CN117534646A - Preparation method of procyanidine B2 - Google Patents

Preparation method of procyanidine B2 Download PDF

Info

Publication number
CN117534646A
CN117534646A CN202311542888.7A CN202311542888A CN117534646A CN 117534646 A CN117534646 A CN 117534646A CN 202311542888 A CN202311542888 A CN 202311542888A CN 117534646 A CN117534646 A CN 117534646A
Authority
CN
China
Prior art keywords
reaction
procyanidin
producing
acid
procyanidine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202311542888.7A
Other languages
Chinese (zh)
Inventor
吕庆华
梁耀福
张剑辉
吴晓枫
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Langhua Biosciences Shenzhen Co ltd
Original Assignee
Langhua Biosciences Shenzhen Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Langhua Biosciences Shenzhen Co ltd filed Critical Langhua Biosciences Shenzhen Co ltd
Priority to CN202311542888.7A priority Critical patent/CN117534646A/en
Publication of CN117534646A publication Critical patent/CN117534646A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
    • C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention discloses a preparation method of procyanidine B2. The preparation method of the invention has the advantages of simple and easily obtained raw materials, economy, no need of column chromatography purification to obtain high-yield and high-purity raw materials, great reduction of material, labor and time costs, and suitability for large-scale preparation. The invention selects proper proton solvent to make the coupling reaction of the raw material 1 and the intermediate 3 and the deprotection of the silyl ether simultaneously proceed, which can greatly reduce the reaction time and operation steps. The synthesis period is greatly shortened. The invention realizes the high-yield catalytic coupling of the equimolar feeding of the raw material 1 and the intermediate 3, and can greatly inhibit the self-coupling side reaction of the intermediate 3.

Description

Preparation method of procyanidine B2
Technical Field
The invention relates to a preparation method of procyanidine B2.
Background
Procyanidin B2, CAS number: 29106-49-8, molecular formula: c (C) 30 H 26 O 12 Molecular weight: 578.52 the structural formula of procyanidin B2 is as follows:
the procyanidine B2 has the functions of protecting cardiovascular system, preventing hypertension, resisting tumor, resisting radiation, resisting mutation, beautifying and the like, and is widely applied to the fields of biological medicine and the like.
Procyanidine B2 raw material in the market is extracted from natural product grape seeds and then repeatedly purified. Although procyanidins B2 are widely distributed, the relative content is low, resulting in very expensive extraction and purification costs. The traditional organic synthesis can realize laboratory scale synthesis of procyanidine B2, but the synthesis process involves multiple steps of multi-step hydroxyl protection, benzyl oxidation, deprotection and the like, has extremely low yield, generates a large amount of solid waste and liquid waste, and is difficult to be used for scale production.
In US9133176B the following preparation route one is disclosed:
"Condensation of catechin and epicatechin incorporating a TBS-protective group, DOI:10.3987/com-11-s (p) 58" discloses the following preparation route II:
"An Improved Synthesis of Procyanidin Dimers:Regio-and Stereocontrol of the Interflavan Bond, DOI:10.1002/ejoc.200600668" discloses the following preparation route three:
the procyanidine B2 prepared by the traditional method is subjected to multi-step column purification, cannot be prepared on a large scale, and can generate a large amount of solid waste and liquid waste. And dimerization and deprotection are required to be carried out respectively, so that the preparation period is prolonged.
The preparation routes disclosed in the above prior art all have some drawbacks. Specifically, one of the starting materials is required to be in excess (4-5 eq) in both route one and route two, and high-yield dimerization of the starting materials cannot be achieved by equimolar feeding. The yield of the first route is extremely low, only about 30% of the yields are obtained in the two steps of coupling and deprotection, and a large amount of Pd catalyst is needed for the debenzylation protection, so that the method is high in price and cost. In the second route, the problem of racemization of coupling is controlled, and an acetoxyl protecting group is introduced into 3-OH, so that the final deprotection condition is extremely harsh and cannot be effectively removed. Following synthesis of intermediate 3 in scheme three, self-coupling occurs readily due to higher activity resulting from polymer 4, requiring additional C-8 protection to inhibit self-coupling.
Therefore, a more efficient, environment-friendly and simple preparation method of procyanidine B2 is needed.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of procyanidine B2, which improves purity and yield, reduces raw material cost and shortens preparation time.
The invention provides a preparation method of procyanidine B2, which comprises the following steps:
(1) Starting material 1 and compound R 1 Cl or (R) 1 ) 2 NH is subjected to substitution reaction to obtain an intermediate 2; wherein R is 1 Selected from trimethylsilyl, triethylsilyl, and benzhydryl;
(2) Intermediate 2 and R 2 H is subjected to oxidation reaction in the presence of an oxidant and a nucleophilic reagent to obtain an intermediate 3; wherein R is 2 Selected from ethylene glycol ethoxy, diethylene glycol ethoxy, methoxy, ethoxy, hydroxy, t-butyldimethylsilyloxy ethoxy, acetoxy; preferably, R 2 Selected from ethylene glycol ethoxy, methoxy, acetoxy;
(3) And (3) simultaneously carrying out coupling reaction and silyl ether deprotection on the raw material 1 and the intermediate 3 to obtain the procyanidine B2.
Preferably, the reaction of step (1) is carried out in the presence of a lewis base; preferably, the lewis base is selected from one or more of triethylamine, imidazole, sodium bicarbonate, sodium carbonate, cesium carbonate.
Preferably, in step (1), starting material 1 is reacted with compound R 1 Cl or (R) 1 ) 2 The molar ratio of NH is 1:5-1:7.
Preferably, the step (1) is carried out in the presence of one or more solvents selected from acetonitrile, tetrahydrofuran, dichloromethane, N-dimethylformamide and acetone, and the reaction temperature is 0-30 ℃; the reaction time is 1-12 hours.
Preferably, the oxidizing agent of step (2) is selected from DDQ, mnO 2 Potassium peroxomonosulphonate, K 2 S 2 O 8 One or more of 2-iodoxybenzoic acid, silver oxide, ceric ammonium nitrate and manganese triacetate; the nucleophile is selected from water, methanol, ethanol, acetic acid, tert-butyl dimethyl hydroxyethoxy silane, ethylene glycol monoethyl ether, diethylene glycol diethyl ether.
Preferably, in step (2), intermediate 2 is reacted with compound R 2 The molar ratio of H is 1:1.5-1:20; the mol ratio of the intermediate 2 to the oxidant is 1:1.5-1:6;
preferably, step (2) is carried out in the presence of one or more solvents selected from n-hexane, n-heptane, n-pentane, dichloromethane, chloroform, 1, 2-dichloroethane, 1-dichloroethylene, 1, 2-dichloroethylene, cyclohexane, ethylbenzene, toluene, xylene, chlorobenzene, acetonitrile, t-butyl methyl ether, 1, 4-dioxane, water, at a reaction temperature of from 0 ℃ to 30 ℃ and for a reaction time of from 1 to 12 hours.
Preferably, in step (3), the molar ratio of the raw material 1 to the intermediate 3 is 1:1 to 1:1.2.
Preferably, step (3) is carried out in the presence of a solvent; the solvent is at least one of petroleum ether, N-hexane, cyclohexane, N-heptane, methylene dichloride, methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, 1, 4-dioxane, water and N, N-dimethylformamide; preferably, the solvent is at least one of ethanol, 1, 4-dioxane, petroleum ether and isopropanol; more preferably, the solvent is a mixed solvent of petroleum ether, 1, 4-dioxane and isopropanol, and the volume ratio is (1-2); more preferably, the solvent is a mixed solvent of petroleum ether, 1, 4-dioxane and isopropanol in a volume ratio of 1:1:1;
preferably, step (3) is carried out in the presence of a catalyst; the catalyst is at least one of hydrochloric acid, acetic acid, formic acid, camphorsulfonic acid, montmorillonite K-10, lithium bromide, lithium bis (trifluoromethanesulfonyl) imide, silver tetrafluoroborate, phenylboronic acid compounds, 2, 6-dichloro-3-pyridine boric acid, boron trifluoride diethyl ether, trifluoromethanesulfonic acid, cerium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate and tin tetrachloride. Preferably, the catalyst is montmorillonite K-10.
Preferably, the reaction temperature of step (3) is from 0 ℃ to 50 ℃, preferably from 25 ℃ to 45 ℃. Preferably, the reaction time of step (3) is from 0.5 to 12 hours.
The preparation method of the procyanidine B2 can further comprise the following step (4), and the obtained crude procyanidine B2 is further refined:
(4) Filtering crude procyanidine B2, concentrating, pulping in mixed solution of dichloromethane and methanol, filtering to remove R removed after reaction 1 And R is 2 The radical and the filter cake are dried to obtain light brown crude solid powder of procyanidine B2. Preferably, the volume ratio of the dichloromethane to the methanol is 5:1-30:1.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the preparation of the raw materials is simple, and the intermediate 3 with high purity and high yield is prepared by crystallization and extraction; by using a proper solvent system through the polarity difference of the raw material 1 and the intermediate 3, the aim of inhibiting self-coupling of the intermediate 3 under the condition of equimolar feeding can be fulfilled, so that the coupling of the raw material 1 and the intermediate 3 is improved.
The existence of the C-3 protecting group of the intermediate 3 of the invention causes that the raw material 1 and the intermediate 3 only generate procyanidine dimer with single chirality in the process of carrying out SN1 reaction due to the steric hindrance effect of the hydroxyl protecting group.
The beneficial effects are that: the preparation method of the invention has the advantages of simple and easily obtained raw materials, economy, no need of column purification to obtain high-yield and high-purity raw materials, great reduction of material, labor and time costs, and suitability for large-scale preparation. The invention selects proper proton solvent to make the coupling reaction of the raw material 1 and the intermediate 3 and the deprotection of the silyl ether simultaneously proceed, which can greatly reduce the reaction time and operation steps. The synthesis period is greatly shortened. The invention realizes the high-yield catalytic coupling of the equimolar feeding of the raw material 1 and the intermediate 3, and can greatly inhibit the self-coupling side reaction of the intermediate 3.
Drawings
FIG. 1 is a procyanidin B2 prepared by example 4 of the present invention 1 H-NMR spectrum;
FIG. 2 is a procyanidin B2 prepared by example 4 of the present invention 13 C-NMR spectrum;
FIG. 3 is an HPLC chart of pure procyanidin B2 product obtained in example 4 of the present invention;
FIG. 4 is a mass spectrum of procyanidin B2 prepared by example 4 of the present invention;
FIG. 5 is an HPLC chart of crude procyanidin B2 produced by example 4 of the present invention;
FIG. 6 is an HPLC chart of crude procyanidin B2 produced by example 5 of the present invention;
FIG. 7 is a chiral HPLC chart of procyanidin B2 and natural procyanidin B2 prepared by the present invention analyzed in example 8 of the present invention.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
In the context of the various embodiments of the present invention, 1 HNMR was recorded by a BRUKER AVANCE NEO 600mhz jnm-ECZ400s nuclear magnetic resonance spectrometer, chemical shift expressed as δ (ppm): liquid chromatography-mass spectrometry (LCMS) was recorded by Shimadzu LC-20AD,Agilent 1260 type and Agilent 1200 type mass spectrometers.
Abbreviations (abbreviations)
EXAMPLE 1 (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (benzhydrylsiloxy) -4-acetoxyflavan-3, 4-diol
(1) (2R, 3R) - (3 ',4',3,5, 7) -penta (benzhydrylsiloxy) flavan-3-ol
At N 2 20g of (2R, 3R) -flavan-3-ol and 47g of imidazole (10 eq) were dissolved in 200mL of a mixed solvent of THF (tetrahydrofuran) and DCM (dichloromethane) (volume ratio 3:1) under an atmosphere. Then 73mL DPMSCl (5 eq) was added dropwise to the reaction flask at room temperature and the reaction was continued for 6h at room temperature until the starting material disappeared. After the reaction, the residue was recrystallized from n-hexane to give (2R, 3R) - (3 ',4',3,5, 7) -penta (benzhydrylsiloxy) flavan-3-ol in 93% yield.
1 H NMR(600MHz,CDCl 3 )δ7.57-7.61(m,20H),7.35-7.38(m,30H),6.67(dd,J＝8.2,2.1Hz,1H),6.66(d,J＝2.1Hz,1H),6.65(d,J＝8.2Hz,1H),6.01(d,J＝2.3Hz,1H),5.85(d,J＝2.3Hz,1H),4.88(d,J＝2.2Hz,1H),4.76(dd,J＝2.6,1.2Hz,1H),2.85(dd,J＝16.2,4.6Hz,1H),2.60(dd,J＝16.2,4.6Hz,1H),0.66(s,15H).
(2) (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (benzhydrylsiloxy) -4-acetoxyflavan-3, 4-diol
At N 2 The (2R, 3R) - (3 ',4',3,5, 7) -penta (benzhydryl) flavan-3-ol synthesized in step (1) was dissolved in 500mL of methylene chloride under an atmosphere. Then, 29g of DDQ (2.0 eq) was added in portions to the reaction flask at 0 ℃. Subsequently, 23mL of acetic acid solution was added dropwise, and the reaction was continued at room temperature for 3 hours until the starting material disappeared. At 0 ℃, willSaturated aqueous sodium hydrogencarbonate solution was slowly dropped into the reaction solution, the pH of the reaction solution was adjusted to neutrality, 9.4g of DMAP (1.2 eq) was added into the reaction flask, stirring was continued for 10min, after which filtration through a celite pad, concentration under reduced pressure was performed to remove the solvent, ethyl acetate was added for extraction, the organic phase was extracted, washed with brine, dried, and concentrated under reduced pressure to obtain a yellowish brown oil (purity 90%, yield 47%).
1 H NMR(600MHz,CDCl 3 )δ7.63-7.51(m,20H),7.38-7.35(m,30H),6.88(dd,J＝8.2,2.1Hz,1H),6.79(d,J＝2.1Hz,1H),6.75(d,J＝8.2Hz,1H),6.11(d,J＝2.3Hz,1H),5.93(d,J＝2.3Hz,1H),5.42(d,J＝2.2Hz,1H),4.92(dd,J＝2.6,1.2Hz,1H),4.86(d J＝2.3Hz,1H),2.19(s 3H),0.66(s,15H).
EXAMPLE 2 (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (trimethylsiloxy) -4- (2-ethanediol) flavan-3, 4-diol
(1) (2R, 3R) - (3 ',4',3,5, 7) -penta (trimethylsiloxy) flavan-3-ol
At N 2 20g of (2R, 3R) -flavan-3-ol are dissolved in 200mL of acetonitrile solution under an atmosphere. 72mL of HMDS (5 eq) was then added dropwise to the reaction flask at 0deg.C and reacted for 3h at room temperature until the starting material disappeared. After the reaction, the mixture was concentrated under reduced pressure, and the residue was recrystallized from petroleum ether to give (2R, 3R) - (3 ',4',3,5, 7) -penta (trimethylsiloxy) flavan-3-ol in 98% yield.
1 H NMR(600MHz,CDCl 3 )δ6.93(dd,J＝8.2,2.1Hz,1H),6.88(d,J＝2.1Hz,1H),6.81(d,J＝8.2Hz,1H),6.14(d,J＝2.3Hz,1H),5.97(d,J＝2.3Hz,1H),4.89–4.85(m,1H),4.14(td,J＝4.3,2.0Hz,1H),2.80(dd,J＝16.5,4.5Hz,1H),2.58(dd,J＝16.6,4.0Hz,1H),0.26(s,9H),0.25(s,9H),0.24(s,9H),0.23(s,9H),-0.11(s,9H)； 13 C NMR(125MHz,CDCl 3 )δ155.84,154.64,154.37,146.21,145.95,132.93,120.74,120.62,119.86,105.21,104.24,101.87,78.82,67.48,29.08,0.58,0.52,0.43,0.41,-0.08.
(2) (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (trimethylsiloxy) -4- (2-ethanediol) flavan-3, 4-diol
At N 2 The (2R, 3R) - (3 ',4',3,5, 7) -penta (trimethylsiloxy) flavan-3-ol synthesized in step (1) was dissolved in 500mL of methylene chloride under an atmosphere. Then, DDQ (2.0 eq) was added in portions to the reaction flask at 0 ℃. Subsequently, 67mL of ethylene glycol diethyl ether (10 eq) was added dropwise and the reaction was continued at room temperature for 3 hours until the starting material disappeared. Subsequently, 10g of DMAP (1.2 eq) was added to the reaction flask at 0℃and after stirring continued for 10min, filtration was carried out through a pad of celite. After concentrating the filtrate, diluting with ethyl acetate and extracting with water, the organic phase was extracted, washed with brine, dried, and concentrated under reduced pressure to give a yellow-brown oil (purity 93%, yield 48%).
1 H NMR(600MHz,CDCl 3 )δ6.97(dd,J＝8.2,2.1Hz,1H),6.92(d,J＝2.1Hz,1H),6.84(d,J＝8.2Hz,1H),6.12(d,J＝2.3Hz,1H),5.98(d,J＝2.3Hz,1H),5.06(s,1H),4.25(d,J＝2.8Hz,1H),3.91(dd,J＝2.8,1.4Hz,1H),3.85(dd,J＝6.0,4.2Hz,2H),3.62(dd,J＝5.7,4.3Hz,2H),3.56(qt,J＝7.0,3.3Hz,2H),1.23(t,J＝7.0Hz,3H),0.31(s,9H),0.25(s,18H),0.24(s,9H),-0.21(s,9H)； 13 C NMR(125MHz,CDCl 3 )δ156.8,156.6,156.2,146.3,146.0,132.9,120.9,120.8,120.1,105.7,103.6,101.6,75.2,71.8,70.2,69.4,69.1,66.8,15.4,0.7,0.6,0.4,-0.21.
EXAMPLE 3 (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (triethylsiloxy) -4-methoxyflavan-3, 4-diol
(1) (2R, 3R) - (3 ',4',3,5, 7) -penta (triethylsiloxy) flavan-3-ol
At N 2 20g of (2R, 3R) -flavan-3-ol and 47g of imidazole (10 eq) were dissolved in 200mL of a mixed solvent of THF (tetrahydrofuran) and DCM (dichloromethane) (volume ratio 3:1) under an atmosphere. 58mL of TESCl (5 eq) were then added dropwise to the reaction flask at room temperature and the reaction was continued at room temperature for 6h until the starting material disappeared. After the reaction, concentrating under reduced pressure, and collecting the residue in n-hexaneRecrystallization gave (2 r,3 r) - (3 ',4',3,5, 7) -penta (triethylsiloxy) flavan-3-ol in 98% yield.
1 H NMR(600MHz,CDCl 3 )δ6.87(dd,J＝8.4,2.3Hz,1H),6.79(d,J＝2.3Hz,1H),6.65(d,J＝8.4Hz,1H),5.98(d,J＝2.3Hz,1H),5.95(d,J＝2.3Hz,1H),4.95(s,1H),4.45(td,J＝4.3,1.3Hz,1H),2.97(dd,J＝16.6,4.4Hz,1H),2.63(dd,J＝16.6,4.5Hz,1H),1.21(t,J＝7.8Hz,9H),1.09(t,J＝7.9Hz,18H),1.06(t,J＝8.0Hz,9H),1.01(t,J＝7.9Hz,9H),0.83(q,J＝7.8Hz,6H),0.80(q,J＝7.9Hz,12H),0.78(q,J＝8.0Hz,6H),0.76(q,J＝7.9Hz,6H)； 13 C NMR(125MHz,CDCl 3 )δ156.3,155.3,155.2,147.2,144.4,131.3,122.3,120.8,119.1,107.7,104.1,99.5,86.7,84.5,29.1,11.2,10.8,10.7,10.6,10.5,7.0,6.9,6.8,6.7,6.6.
(2) (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (triethylsiloxy) -4-methoxyflavan-3, 4-diol
At N 2 The (2R, 3R) - (3 ',4',3,5, 7) -penta (triethylsiloxy) flavan-3-ol synthesized in step (1) was dissolved in 500mL of methylene chloride solvent under an atmosphere. Then, 15.6g of DDQ (1.0 eq) was added in portions to the reaction flask at 0 ℃. Subsequently, 2.8mL of methanol was added dropwise, and the reaction was continued at room temperature for 3 hours until the starting material disappeared. Subsequently, 10g of DMAP (1.2 eq) was added to the reaction flask at 0℃and after stirring continued for 10min, filtration was carried out through a pad of celite. The filtrate was concentrated, diluted with ethyl acetate and extracted with water to give an organic phase, which was washed with brine, dried and concentrated under reduced pressure to give a light brown oil (92% purity, 48% yield)
1 H NMR(600MHz,CDCl 3 )δ7.03(d,J＝2.2Hz,1H),6.91(dd,J＝8.3,2.2Hz,1H),6.85(d,J＝8.2Hz,1H),6.14(d,J＝2.2Hz,1H),6.01(d,J＝2.2Hz,1H),5.92(d,J＝2.7Hz,1H),4.95(s,1H),4.01(dd,J＝5.8,2.6Hz,2H),3.17(s,3H),1.24(t,J＝7.8Hz,9H),1.12(t,J＝7.9Hz,18H),1.09(t,J＝8.0Hz,9H),1.05(t,J＝7.9Hz,9H),0.83(q,J＝7.8Hz,6H),0.80(q,J＝7.9Hz,12H),0.77(q,J＝8.0Hz,6H),0.75(q,J＝7.9Hz,6H)； 13 C NMR(125MHz,CDCl 3 )δ156.3,155.3,155.2,147.2,144.4,131.3,122.3,120.8,119.1,107.7,104.1,99.5,86.7,84.5,29.1,11.2,10.8,10.7,10.6,10.5,7.0,6.9,6.8,6.7,6.6.
EXAMPLE 4 Synthesis of procyanidin B2
A500 mL round bottom two-necked flask was taken, 0.5mL of concentrated hydrochloric acid was dissolved in 200mL of a mixed solvent of petroleum ether/1, 4-dioxane/isopropanol (volume ratio 1:1:1), 10g of epicatechin and 25.5g of (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (trimethylsiloxy) -4- (2-ethylene glycol) flavan-3, 4-diol (prepared in example 2) were further added, dissolved, and the mixture was stirred at room temperature under nitrogen protection for 1 hour until the raw material (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (trimethylsiloxy) -4- (2-ethylene glycol) flavan-3, 4-diol disappeared, after the reaction was completed, the reaction solution was concentrated under reduced pressure, and slurried with 100mL of methylene chloride/methanol (volume ratio 20:1) to obtain crude procyanidin B2, which was subjected to silica gel column chromatography with methylene chloride: methanol (volume ratio 10:1) as eluent to obtain procyanidin B2 (13.2 g, purification yield 66%).
Procyanidin B2 has multiple rotameric conformations around a C4-C8' single bond, resulting in it 1 NMR 13 NMR spectra exhibited broad peak characteristics: 1 H NMR(600MHz,CD 3 OD)7.10(1H，br s)，6.90(1H，br s)，6.78-6.62(4H，m)，6.05-5.80(3H，m)，5.06-4.95(1H，m)，5.00-4.90(1H，m)，4.62(1H，br s)，4.35-4.20(1H，m)，3.90(1H，br s)，2.90-2.83(1H，m)，2.82-2.70(1H，m)； 13 CNMR：158.36，157.84，156.45，154.44，145.79，145.78，145.53，145.52，132.51，132.06，119.22，119.21，115.92，115.91，115.21，115.20，107.25，101.37，100.46，97.36，96.48，96.08，96.07，79.64，77.02，73.46，66.91，61.59，37.06，29.67。
EXAMPLE 5 Synthesis of procyanidin B2
A2L round bottom two-neck flask was taken, 100g epicatechin and 255g (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (trimethylsiloxy) -4- (2-ethylene glycol) flavan-3, 4-diol (1 eq) (prepared in example 2) were dissolved in a mixed solvent of 1L petroleum ether/1, 4-dioxane/isopropanol (volume ratio 1:1:1), 195g montmorillonite K-10 (2 eq) was added, and the reaction was stirred at room temperature under nitrogen protection for 1 hour until the starting material (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (trimethylsiloxy) -4- (2-ethylene glycol) flavan-3, 4-diol disappeared, after the reaction was completed, montmorillonite K-10 was removed by filtration, the filtrate was concentrated under reduced pressure, and after pulping with 600mL methylene chloride/methanol (volume ratio 20:1), crude procyanidin B2 was obtained by silica gel column chromatography with methylene chloride: methanol (volume ratio 10:1) as eluent to obtain procyanidin B2 (143 g, purification yield 72%). The structure detection data are substantially the same as in example 4.
EXAMPLE 6 Synthesis of procyanidin B2
A2L round-bottom two-necked flask was taken, 50g of epicatechin and 230g of (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (benzhydryloxy) flavan-3, 4-diol (1 eq) (prepared in example 1) were dissolved in 1L of methanol/tetrahydrofuran/dichloromethane (volume ratio 1:1:1), 30g of lithium bromide (2 eq) was added, and the reaction was stirred at 45℃for 3 hours under nitrogen until the starting material (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (benzhydryloxy) -4-acetoxyflavan-3, 4-diol disappeared, after the reaction was completed, the filtrate was concentrated under reduced pressure and chromatographed on silica gel with dichloromethane: methanol (volume ratio 10:1) as eluent to obtain procyanidin B2 (47.5 g, purification yield 48%). The structure detection data are substantially the same as in example 4.
EXAMPLE 7 Synthesis of procyanidin B2
A1L round-bottom two-necked flask was taken, 50g of epicatechin and 153g of (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (triethylsiloxy) -4-methoxyflavan-3, 4-diol (1 eq) (prepared in example 3) were dissolved in 800mL of methanol/1, 4, dioxane (volume ratio 1:1), 21.4g of ytterbium triflate (0.2 eq) was added, and the reaction was stirred at room temperature under nitrogen protection for 1 hour until the starting material (2R, 3R, 4S) - (3 ',4',3,5, 7) -penta (triethylsiloxy) -4-methoxyflavan-3, 4-diol disappeared, after the reaction was completed, the filtrate was concentrated under reduced pressure and chromatographed on silica gel with methylene chloride: methanol (volume ratio 10:1) as eluent to obtain procyanidin B2 (62.5 g, purification yield 63%). The structure detection data are substantially the same as in example 4.
EXAMPLE 8 chiral configurational analysis of procyanidin B2 prepared according to the present invention
To further verify the procyanidin B2 prepared according to the present invention with native procyanidin B2 (purchasedIn Yunnan Siderurgica Biotechnology Co., ltd.) has a consistent absolute configuration, and is analyzed by the following method: instrument model: agilent1120; chromatographic column:IA; chromatographic column specification: 250mm by 4.6mm; chromatographic column packing particle size: 5 μm; mobile phase ratio: 0.1% tfa n-hexane: ethanol=20: 80; flow rate: 1.000mL/min; column temperature: 25 ℃; detection wavelength: 280nm; sample injection amount: 20. Mu.L. Under the chiral analysis conditions, the peak-out time of the procyanidine B2 synthesized by the invention and the natural procyanidine B2 is consistent through repeated experiments.

Claims (9)

1. The preparation method of the procyanidine B2 is characterized by comprising the following steps:
(1) Starting material 1 and compound R 1 Cl or (R) 1 ) 2 NH is subjected to substitution reaction to obtain an intermediate 2; wherein R is 1 Selected from trimethylsilyl, triethylsilyl, and benzhydryl;
(2) Intermediate 2 and R 2 H is subjected to oxidation reaction in the presence of an oxidant and a nucleophilic reagent to obtain an intermediate 3; wherein R is 2 Selected from ethylene glycol ethoxy, diethylene glycol ethoxy, methoxy, ethoxy, hydroxy, t-butyldimethylsilyloxy ethoxy, acetoxy;
(3) And (3) simultaneously carrying out coupling reaction and deprotection of the silyl ether on the raw material 1 and the intermediate 3 to obtain the procyanidine B2.
2. The method for preparing procyanidin B2 according to claim 1, wherein: r is R 2 Selected from ethylene glycol ethoxy, methoxy, acetoxy.
3. The method for producing procyanidin B2 according to claim 1 or 2, characterized in that: the reaction of step (1) is carried out in the presence of a lewis base; the Lewis base is selected from one or more of triethylamine, imidazole, sodium bicarbonate, sodium carbonate and cesium carbonate.
4. The method for producing procyanidin B2 according to claim 1 or 2, characterized in that: the oxidant in step (2) is selected from DDQ, mnO 2 Potassium peroxomonosulphonate, K 2 S 2 O 8 One or more of 2-iodoxybenzoic acid, silver oxide, ceric ammonium nitrate and manganese triacetate; the nucleophile is selected from water, methanol, ethanol, acetic acid, tert-butyl dimethyl hydroxyethoxy silane, ethylene glycol monoethyl ether, diethylene glycol diethyl ether.
5. The method for producing procyanidin B2 according to claim 1 or 2, characterized in that: step (3) is carried out in the presence of a catalyst; the catalyst is at least one of hydrochloric acid, acetic acid, formic acid, camphorsulfonic acid, montmorillonite K-10, lithium bromide, lithium bis (trifluoromethanesulfonyl) imide, silver tetrafluoroborate, phenylboronic acid compounds, 2, 6-dichloro-3-pyridine boric acid, boron trifluoride diethyl ether, trifluoromethanesulfonic acid, cerium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate and tin tetrachloride.
6. The method for producing procyanidin B2 according to claim 1 or 2, characterized in that:
in step (1), starting material 1 and compound R 1 Cl or (R) 1 ) 2 The molar ratio of NH is 1:5-1:7;
in step (2), intermediate 2 is reacted with compound R 2 The molar ratio of H is 1:1.5-1:20; the mol ratio of the intermediate 2 to the oxidant is 1:1.5-1:6;
in the step (3), the molar ratio of the raw material 1 to the intermediate 3 is 1:1-1:1.2.
7. The method for producing procyanidin B2 according to claim 1 or 2, characterized in that:
step (1) is carried out in the presence of one or more solvents selected from acetonitrile, tetrahydrofuran, dichloromethane, N-dimethylformamide and acetone, and the reaction temperature is 0-30 ℃; the reaction time is 1-12 hours.
8. The method for producing procyanidin B2 according to claim 1 or 2, characterized in that: the step (2) is carried out in the presence of one or more solvents of n-hexane, n-heptane, n-pentane, methylene dichloride, chloroform, 1, 2-dichloroethane, 1-dichloroethylene, 1, 2-dichloroethylene, cyclohexane, ethylbenzene, toluene, xylene, chlorobenzene, acetonitrile, tert-butyl methyl ether, 1, 4-dioxane and water, the reaction temperature is 0-30 ℃ and the reaction time is 1-12 hours.
9. The method for producing procyanidin B2 according to claim 1 or 2, characterized in that: step (3) is carried out in the presence of a solvent; the solvent is at least one of petroleum ether, N-hexane, cyclohexane, N-heptane, methylene dichloride, methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, 1, 4-dioxane, water and N, N-dimethylformamide; the reaction temperature is 0-50 ℃ and the reaction time is 0.5-12 hours.
CN202311542888.7A 2023-11-20 2023-11-20 Preparation method of procyanidine B2 Pending CN117534646A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202311542888.7A CN117534646A (en) 2023-11-20 2023-11-20 Preparation method of procyanidine B2

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202311542888.7A CN117534646A (en) 2023-11-20 2023-11-20 Preparation method of procyanidine B2

Publications (1)

Publication Number Publication Date
CN117534646A true CN117534646A (en) 2024-02-09

Family

ID=89781985

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202311542888.7A Pending CN117534646A (en) 2023-11-20 2023-11-20 Preparation method of procyanidine B2

Country Status (1)

Country Link
CN (1) CN117534646A (en)

Similar Documents

Publication Publication Date Title
CA2569498C (en) Semi-synthesis of taxane intermediates and their conversion to paclitaxel and docetaxel
MXPA06000951A (en) Regioselective synthesis of cci-779.
CN105237452A (en) Novel crystalline form of doxercalciferol and preparation method for novel crystalline form
CN114380675A (en) Method for synthesizing aryl phenol by reaction of halogenated aromatic hydrocarbon and phenol compound induced by visible light
CN114014872A (en) Artesunate derivative and preparation method and application thereof
CN101402655B (en) Process for producing platinum
CN105026384A (en) Novel approach for synthesis of catechins
CN108892601B (en) Preparation method of polycyclic aromatic hydrocarbon with benzofluorene structure
CN113061077B (en) Alpha, alpha-dideuteroalcohol compounds, deuterated drugs and preparation method thereof
CN101863861A (en) Simple and efficient method for preparing paclitaxel analogue Larotaxel
CN117534646A (en) Preparation method of procyanidine B2
EP1255745B1 (en) Synthesis of water soluble 9-dihydro-paclitaxel derivatives from 9-dihydro-13-acetylbaccatin iii
CN111533745A (en) Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester
CN109776295B (en) Aryl iodine compound containing difluoromethylene at ortho-position and preparation method thereof
CN114573631A (en) Method for synthesizing paclitaxel side chain and analog thereof in one step by utilizing three-component reaction and application thereof
CN111217847B (en) Thiosilane ligand, preparation method thereof and application thereof in aryl boronization catalytic reaction
CN111423365B (en) Bifunctional group pillar aromatic hydrocarbon derivative ligand, metal organic cage and preparation method
Ley et al. Towards the synthesis of the C37-C42 fragment of rapamycin: intramolecular reactions of allyl silanes with oxonium ions generated from α-alkoxy sulfones.
CN106632160A (en) Methods for preparing semi-synthetic paclitaxel and intermediate thereof
CN107603271B (en) Preparation method of long-chain alkoxy BODIPY compound
CN101805339A (en) Entecavir compound prepared in novel method
CN112778191A (en) Visible light mediated method for synthesizing allyl alcohol compound containing indole skeleton
CN117658967A (en) Preparation method of flavan-3, 4-diol derivative
JP4084364B2 (en) Chiral sensor and chiral sensing method
Williams et al. Novel synthesis and characterisation of ruthenium tris (4-methyl-4′-vinyl-2, 2′-bipyridine) complexes

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination