solvent, in the presence of a base, under the action of a catalyst, compound 2 is subjected to an acetylation reaction with an acylating agent to obtain compound 4.

[0193]

[0194] The conditions and operations of the solvent, the base, the catalyst, the compound 2, the acylating agent, and the acetylation reaction can be as described in any one of the schemes of the present application.

[0195] Scheme 2 comprises the following step: bromination reaction of compound 3 with a bromination reagent in a solvent to obtain compound 4;

[0196]

[0197] The solvent, the compound 3, the bromination reagent, and the conditions and operations of the bromination reaction can be as described in any one of the present application.

[0198] Preferably, the method for preparing the compound 4 further comprises the above-mentioned bromination reaction A or the acetylation reaction A to prepare the compound 2 or the compound 3.

[0199] The present application provides an application of the above-mentioned compound 6 or compound 4 in the preparation of procyanidin B3. Preferably, in the application, the compound 4 is subjected to the above-mentioned condensation reaction to prepare the compound 6.

[0200] Unless otherwise specified, the term "alkyl" or "alkane" refers to a straight-chain or branched alkyl or alkane having a specified number of carbon atoms (for example, C1-C4, C1-C3, or C1). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl.

[0201] Without deviating from the common knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e., to obtain each preferred example of the present application.

[0202] The reagents and raw materials used in the present application are commercially available.

[0203] The positive progress effect of the present application is that the preparation method has one or more of the following advantages:

[0204] (1) high reaction yield, good efficiency, and simple operation;

[0205] (2) by selecting compound 4 as the raw material for the condensation reaction, the material loss is reduced, and the use of column chromatography purification in the post-processing of the condensation reaction is avoided;

[0206] (3) the present application needs to undergo five-step reaction conversion of bromination, acetylation, condensation, hydrolysis, and hydrogenolysis to prepare the product procyanidin B3 from the raw material, the intermediates can be directly used for the next step reaction without chromatographic purification, and only one step of column chromatography purification is needed after the hydrogenolysis reaction to obtain procyanidin B3 to obtain high-purity product, thereby reducing the cost. DETAILED DESCRIPTION

[0207] The present application will be further described by way of examples, but the present application is not limited to the scope of the examples. In the following examples, the experimental methods not specified in the specific conditions are selected according to the conventional methods and conditions, or according to the instructions of the commodity.

[0208] The starting compound 1 used in the present application can be simply prepared by the method disclosed in "Synthetic studies of proanthocyanidins. Part 2: Stereoselective gram-scale synthesis of procyanidin-B3, DOI: 10.1016 / s0040-4020(02)00936-5", and a high purity starting material can be obtained without performing column chromatography purification.

[0209] The starting compound 5 used in the present application can be simply prepared by the method disclosed in "Scale-Up Syntheses of Two Naturally Occurring Procyanidins: (-)-Epicatechin-(4β,8)-(+)-catechin and (-)-Epicatechin-3-O-galloyl-(4β,8)-(-)-epicatechin-3-O-gallate, DOI: 10.1021 / op700031n", and a high purity starting material can be obtained without performing column chromatography purification.

[0210] Analysis of stereoselectivity of condensation reaction: In order to investigate the stereoselectivity of the condensation reaction used in the present application, when the test substance is compound 6a, the analysis method in the literature "Synthetic studies of proanthocyanidins. Part 2: Stereoselective gram-scale synthesis of procyanidin-B3, DOI: 10.1016 / s0040-4020(02)00936-5" was used to determine the diastereomer ratio by nuclear magnetic resonance hydrogen spectrum after the test substance reference example 2 was subjected to the usual acetylation.

[0211] When the test substance is compound 6 or 7, the test substance reference example 2 was subjected to the usual acetylation, and then analyzed by the following method: After the acetylation reaction was completed, the reaction mixture was concentrated to dryness, dissolved in deuterated chloroform, and the nuclear magnetic resonance hydrogen spectrum was measured. In the nuclear magnetic resonance hydrogen spectrum, the diastereomer ratio was determined by the area ratio of the proton signals δ 5.75 (m, 0.5H, C3-H), 5.65 (m, 0.5H, C3-H) of the 4-α isomer and δ 5.53 (m, 1H, C3-H), 5.44 (m, 1H, C2-H) of the 4-β isomer.

[0212] In various embodiments, column chromatography was used for separation and purification using silica gel (100-200 mesh) or octadecylsilane-bonded silica gel (ODS, 50 microns); specific optical rotation was determined using a Rudolph Antopol IV polarimeter; 1 H-NMR and 13 C-NMR were recorded by a Bruker DRX-400 NMR spectrometer, and chemical shifts were expressed in δ (ppm); ultra-high performance liquid chromatography-high resolution mass spectrometry analysis was performed using a Thermo Scientific Vanquish ultra-high performance liquid chromatography system and a Q Exactive Focus mass spectrometer.

[0213] Example 1

[0214] (2R,3S,4S)-5,7-Di(benzyloxy)-2-(3,4-di(benzyloxy)phenyl)-8-bromo-4-(2- ethoxyethoxy)benzodihydro The reaction mixture was quenched with saturated sodium bicarbonate solution (1 mL) and stirred for 10 minutes before washing with saturated sodium chloride solution (1 mL),

[0215]

[0216] Compound 1 (200 mg, 0.27 mmol, CAS No: 478796-20-2), dichloromethane (2 mL) were added into a reaction flask, and protected by nitrogen. NBS (50 mg, 0.28 mmol) was added at 0 °C, and after complete dissolution, the temperature was raised to 25 °C and stirred for 3 hours. After the reaction was completed, 3% sodium thiosulfate aqueous solution was added for washing, and after standing and separation of layers, the organic phase was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1, V / V) to obtain a light yellow solid product 179 mg (yield 81%).

[0217] (c 0.60, CH2Cl2). 1 H-NMR (400 MHz, CDCl3, δ ppm): 7.48-7.25 (m, 20H), 7.19 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.2, 2.0 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.24 (s, 1H), 5.16 (s, 2H), 5.15 (s, 2H), 5.11 (s, 2H), 5.06-4.96 (m, 3H), 4.75 (d, J = 2.9 Hz, 1H), 3.97-3.71 (m, 3H), 3.57-3.43 (m, 4H), 1.19 (t, J = 6.9 Hz, 3H). 13C-NMR (100 MHz, CDC13, δ ppm): 157.25, 156.81, 152.58, 149.11, 148.94, 137.56, 137.45, 136.54, 136.26, 131.76, 128.76-127.03 (CHBn), 121.17, 114.65, 114.38, 105.78, 92.73, 92.10, 71.78, 71.50, 71.39, 71.33, 71.20, 70.85, 70.71, 70.07, 66.68, 15.16. HRMS (ESI) calcd for C 47 H 46 BrO8[M+H] + 817.2376, found 817.2379.

[0218] Example 2

[0219] Synthesis of (2R, 3S, 4S)-5, 7-di(benzyloxy)-2-(3, 4-di(benzyloxy)phenyl)-4-(2- ethoxyethoxy)chroman-3-yl acetate (3)

[0220]

[0221] Compound 1 (100 mg, 0.14 mmol), dichloromethane (2 mL), DMAP (0.8 mg, 6.55 μmol), triethylamine (34 mg, 0.34 mmol) were added to the reaction bottle, acetic anhydride (17 mg, 0.17 mmol) was added to the reaction system at 5-10 °C, then stirred at 25 °C for 3 hours. After the reaction was completed, water (2 mL) was added to wash, 10% aqueous hydrochloric acid was added to acidify the aqueous phase to pH = 6, and then the mixture was allowed to stand, separated, and the organic phase was washed with saturated aqueous sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the product 103 mg (yield 97%) as a light yellow oil.

[0222] 1H-NMR (400 MHz, CDC13, δ ppm): 7.51 - 7.24 (m, 20H), 7.07 (d, J = 1.8 Hz, 1H), 6.98 (dd, J = 8.3, 1.8 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.25 (d, J = 2.2 Hz, 1H), 6.15 (d, J = 2.2 Hz, 1H), 5.28 (d, J = 10.8 Hz, 1H), 5.22 (dd, J = 10.8, 3.0 Hz, 1H), 5.17 (s, 2H), 5.15 (s, 2H), 5.09 - 4.94 (m, 4H), 4.87 (d, J = 3.0 Hz, 1H), 3.77 (m, 2H), 3.50 - 3.35 (m, 4H), 1.81 (s, 3H), 1.15 (t, J = 7.0 Hz, 3H). HRMS (ESI) calcd for C 49 H 48 NaO9[M + Na] + 803.3196, found 803.3199.

[0223] Example 3

[0224] Synthesis of (2R,3S,4S)-5,7-di(benzyloxy)-2-(3,4-di(benzyloxy)phenyl)-8- bromo-4-(2-ethoxyethoxy)chroman-3-yl acetate (4)

[0225]

[0226] Using compound 2 as starting material: compound 2 (113 mg, 0.14 mmol), dichloromethane (2 mL), DMAP (0.8 mg, 6.55 μmol), triethylamine (34 mg, 0.34 mmol) were added to the reaction flask, acetic anhydride (17 mg, 0.16 mmol) was added to the reaction system at 5-10 °C, then stirred at 25 °C for 3 hours. After the reaction was completed, water (2 mL) was added to wash, 10% aqueous hydrochloric acid was added to acidify the aqueous phase to pH = 6, and then the mixture was allowed to stand and separate, the organic phase was washed with saturated aqueous sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, and then concentrated under vacuum to obtain the product 115 mg (yield 97%) as a yellow oil.

[0227]

[0228] With compound 3 as raw material: compound 3 (211 mg, 0.27 mmol), dichloromethane (2 mL) were added to the reaction bottle, and protected by nitrogen. At 0°C, NBS (50 mg, 0.28 mmol) was added, and after complete dissolution, the temperature was raised to 25°C and stirred for 3 hours. After the reaction was completed, 3% sodium thiosulfate aqueous solution was added for washing, and after standing, layering, the organic phase was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1, V / V) to obtain a yellow oil product 208 mg (yield 90%).

[0229] (c 1.00, CH2Cl2). 1 H-NMR (400 MHz, CDC13, δ ppm): 7.51-7.27 (m, 20H), 7.15 (d, J = 1.8 Hz, 1H), 7.02 (dd, J = 8.3, 1.8 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.25 (s, 1H), 5.39 (d, J = 10.7 Hz, 1H), 5.20-5.15 (m, 4H), 5.13 (s, 2H), 5.08 (dd, J = 10.7, 3.1 Hz, 1H), 5.06-4.97 (m, 2H), 4.90 (d, J = 3.1 Hz, 1H), 3.77 (m, 2H), 3.53-3.38 (m, 4H), 1.85 (s, 3H), 1.17 (t, J = 6.9 Hz, 3H). 13 C-NMR (100 MHz, CDC13, δ ppm): 169.69, 157.20, 157.03, 152.36, 149.25, 148.93, 137.40, 137.35, 136.54, 136.31, 130.61, 128.81-127.11 (CHBn), 121.11, 114.77, 114.36, 105.12, 92.77, 92.41, 74.60, 73.00, 71.44, 71.39, 71.29, 70.87, 70.81, 69.85, 68.13, 66.58, 20.87, 15.36. HRMS (ESI) calcd for C 49 H 47 BrNaO9[M+Na] + 881.2301, found 881.2307.

[0230] Example 4

[0231] Synthesis of (2R, 2'R, 3S, 3'S, 4R)-5,5',7,7'-tetra(benzyloxy)-2,2'-di(3,4-di(benzyloxy)phenyl)-8-bromo-3'-hydroxy-[4,8'-bipyran]-3-yl acetate (6)

[0232]

[0233] Compound 4 (100 mg, 0.12 mmol), compound (2R, 3S)-5,7-di(benzyloxy)-2-(3,4-di(benzyloxy)phenyl)chromane-3-yl acetate (5, 76 mg, 0.12 mmol, CAS No: 20728-73-8), dichloromethane (3 mL) were added into a reaction flask, TMSOTf (26 mg, 0.12 mmol) was added at -60 °C and stirred for 30 min. After the reaction was completed, it was gradually warmed up to 0 °C, quenched by saturated sodium bicarbonate solution (1 mL), stirred for 10 min, washed by saturated sodium chloride solution (1 mL), the organic phase was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1, V / V) to obtain the product 153 mg (yield 92%) as a white solid. The diastereomeric ratio of the product was determined by nuclear magnetic resonance hydrogen spectrum after acetylation as 52: 1.

[0234] (c 1.00, CH2Cl2). 1 H-NMR (400 MHz, CDC13, 1: 1 mixture of rotational isomers, δ ppm): 7.53 - 7.08 (m, 40H), 7.01 - 6.69 (m, 5.5H), 6.32 (dd, J = 8.3, 1.6 Hz, 0.5H), 6.26 (s, 0.5H), 6.21 (s, 0.5H), 6.19 (s, 0.5H), 5.99 (s, 0.5H), 5.84 - 5.73 (m, 1H), 5.22 - 4.55 (m, 18H), 4.50 (d, J = 10.7 Hz, 0.5H), 3.78 (m, 0.5H), 3.57 (m, 0.5H), 3.41 (d, J = 8.8 Hz, 0.5H), 3.04 (dd, J = 16.2, 5.4 Hz, 0.5H), 2.99 (dd, J = 16.5, 5.5 Hz, 0.5H), 2.69 (dd, J = 16.5, 8.2 Hz, 0.5H), 2.36 (dd, J = 16.2, 9.7 Hz, 0.5H), 1.63 (s, 1.5H), 1.56 (s, 1.5H). 13C-NMR (100 MHz, CDC13, 1 : 1 mixture of rotational isomers), δ ppm): 169.27, 168.80, 158.78, 156.43, 156.41, 156.01, 155.92, 155.81, 154.41, 153.78, 153.45, 153.22, 152.99, 149.41, 149.05, 149.01, 148.98, 148.68, 148.34, 137.95, 137.50, 137.49, 137.46, 137.38, 137.36, 137.31, 137.29, 137.11, 137.09, 136.96, 136.70, 136.40, 131.77, 131.03, 130.68, 130.67, 128.66 - 126.83 (CHBn), 121.06, 120.70, 120.40, 119.59, 115.55, 115.06, 114.81, 114.68, 114.51, 114.18, 113.89, 110.28, 110.19, 110.11, 110.04, 102.95, 102.37, 93.76, 93.65, 93.60, 91.19, 91.17, 81.06, 80.47, 80.29, 79.94, 72.89, 72.59, 71.71 - 69.87 (CH2Bn), 68.94, 68.39, 35.58, 35.41, 28.69, 27.51, 20.77, 20.56. HRMS (ESI) calcd for C 88 H 75 BrNaO 13 [M+Na] + 1441.4289, found 1441.4286.

[0235] Example 5

[0236] Synthesis of (2R,2'R,3S,3'S,4R)-5,5',7,7'-tetra(benzyloxy)-2,2'-di(3,4-di(benzyloxy)phenyl)-8-bromo-[4,8'-bipyran]-3,3'-diol (7)

[0237]

[0238] Compound 6 (1.0 g, 0.70 mmol), tetrahydrofuran (4 mL), and methanol (6 mL) were added to a reaction flask. Sodium hydroxide (112 mg, 2.80 mmol) was slowly added, and the mixture was heated to reflux and stirred for 4 hours. After the reaction was completed, the mixture was concentrated, dissolved in ethyl acetate (5 mL), washed once with saturated sodium chloride aqueous solution (5 mL), and the organic phase was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1, V / V) to give 895 mg of a pale yellow solid product (yield 92%).

[0239] 1 ¹H-NMR (400MHz, CDCl₃, 63:37 mixture of rotationalisomes), δppm: 7.51–7.15 (m, 40H), 7.14–6.68 (m, 6H), 6.26 (s, 0.63H), 6.19 (s, 0.37H), 6.17 (s, 0.63H), 6.09 (s, 0.37H), 5.20–4.44 (m, 18H), 4.37 (d, J = 8.6Hz, 0.37H), 4.22 (m, 0.63H). 63H), 4.08(m, 0.37H), 3.75–3.57(m, 1.63H), 3.19(dd, J = 16.5, 5.9Hz, 0.37H), 3.05(dd, J = 16.2, 5.3Hz, 0.63H), 2.64(dd, J = 16.5, 9.6Hz, 0.37H), 2.40(dd, J = 16.2, 8.9Hz, 0.63H). HRMS (ESI) calculated value C 86 H 73 BrNaO 12 [M+Na] + 1399.4183, measured value 1399.4186.

[0240] Example 6

[0241] Synthesis of (2R,2'R,3S,3'S,4S)-2,2'-bis(3,4-dihydroxyphenyl)-[4,8'-dibenzodihydropyran]-3,3',5,5',7,7'-hexaol (proanthocyanidin B3,8)

[0242]

[0243] Compound 7 (0.5 g, 0.36 mmol), tetrahydrofuran (2.5 mL), methanol (5 mL) were added to a reactor and dissolved, then sodium bicarbonate (92 mg, 1.09 mmol), 20% palladium hydroxide carbon (62.5% water, 0.1 g, 20 wt%) were added. Nitrogen was replaced five times, then hydrogen was replaced five times, stirred at 15 psi pressure, 20 °C for 6 hours. After the reaction was completed, nitrogen was replaced three times, acetic acid (46 mg, 0.76 mmol) was added to adjust the pH, stirred for 10 minutes, then filtered with a microporous filter membrane (nylon 6, 0.45 μm), the filtrate was concentrated under vacuum, then the obtained product solution was concentrated to remove methanol under vacuum, then frozen and freeze-dried to obtain a white solid product 175 mg (yield 84%).

[0244] (c 1.00, CH3OH). 1 H-NMR (400 MHz, CD3OD, mixture of rotational isomers, δ ppm): 6.96 (d, J = 2.7 Hz, 0.67H), 6.83 (m, 0.33H), 6.79-6.72 (m, 1.67H), 6.70-6.65 (m, 1.32H), 6.60 (d, J = 2.7 Hz, 0.67H), 6.47 (dd, J = 8.2, 2.7 Hz, 0.67H), 6.26 (dd, J = 8.2, 2.7 Hz, 0.67H), 6.08 (s, 0.67H), 5.95 (s, 0.33H), 5.90 (d, J = 2.6 Hz, 0.67H), 5.84 (d, J = 2.5 Hz, 0.33H), 5.81 (d, J = 2.5 Hz, 0.33H), 5.80 (d, J = 2.6 Hz, 0.67H), 4.75 (d, J = 7.9 Hz, 0.33H), 4.54 (d, J = 7.2 Hz, 0.67H), 4.44-4.39 (m, 1H), 4.38-4.32 (m, 1H), 4.28-4.23 (m, 1H), 4.08 (m, 0.33H), 3.79 (m, 0.67H), 2.82 (dd, J = 16.2, 5.7 Hz, 0.33H), 2.76 (dd, J = 16.3, 5.6 Hz, 0.67H), 2.59 (dd, J = 16.2, 7.7 Hz, 0.33H), 2.50 (dd, J = 16.3, 8.0 Hz, 0.67H). 13C-NMR (100 MHz, CD3OD, mixture of rotational isomers, δ ppm): 158.58, 158.56, 157.37, 157.24, 157.07, 157.04, 155.81, 155.79, 155.71, 155.58, 154.90, 154.80, 146.29, 146.04, 146.00, 145.70, 145.54, 145.39, 132.59, 132.37, 132.15, 131.85, 121.04, 120.63, 120.15, 119.87, 116.40, 116.19, 116.17, 116.12, 116.06, 115.93, 115.47, 115.17, 108.27, 108.16, 107.19, 107.12, 102.21, 100.47, 97.56, 97.52, 97.33, 96.85, 96.25, 96.10, 84.03, 83.88, 82.84, 82.37, 73.66, 73.60, 68.86, 68.51, 38.54, 38.51, 28.67, 28.37. HRMS (ESI) calcd for C 30 H 27 O 12 [M+H] + 579.1503, found 579.1506.

[0245] Example 7 Synthesis process of procyanidin B3

[0246]

[0247] Compound 1 (50.0 g, 67.72 mmol, CAS No: 478796-20-2), dichloromethane (250 mL), DMAP (414 mg, 3.39 mmol), triethylamine (17.1 g, 0.17 mol) were added into a reaction flask, acetic anhydride (8.3 g, 81.26 mmol) was slowly added into the reaction system at 5-10 °C, and stirred at 25 °C for 3 hours. After the reaction was completed, water (300 mL) was added for washing, 10% hydrochloric acid aqueous solution was added for acidification until the pH of the aqueous phase was 6, and then it was allowed to stand and separate, the organic phase was washed with saturated sodium chloride aqueous solution (300 mL), dried over anhydrous sodium sulfate, and then a dichloromethane solution of compound 3 was obtained, which was directly used in the next step reaction.

[0248] To the solution of compound 3 in dichloromethane (300 mL) was added dichloromethane (300 mL) under nitrogen protection. NBS (12.4 g, 69.75 mmol) was added at 0 °C, and after complete dissolution, the temperature was raised to 25 °C and stirred for 3 hours. After the reaction was completed, 3% sodium thiosulfate aqueous solution (50 mL) was added to wash, and after standing and separation, the organic phase was dried over anhydrous sodium sulfate to obtain a dichloromethane solution of compound 4, which was directly used in the next step reaction.

[0249] To the solution of compound 4 in dichloromethane (100 mL) was added compound 5 (44.0 g, 67.72 mmol, CAS No: 20728-73-8) into the reaction flask, and TMSOTf (15.1 g, 67.72 mmol) was added at -60 °C and stirred for 30 minutes. After the reaction was completed, the temperature was gradually raised, and saturated sodium bicarbonate solution (290 mL) was added at 0 °C to quench, and after stirring for 10 minutes, saturated sodium chloride solution (290 mL) was added to wash, and after standing and separation, the organic phase was concentrated under vacuum to obtain a light red solid crude compound 6, which was directly used in the next step reaction.

[0250] The crude compound 6, tetrahydrofuran-methanol mixed solution (2:3, 960 mL) was added into the reaction flask, and sodium hydroxide (10.8 g, 0.27 mol) was slowly added, and the temperature was raised to reflux and stirred for 4 hours. After the reaction was completed, it was concentrated, dissolved in ethyl acetate (480 mL), washed once with saturated aqueous sodium chloride solution (480 mL), and after standing and separation, the organic phase was concentrated under vacuum to obtain a yellow solid crude compound 7, and 10 mg of the crude compound 7 was acetylated, and the diastereoisomer ratio was determined by nuclear magnetic resonance hydrogen spectrum to be 54:1.

[0251] The remaining crude compound 7 (theoretical amount 93.2 g), tetrahydrofuran-methanol mixed solution (1:2, 1.4 L) was added into the hydrogenation kettle, and 186 mL of sodium bicarbonate aqueous solution (17.1 g, 0.20 mol), 20% palladium hydroxide carbon (62.5% water, 18.6 g, 20 wt%) was added. After five times of nitrogen replacement, five times of hydrogen replacement, it was stirred at 15 psi pressure and 20 °C for 6 hours. After the reaction was completed, it was replaced with nitrogen for three times, and acetic acid (8.5 g, 0.14 mol) was added, and after stirring for 10 minutes, it was filtered with a microporous filter membrane (nylon 6, 0.45 μm), and the filtrate was concentrated under vacuum, and the product solution was purified by ODS column chromatography (water:methanol = 4:1, V / V), and after removing methanol by vacuum concentration, it was frozen and freeze-dried to obtain a light yellow solid product 26.8 g (total yield of five steps 68%).

[0252] Comparative Experiment 1

[0253] Reference "Synthetic studies of proanthocyanidins. Part 2: Stereoselective gram-scale synthesis of procyanidin-B3, DOI: 10.1016 / s0040-4020(02)00936-5" and the method in Example 1.

[0254] Into a reaction flask, compound 2, 4, 4a-4c (0.12 mmol), compound (2R, 3S)-5, 7-di(benzyloxy)-2-(3, 4-di(benzyloxy)phenyl)chroman-3-yl acetate (5, 76 mg, 0.12 mmol, CAS No: 20728-73-8), dichloromethane (3 mL) were added, and the catalyst (0.12 mmol) was added under the specified temperature and the reaction was stirred. After the reaction was monitored to end by HPLC, TLC, the temperature control was stopped, and the system was gradually returned to room temperature. When the system was greater than 0℃, the reaction was stopped. Item acid After the organic phase was concentrated under vacuum, it was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1, V / V) to obtain a white solid product. After acetylation of the product, the diastereoisomer ratio was determined by nuclear magnetic resonance hydrogen spectrum. The yield and diastereoisomer ratio are shown in Table 1 below.

[0255] Table 1

[0256]

[0257] From the above data, it can be seen that the yield and stereoselectivity of the condensation reaction using the above different intermediates as raw materials have significant differences. The present application selects a specific intermediate, which significantly reduces the polymeric impurities (item 1), and the effect is obviously improved. The introduction of 8-Br by any intermediate (items 2, 3, 6, 7) can maintain good yield and selectivity, and the effect of the introduction of 8-Br in the intermediate of the present application is better. The effect of the introduction of 8-Br under the catalyst system of the present application (items 3-8) is better, and the selectivity and yield of the reaction system of TiCl4 and Yb(OTf)3 are poor, and the reaction time is significantly increased. The crude product obtained according to the technical scheme of the present application can be directly used for the next step reaction without column chromatography purification, which is beneficial to scale-up production.

[0258] Comparative Experiment 2

[0259] Into a reaction flask, compound 6 (10.0 g, 7.05 mmol), tetrahydrofuran (40 mL), methanol (60 mL) were added, and the equivalent of sodium hydroxide in Table 2 was slowly added. The reaction was controlled at the specified temperature, and the reaction was monitored by HPLC. The results are shown in Table 2.

[0260] Table 2

[0261]

[0262]

[0263] From the above data, the method of the present application achieves good reaction efficiency and conversion rate (item 4), avoids the use of highly toxic reagents, and is conducive to scale-up production.

[0264] Comparative Experiment 3

[0265] Compound 7 (0.5 g, 0.36 mmol), tetrahydrofuran (2.5 mL), methanol (5 mL) were added to the reactor and dissolved, then sodium bicarbonate (92 mg, 1.09 mmol), 20% palladium hydroxide carbon (62.5% water, 0.1 g, 20 wt%) were added. Five times of nitrogen replacement were performed, followed by five times of hydrogen replacement. Stirring was performed at 15 psi pressure and 20°C for 6 hours. After the reaction was completed, three times of nitrogen replacement were performed, and different acids were added to adjust the pH to 6 or no acid was added. After stirring for 10 minutes, microfiltration membrane (nylon 6, 0.45 μm) was used for filtration, and sampling was performed for HPLC detection. The filtrate was placed at room temperature in the dark for 42 hours, and sampling was performed again for HPLC detection. The results are shown in Table 3.

[0266] Table 3

[0267] Purity after filtration (AUC %) Purity after 42 h standing (AUC %) L-ascorbic acid acetic acid 1 none 92 91 2 ​ 92 92 3 ​ 82 72

[0268] From the above data, it can be seen that the use of acid to adjust the pH in the post-processing step of the hydrogenolysis reaction has good effects and helps to stabilize the product.

[0269] Comparative Experiment 4

[0270] Compound 7 (0.5 g, 0.36 mmol), the corresponding solvent (7.5 mL) were added to the reactor and dissolved, then different types and amounts of base, 20% palladium hydroxide carbon (62.5% water, 0.1 g, 20 wt%) were added. Five times of nitrogen replacement were performed, followed by five times of hydrogen replacement. Stirring was performed at 15 psi pressure and 20°C for 6 hours. After the reaction was completed, three times of nitrogen replacement were performed, and acetic acid was added to adjust the pH to 6. After stirring for 10 minutes, microfiltration membrane (nylon 6, 0.45 μm) was used for filtration, and the filtrate was vacuum concentrated and then purified by ODS column chromatography (water:methanol = 4:1, V / V). The obtained product solution was vacuum concentrated to remove methanol, then frozen and freeze-dried to obtain a white solid product. The reaction yield is shown in Table 4.

[0271] Table 4

[0272]

[0273]

[0274] From the above data, it can be seen that the types of solvent and base affect the hydrogenolysis reaction effect, and the hydrogenolysis reaction has good reaction yield and effect.

Claims

1. A process for the preparation of compound 6, characterized in that, comprising the step of condensation of compound 4 and compound 5 in a solvent in the presence of a catalyst to obtain compound 6; The catalyst is (R)3SiOTf, each R is independently a C 1-4 alkyl or phenyl.

2. The production method according to claim 1, wherein which satisfies one or more of the following conditions: Condition (1) the solvent is selected from one or more of halogenated alkane solvents, ether solvents and aromatic hydrocarbon solvents, preferably halogenated alkane solvents; the halogenated alkane solvents can be chlorinated C1-C4 alkane solvents, wherein the C 1-4 The alkane can be methane, ethane, n-propane or isopropane; the halogenated alkane solvents are further preferably selected from one or more of dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane and chloroform, for example dichloromethane; the ether solvents can be selected from one or more of 1,4-dioxane, tetrahydrofuran, diethyl ether and methyl tert-butyl ether; the aromatic hydrocarbon solvents can be selected from one or more of toluene, xylene and ethylbenzene; C as described in condition (2) 1-4 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, for example methyl; preferably the catalyst is selected from one or more of trimethylsilyl triflate, t-butyldimethylsilyl triflate, triethylsilyl triflate, triisopropylsilyl triflate, t-butyldiphenylsilyl triflate, for example trimethylsilyl triflate; condition (3) the molar volume of compound 4 to the solvent is 0.02 to 0.4 mol / L, for example 0.04 mol / L; condition (4) the molar ratio of compound 4 to compound 5 is 1:0.8-1:1.5, for example 1:1; condition (5) the molar ratio of compound 4 to the catalyst is 1:0.01~1:2, for example 1:1; condition (6) the condensation reaction is carried out at -80℃ to -40℃, preferably at -80℃ to -60℃, for example -50℃, -70℃ or -60℃; condition (7) the raw materials of the condensation reaction are the solvent, the catalyst, compound 4 and compound 5.

3. The production method according to claim 1, wherein The condensation reaction comprises the following post-processing steps: after the reaction is completed, quenching, washing, separation, concentration, preferably direct follow-up reaction after concentration; or, in the post-processing step, purification after concentration, for example silica gel chromatography purification, to obtain compound 6; Preferably, the preparation method comprises the step of condensation of compound 4 and compound 5 in a chlorinated C1-C4 alkane solvent at -80 to -60℃ in the presence of a catalyst to obtain compound 6, and the catalyst is trimethylsilyl trifluoromethanesulfonate; Further preferably comprising the step of condensation of compound 4 and compound 5 in a chlorinated C1-C4 alkane solvent at -80℃ to -60℃ in the presence of trimethylsilyl trifluoromethanesulfonate to obtain compound 6, and after the reaction is completed, quenching, washing, separation, concentration; preferably direct follow-up reaction after concentration.

4. The production method according to claim 1, wherein which further comprises the steps described in Scheme 1 or Scheme 2: Scheme 1 comprises the step of acetylation of compound 2 with acylating agent in the presence of a base in a solvent in the presence of a catalyst to obtain compound 4; Scheme 2 comprises the step of bromination of compound 3 with brominating agent in a solvent to obtain compound 4; Preferably, the scheme 1 satisfies one or more of the following conditions: Condition (1) the solvent is a halogenated alkane solvent, for example a chlorinated C1-C4 alkane solvent, wherein the C 1-4 The alkane can be methane, ethane, n-propane or i-propane, preferably selected from one or more of dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane and chloroform, for example dichloromethane; condition (2) the catalyst is 4-dimethylaminopyridine; condition (3) the base is an organic base, for example triethylamine; condition (4) the acylating agent is acetic anhydride; condition (5) the molar volume of compound 2 to the solvent is 0.02 to 0.4 mol / L, for example 0.07 mol / L; condition (6) the molar ratio of compound 2 to the catalyst is 1:0.01 to 1:0.2, for example 1:0.05; condition (7) the molar ratio of compound 2 to the base is 1:1~1:5, for example 1:2.5 or 1:2.4; condition (8) the molar ratio of compound 2 to the acylating agent is 1:0.8~1:3, for example 1:1.2 or 1:1.1; condition (9) the acetylation reaction is carried out at 0℃ to 50℃, for example 25℃, preferably the acylating agent is added at 5-10℃, and the acetylation reaction is carried out at 0℃ to 50℃; Condition (10) the raw materials of the acetylation reaction are the solvent, the catalyst, the base, the compound 2 and the acylating agent; preferably, in the acetylation reaction, the catalyst, the base and the acylating agent are added in the mixture of compound 2 and the solvent; Condition (11) the acetylation reaction comprises the following post-processing steps: after the reaction is completed, washing, adjusting pH, separating, washing, drying, preferably directly performing the subsequent reaction after drying, or, after drying, concentrating to obtain compound 4; further preferably, the acetylation reaction comprises the following steps: under the action of 4-dimethylaminopyridine, in the presence of the base, in the chlorinated C1-C4 alkane solvent, compound 2 and the acylating agent are subjected to acetylation reaction to obtain compound 4, after the reaction is completed, washing, adjusting pH, separating, washing, drying, preferably directly performing the subsequent reaction after drying. Preferably, the scheme 2 satisfies one or more of the following conditions: Condition (1) the solvent is selected from one or more of a nitrile solvent, a halogenated alkane solvent, an ether solvent, a nitrogen-containing compound solvent, a ketone solvent, and an ester solvent, preferably a halogenated alkane solvent; the halogenated alkane solvent can be a chlorinated C1-C4 alkane solvent, wherein the C 1-4 The alkane can be methane, ethane, n-propane, or i-propane; the halogenated alkane solvent is further preferably selected from one or more of dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, and chloroform, for example dichloromethane; the nitrile solvent can be acetonitrile; the ether solvent can be selected from one or more of 1,4-dioxane, tetrahydrofuran, diethyl ether, and methyl tert-butyl ether; the nitrogen-containing compound solvent can be N,N-dimethylformamide; the ketone solvent can be acetone; and the ester solvent can be ethyl acetate. Condition (2) the brominating agent is selected from one or more of bromine, N-bromosuccinimide, N-bromophthalimide, 1,3,5-tribromo-1,3,5-thiazinan-2,4,6-trione, N-bromoacetamide, 2-bromo-1,2-benzisothiazol-3(2H)-one-1,1-dioxide and dibromoisocyanuric acid, for example, the brominating agent is N-bromosuccinimide; Condition (3) the bromination reaction is carried out in a protective gas, for example, nitrogen; Condition (4) the molar volume of compound 3 and the solvent is 0.02 to 0.4 mol / L, for example, 0.135 mol / L; Condition (5) the molar ratio of compound 3 to the brominating agent is 1:0.8 to 1:2, for example, 1:1.03; Condition (6) the bromination reaction is carried out at 0°C to 50°C, for example, 25°C; Condition (7) the raw materials of the bromination reaction are the solvent, compound 3 and the brominating agent; Condition (8) the bromination reaction comprises the following post-processing steps: after the reaction is completed, washing, separating, drying; preferably, directly performing the subsequent reaction after drying; or, in the post-processing steps, after separating, concentrating and purifying, for example, silica gel chromatography, to obtain compound 4; further preferably, the bromination reaction comprises the following steps: under the action of 4-dimethylaminopyridine, in the presence of the base, in the chlorinated C1-C4 alkane solvent, compound 3 and the brominating agent are subjected to bromination reaction to obtain compound 4, after the reaction is completed, washing, separating, drying, preferably directly performing the subsequent reaction after drying.

5. The production method according to claim 4, wherein It further comprises the following step: in a solvent, compound 1 is subjected to bromination reaction A with a brominating agent to obtain compound 2; Or, the preparation method further comprises the following step: in a solvent, in the presence of a base, under the action of a catalyst, compound 1 is subjected to acetylation reaction A with an acylating agent to obtain compound 3; Preferably, the bromination reaction A satisfies one or more of the following conditions: Condition (1) the solvent is selected from one or more of a nitrile solvent, a halogenated alkane solvent, an ether solvent, a nitrogen-containing compound solvent, a ketone solvent, and an ester solvent, preferably a halogenated alkane solvent; the halogenated alkane solvent can be a chlorinated C1-C4 alkane solvent, wherein the C 1-4 The alkane can be methane, ethane, n-propane, or i-propane; the halogenated alkane solvent is further preferably selected from one or more of dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane, and chloroform, for example dichloromethane; the nitrile solvent can be acetonitrile; the ether solvent can be selected from one or more of 1,4-dioxane, tetrahydrofuran, diethyl ether, and methyl tert-butyl ether; the nitrogen-containing compound solvent can be N,N-dimethylformamide; the ketone solvent can be acetone; and the ester solvent can be ethyl acetate. Preferably, the bromination reaction B satisfies one or more of the following conditions: Condition (2) the bromination reagent is selected from one or more of bromine, N-bromosuccinimide, N-bromophthalimide, 1,3,5-tribromo-1,3,5-thiazinan-2,4,6-trione, N-bromoacetamide, 2-bromo-1,2-benzisothiazol-3(2H)-one-1,1-dioxide and dibromoisocyanuric acid, for example the bromination reagent is N-bromosuccinimide; Condition (3) the bromination reaction is carried out in a protective gas, for example nitrogen; Condition (4) the molar volume of compound 1 to the solvent is 0.02 to 0.4 mol / L, for example 0.135 mol / L; Condition (5) the molar ratio of compound 1 to the bromination reagent is 1:0.8 to 1:2, for example 1:1.03; Condition (6) the bromination reaction is carried out at 0°C to 50°C, for example 25°C; Condition (7) the raw materials of the bromination reaction are the solvent, compound 1 and the bromination reagent; Condition (8) the bromination reaction comprises the following post-treatment steps: after the reaction is completed, washing, separation, drying; preferably after drying, the subsequent reaction is directly carried out; or in the post-treatment steps, after separation, concentration and purification are carried out, for example silica gel chromatography purification, to obtain compound 2; further preferably, the bromination reaction comprises the following steps: compound 1 and the bromination reagent are subjected to a bromination reaction in the chlorinated C1-C4 alkane solvent at 0°C to 50°C, to obtain compound 2, after the reaction is completed, washing, separation, drying, and preferably after drying, the subsequent reaction is directly carried out; Condition (1) the solvent is a halogenated alkane solvent, for example a chlorinated C1-C4 alkane solvent, wherein the C 1-4 The alkane can be methane, ethane, n-propane or i-propane, preferably selected from one or more of dichloromethane, 1,1-dichloroethane, 1,2-dichloroethane and chloroform, for example dichloromethane; Preferably, the acetylation reaction A satisfies one or more of the following conditions: Condition (2) the catalyst is 4-dimethylaminopyridine; Condition (3) the base is an organic base, for example triethylamine; Condition (4) the acylating reagent is acetic anhydride; Condition (5) the molar volume of compound 1 to the solvent is 0.02 to 0.4 mol / L, for example 0.07 mol / L or 0.27 mol / L; Condition (6) the molar ratio of compound 1 to the catalyst is 1:0.01 to 1:0.2, for example 1:0.05; Condition (7) the molar ratio of compound 1 to the base is 1:1 to 1:5, for example 1:2.5 or 1:2.4; Condition (8) the molar ratio of compound 1 to the acylating reagent is 1:0.8 to 1:3, for example 1:1.2 or 1:1.1; Condition (9) the acetylation reaction A is carried out at 0°C to 50°C, for example 25°C, preferably the acylating reagent is added at 5-10°C, and the acetylation reaction is carried out at 0°C to 50°C; Condition (10) the raw materials of the acetylation reaction A are the solvent, the catalyst, the base, compound 1 and the acylating reagent; preferably in the acetylation reaction, the catalyst, the base and the acylating reagent are added in the mixture of compound 1 and the solvent. Condition (11) the acetylation reaction A comprises the following work-up steps: after the reaction is completed, washing, adjusting pH, separating, washing, drying, preferably directly conducting subsequent reaction after drying, or, after drying, concentrating to obtain compound 3; further preferably, the acetylation reaction A comprises the following steps: acetylation reaction of compound 2 and the acylating reagent in the presence of the base under the action of 4-dimethylaminopyridine in the chlorinated C1-C4 alkane solvent at 0-50℃ to obtain compound 3, after the reaction is completed, washing, adjusting pH, separating, washing, drying, preferably directly conducting subsequent reaction after drying.

6. A method of preparing compound 8, characterized by, It comprises the following steps: Step (1) obtaining compound 6 according to the preparation method of compound 6 as claimed in any one of claims 1-5; Step (2) hydrolysis reaction of compound 6 in the presence of a base in a solvent to obtain compound 7; Step (3) hydrogenolysis reaction of compound 7 in the presence of a base in a solvent under the action of a catalyst to obtain compound 8; 7. The production method according to claim 6, wherein It meets one or more of the following conditions: Condition (1) in the hydrolysis reaction, the solvent is selected from one or more of nitrile solvents, ether solvents, alcohol solvents, aromatic hydrocarbon solvents and water, preferably a mixed solvent of ether solvents and alcohol solvents; the nitrile solvent can be acetonitrile, the ether solvent can be selected from one or more of 1,4-dioxane, tetrahydrofuran, diethyl ether and methyl tert-butyl ether; the alcohol solvent can be selected from one or more of methanol, ethanol and isopropanol; the aromatic hydrocarbon solvent can be selected from one or more of toluene, xylene and ethylbenzene; further preferably, the mixed solvent of ether solvents and alcohol solvents is a mixed solvent of tetrahydrofuran and methanol, wherein the volume ratio of tetrahydrofuran to methanol can be 2:3; Condition (2) in the hydrolysis reaction, the base is MOH, M is an alkali metal, the alkali metal is preferably Na, K or Li, for example, the base is NaOH; Condition (3) in the hydrolysis reaction, the molar volume of compound 6 and the solvent is 0.02-0.14 mol / L, for example 0.07 mol / L; Condition (4) in the hydrolysis reaction, the molar ratio of compound 6 to the base is 1:1-1:10, for example 1:2, 1:3, 1:4 or 1:5; Condition (5) the hydrolysis reaction is carried out at 40-80℃, for example 62℃, preferably when the solvent is a mixed solvent of tetrahydrofuran and methanol, the reaction is carried out at reflux temperature; Condition (6) the raw materials of the hydrolysis reaction are the solvent, the base and compound 6; Condition (7) the hydrolysis reaction comprises the following post-processing steps: after the reaction is completed, concentrated, adding an ester solvent, washing, separating, concentrated, preferably after the second concentration, directly proceed to the subsequent reaction; or, in the post-processing step, after the second concentration, purification is carried out, for example, silica gel chromatography purification, to obtain compound 7; further preferably, the hydrolysis reaction comprises the following steps: compound 6 is subjected to a hydrolysis reaction under the action of a base in a mixed solvent of the ether solvent and the alcohol solvent, the base is MOH, M is an alkali metal, to obtain compound 7, after the reaction is completed, concentrated, adding an ester solvent, washing, separating, concentrated, preferably after the second concentration, directly proceed to the subsequent reaction; Condition (8) in the hydrogenolysis reaction, the solvent is a mixed solvent of an ether solvent and an alcohol solvent; the ether solvent can be selected from one or more of 1,4-dioxane, tetrahydrofuran, diethyl ether and methyl tert-butyl ether; the alcohol solvent can be selected from one or more of methanol, ethanol and isopropanol; preferably, the mixed solvent of the ether solvent and the alcohol solvent is a mixed solvent of tetrahydrofuran and methanol, and the volume ratio of tetrahydrofuran to methanol can be 1:2; Condition (9) in the hydrogenolysis reaction, the base is an inorganic base, for example, a salt of an alkali metal, the anion of the salt of the alkali metal is hydroxide, carbonate or bicarbonate, and the alkali metal is preferably Na, K or Li, for example, the base is sodium bicarbonate; Condition (10) in the hydrogenolysis reaction, the catalyst is a palladium hydroxide on carbon catalyst, preferably a 20% palladium hydroxide on carbon catalyst; Condition (11) in the hydrogenolysis reaction, the hydrogenolysis reaction is the reaction of compound 7 with hydrogen, and the hydrogen pressure is preferably 15 psi to 150 psi, for example, 15 psi; Condition (12) in the hydrogenolysis reaction, the molar volume of compound 7 and the solvent is 0.02 to 0.24 mol / L, for example, 0.36 / 7.5 mol / L; Condition (13) in the hydrogenolysis reaction, the molar ratio of compound 7 to the base is 1:2-1:3.5, for example, 1:3; Condition (14) in the hydrogenolysis reaction, the mass ratio of compound 7 to the catalyst is 20:1 to 1:1, for example, 5:1; Condition (15) the hydrogenolysis reaction is carried out at 0°C to 50°C, preferably at 20°C; Condition (16) the raw materials of the hydrogenolysis reaction are the solvent, hydrogen, the base, the catalyst and compound 7; Condition (17) the hydrogenolysis reaction comprises the following post-processing steps: after the reaction is completed, the pH is adjusted to 5-7, and compound 8 is obtained by purification, preferably the pH is adjusted to 6; further preferably, the hydrogenolysis reaction comprises the following steps: the inorganic base and the catalyst are added to the mixture of compound 7, the ether solvent and the alcohol solvent, and the hydrogenolysis reaction is carried out in a hydrogen environment at 15 psi to 150 psi; after the reaction is completed, the pH is adjusted, filtered, concentrated, purified and dried to obtain compound 8.

8. The process according to claim 6 or 7 for the preparation of compound 8, characterized by, which satisfies one or more of the following conditions: In condition (a), the preparation method comprises the following steps: (1) preparing compound 6 according to any one of claims 1-5; (2) performing hydrolysis reaction on compound 6 in the presence of a base in a solvent to obtain compound 7, wherein the base is MOH and M is an alkali metal; (3) performing hydrogenolysis reaction on compound 7 in the presence of a base in a solvent under the action of a catalyst to obtain compound 8, wherein the solvent is a mixed solvent of an ether solvent and an alcohol solvent, and the base is an inorganic base; In condition (b), the hydrogenolysis reaction comprises the following post-processing steps: after the reaction is completed, adjusting the pH to 5-7, filtering, concentrating, purifying, and drying to obtain compound 8; preferably, the pH is adjusted using an acid, and the acid can be selected from one or more of hydrochloric acid, formic acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, ascorbic acid, citric acid, and salicylic acid, for example, acetic acid or ascorbic acid; further preferably, the molar ratio of compound 7 to the acid is 1:0.8-1:10, for example, 1:2.1; In condition (c), in the post-processing step of the hydrogenolysis reaction, the purification is chromatographic purification, preferably, in the chromatography, the filler used is selected from one or more of silica gel, octadecylsilane-bonded silica gel, HW-40 gel resin, NKA-9 macroporous resin, YDKH-9 macroporous resin, ADS-7 macroporous resin, and ADS-21 macroporous resin, for example, octadecylsilane-bonded silica gel; further preferably, when the filler used in the chromatographic purification is silica gel, a mixture of dichloromethane, methanol, and water is used as the eluent, and the volume ratio of dichloromethane, methanol, and water can be (10-2):1:0.1; or, when the filler used is octadecylsilane-bonded silica gel, HW-40 gel resin, NKA-9 macroporous resin, YDKH-9 macroporous resin, ADS-7 macroporous resin, or ADS-21 macroporous resin, a mixture of methanol and water is used as the eluent, and the volume ratio of methanol and water can be 1:19-1:0.05, for example, 1:

4.

9. A process for the preparation of a compound of claim 7, 8 or 4, characterized in that, The preparation method of compound 7 comprises the following steps: performing hydrolysis reaction on compound 6 in the presence of a base in a solvent to obtain compound 7; wherein the base is MOH and M is an alkali metal; The solvent, the base, compound 6, the operation and conditions of the hydrolysis reaction can be as described in claim 7 or 8; preferably, the preparation method of compound 7 further comprises the preparation method of compound 6 according to any one of claims 1-5; Alternatively, the preparation method of compound 8 comprises the following steps: performing hydrogenolysis reaction on compound 7 in the presence of a base in a solvent under the action of a catalyst to obtain compound 8; The solvent is a mixed solvent of an ether solvent and an alcohol solvent, and the base is an inorganic base; wherein the solvent, the inorganic base, compound 7, and the conditions and operation of the hydrogenolysis reaction can be as described in claim 7 or 8; preferably, the preparation method of compound 8 further comprises the preparation method of compound 7; Alternatively, the preparation method of compound 4 comprises the steps described in scheme 1 or scheme 2: Scheme 1 comprises the following step: acetylation of compound 2 with acetylating reagent in solvent in the presence of base under the action of catalyst to obtain compound 4; wherein the solvent, the base, the catalyst, the compound 2, the acetylating reagent, the conditions and operations of the acetylation reaction can be as described in claim 4; Scheme 2 comprises the following step: bromination of compound 3 with brominating reagent in solvent to obtain compound 4; wherein the solvent, the compound 3, the brominating reagent, the conditions and operations of the bromination reaction can be as described in claim 4; Preferably, the preparation method of compound 4 further comprises preparing compound 2 or compound 3 by bromination reaction A or acetylation reaction A as described in claim 5.

10. A compound, characterized in that, which is compound 6 or compound 4,

Images