WO2016041195A1 - Flavone glycoside derivatives and preparation method and use thereof - Google Patents

Flavone glycoside derivatives and preparation method and use thereof Download PDF

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WO2016041195A1
WO2016041195A1 PCT/CN2014/086933 CN2014086933W WO2016041195A1 WO 2016041195 A1 WO2016041195 A1 WO 2016041195A1 CN 2014086933 W CN2014086933 W CN 2014086933W WO 2016041195 A1 WO2016041195 A1 WO 2016041195A1
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flavonoid
glucosyl
benzoyl
methoxy
room temperature
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PCT/CN2014/086933
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French (fr)
Chinese (zh)
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徐必学
梁光义
胡占兴
夏文
姜伟
袁洁
陈洪菊
张丽梅
蒋坤
孙晓军
李星
安巧
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贵州百灵企业集团制药股份有限公司
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Publication of WO2016041195A1 publication Critical patent/WO2016041195A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones

Definitions

  • the invention relates to a flavonoid glycoside derivative, a preparation method thereof and use thereof, and belongs to the field of medicine.
  • Diabetes mellitus is a disorder of sugar metabolism caused by insufficient insulin secretion, insulin deficiency or insulin resistance (IR), resulting in elevated blood sugar, accompanied by various complications, and disorders of sugar, fat and protein metabolism. .
  • Type 1 diabetes is characterized by a lack of insulin secretion and requires daily injections of insulin for treatment.
  • Type 2 diabetes is characterized by the inability of the human body to effectively use insulin, and oral hypoglycemic drugs are needed for intervention. More than 90% of people with diabetes are type 2 diabetes. At present, diabetes has become the third major disease threatening human health after cardiovascular and cerebrovascular diseases and tumors worldwide. The incidence of diabetes is rising sharply in both developed and developing countries.
  • Diabetes is a kind of Severe non-infectious and chronic diseases have become a major public health issue of concern to all countries in the world. With more than 92.4 million type 2 diabetes patients in China, it has become the country with the largest number of diabetic patients in the world.
  • the drugs currently used for the treatment of diabetes are classified into insulin preparations represented by insulin aspart injection, biosynthetic human insulin injection, and protamine biosynthesis human insulin injection; acarbose, vogire A glucose-representative ⁇ -glucosidase inhibitor; a sulfonylurea represented by glimepiride, gliclazide, and gliclazide; a lattice represented by repaglinide and nateglinide Naphthalenes, biguanides represented by metformin; thiazolidinediones represented by rosiglitazone and pioglitazone; compound preparations and dipeptidyl peptidase-4 (DPP-4) inhibitors.
  • insulin preparations represented by insulin aspart injection, biosynthetic human insulin injection, and protamine biosynthesis human insulin injection
  • acarbose vogire
  • a glucose-representative ⁇ -glucosidase inhibitor a sulfon
  • hypoglycemic drugs there are drugs with fast pharmacodynamic effects and good curative effect, but all have some toxic side effects, which are harmful to organs such as liver, kidney, stomach and stomach. Some diabetic patients show obvious resistance to insulin, and existing There is no drug in the drug that can eradicate diabetes. Patients need to take drugs for a long time. Therefore, it is urgent to find new safe and effective diabetes drugs.
  • the starch (polysaccharide) in the food is digested into oral oligosaccharides (or oligosaccharides) and disaccharides and trisaccharides by oral saliva and pancreatic amylase, and is broken down into a single small intestine by ⁇ -glucosidase.
  • Glucose which is absorbed by the small intestine.
  • Competitive inhibition of various ⁇ -glucosidases in the small intestine which slows down the breakdown of starch into glucose, thereby slowing the absorption of glucose in the intestine and reducing postprandial hyperglycemia.
  • Flavonoids are a kind of natural compounds widely found in medicinal and edible plants, and their chemical structure and biological activity are diverse. So far, domestic and foreign scholars have conducted extensive and systematic research on flavonoids in nearly 40 kinds of traditional Chinese medicines and natural medicines, providing a material basis for the clinical application and development of natural flavonoids.
  • the flavonoid compound, its in vitro activity test showed a good inhibitory effect on ⁇ -glucosidase, and can be used as a drug molecule for treating diabetes. Therefore, further exploration of the medicinal value of flavonoids, in view of the relatively weak biological activity of flavonoids, it is particularly necessary to optimize the design and synthesis of the flavonoids and improve the activity of these compounds in the treatment of diabetes.
  • the object of the present invention is to provide a flavonoid glycoside derivative, a preparation method and use thereof.
  • the flavonoid glycoside derivative of the invention is used for preparing a medicament for treating diabetes, has good inhibitory effect on ⁇ -glucosidase, improves the activity of the compound for treating diabetes, and can be used for preparing a better curative effect and higher safety.
  • the drug for treating diabetes is used for preparing a medicament for treating diabetes.
  • R X is R 1 or R 1 ', and R 1 represents ⁇ -D-glucopyranosyl, ⁇ -D-galactopyranosyl, ⁇ -D-lactosyl or ⁇ -D-maltosyl;
  • R 2 represents hydrogen, -CH 3 , -CH 2 CH 3 ,
  • the aforementioned alkyl group and cycloalkyl group may be substituted by 1 to 2 hydroxyl groups, a nitro group, a halogen group, a cyano group or a trifluoromethyl group.
  • the flavonoid glycoside derivative is 3,5,3'-trimethoxy-4'-hydroxy-7-O- ⁇ -D-(2,3,4,6-tetra-O-benzoyl)-glucosyl -flavonoids, 3,5,3'-trimethoxy-4'-hydroxy-7-O- ⁇ -D-glucosyl-flavonoids, 3,5,3'-tris-ethoxy-4'-hydroxy- 7-O- ⁇ -D-glucosyl-flavonoid, 3-methoxy-5-hydroxy-3',4'-O-diphenylmethylidene-7-O- ⁇ -D-benzoyl glucosyl -Flavone, 3-methoxy-5,3',4'-trihydroxy-7-O- ⁇ -D-benzoyl glucosyl-flavonoid, 3-methoxy-5,3',4'- Trihydroxy-7-O- ⁇ -D-glucosyl-flavonoid, 3-methoxy-5,3',4'-tri-n-p
  • the pharmaceutically acceptable salt is obtained by reacting a flavonoid glycoside derivative compound containing a carboxyl group with a basic substance or a flavonoid glycoside derivative compound containing an amino group and an acidic substance.
  • the aforementioned basic substance is an alkali metal or alkaline earth metal hydroxide, carbonate, hydrogencarbonate, trimethylamine or triethylamine;
  • the acidic substance is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid. , trifluoromethanesulfonic acid, formic acid, acetic acid, oxalic acid or citric acid
  • the preparation method of a kind of flavonoid glycoside derivative is carried out according to the following synthetic route I: bis benzylation is used as raw material to obtain I-1, I-1 is acid-hydrolyzed to obtain I-2, and I-2 is alkylated. I-3, I-3 is catalytically hydrogenated to obtain I-4, I-4 is selectively glycosylated to obtain I-5, and I-5 is alkylated to obtain I-6, and I-6 is sodium methoxide. Treatment of deacylation to obtain I-7,
  • reaction conditions i are BnBr, DMF, K 2 CO 3 , room temperature; reaction conditions ii are HCl, MeOH, 60 ° C; reaction conditions iii are R 2 I, DMF, K 2 CO 3 , room temperature ; reaction conditions iv is H 2 , 10% Pd / C, MeOH, room temperature; reaction conditions v is R 1 Br, tetrabutylammonium bromide (TBAB), CHCl 3 /H 2 O, K 2 CO 3 , room temperature; The reaction condition vi is R 5 I, DMF, K 2 CO 3 , room temperature; the reaction condition vii is NaOMe, MeOH, room temperature.
  • a method for preparing a flavonoid glycoside derivative is carried out according to the following synthetic route II: triacetylation of rutin as raw material to obtain II-1, II-1 by acid hydrolysis to obtain II-2, II-2 by alkylation Catalytic hydrogenation of II-3, II-3 to obtain II-4, II-4 and diphenylmethylene chloride to obtain product II-5, II-5 by selective glycosylation to obtain II-6, II- 6 by alkylation reaction to obtain II-7, II-7 by catalytic hydrogenation to obtain II-8, II-8 by alkylation reaction to obtain II-9, II-9 by alkylation reaction to obtain II-10, II -10 is deacylated with sodium methoxide to obtain II-11.
  • reaction conditions i are BnBr, DMF, K 2 CO 3 , room temperature; reaction conditions ii are HCl, MeOH, 60 ° C; reaction conditions iii are R 3 I, DMF, K 2 CO 3 , room temperature
  • the reaction condition iv is H 2 , 10% Pd/C, MeOH, room temperature; the reaction condition v is Ph 2 CCl 2 , Ph 2 O, 180 ° C; the reaction condition vi is R 1 Br, tetrabutylammonium bromide (TBAB) Or tetrabutylammonium iodide (TBAI), CHCl 3 /H 2 O, K 2 CO 3 , room temperature; reaction conditions vii is R 2 I, DMF, K 2 CO 3 , room temperature; reaction condition viii is H 2 , 10% Pd / C, MeOH / THF, room temperature; reaction conditions ix is R 5 I, DMF, K 2 CO 3 , room temperature;
  • the flavonoid glycoside derivative is added, and one or more pharmaceutically acceptable carriers or excipients are added to prepare various therapeutic pharmaceutical preparations for diabetes.
  • the aforementioned pharmaceutical preparation for treating diabetes is an oral preparation: a tablet, a capsule, an oral solution, a suspension; or an injection preparation: an injectable solution, a suspension, a powder injection; or an external preparation: an ointment or a solution.
  • the aforementioned pharmaceutically acceptable carrier or excipient means any diluent, adjuvant or carrier which can be used in the pharmaceutical field, including a binder for an oral preparation, a lubricant, a disintegrant, a solubilizer, a diluent, and a stable Agents, suspending agents, pigments, flavoring agents; preservatives, solubilizers, stabilizers for injection preparations; bases, diluents, lubricants, preservatives for external preparations.
  • the invention has the advantages that the flavonoid glycoside derivative of the invention is used for preparing a medicament for treating diabetes, and can have a good inhibitory effect on ⁇ -glucosidase, thereby slowing down the decomposition of starch into glucose and slowing down the intestine.
  • the absorption of glucose in the tract reduces the postprandial hyperglycemia, improves the activity of the compound for treating diabetes, has lower toxicity, and is more suitable for the treatment of diabetic pharmaceutical preparations. It can be used for the treatment of diabetes with better curative effect and higher safety. drug.
  • the preparation method has the advantages of simple steps, easy availability of raw materials, high product yield and good purity.
  • the flavonoid glycoside derivatives can be prepared into various therapeutic pharmaceutical preparations for diabetes, and are adapted to different medication needs.
  • the nuclear magnetic resonance spectrum was determined by TMS as an internal standard, using an Inova-400MHz superconducting nuclear magnetic resonance spectrometer (Varian, USA); mass spectrometry was determined by HP-5793 mass spectrometer (Hewlett-Packard, USA); silica gel for column chromatography (300-400).
  • the high-efficiency thin-layer boards are all products of Qingdao Ocean Chemical Plant. The remaining reagents are commercially available analytically pure or chemically pure products and are used without treatment unless otherwise stated.
  • Reaction reagents and conditions (i) BnBr, K 2 CO 3 , DMF, room temperature; (ii) concentrated hydrochloric acid, ethanol, 70 ° C, 3 h. (iii) CH 3 I, K 2 CO 3 , DMF, room temperature, 8 h; (iv) H 2 , 10% Pd/C, THF, room temperature 15 h.
  • Reaction reagents and conditions (i) CH 3 CH 2 I, K 2 CO 3 , DMF, room temperature, 8 h; (ii) H 2 , 10% Pd/C, THF, room temperature 15 h.
  • Reaction reagents and conditions (i) BnBr, K 2 CO 3 , DMF, room temperature; (ii) ethanol, concentrated hydrochloric acid, 70 ° C, 3 h.
  • the filter cake is the crude intermediate M-07; (ii) the crude M-07 is directly dissolved in absolute ethanol (600 mL), then concentrated hydrochloric acid (200 mL) is added, and the reaction solution is refluxed at 70 ° C for 3 h until the reaction After completion, it was cooled to room temperature, poured into an ice water bath, and the precipitate precipitated was filtered, washed with water until neutral, and the filter cake was dried to obtain a yellow solid powdery intermediate M-08. The total yield of the two-step reaction was 80%.
  • Reaction reagents and conditions (i) CH 3 I, K 2 CO 3 , DMF, room temperature, 8 h; (ii) H 2 , 10% Pd/C, THF, room temperature 15 h; (iii) dichlorodiphenylmethane, Phenyl ether, 175 ° C, 1 h.
  • Reaction reagents and conditions (i) (CH 3 )CHCH 2 I, K 2 CO 3 , DMF, room temperature, 8 h; (ii) H 2 , 10% Pd/C, THF, room temperature 15 h; (iii) dichlorodi Phenylmethane, diphenyl ether, 175 ° C, 1 h.
  • Reaction reagents and conditions (i) CH 3 CH 2 CH 2 I, K 2 CO 3 , DMF, room temperature, 8 h; (ii) H 2 , 10% Pd/C, THF, room temperature 15 h; (iii) dichloro Phenylmethane, diphenyl ether, 175 ° C, 1 h.
  • Reaction reagents and conditions (i) CH 3 CH 2 I, K 2 CO 3 , DMF, room temperature, 8 h; (ii) H 2 , 10% Pd/C, THF, room temperature 15 h; (iii) dichlorodiphenylmethane , diphenyl ether, 175 ° C, 1 h.
  • Reaction reagents and conditions (i) benzoyl chloride, pyridine, room temperature; (ii) 33% hydrobromic acid acetic acid solution, 1,2-dichloroethane, room temperature.
  • Reaction reagents and conditions (i) benzoyl chloride, pyridine, room temperature; (ii) 33% hydrobromic acid acetic acid solution, 1,2-dichloroethane, room temperature.
  • Preparation step using the synthetic operation of S-02 in Example 8 and taking D-galactose instead of D-glucose as a raw material, 2,3,4,6-tetra-O-benzoyl- ⁇ - can be prepared.
  • Reaction reagents and conditions (i) KOH, tetrabutylammonium bromide (TBAB), CHCl 3 /H 2 O, room temperature;
  • Preparation step Take M-05 (100 mg, 0.29 mmol) and TBAB (18.7 mg, 0.058 mmol) in a reaction flask, add KOH aqueous solution (2 mL, 0.29 M, 0.58 mmol), stir at room temperature for 15 min, slowly add 2 mL of chloroform to dissolve. After stirring for 48 hours at room temperature, the reaction mixture was adjusted to pH 2-3 with dilute aqueous hydrochloric acid, and ethyl acetate was evaporated. The organic layer was washed with water, dried over anhydrous magnesium sulfate The ester was dried to dryness.
  • Reaction reagents and conditions CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Preparation step The sample T-01 (90 mg, 0.097 mmol) synthesized in Example 10 was taken in a reaction flask, dissolved in 4 mL of methanol and 1 mL of dichloromethane, and sodium methoxide (0.41 M, 0.195 mmol) was slowly added, and stirred at room temperature for 30 min. The mixture was neutralized by stirring with a cation exchange resin, and the pH was adjusted to 5-6, and the filtrate was concentrated to dryness. The obtained residue was purified by silica gel column chromatography .
  • Reaction reagents and conditions (i) KOH, TBAB, CHCl 3 -H 2 O, room temperature; (ii) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Reaction reagents and conditions (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Reaction reagents and conditions (i) CH 3 (CH 2 ) 4 Br, K 2 CO 3 , DMF, room temperature;
  • Preparation step Take T-05 (100 mg, 0.112 mmol) in 4 mL of anhydrous DMF and dissolve completely, add anhydrous potassium carbonate (231 mg, 1.68 mmol), under argon, bromopentane (166 ⁇ L, 1.34 mmol) The reaction mixture was poured into a reaction flask, and the reaction mixture was stirred at room temperature for 12 hours. The obtained reaction mixture was evaporated to ethyl acetate and water, and the organic layer was washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated to dryness.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Preparation step Take T-07 (75mg, 0.068mmol) in a reaction flask, add 4mL methanol and 1mL dichloromethane to dissolve, slowly add sodium methoxide (0.5ml, 0.41M, 0.20mmol), stir at room temperature for 30min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated to dryness.
  • Reaction reagents and conditions (i) CH 3 I, K 2 CO 3 , DMF, room temperature; (ii) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O;
  • T-09-M Purify to give the pale yellow oily intermediate T-09-M, yield 70%; (ii) take T-09-M (530 mg, 0.49 mmol) in a reaction flask, add 100 mL of methanol, 25 mL of tetrahydrofuran and 1.25 mL of water Dissolved, 530 mg of 10% Pd/C was added, and hydrogenation reaction was carried out at room temperature for 48 h, and the palladium carbon was removed by filtration. The solvent was evaporated to dryness. 71%.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Reaction reagents and conditions (i) CH 3 CH 2 I, K 2 CO 3 , DMF, room temperature.
  • T-04 (620 mg, 0.58 mmol) was dissolved in 8 mL of anhydrous DMF, and anhydrous potassium carbonate (243 mg, 1.76 mmol) was added. Under argon atmosphere, ethyl iodide (141 ⁇ L, 1.76 mmol) was added. The reaction flask was poured into the reaction flask, and the reaction was stirred at room temperature for 12 hours. The reaction mixture is added to ethyl acetate and water, and the mixture is evaporated. EtOAcjjjjjjjjjj T-11, yield 78%.
  • Reaction reagents and conditions (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O.
  • Preparation steps Take T-11 (480 mg, 0.44 mmol) in a reaction flask, add 80 mL of methanol, 20 mL of tetrahydrofuran and 1 mL of water to dissolve, add 10% Pd/C (480 mg), hydrogenolysis at room temperature for 48 h, filter to remove palladium. The carbon was recovered under reduced pressure to dryness.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Reaction reagents and conditions (i) CH 3 CH 2 CH 2 I, K 2 CO 3 , DMF, room temperature.
  • Reaction reagents and conditions (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O.
  • Preparation steps Take T-14 (190mg, 0.172mmol) in a reaction flask, add 40mL methanol, 10mL tetrahydrofuran and 0.5mL water to dissolve, add 10% Pd / C (190mg), hydrogenolysis reaction at room temperature for 48h, filter removal The palladium carbon was recovered under reduced pressure to dryness.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Preparation step Take T-15 (102 mg, 0.11 mmol) in a reaction flask, add 4 mL of methanol and 1 mL of dichloromethane to dissolve, slowly add sodium methoxide (0.8 mL, 0.41 M, 0.33 mmol), stir at room temperature for 30 min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated.
  • Reaction reagents and conditions (i) ClCH 2 COOCH 2 CH 3 , K 2 CO 3 , DMF, room temperature.
  • T-04 (200 mg, 0.189 mmol) was dissolved in 4 mL of anhydrous DMF, and anhydrous potassium carbonate (104 mg, 0.755 mmol) was added, and ethyl chloroacetate (80.5 ⁇ L, 0.755) was added under argon atmosphere.
  • the reaction mixture was poured into a reaction flask, and the reaction mixture was stirred at room temperature for 12 hours.
  • the reaction mixture was evaporated to ethyl acetate and water, and then evaporated.
  • the organic layer was washed with water and dried over anhydrous magnesium sulfate. Purification by chromatography gave the title product T-17 as a pale yellow oil.
  • Reaction reagents and conditions (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Reagents and conditions (i) K 2 CO 3 , TBAI, CHCl 3 /DMF/H 2 O, 45 ° C.
  • Reaction reagents and conditions (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
  • Preparation steps Take T-20 (240mg, 0.224mmol) in a reaction flask, add 60mL methanol, 15mL tetrahydrofuran and 0.75mL water to dissolve, add 10% Pd / C (240mg), hydrogen sulfide reaction at room temperature for 48h, filter to remove Palladium on carbon, and the solvent was evaporated to dryness.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • T-21 (88 mg, 0.097 mmol) was taken in a reaction flask, and 4 mL of methanol and 1 mL of dichloromethane were added to dissolve, and sodium methoxide (0.41 M, 0.29 mmol) was slowly added and stirred at room temperature for 30 min.
  • the cation exchange resin was added to the mixture to adjust the pH to 5-6, and the residue was purified by silica gel column chromatography.
  • Reagents and conditions (i) K 2 CO 3 , TBAI, CHCl 3 /DMF/H 2 O, 45 ° C.
  • Reaction reagents and conditions (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Reaction reagents and conditions (i) CH 3 I, K 2 CO 3 , DMF, room temperature.
  • Preparation step T-23 (771 mg, 0.709 mmol) and potassium carbonate (147 mg, 1.06 mmol) were mixed in a reaction flask, and 8 mL of DMF and CH 3 I (65 ⁇ L, 149 mg, 1.06 mmol) were added, and reacted at room temperature for 12 h. The liquid was dispersed with ethyl acetate and water, and the mixture was evaporated. EtOAcjjjjjjjjjjjj -26, the yield is 70%.
  • Reaction reagents and conditions (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Preparation step Take T-27 (58mg, 0.062mmol) in a reaction flask, add 4mL methanol and 1mL dichloromethane to dissolve, slowly add sodium methoxide (0.44mL, 0.41M, 0.18mmol), stir at room temperature for 30min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated to dryness.
  • Reaction reagents and conditions (i) BrCH 2 CH 2 CH 2 OH, K 2 CO 3 , DMF, room temperature; (ii) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Reagents and conditions (i) K 2 CO 3 , TBAI, CHCl 3 /DMF/H 2 O, 45 ° C.
  • Reaction reagents and conditions (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
  • Preparation steps Take T-30 (700mg, 0.63mmol) in a reaction flask, add 120mL methanol, 30mL tetrahydrofuran and 1.5mL water to dissolve, add 10% Pd / C (720mg), hydrogen sulfide reaction at room temperature for 48h, filter to remove Palladium on carbon, and the solvent was evaporated to dryness.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH-CH 2 Cl 2 , room temperature.
  • Preparation step Take T-31 (100 mg, 0.107 mmol) in a reaction flask, add 4 mL of methanol and 1 mL of dichloromethane to dissolve, slowly add sodium methoxide (0.78 mL, 0.41 M, 0.32 mmol), stir at room temperature for 30 min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated to dryness.
  • Reaction reagents and conditions (i) CH 3 I, K 2 CO 3 , DMF, room temperature.
  • T-32 120 mg, 0.128 mmol
  • potassium carbonate 177 mg, 1.28 mmol
  • 4 mL of DMF and CH 3 I 48 ⁇ L, 109 mg, 0.77 mmol
  • the reaction was carried out for 11 h at room temperature.
  • Dissolve with ethyl acetate and water, extract, and the organic layer is washed with EtOAc EtOAc.
  • T-33 yield 47%.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Preparation step Take T-33 (49mg, 0.050mmol) in a reaction flask, add 4mL methanol and 1mL dichloromethane to dissolve, slowly add sodium methoxide (0.41M, 0.15mmol), stir at room temperature for 30min, then add cation exchange with stirring The pH of the resin was adjusted to 5-6, and the filtrate was concentrated to dryness.
  • Reaction reagents and conditions (i) CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 Br, K 2 CO 3 , DMF, room temperature.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Reaction reagents and conditions (i) BrCH 2 CH 2 CH 2 OH, K 2 CO 3 , DMF, room temperature.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Preparation step Take T-37 (44 mg, 0.040 mmol) in a reaction flask, add 4 mL of methanol and 1 mL of dichloromethane to dissolve, slowly add sodium methoxide (0.3 mL, 0.41 M, 0.12 mmol), stir at room temperature for 30 min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated to dryness.
  • Reaction reagents and conditions (i) KOH, TBAB, CHCl 3 /H 2 O, room temperature; (ii) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Reaction reagents and conditions (i) KOH, TBAB, CHCl 3 /H 2 O, room temperature; (ii) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Example 50 3-Methoxy-5-hydroxy-3',4'-O-diphenylmethylidene-7-O- ⁇ -D-benzoylgalactosyl-flavonoid (T-41)
  • Reaction reagents and conditions (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • T-42 (69 mg, 0.77 mmol) was taken in a reaction flask, and 4 mL of methanol and 1 mL of dichloromethane were added to dissolve, and sodium methoxide (0.41 M, 0.23 mmol) was slowly added and stirred at room temperature for 30 min.
  • the cation exchange resin was added thereto under stirring to adjust the pH to 5-6, and the filtrate was concentrated to dryness.
  • Reagents and conditions (i) KOH, TBAB, CHCl 3 /H 2 O, room temperature.
  • Reaction reagents and conditions (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
  • Reaction reagents and conditions (i) Ac 2 O, pyridine, room temperature.
  • Preparation step Take T-06 (47 mg, 0.098 mmol) in a reaction flask, add 3 mL of pyridine to dissolve, and slowly add 1.5 mL of acetic anhydride under ice cooling, and after stirring, stir at room temperature for 10 h, and pour the reaction solution. The mixture was extracted with ethyl acetate and EtOAc (EtOAc)EtOAc. Yellow powdery target product T-46, yield 85%.
  • Reaction reagents and conditions (i) CH 3 I, K 2 CO 3 , DMF, room temperature.
  • Preparation step T-20 (771 mg, 0.71 mmol) and potassium carbonate (147 mg, 1.06 mmol) were mixed in a reaction flask, and 8 mL of DMF and CH 3 I (65 ⁇ L, 149 mg, 1.06 mmol) were added, and reacted at room temperature for 12 h. The liquid was dispersed with ethyl acetate and water, and the mixture was evaporated. EtOAcjjjjjjjjjjjj -47, yield 68%.
  • Reaction reagents and conditions (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
  • Reaction reagents and conditions (i) BnBr, K 2 CO 3 , DMF, room temperature.
  • Reaction reagents and conditions (i) BnBr, K 2 CO 3 , DMF, room temperature.
  • Reaction reagents and conditions (i) CH 3 CH 2 CH 2 I, K 2 CO 3 , DMF, room temperature.
  • Preparation step T-50 (99 mg, 0.10 mmol) and potassium carbonate (45 mg, 0.3 mmol) were mixed in a reaction flask while 4 mL of DMF and CH 3 CH 2 CH 2 I (29 ⁇ L, 0.3 mmol) were added, and the reaction was carried out at room temperature overnight. The reaction mixture is separated with ethyl acetate and water, and the organic layer is washed with EtOAc EtOAc. Oily target product T-51, yield 82%.
  • Reaction reagents and conditions (i) BrCH 2 CH 2 OH, K 2 CO 3 , DMF, room temperature.
  • T-09 (91 mg, 0.1 mmol) and potassium carbonate (46 mg, 0.31 mmol) were mixed in a reaction flask, and 4 mL of DMF and BrCH 2 CH 2 OH (21 ⁇ L, 0.3 mmol) were added thereto, and reacted at room temperature for 24 hours.
  • the title product T-52 was obtained as a yellow oil, which was purified by silica gel column chromatography. The yield was 42%.
  • Reaction reagents and conditions (i) BnBr, K 2 CO 3 , DMF, room temperature.
  • T-01 (93 mg, 0.1 mmol) was weighed into a reaction flask, 5 mL of anhydrous DMF was added, stirred and dissolved, and anhydrous K 2 CO 3 (16.5 mg, 0.12 mmol, 1.2 eq) and benzyl bromide were added. 13 ⁇ L, 0.11 mmol, 1.1 eq), mp. The residue was purified by silica gel column chromatography to give the desired product T-53.
  • ⁇ -glucosidase bovine serum albumin (BSA) was purchased from Sigma; p-nitrophenyl- ⁇ -glucose (PNPG) was purchased from F1uka; acarbose was manufactured by Bayer; other reagents were imported or Domestic analytically pure; flavonoid glycoside derivatives are the target compounds synthesized in the foregoing examples of the patent.
  • BSA bovine serum albumin
  • PNPG p-nitrophenyl- ⁇ -glucose
  • flavonoid glycoside derivatives are the target compounds synthesized in the foregoing examples of the patent.
  • 550 type microplate reader Bio-Rad, USA); single-channel, multi-channel pipette (Eppendorf, Germany); 96-well microtiter plate (Greiner, Germany).
  • ⁇ --glucosidase The enzyme lyophilized powder is prepared into a solution by using 0.1 mol ⁇ L -1 phosphate buffer (PB) containing 0.1% BSA at pH 7.4, and dispensing Store at -20 °C for later use.
  • PB 0.1 mol ⁇ L -1 phosphate buffer
  • PNPG substrate
  • test sample to be tested The flavonoid glycoside derivative to be tested was dissolved in DMSO at a concentration of 1 ⁇ 10 -2 mol ⁇ L -1 and diluted 10 times with 0.1 mol ⁇ L -1 PB for use.
  • Activity measurement 10 ⁇ L of the diluted sample to be tested was mixed with 50 ⁇ L of LPB and 20 ⁇ L of the enzyme solution, incubated at 37 ° C for 10 min, then 20 ⁇ L of the substrate was added, reacted at 37 ° C for 10 min, and the 405 nm OD value was measured after the reaction terminator was added.
  • Acarbose is a positive control drug.
  • the screening model constructed with ⁇ -glucosidase as the enzyme source has a signal-to-noise ratio of 10.4.
  • the screening results of some representative flavonoid glycoside derivatives are shown in Table 1 and Table 2.
  • the better activity of the T--24 sample has an IC 50 value of 1.93 ⁇ 10 -5 mol ⁇ L -1 , and the positive drug Aka
  • the IC 50 value of the wave sugar is 2.47 ⁇ 10 -9 mol ⁇ L -1 .
  • the flavonoid glycoside derivative provided by the invention exhibits a good inhibitory effect on ⁇ -glucosidase, thereby slowing down the decomposition of starch into glucose, thereby slowing the absorption of glucose in the intestinal tract and reducing postprandial hyperglycemia.
  • Acarbose is a positive control with a molecular weight of 645.6;
  • Acarbose is a positive control with a molecular weight of 645.6;

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Abstract

Disclosed is a class of flavone glycoside derivatives, compounds of structural general formula (I) described below or pharmaceutically acceptable salts or hydrates thereof, comprising racemates, optical isomers and epimers thereof. Also disclosed are a method for preparing the flavone glycoside derivatives and a use thereof in preparing drugs for treating diabetes. The flavone glycoside derivatives of the present invention are used to prepare drugs for treating diabetes, and have a relatively good inhibition effect on alpha-glucosidase, thereby slow down the decomposition rate from starches to glucose and the intestinal absorption of glucose, so lower postprandial hyperglycemia, improve the activity of such compounds for treating diabetes, and have less toxicity. Their physicochemical properties are more suitable for pharmaceutical preparations for treating diabetes, thus can be used for preparing drugs for treating diabetes which have better efficacy and higher safety. In their preparation method, the steps are simple, raw materials are readily available, the product yield is high and the purity is good. The flavone glycoside derivative can be prepared into various pharmaceutical preparations for treating diabetes.

Description

一类黄酮糖苷衍生物及其制备方法和用途Flavonoid glycoside derivative, preparation method and use thereof 技术领域Technical field
本发明涉及一类黄酮糖苷衍生物及其制备方法和用途，属于药物学领域。The invention relates to a flavonoid glycoside derivative, a preparation method thereof and use thereof, and belongs to the field of medicine.
背景技术Background technique
糖尿病(diabetes mellitus)是以胰岛素分泌不足、胰岛素作用低下或胰岛素抵抗(IR)所引起的糖代谢紊乱，导致血糖升高、伴随多种并发症并存为特征的糖、脂肪和蛋白质代谢障碍的疾病。1型糖尿病的特征是缺乏胰岛素分泌能力，需每天注射胰岛素进行治疗。2型糖尿病的特征是人体不能有效利用胰岛素，需口服降糖药物进行干预治疗。在糖尿病患者中，大约90％以上为2型糖尿病。目前，糖尿病已在全球范围内成为继心脑血管疾病和肿瘤之后威胁人类健康的第三个重大疾病，无论是在发达国家或发展中国家，糖尿病的发病率都在急剧上升，糖尿病作为一种严重的非传染性、慢性疾病，已成为世界各国关注的重大公共卫生问题，我国2型糖尿病患者超过9240万人，已成为世界上糖尿病患病人数最多的国家。Diabetes mellitus is a disorder of sugar metabolism caused by insufficient insulin secretion, insulin deficiency or insulin resistance (IR), resulting in elevated blood sugar, accompanied by various complications, and disorders of sugar, fat and protein metabolism. . Type 1 diabetes is characterized by a lack of insulin secretion and requires daily injections of insulin for treatment. Type 2 diabetes is characterized by the inability of the human body to effectively use insulin, and oral hypoglycemic drugs are needed for intervention. More than 90% of people with diabetes are type 2 diabetes. At present, diabetes has become the third major disease threatening human health after cardiovascular and cerebrovascular diseases and tumors worldwide. The incidence of diabetes is rising sharply in both developed and developing countries. Diabetes is a kind of Severe non-infectious and chronic diseases have become a major public health issue of concern to all countries in the world. With more than 92.4 million type 2 diabetes patients in China, it has become the country with the largest number of diabetic patients in the world.
目前用于治疗糖尿病的药物按类型分类有：以门冬胰岛素注射液、生物合成人胰岛素注射液和精蛋白生物合成人胰岛素注射液等为代表的胰岛素制剂；以阿卡波糖、伏格列波糖为代表的α-葡萄糖苷酶抑制剂；格列美脲、格列齐特和格列喹酮为代表的磺酰脲类、以瑞格列奈、那格列奈为代表的格列奈类、以二甲双胍为代表的双胍类；以罗格列酮和吡格列酮为代表的噻唑烷二酮类；复方制剂类以及二肽基肽酶-4(DPP-4)抑制剂等。以上这些降糖药物中有药效作用快、疗效好的药物，但均存在一定毒副作用，对肝、肾、肠胃等器官有损害，部分糖尿病患者对胰岛素表现出明显的抗药性，并且现有药物中还没有一个药物能根除糖尿病，患者需要长期服药，因此，发现新的安全有效的糖尿病治疗药物是目前社会的迫切需要。The drugs currently used for the treatment of diabetes are classified into insulin preparations represented by insulin aspart injection, biosynthetic human insulin injection, and protamine biosynthesis human insulin injection; acarbose, vogire A glucose-representative α-glucosidase inhibitor; a sulfonylurea represented by glimepiride, gliclazide, and gliclazide; a lattice represented by repaglinide and nateglinide Naphthalenes, biguanides represented by metformin; thiazolidinediones represented by rosiglitazone and pioglitazone; compound preparations and dipeptidyl peptidase-4 (DPP-4) inhibitors. Among these hypoglycemic drugs, there are drugs with fast pharmacodynamic effects and good curative effect, but all have some toxic side effects, which are harmful to organs such as liver, kidney, stomach and stomach. Some diabetic patients show obvious resistance to insulin, and existing There is no drug in the drug that can eradicate diabetes. Patients need to take drugs for a long time. Therefore, it is urgent to find new safe and effective diabetes drugs.
食物中的淀粉(多糖)经口腔唾液、胰淀粉酶消化成含少数葡萄糖分子的低聚糖(或称寡糖)以及双糖与三糖，进入小肠经α-葡萄糖苷酶作用下分解为单个 葡萄糖，为小肠吸收。竞争性抑制位于小肠的各种α-葡萄糖苷酶，使淀粉类分解为葡萄糖的速度减慢，从而能够减缓肠道内葡萄糖的吸收，降低餐后高血糖。The starch (polysaccharide) in the food is digested into oral oligosaccharides (or oligosaccharides) and disaccharides and trisaccharides by oral saliva and pancreatic amylase, and is broken down into a single small intestine by α-glucosidase. Glucose, which is absorbed by the small intestine. Competitive inhibition of various α-glucosidases in the small intestine, which slows down the breakdown of starch into glucose, thereby slowing the absorption of glucose in the intestine and reducing postprandial hyperglycemia.
天然药物的降糖作用日益引起高度重视，黄酮类化合物是一类在药用、食用植物中广泛存在的天然化合物，其化学结构和生物活性具有多样性。迄今为止，国内外学者对近40种中药及天然药物中的黄酮类成分进行了广泛系统的研究，为天然黄酮药物的临床应用开发提供了物质基础。黄酮化合物，其体外活性测试显示出对α-葡萄糖苷酶具有较好抑制作用，可以作为治疗糖尿病的药物分子进行研究。因此进一步发掘黄酮类化合物药用价值，针对黄酮类化合物生物活性相对较弱的不足，对其进行结构优化设计与合成，提高该类化合物治疗糖尿病的活性，显得尤为必要。The hypoglycemic effect of natural medicines has been paid more and more attention. Flavonoids are a kind of natural compounds widely found in medicinal and edible plants, and their chemical structure and biological activity are diverse. So far, domestic and foreign scholars have conducted extensive and systematic research on flavonoids in nearly 40 kinds of traditional Chinese medicines and natural medicines, providing a material basis for the clinical application and development of natural flavonoids. The flavonoid compound, its in vitro activity test showed a good inhibitory effect on α-glucosidase, and can be used as a drug molecule for treating diabetes. Therefore, further exploration of the medicinal value of flavonoids, in view of the relatively weak biological activity of flavonoids, it is particularly necessary to optimize the design and synthesis of the flavonoids and improve the activity of these compounds in the treatment of diabetes.
发明内容Summary of the invention
为解决现有技术的不足，本发明的目的在于提供一类黄酮糖苷衍生物及其制备方法和用途。本发明的黄酮糖苷衍生物用于制备治疗糖尿病的药物，能够对α-葡萄糖苷酶具有较好抑制作用，提高了该类化合物治疗糖尿病的活性，可以用于制备疗效更好、安全性更高的治疗糖尿病的药物。In order to solve the deficiencies of the prior art, the object of the present invention is to provide a flavonoid glycoside derivative, a preparation method and use thereof. The flavonoid glycoside derivative of the invention is used for preparing a medicament for treating diabetes, has good inhibitory effect on α-glucosidase, improves the activity of the compound for treating diabetes, and can be used for preparing a better curative effect and higher safety. The drug for treating diabetes.
为了实现上述目标，本发明采用如下的技术方案：In order to achieve the above objectives, the present invention adopts the following technical solutions:
一类黄酮糖苷衍生物，结构通式为下述通式I的化合物或其药学上可接受的盐或水合物，包括其消旋体、光学异构体及差向异构体：A flavonoid glycoside derivative having the general formula: a compound of the formula I or a pharmaceutically acceptable salt or hydrate thereof, including racemates, optical isomers and epimers thereof:
Figure PCTCN2014086933-appb-000001
Figure PCTCN2014086933-appb-000001
其中，RX为R1或R1'，R1代表β-D-吡喃葡萄糖基、β-D-吡喃半乳糖基、β-D-乳糖基或β-D-麦芽糖基；R1'代表2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖基、2,3,4,6-四-O-苯甲酰基-β-D-吡喃葡萄糖基、2,3,4,6-四-O-苯甲酰基-β-D-吡喃半乳糖基、2,3,6,2',3',4',6'-七-O-苯甲酰基-β-D-乳糖基或2,3,6,2',3',4',6'-七-O-苯甲酰基-β-D-麦芽糖基；R2代表氢、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3、-CH(CH3)CH2CH3或-CH2CH(CH3)CH3；R3和R4分别选自氢、C1-C6直链或支 链烷基、苄基、-COR、-CH2CH2OH、-CH2CH2CH2OH、-(CH2)nNRR'或-(CH2)nCOOH；R5选自氢、C1-C6直链或支链烷基、苄基、-COR、-CH2CH2OH、-CH2CH2CH2OH、-(CH2)nNRR'、-(CH2)nCOOH、β-D-吡喃葡萄糖基、β-D-吡喃半乳糖基；前述R、R'选自相同或不同的C1-C6直链或支链烷基，或C3-C7环烷基；n为1至4的整数。Wherein R X is R 1 or R 1 ', and R 1 represents β-D-glucopyranosyl, β-D-galactopyranosyl, β-D-lactosyl or β-D-maltosyl; R 1 'Represents 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl, 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl , 2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl, 2,3,6,2',3',4',6'-seven-O-benzene Formyl-β-D-lactosyl or 2,3,6,2',3',4',6'-hepta-O-benzoyl-β-D-maltosyl; R 2 represents hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 or -CH 2 CH ( CH 3 )CH 3 ; R 3 and R 4 are each independently selected from the group consisting of hydrogen, C1-C6 straight or branched alkyl, benzyl, -COR, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, - (CH 2 )nNRR' or -(CH 2 )nCOOH; R 5 is selected from hydrogen, C 1 -C 6 straight or branched alkyl, benzyl, -COR, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, —(CH 2 ) n NRR′, —(CH 2 ) n COOH, β-D-glucopyranosyl, β-D-galactopyranosyl; the foregoing R, R′ are selected from the same or Different C1-C6 linear or branched alkyl groups, or C3-C7 cycloalkyl groups; n is an integer from 1 to 4.
前述烷基和环烷基可被1～2个羟基、硝基、卤代基、氰基或三氟甲基取代。The aforementioned alkyl group and cycloalkyl group may be substituted by 1 to 2 hydroxyl groups, a nitro group, a halogen group, a cyano group or a trifluoromethyl group.
前述黄酮糖苷衍生物为3,5,3'-三甲氧基-4'-羟基-7-O-β-D-(2,3,4,6-四-O-苯甲酰基)-葡萄糖基-黄酮、3,5,3'-三甲氧基-4'-羟基-7-O-β-D-葡萄糖基-黄酮、3,5,3'-三-乙氧基-4'-羟基-7-O-β-D-葡萄糖基-黄酮、3-甲氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5,3',4'-三羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5,3',4'-三羟基-7-O-β-D-葡萄糖基-黄酮、3-甲氧基-5,3',4'-三正戊氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5,3',4'-三正戊氧基-7-O-β-D-葡萄糖基-黄酮、3,5-二甲氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3,5-二甲氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-甲氧基-5-乙氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-乙氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-乙氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-甲氧基-5-丙氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-丙氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-丙氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-甲氧基-5-乙氧羰基甲氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-乙氧羰基甲氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-羧甲氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-乙氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-乙氧基-5-羟基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-乙氧基-5-羟基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-丙氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-丙氧基-5-羟基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-丙氧基-5-羟基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-丙氧基-5-甲氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-丙氧基-5-甲氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-丙氧基-5-甲氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-丙氧基-5-甲氧 基-3'-二羟基-4'-羟丙氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-异丁氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-异丁氧基-5-羟基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-异丁氧基-5-羟基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-异丁氧基-5,3',4'-三甲氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-异丁氧基-5,3',4'-三甲氧基-7-O-β-D-葡萄糖基-黄酮、3-异丁氧基-5,3',4'-三正己氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-异丁氧基-5,3',4'-三正己氧基-7-O-β-D-葡萄糖基-黄酮、3-异丁氧基-5,3',4'-三-(羟丙氧基)-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-异丁氧基-5,3',4'-三-(羟丙氧基)-7-O-β-D-葡萄糖基-黄酮、3,5,3'-三甲氧基-4'-羟基-7-O-β-D-半乳糖基-黄酮、3,5,3'-三乙氧基-4'-羟基-7-O-β-D-半乳糖基-黄酮、3-甲氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基半乳糖基-黄酮、3-甲氧基-5,3',4'-三羟基-7-O-β-D-苯甲酰基半乳糖基-黄酮、3-甲氧基-5,3',4'-三羟基-7-O-β-D-半乳糖基-黄酮、3,5,3'-三甲氧基-7,4’-二-O-β-D-(2,3,4,6-四-O-苯甲酰基)-葡萄糖基-黄酮、3,5,3'-三甲氧基-7,4’-二-O-β-D-葡萄糖基-黄酮、3-甲氧基-5,3',4'-三-(乙酰氧基)-7-O-β-D-乙酰基葡萄糖基-黄酮、3-乙氧基-5-甲氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮或3-乙氧基-5-甲氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-乙氧基-3'-羟基-4'-苄氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5,3'-二-羟基-4'-苄氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5,3'-二-丙氧基-4'-苄氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3,5-二-甲氧基-3',4'-二-羟丙氧基7-O-β-D-苯甲酰基葡萄糖基-黄酮或3,5,3'-三-甲氧基-4'-苄氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮。The flavonoid glycoside derivative is 3,5,3'-trimethoxy-4'-hydroxy-7-O-β-D-(2,3,4,6-tetra-O-benzoyl)-glucosyl -flavonoids, 3,5,3'-trimethoxy-4'-hydroxy-7-O-β-D-glucosyl-flavonoids, 3,5,3'-tris-ethoxy-4'-hydroxy- 7-O-β-D-glucosyl-flavonoid, 3-methoxy-5-hydroxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl -Flavone, 3-methoxy-5,3',4'-trihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5,3',4'- Trihydroxy-7-O-β-D-glucosyl-flavonoid, 3-methoxy-5,3',4'-tri-n-pentyloxy-7-O-β-D-benzoyl glucosyl- Flavonoids, 3-methoxy-5,3',4'-tri-n-pentyloxy-7-O-β-D-glucosyl-flavonoids, 3,5-dimethoxy-3', 4'- Dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3,5-dimethoxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid, 3-methoxy-5-ethoxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5- Ethoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5-ethoxy-3',4'-dihydroxy- 7-O-β-D-glucosyl-flavonoids, 3- Oxy-5-propoxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5-propoxy -3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5-propoxy-3',4'-dihydroxy-7-O -β-D-glucosyl-flavonoid, 3-methoxy-5-ethoxycarbonylmethoxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl Glucosyl-flavonoid, 3-methoxy-5-ethoxycarbonylmethoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy -5-carboxymethoxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid, 3-ethoxy-5-hydroxy-3',4'-O-diphenyl 4-methyl-glucosyl-flavonoid, 3-ethoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-benzoyl Glucosyl-flavonoids, 3-ethoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoids, 3-propoxy-5-hydroxy-3', 4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid, 3-propoxy-5-hydroxy-3',4'-dihydroxy-7-O- β-D-benzoyl glucosyl-flavonoid, 3-propoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid, 3-propoxy- 5- Oxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid, 3-propoxy-5-methoxy-3', 4' -dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-propoxy-5-methoxy-3',4'-dihydroxy-7-O-β-D-glucose Radical-flavonoid, 3-propoxy-5-methoxy -3'-dihydroxy-4'-hydroxypropoxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-isobutoxy-5-hydroxy-3', 4'-O -diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid, 3-isobutoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D -benzoylglucosyl-flavonoids, 3-isobutoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoids, 3-isobutoxy-5 , 3',4'-trimethoxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-isobutoxy-5,3',4'-trimethoxy-7-O- β-D-glucosyl-flavonoid, 3-isobutoxy-5,3',4'-tri-n-hexyloxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-isobutoxy 5-,3',4'-tri-n-hexyloxy-7-O-β-D-glucosyl-flavonoid, 3-isobutoxy-5,3',4'-tris-(hydroxypropoxyl) )-7-O-β-D-benzoyl glucosyl-flavonoid, 3-isobutoxy-5,3',4'-tris-(hydroxypropoxy)-7-O-β-D- Glucosyl-flavonoids, 3,5,3'-trimethoxy-4'-hydroxy-7-O-β-D-galactosyl-flavonoids, 3,5,3'-triethoxy-4'- Hydroxy-7-O-β-D-galactosyl-flavonoid, 3-methoxy-5-hydroxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoic acid Acylgalactosyl-flavonoids, 3-methoxy-5 , 3',4'-trihydroxy-7-O-β-D-benzoylgalactosyl-flavonoid, 3-methoxy-5,3',4'-trihydroxy-7-O-β- D-galactosyl-flavonoid, 3,5,3'-trimethoxy-7,4'-di-O-β-D-(2,3,4,6-tetra-O-benzoyl)- Glucosyl-flavonoids, 3,5,3'-trimethoxy-7,4'-di-O-β-D-glucosyl-flavonoids, 3-methoxy-5,3',4'-tri- (Acetoxy)-7-O-β-D-acetylglucosyl-flavonoid, 3-ethoxy-5-methoxy-3',4'-O-diphenylmethylidene-7-O -β-D-benzoyl glucosyl-flavonoid or 3-ethoxy-5-methoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5-ethoxy-3'-hydroxy-4'-benzyloxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5,3' -di-hydroxy-4'-benzyloxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5,3'-di-propoxy-4'-benzyloxy -7-O-β-D-benzoyl glucosyl-flavonoid, 3,5-di-methoxy-3',4'-di-hydroxypropoxy 7-O-β-D-benzoic acid Acylglucosyl-flavonoids or 3,5,3'-tris-methoxy-4'-benzyloxy-7-O-β-D-benzoyl glucosyl-flavonoids.
药学上可接受的盐为含有羧基的黄酮糖苷衍生物化合物与碱性物质反应得到或者含有氨基的黄酮糖苷衍生物化合物与酸性物质反应得到。The pharmaceutically acceptable salt is obtained by reacting a flavonoid glycoside derivative compound containing a carboxyl group with a basic substance or a flavonoid glycoside derivative compound containing an amino group and an acidic substance.
前述的碱性物质为碱金属或碱土金属的氢氧化物、碳酸盐、碳酸氢盐、三甲胺、三乙胺；所述的酸性物质为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、三氟甲磺酸、甲酸、乙酸、草酸或柠檬酸The aforementioned basic substance is an alkali metal or alkaline earth metal hydroxide, carbonate, hydrogencarbonate, trimethylamine or triethylamine; the acidic substance is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid. , trifluoromethanesulfonic acid, formic acid, acetic acid, oxalic acid or citric acid
一类黄酮糖苷衍生物的制备方法，按照以下合成路线I进行：以芦丁为原料经双苄基化得I-1，I-1经酸水解得I-2，I-2经烷基化得I-3，I-3经催化氢化得I-4，I-4经选择性糖基化反应得I-5，I-5经烷基化反应得I-6，I-6经甲醇钠处理脱酰基保护得I-7， The preparation method of a kind of flavonoid glycoside derivative is carried out according to the following synthetic route I: bis benzylation is used as raw material to obtain I-1, I-1 is acid-hydrolyzed to obtain I-2, and I-2 is alkylated. I-3, I-3 is catalytically hydrogenated to obtain I-4, I-4 is selectively glycosylated to obtain I-5, and I-5 is alkylated to obtain I-6, and I-6 is sodium methoxide. Treatment of deacylation to obtain I-7,
Figure PCTCN2014086933-appb-000002
Figure PCTCN2014086933-appb-000002
其中，Ry为芸香糖基，反应条件i为BnBr，DMF，K2CO3，室温；反应条件ii为HCl，MeOH，60℃；反应条件iii为R2I，DMF，K2CO3，室温；反应条件iv为H2，10％Pd/C，MeOH，室温；反应条件v为R1Br，四丁基溴化铵(TBAB)，CHCl3/H2O，K2CO3，室温；反应条件vi为R5I，DMF，K2CO3，室温；反应条件vii为NaOMe，MeOH，室温。Wherein Ry is a rutose group, reaction conditions i are BnBr, DMF, K 2 CO 3 , room temperature; reaction conditions ii are HCl, MeOH, 60 ° C; reaction conditions iii are R 2 I, DMF, K 2 CO 3 , room temperature ; reaction conditions iv is H 2 , 10% Pd / C, MeOH, room temperature; reaction conditions v is R 1 Br, tetrabutylammonium bromide (TBAB), CHCl 3 /H 2 O, K 2 CO 3 , room temperature; The reaction condition vi is R 5 I, DMF, K 2 CO 3 , room temperature; the reaction condition vii is NaOMe, MeOH, room temperature.
一类黄酮糖苷衍生物的制备方法：按照以下合成路线II进行：以芦丁为原料经三苄基化得II-1，II-1经酸水解得II-2，II-2经烷基化得II-3，II-3经催化氢化得II-4，II-4与二苯基二氯甲烷反应得产物II-5，II-5经选择性糖基化反应得II-6，II-6经烷基化反应得II-7，II-7经催化氢化得得II-8，II-8经烷基化反应得II-9，II-9经烷基化反应得II-10，II-10经甲醇钠处理脱酰基保护得II-11，A method for preparing a flavonoid glycoside derivative is carried out according to the following synthetic route II: triacetylation of rutin as raw material to obtain II-1, II-1 by acid hydrolysis to obtain II-2, II-2 by alkylation Catalytic hydrogenation of II-3, II-3 to obtain II-4, II-4 and diphenylmethylene chloride to obtain product II-5, II-5 by selective glycosylation to obtain II-6, II- 6 by alkylation reaction to obtain II-7, II-7 by catalytic hydrogenation to obtain II-8, II-8 by alkylation reaction to obtain II-9, II-9 by alkylation reaction to obtain II-10, II -10 is deacylated with sodium methoxide to obtain II-11.
Figure PCTCN2014086933-appb-000003
Figure PCTCN2014086933-appb-000003
Figure PCTCN2014086933-appb-000004
Figure PCTCN2014086933-appb-000004
其中，Ry为芸香糖基，反应条件i为BnBr，DMF，K2CO3，室温；反应条件ii为HCl，MeOH，60℃；反应条件iii为R3I，DMF，K2CO3，室温；反应条件iv为H2，10％Pd/C，MeOH，室温；反应条件v为Ph2CCl2，Ph2O，180℃；反应条件vi为R1Br，四丁基溴化铵(TBAB)或四丁基碘化铵(TBAI)，CHCl3/H2O，K2CO3，室温；反应条件vii为R2I，DMF，K2CO3，室温；反应条件viii为H2，10％Pd/C，MeOH/THF，室温；反应条件ix为R5I，DMF，K2CO3，室温；反应条件x为R4I，DMF，K2CO3，室温；反应条件xi为NaOMe，MeOH，室温。Wherein Ry is a rutose group, reaction conditions i are BnBr, DMF, K 2 CO 3 , room temperature; reaction conditions ii are HCl, MeOH, 60 ° C; reaction conditions iii are R 3 I, DMF, K 2 CO 3 , room temperature The reaction condition iv is H 2 , 10% Pd/C, MeOH, room temperature; the reaction condition v is Ph 2 CCl 2 , Ph 2 O, 180 ° C; the reaction condition vi is R 1 Br, tetrabutylammonium bromide (TBAB) Or tetrabutylammonium iodide (TBAI), CHCl 3 /H 2 O, K 2 CO 3 , room temperature; reaction conditions vii is R 2 I, DMF, K 2 CO 3 , room temperature; reaction condition viii is H 2 , 10% Pd / C, MeOH / THF, room temperature; reaction conditions ix is R 5 I, DMF, K 2 CO 3 , room temperature; reaction conditions x is R 4 I, DMF, K 2 CO 3 , room temperature; reaction conditions xi is NaOMe, MeOH, room temperature.
上述黄酮糖苷衍生物在制备治疗糖尿病药物中的应用。The use of the above flavonoid glycoside derivative in the preparation of a medicament for treating diabetes.
进一步地，取黄酮糖苷衍生物，加入一种或多种药学上可接受的载体或赋形剂，制备成各种治疗糖尿病药物制剂。Further, the flavonoid glycoside derivative is added, and one or more pharmaceutically acceptable carriers or excipients are added to prepare various therapeutic pharmaceutical preparations for diabetes.
前述的治疗糖尿病药物制剂为口服制剂：片剂、胶囊剂、口服液、混悬液；或者注射制剂：可注射的溶液、混悬液、粉针剂；或者外用制剂：软膏或溶液。The aforementioned pharmaceutical preparation for treating diabetes is an oral preparation: a tablet, a capsule, an oral solution, a suspension; or an injection preparation: an injectable solution, a suspension, a powder injection; or an external preparation: an ointment or a solution.
前述药学上可接受的载体或赋形剂是指任何可用于药学领域的稀释剂、辅助剂或载体，包括口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、色素、矫味剂；注射制剂用的防腐剂、助溶剂、稳定剂；外用制剂用的基质、稀释剂、润滑剂、防腐剂。 The aforementioned pharmaceutically acceptable carrier or excipient means any diluent, adjuvant or carrier which can be used in the pharmaceutical field, including a binder for an oral preparation, a lubricant, a disintegrant, a solubilizer, a diluent, and a stable Agents, suspending agents, pigments, flavoring agents; preservatives, solubilizers, stabilizers for injection preparations; bases, diluents, lubricants, preservatives for external preparations.
本发明的有益之处在于：本发明的黄酮糖苷衍生物用于制备治疗糖尿病的药物，能够对α-葡萄糖苷酶具有较好抑制作用，从而使淀粉类分解为葡萄糖的速度减慢，减缓肠道内葡萄糖的吸收，降低餐后高血糖，提高了该类化合物治疗糖尿病的活性，毒性更低、理化性质更适合治疗糖尿病药物制剂，可以用于制备疗效更好、安全性更高的治疗糖尿病的药物。其制备方法，步骤简单，原料易得，且产品得率高，纯度好。该黄酮糖苷衍生物可以制备成各种治疗糖尿病药物制剂，适应不同的用药需求。The invention has the advantages that the flavonoid glycoside derivative of the invention is used for preparing a medicament for treating diabetes, and can have a good inhibitory effect on α-glucosidase, thereby slowing down the decomposition of starch into glucose and slowing down the intestine. The absorption of glucose in the tract reduces the postprandial hyperglycemia, improves the activity of the compound for treating diabetes, has lower toxicity, and is more suitable for the treatment of diabetic pharmaceutical preparations. It can be used for the treatment of diabetes with better curative effect and higher safety. drug. The preparation method has the advantages of simple steps, easy availability of raw materials, high product yield and good purity. The flavonoid glycoside derivatives can be prepared into various therapeutic pharmaceutical preparations for diabetes, and are adapted to different medication needs.
具体实施方式detailed description
以下结合具体实施例对本发明作具体的介绍。The present invention will be specifically described below in conjunction with specific embodiments.
核磁共振谱以TMS为内标,用Inova-400MHz型超导核磁共振仪(美国Varian公司)测定；质谱用HP-5793质谱仪测定(美国Hewlett-Packard公司)；柱色谱用硅胶(300～400目)及高效薄层板均为青岛海洋化工厂产品。其余试剂均为市售分析纯或化学纯产品,除特别说明外,未经处理直接使用。The nuclear magnetic resonance spectrum was determined by TMS as an internal standard, using an Inova-400MHz superconducting nuclear magnetic resonance spectrometer (Varian, USA); mass spectrometry was determined by HP-5793 mass spectrometer (Hewlett-Packard, USA); silica gel for column chromatography (300-400). The high-efficiency thin-layer boards are all products of Qingdao Ocean Chemical Plant. The remaining reagents are commercially available analytically pure or chemically pure products and are used without treatment unless otherwise stated.
(一)苷元的合成制备(1) Synthesis of aglycones
实施例1 苷元中间体7,4'-二-羟基-3,5,3'-三-甲氧基-黄酮(M-04)的合成Example 1 Synthesis of aglycone intermediate 7,4'-di-hydroxy-3,5,3'-tri-methoxy-flavone (M-04)
Figure PCTCN2014086933-appb-000005
Figure PCTCN2014086933-appb-000005
反应试剂与条件：(i)BnBr，K2CO3，DMF，室温；(ii)浓盐酸，乙醇，70℃，3h。(iii)CH3I，K2CO3，DMF，室温，8h；(iv)H2，10％Pd/C，THF，室温15h。Reaction reagents and conditions: (i) BnBr, K 2 CO 3 , DMF, room temperature; (ii) concentrated hydrochloric acid, ethanol, 70 ° C, 3 h. (iii) CH 3 I, K 2 CO 3 , DMF, room temperature, 8 h; (iv) H 2 , 10% Pd/C, THF, room temperature 15 h.
制备步骤：(i)称取所得无水芦丁(50g，80mmol)置于1000mL反应瓶中，加入600mL无水DMF，搅拌溶解后加入无水K2CO3(23.8g，168mmol，2.1eq)和溴苄(19.4mL，160mmol，2eq)。室温反应过夜，将所得反应液倒入冰水浴中，加HCl调pH＝6，析出大量沉淀，过滤，滤饼水洗即得M-01；(ii) 取前一步反应所得M-01粗品用无水600mL乙醇加热溶解，再加入200mL浓盐酸，70℃回流3h，反应混合物冷却到室温后，倒入冰水浴，过滤，滤饼用水洗至中性，烘干，得到黄褐色固体粉末M-02粗品(Rf＝0.15，石油醚-乙酸乙酯＝2 1)；(iii)称取前一步反应所得M-02粗品10g置于500mL反应瓶中，加入150mL无水DMF，搅拌溶解后加入无水K2CO3(25.8g，186mmol，9eq)和CH3I(5.2mL，82.8mmol，4eq)，于40℃搅拌反应8h，所得混合物以乙酸乙酯和水分散，萃取，有机层依次以0.1M的酸水、水和饱和食盐水洗涤，无水硫酸镁干燥，浓缩至干，并经硅胶柱层析纯化得到白色粉末状M-03纯品，三步反应总产率81％；ESI-MSm/z:547.2[M+Na]+(iv)称取M-03纯品10g(19.1mmol)置于1000mL的反应瓶中，加入无水乙醇和四氢呋喃各250mL，加热搅拌溶解完全，加入10％Pd(500mg)，并以氢气置换反应体系中的空气后，以氢气球密封反应体系，将反应液于50℃油浴搅拌过夜，冷却，过滤，浓缩滤液，得到淡黄色固体粉末状样品M-4。产率96％。ESI-MSm/z:367.1[M+Na]+；1HNMR(400MHz,DMSO-d6)δ7.58(d,J＝2.1Hz,1H),7.49(dd,J＝8.4,2.1Hz,1H),6.92(d,J＝8.4Hz,1H),6.49(d,J＝2.1Hz,1H),6.34(d,J＝2.1Hz,1H),3.83(s,3H),3.79(s,3H),3.70(s,3H)。Preparation steps: (i) Weighed anhydrous rutin (50 g, 80 mmol) was placed in a 1000 mL reaction flask, 600 mL of anhydrous DMF was added, stirred and dissolved, and anhydrous K 2 CO 3 (23.8 g, 168 mmol, 2.1 eq) was added. And bromobenzyl (19.4 mL, 160 mmol, 2 eq). After reacting at room temperature overnight, the obtained reaction solution was poured into an ice water bath, adjusted to pH=6 with HCl, and a large amount of precipitate was precipitated, and filtered, and the filter cake was washed with water to obtain M-01; (ii) the obtained M-01 crude product obtained by the previous step was used. Water 600mL ethanol was dissolved by heating, and then added with 200mL concentrated hydrochloric acid, refluxed at 70 ° C for 3h, the reaction mixture was cooled to room temperature, poured into an ice water bath, filtered, the filter cake was washed with water until neutral, and dried to obtain a yellow-brown solid powder M-02 Crude (R f = 0.15, petroleum ether - ethyl acetate = 2 1); (iii) Weigh 10 g of the crude M-02 obtained in the previous step, placed in a 500 mL reaction flask, add 150 mL of anhydrous DMF, stir and dissolve, and add no Water K 2 CO 3 (25.8 g, 186 mmol, 9 eq) and CH 3 I (5.2 mL, 82.8 mmol, 4 eq), and the mixture was stirred at 40 ° C for 8 h. The mixture was washed with aq. EtOAc EtOAc. -MSm / z: 547.2 [M + Na] + (iv) M-03 was weighed pure product 10g (19.1mmol) was placed in 1000mL reaction flask, absolute ethanol was added 250 mL of each of tetrahydrofuran, completely dissolved by heating and stirring, 10% Pd (500 mg) was added, and the air in the reaction system was replaced with hydrogen, and the reaction system was sealed with a hydrogen balloon, and the reaction solution was stirred in an oil bath at 50 ° C overnight, cooled, and filtered. The filtrate was concentrated to give a pale yellow solid powdery sample M-4. The yield was 96%. ESI-MS m/z: 367.1 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J = 2.1 Hz, 1H), 7.49 (dd, J = 8.4, 2.1 Hz, 1H) , 6.92 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 2.1 Hz, 1H), 6.34 (d, J = 2.1 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H) , 3.70 (s, 3H).
实施例2 苷元中间体7,4'-二-羟基-3,5,3'-三-乙氧基-黄酮(M-06)的合成Example 2 Synthesis of aglycone intermediate 7,4'-di-hydroxy-3,5,3'-tri-ethoxy-flavone (M-06)
Figure PCTCN2014086933-appb-000006
Figure PCTCN2014086933-appb-000006
反应试剂与条件：(i)CH3CH2I，K2CO3，DMF，室温，8h；(ii)H2，10％Pd/C，THF，室温15h。Reaction reagents and conditions: (i) CH 3 CH 2 I, K 2 CO 3 , DMF, room temperature, 8 h; (ii) H 2 , 10% Pd/C, THF, room temperature 15 h.
制备步骤：(i)称取前述合成中间体M-02(10g，20.7mmol)置500mL的反应瓶中，加入150mL无水DMF溶解完全后，再加入无水K2CO3(25.8g，186mmol，9eq)和CH3CH2I(6.6mL，82.8mmol，4eq)，于40℃反应8h后，反应液用乙酸乙酯和水分散，萃取，所得有机层依次以稀盐酸(0.1M)，水和饱和食盐水洗涤，无水硫酸镁干燥，浓缩，残留物经硅胶柱层析纯化，得到淡黄色粉末状M-05纯品，产率90％。(ii)称取M-05纯品10g(17.7mmol)置1000mL 的反应瓶中，加入无水乙醇和四氢呋喃各250mL，加热搅拌溶解后加入10％Pd(500mg)，并以氢气置换反应体系中的空气后，以氢气球密封反应体系，将反应液于50℃油浴反应过夜，次日冷却后，过滤，浓缩滤液，即得到淡黄色固体粉末状中间体M-06，产率95％。ESI-MSm/z:409.1[M+Na]+；Preparation steps: (i) Weigh the above-mentioned synthetic intermediate M-02 (10 g, 20.7 mmol) into a 500 mL reaction flask, and add 150 mL of anhydrous DMF to dissolve completely, then add anhydrous K 2 CO 3 (25.8 g, 186 mmol). , 9 eq) and CH 3 CH 2 I (6.6 mL, 82.8 mmol, 4 eq), after reacting at 40 ° C for 8 h, the reaction mixture was partitioned with ethyl acetate and water, and extracted, The mixture was washed with EtOAc EtOAc EtOAc. (ii) Weigh 10g (17.7mmol) of M-05 pure product into a 1000mL reaction flask, add 250mL of absolute ethanol and tetrahydrofuran, add and dissolve with heat, add 10% Pd (500mg), and replace the reaction system with hydrogen. After the air, the reaction system was sealed with a hydrogen balloon, and the reaction mixture was reacted in an oil bath at 50 ° C overnight. After cooling for the next day, the filtrate was concentrated to give a pale yellow solid powdery intermediate M. ESI-MS m/z: 409.1 [M+Na] + ;
实施例3 苷元中间体3,5-二-羟基-7,3',4'-三-苄氧基-黄酮(M-08)的合成Example 3 Synthesis of aglycone intermediate 3,5-di-hydroxy-7,3',4'-tri-benzyloxy-flavone (M-08)
Figure PCTCN2014086933-appb-000007
Figure PCTCN2014086933-appb-000007
反应试剂与条件：(i)BnBr，K2CO3，DMF，室温；(ii)乙醇，浓盐酸，70℃，3h。Reaction reagents and conditions: (i) BnBr, K 2 CO 3 , DMF, room temperature; (ii) ethanol, concentrated hydrochloric acid, 70 ° C, 3 h.
制备步骤：(i)称所得取无水芦丁(50g，0.08mol)置1000mL反应瓶中，加入600mL无水DMF，搅拌溶解后加入无水K2CO3(56g，0.41mol，5eq)和溴苄(36.9mL，0.3mol，3.8eq)，室温反应2.5天，薄层色谱(TLC)检测反应完全后，将反应液倒入冰水浴中，以浓盐酸调pH至6，析出大量沉淀，过滤，滤饼即为中间体M-07粗品；(ii)将M-07粗品直接用无水乙醇(600mL)加热溶解，再加入浓盐酸(200mL)，反应液于70℃回流3h，至反应完全后，冷却到室温，倒入冰水浴中，过滤所析出的沉淀，水洗至中性，滤饼干燥即得到土黄色固体粉末状中间体M-08。两步反应总产率80％。ESI-MSm/z:595.2[M+Na]+；实施例4 苷元中间体3-甲氧基-5,7-二羟基-3',4'-O-二苯基甲叉-黄酮(M-11)的合成Preparation steps: (i) The obtained anhydrous rutin (50 g, 0.08 mol) was placed in a 1000 mL reaction flask, 600 mL of anhydrous DMF was added, stirred and dissolved, and anhydrous K 2 CO 3 (56 g, 0.41 mol, 5 eq) was added. Bromobenzyl (36.9 mL, 0.3 mol, 3.8 eq) was reacted at room temperature for 2.5 days. After the reaction was completed by thin layer chromatography (TLC), the reaction solution was poured into an ice water bath, and the pH was adjusted to 6 with concentrated hydrochloric acid to precipitate a large amount of precipitate. Filtration, the filter cake is the crude intermediate M-07; (ii) the crude M-07 is directly dissolved in absolute ethanol (600 mL), then concentrated hydrochloric acid (200 mL) is added, and the reaction solution is refluxed at 70 ° C for 3 h until the reaction After completion, it was cooled to room temperature, poured into an ice water bath, and the precipitate precipitated was filtered, washed with water until neutral, and the filter cake was dried to obtain a yellow solid powdery intermediate M-08. The total yield of the two-step reaction was 80%. ESI-MS m/z: 595.2 [M+Na] + ; Example 4 aglycone intermediate 3-methoxy-5,7-dihydroxy-3',4'-O-diphenylmethylidene-flavonoid ( Synthesis of M-11)
Figure PCTCN2014086933-appb-000008
Figure PCTCN2014086933-appb-000008
反应试剂与条件：(i)CH3I，K2CO3，DMF，室温，8h；(ii)H2，10％Pd/C， THF，室温15h；(iii)二氯二苯甲烷，二苯基醚，175℃，1h。Reaction reagents and conditions: (i) CH 3 I, K 2 CO 3 , DMF, room temperature, 8 h; (ii) H 2 , 10% Pd/C, THF, room temperature 15 h; (iii) dichlorodiphenylmethane, Phenyl ether, 175 ° C, 1 h.
制备步骤：(i)称取中间体M-08纯品(10g，17.5mmol)置500mL反应瓶中，加入150mL无水DMF，搅拌溶解后加入无水K2CO3(4.3g，31.5mmol，1.8eq)和CH3I(1.3mL，21mmol，1.2eq)，室温反应5h，反应液用乙酸乙酯和水分散，萃取，有机层依次以0.1M稀盐酸和水萃取，无水硫酸镁干燥，浓缩至干，残留物经硅胶柱层析纯化，得黄色固体粉末状中间体M-09纯品，产率85％；(ii)称取M-09纯品(5g，9mmol)置500mL反应瓶中，加入无水乙醇和四氢呋喃各100mL，加热搅拌溶解后加入10％Pd(250mg)，并以氢气置换反应体系中的空气后，以氢气球密封反应体系，将反应液于50℃反应过夜，冷却、过滤，滤液浓缩至干，得到黄色固体粉末状M-10(Rf＝0.3(CHCl3-CH3OH＝20:1)，产率97％。1HNMR(400MHz,DMSO-d6)δ12.67(s,1H),7.52(d,J＝2.1Hz,1H),7.43(dd,J＝8.5,2.1Hz,1H),6.89(d,J＝8.5Hz,1H),6.40(d,J＝1.9Hz,1H),6.18(d,J＝1.9Hz,1H),3.75(s,3H)；(iii)称取M-10(3.16g，10mmol)置250mL反应瓶中，氩气保护，加入90mL无水二苯基醚，搅拌溶解后加入二氯二苯甲烷(2.9mL，0.15mol，1.5eq)，所得混合物置于175℃反应1h后，用氯仿和饱和碳酸氢钠水溶液分散，萃取，有机相以水洗涤，无水硫酸镁干燥，浓缩至干，残留物经硅胶柱纯化，得土黄色固体粉末状中间体M-11，产率68％。1HNMR(400MHz,DMSO-d6)δ12.56(s,1H),7.67(d,J＝0.9Hz,1H),7.57–7.53(m,4H),7.48–7.42(m,6H),7.23(dd,J＝7.8,1.0Hz,1H),6.45(d,J＝2.1Hz,1H),6.19(d,J＝2.1Hz,1H),3.77(s,3H)；13CNMR(101MHz,DMSO-d6)δ177.92,164.27,161.18,156.37,154.61,148.48,146.74,139.25,138.19,129.57,128.65,125.77,124.12,123.90,117.32,108.99,108.36,104.28,98.65,93.86,59.84。Preparation steps: (i) Weigh the intermediate M-08 pure product (10 g, 17.5 mmol) into a 500 mL reaction flask, add 150 mL of anhydrous DMF, stir to dissolve, and add anhydrous K 2 CO 3 (4.3 g, 31.5 mmol, 1.8 eq) and CH 3 I (1.3 mL, 21 mmol, 1.2 eq), EtOAc (EtOAc, EtOAc) The residue is concentrated to dryness. The residue is purified by silica gel column chromatography. To the bottle, 100 mL of anhydrous ethanol and tetrahydrofuran were added, dissolved by heating, and then 10% Pd (250 mg) was added. After replacing the air in the reaction system with hydrogen, the reaction system was sealed with a hydrogen balloon, and the reaction solution was reacted at 50 ° C overnight. , cooled, filtered and the filtrate was concentrated to dryness to give a yellow solid powder M-10 (R f = 0.3 (CHCl 3 -CH 3 OH = 20:. 1), yield 97% 1 HNMR (400MHz, DMSO -d6) δ 12.67 (s, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.43 (dd, J = 8.5, 2.1 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.40 (d) , J = 1.9 Hz, 1H), 6.18 (d, J = 1.9 Hz, 1H), 3.75 (s, 3H); (iii) weighing M-10 (3.16g, 10mmol) was placed in a 250mL reaction flask, protected with argon, added with 90mL of anhydrous diphenyl ether, stirred and dissolved, then dichlorodiphenylmethane (2.9mL, 0.15mol, 1.5eq) was added. After being reacted at 175 ° C for 1 h, it was separated with chloroform and a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. member m-11, yield 68%. 1 HNMR (400MHz, DMSO-d6) δ12.56 (s, 1H), 7.67 (d, J = 0.9Hz, 1H), 7.57-7.53 (m, 4H), 7.48 – 7.42 (m, 6H), 7.23 (dd, J = 7.8, 1.0 Hz, 1H), 6.45 (d, J = 2.1 Hz, 1H), 6.19 (d, J = 2.1 Hz, 1H), 3.77 (s, 3H); 13 CNMR (101MHz, DMSO-d6) δ 177.92, 164.27, 161.18, 156.37, 154.61, 148.48, 146.74, 139.25, 138.19, 129.57, 128.65, 125.77, 124.12, 123.90, 117.32, 108.99, 108.36, 104.28, 98.65, 93.86, 59.84.
实施例5 苷元中间体3-异丁氧基-5,7-二羟基-3',4'-O-二苯基甲叉-黄酮(M-14)的合成 Example 5 Synthesis of aglycone intermediate 3-isobutoxy-5,7-dihydroxy-3',4'-O-diphenylmethine-flavonoid (M-14)
Figure PCTCN2014086933-appb-000009
Figure PCTCN2014086933-appb-000009
反应试剂与条件：(i)(CH3)CHCH2I，K2CO3，DMF，室温，8h；(ii)H2，10％Pd/C，THF，室温15h；(iii)二氯二苯甲烷，二苯基醚，175℃，1h。Reaction reagents and conditions: (i) (CH 3 )CHCH 2 I, K 2 CO 3 , DMF, room temperature, 8 h; (ii) H 2 , 10% Pd/C, THF, room temperature 15 h; (iii) dichlorodi Phenylmethane, diphenyl ether, 175 ° C, 1 h.
制备步骤：(i)～(iii)同M-11合成操作(见实施例4)，取中间体M-08纯品为原料，以碘代异丁烷代替M-11合成中的碘甲烷，即可合成得土黄色固体粉末状中间体M-14。ESI-MSm/z:545.1[M+Na]+；1HNMR(400MHz,DMSO-d6)δ12.59(s,1H),7.65–7.60(m,2H),7.57–7.51(m,4H),7.48–7.41(m,6H),7.20(d,J＝8.3Hz,1H),6.43(d,J＝2.1Hz,1H),6.18(d,J＝2.1Hz,1H),3.68(d,J＝6.4Hz,2H),1.92–1.80(m,1H),0.84(d,J＝6.7Hz,6H)。13CNMR(101MHz,DMSO-d6)δ178.15,164.37,161.39,156.59,155.28,148.59,146.74,139.38,137.58,129.76,128.82,125.92,124.27,124.18,117.41,109.02,108.99,104.51,98.81,94.00,78.64,28.56,19.13。Preparation steps: (i) to (iii) with the M-11 synthesis operation (see Example 4), taking the intermediate M-08 pure product as the raw material, replacing the methyl iodide in the M-11 synthesis with iodoisobutane. A yellowish solid powdery intermediate M-14 was obtained. ESI-MS m/z: 545.1 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 7.65 - 7.60 (m, 2H), 7.57 - 7.51 (m, 4H), 7.48–7.41 (m, 6H), 7.20 (d, J = 8.3 Hz, 1H), 6.43 (d, J = 2.1 Hz, 1H), 6.18 (d, J = 2.1 Hz, 1H), 3.68 (d, J) = 6.4 Hz, 2H), 1.92 - 1.80 (m, 1H), 0.84 (d, J = 6.7 Hz, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 178.15, 164.37, 161.39, 156.59, 155.28, 148.59, 146.74, 139.38, 137.58, 129.76, 128.82, 125.92, 124.27, 124.18,117.41,109.02,108.99,104.51,98.81,94.00,78.64 , 28.56, 19.13.
实施例6 苷元中间体3-丙氧基-5,7-二羟基-3',4'-O-二苯基甲叉-黄酮(M-17)的合成Example 6 Synthesis of aglycone intermediate 3-propoxy-5,7-dihydroxy-3',4'-O-diphenylmethine-flavonoid (M-17)
Figure PCTCN2014086933-appb-000010
Figure PCTCN2014086933-appb-000010
反应试剂与条件：(i)CH3CH2CH2I，K2CO3，DMF，室温，8h；(ii)H2，10％Pd/C，THF，室温15h；(iii)二氯二苯甲烷，二苯基醚，175℃，1h。Reaction reagents and conditions: (i) CH 3 CH 2 CH 2 I, K 2 CO 3 , DMF, room temperature, 8 h; (ii) H 2 , 10% Pd/C, THF, room temperature 15 h; (iii) dichloro Phenylmethane, diphenyl ether, 175 ° C, 1 h.
制备步骤：(i)～(iii)同M-11合成操作(见实施例4)，取中间体M-08纯 品为原料，以碘代丙烷代替M-11合成中的碘甲烷，即可合成得土黄色固体粉末状中间体M-17。1HNMR(400MHz,DMSO)δ12.59(s,1H),7.69–7.65(m,2H),7.57–7.53(m,4H),7.48–7.42(m,7H),7.22(d,J＝8.8Hz,1H),6.44(d,J＝2.1Hz,1H),6.19(d,J＝2.1Hz,1H),3.88(t,J＝6.5Hz,2H),1.66–1.52(m,2H),0.83(t,J＝7.4Hz,3H)；13CNMR(101MHz,DMSO)δ178.21,164.37,161.36,156.57,155.19,148.57,146.78,139.38,137.44,129.76,128.82,125.91,124.34,124.17,117.42,109.06,108.78,104.45,98.79,94.00,74.00,22.89,10.51。Preparation steps: (i) to (iii) with the M-11 synthesis operation (see Example 4), taking the intermediate M-08 pure product as the raw material, and replacing the methyl iodide in the M-11 synthesis with iodopropane. The organic yellow powdery intermediate M-17 was synthesized. 1 H NMR (400 MHz, DMSO) δ 12.59 (s, 1H), 7.69 - 7.65 (m, 2H), 7.57 - 7.53 (m, 4H), 7.48 - 7.42 (m, 7H), 7.22 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 6.19 (d, J = 2.1 Hz, 1H), 3.88 (t, J = 6.5 Hz, 2H), 1.66 - 1.52 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, DMSO) δ 178.21, 164.37, 161.36, 156.57, 155.19, 148.57, 146.78, 139.38, 137.44, 129.76, 128.82, 125.91, 124.34, 124.17, 117.42, 109.06 , 108.78, 104.45, 98.79, 94.00, 74.00, 22.89, 10.51.
实施例7 苷元中间体3-乙氧基-5,7-二羟基-3',4'-O-二苯基甲叉-黄酮(M-20)的合成Example 7 Synthesis of aglycone intermediate 3-ethoxy-5,7-dihydroxy-3',4'-O-diphenylmethine-flavonoid (M-20)
Figure PCTCN2014086933-appb-000011
Figure PCTCN2014086933-appb-000011
反应试剂与条件：(i)CH3CH2I，K2CO3，DMF，室温，8h；(ii)H2，10％Pd/C，THF，室温15h；(iii)二氯二苯甲烷，二苯基醚，175℃，1h。Reaction reagents and conditions: (i) CH 3 CH 2 I, K 2 CO 3 , DMF, room temperature, 8 h; (ii) H 2 , 10% Pd/C, THF, room temperature 15 h; (iii) dichlorodiphenylmethane , diphenyl ether, 175 ° C, 1 h.
制备步骤：(i)～(iii)同M-11合成操作(见实施例4)，取中间体M-08纯品为原料，以碘乙烷代替M-11合成中的碘甲烷，即可合成得土黄色固体粉末状中间体M-20。ESI-MSm/z:517.1[M+Na]+。Preparation steps: (i) to (iii) with the M-11 synthesis operation (see Example 4), taking the intermediate M-08 pure product as the raw material, and replacing the methyl iodide in the M-11 synthesis with iodoethane. The organic yellow powdery intermediate M-20 was obtained. ESI-MS m/z: 517.1 [M+Na] + .
(二)糖给体的制备(2) Preparation of sugar donor
实施例8 2,3,4,6-四-O-苯甲酰基-α-D-溴代吡喃葡萄糖(S-02)的合成Example 8 Synthesis of 2,3,4,6-tetra-O-benzoyl-α-D-bromoglucopyranose (S-02)
Figure PCTCN2014086933-appb-000012
Figure PCTCN2014086933-appb-000012
反应试剂与条件：(i)苯甲酰氯，吡啶，室温；(ii)33％氢溴酸乙酸溶液，1，2-二氯乙烷，室温。 Reaction reagents and conditions: (i) benzoyl chloride, pyridine, room temperature; (ii) 33% hydrobromic acid acetic acid solution, 1,2-dichloroethane, room temperature.
制备步骤：(i)取D-葡萄糖(15g，83.26mmol)于反应瓶中，加入150mL无水吡啶，室温搅拌30min，冰水浴充分冷却下滴加苯甲酰氯(60mL，520.7mmol)。滴加完毕，于室温搅拌15min后，再于60℃继续反应2h。将反应液倒入冰水中，静置至固化后，过滤，滤饼依次用稀盐酸、水和甲醇洗涤，干燥，得白色粉末状样品S-1(53.47g，收率91.7％)。(ii)取S-1(20g，28.54mmol)于反应瓶中，加入100mL1,2-二氯乙烷，冰水浴充分冷却下滴加33％氢溴酸/乙酸溶液(80mL，463.3mmol)。滴加完毕，再于室温搅拌2h。将反应液倒入乙酸乙酯和冰水混合物中，萃取，所得有机相依次用饱和碳酸氢钠和水洗涤，无水硫酸镁干燥，减压回收乙酸乙酯，所得残留物以300mL环己烷分散，超声，析出固体，过滤，滤饼干燥，即得白色粉末状2,3,4,6-四-O-苯甲酰基-α-D-溴代吡喃葡萄糖(S-02)17.4g，收率92％。ESI-MSm/z:681.0(100.0％),683.0(97.3％),682.0(36.8％)[M+Na]+。Preparation steps: (i) D-glucose (15 g, 83.26 mmol) was taken in a reaction flask, 150 mL of anhydrous pyridine was added, stirred at room temperature for 30 min, and benzoyl chloride (60 mL, 520.7 mmol) was added dropwise under ice-cooling. After the dropwise addition was completed, the mixture was stirred at room temperature for 15 min, and then the reaction was continued at 60 ° C for 2 h. The reaction mixture was poured into ice water, and the mixture was allowed to stand until it was solidified, and then filtered. The filter cake was washed with dilute hydrochloric acid, water and methanol, and dried to give a white powdery sample S-1 (53.47 g, yield 91.7%). (ii) S-1 (20 g, 28.54 mmol) was taken in a reaction flask, 100 mL of 1,2-dichloroethane was added, and a 33% hydrobromic acid/acetic acid solution (80 mL, 463.3 mmol) was added dropwise under ice cooling. The addition was completed and stirred at room temperature for 2 h. The reaction mixture was poured into a mixture of ethyl acetate and ice water, and the mixture was evaporated. Dispersion, sonication, precipitation of solids, filtration, and drying of the filter cake, which gave a white powder of 2,3,4,6-tetra-O-benzoyl-α-D-bromoglucopyranose (S-02) 17.4g The yield was 92%. ESI-MS m/z: 681.0 (100.0%), 683.0 (97.3%), 682.0 (36.8%) [M+Na] + .
实施例9 2,3,4,6-四-O-苯甲酰基-α-D-溴代吡喃半乳糖(S-04)的制备Example 9 Preparation of 2,3,4,6-tetra-O-benzoyl-α-D-bromogalactopyranosole (S-04)
Figure PCTCN2014086933-appb-000013
Figure PCTCN2014086933-appb-000013
反应试剂与条件：(i)苯甲酰氯，吡啶，室温；(ii)33％氢溴酸乙酸溶液，1，2-二氯乙烷，室温。Reaction reagents and conditions: (i) benzoyl chloride, pyridine, room temperature; (ii) 33% hydrobromic acid acetic acid solution, 1,2-dichloroethane, room temperature.
制备步骤：采用实施例8项下S-02的合成操作，取D-半乳糖替换D-葡萄糖作为原料，即可制备得2,3,4,6-四-O-苯甲酰基-α-D-溴代吡喃半乳糖(S-04)。ESI-MSm/z:681.1(100.0％),683.1(97.3％),682.1(36.8％)[M+Na]+。Preparation step: using the synthetic operation of S-02 in Example 8 and taking D-galactose instead of D-glucose as a raw material, 2,3,4,6-tetra-O-benzoyl-α- can be prepared. D-Bromopyranose (S-04). ESI-MS m/z: 681.1 (100.0%), 683.1 (97.3%), 682.1 (36.8%) [M+Na] + .
(三)目标产物黄酮糖苷的制备(III) Preparation of target product flavonoid glycoside
实施例10：3,5,3'-三甲氧基-4'-羟基-7-O-β-D-(2,3,4,6-四-O-苯甲酰基)-葡萄糖基-黄酮(T-01)Example 10: 3,5,3'-Trimethoxy-4'-hydroxy-7-O-β-D-(2,3,4,6-tetra-O-benzoyl)-glucosyl-flavonoid (T-01)
Figure PCTCN2014086933-appb-000014
Figure PCTCN2014086933-appb-000014
反应试剂与条件：(i)KOH，四丁基溴化铵(TBAB)，CHCl3/H2O，室温；Reaction reagents and conditions: (i) KOH, tetrabutylammonium bromide (TBAB), CHCl 3 /H 2 O, room temperature;
制备步骤：取M-05(100mg，0.29mmol)和TBAB(18.7mg，0.058mmol)于反应瓶中，加入KOH水溶液(2mL，0.29M，0.58mmol)，室温搅拌15min，缓慢加入用2mL氯仿溶解的S-02(383mg，0.58mmol)，室温搅拌48h后，反应液用稀盐酸调pH至2-3，乙酸乙酯萃取，有机层以水洗涤，无水硫酸镁干燥，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得淡黄色油状目标产物T-01，收率49％。ESI-MSm/z:945.2[M+Na]+；1HNMR(400MHz,CDCl3)δ8.00–7.93(m,4H),7.92–7.87(m,4H),7.63(d,J＝2.0Hz,1H),7.53(dd,J＝8.6,1.9Hz,3H),7.48(t,J＝7.4Hz,1H),7.41–7.31(m,7H),7.19(t,J＝7.8Hz,2H),6.98(d,J＝8.5Hz,1H),6.66(d,J＝2.2Hz,1H),6.39(d,J＝2.1Hz,1H),6.02(t,J＝9.1Hz,1H),5.84–5.75(m,2H),5.64(d,J＝7.2Hz,1H),4.80–4.73(m,1H),4.54–4.46(m,2H),3.93(s,3H),3.85(s,3H),3.83(s,3H)；13CNMR(101MHz,CDCl3)δ173.98,171.33,166.25,165.82,165.37,165.20,161.31,160.45,158.26,153.07,147.93,146.35,141.17,133.84,133.76,133.63,133.31,130.04,130.00,129.96,129.58,129.29,128.93,128.67,128.56,128.41,122.74,122.36,114.55,110.91,98.26,97.08,95.93,73.05,72.56,71.64,69.41,63.19,60.01,56.62,56.20.。Preparation step: Take M-05 (100 mg, 0.29 mmol) and TBAB (18.7 mg, 0.058 mmol) in a reaction flask, add KOH aqueous solution (2 mL, 0.29 M, 0.58 mmol), stir at room temperature for 15 min, slowly add 2 mL of chloroform to dissolve. After stirring for 48 hours at room temperature, the reaction mixture was adjusted to pH 2-3 with dilute aqueous hydrochloric acid, and ethyl acetate was evaporated. The organic layer was washed with water, dried over anhydrous magnesium sulfate The ester was dried to dryness. ESI-MS m/z: 945.2 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 - 7.93 (m, 4H), 7.92 - 7.87 (m, 4H), 7.63 (d, J = 2.0 Hz) , 1H), 7.53 (dd, J = 8.6, 1.9 Hz, 3H), 7.48 (t, J = 7.4 Hz, 1H), 7.41 - 7.31 (m, 7H), 7.19 (t, J = 7.8 Hz, 2H) , 6.98 (d, J = 8.5 Hz, 1H), 6.66 (d, J = 2.2 Hz, 1H), 6.39 (d, J = 2.1 Hz, 1H), 6.02 (t, J = 9.1 Hz, 1H), 5.84 – 5.75 (m, 2H), 5.64 (d, J = 7.2 Hz, 1H), 4.80–4.73 (m, 1H), 4.54–4.46 (m, 2H), 3.93 (s, 3H), 3.85 (s, 3H) ), 3.83 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 173.98, 171.33, 166.25, 165.82, 165.37, 165.20, 161.31, 160.45, 158.26, 153.07, 147.93, 146.35, 141.17, 133.84, 133.76, 133.63, 133.31 , 130.04, 130.00, 129.96, 129.58, 129.29, 128.93, 128.67, 128.56, 128.41, 122.74, 122.36, 114.55, 110.91, 98.26, 97.08, 95.93, 73.05, 72.56, 71.64, 69.41, 63.19, 60.01, 56.62, 56.20.
实施例11：3,5,3'-三甲氧基-4'-羟基-7-O-β-D-葡萄糖基-黄酮(T-02)Example 11: 3,5,3'-Trimethoxy-4'-hydroxy-7-O-β-D-glucosyl-flavonoid (T-02)
Figure PCTCN2014086933-appb-000015
Figure PCTCN2014086933-appb-000015
反应试剂与条件：CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取实施例10所合成样品T-01(90mg，0.097mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.41M，0.195mmol)，室温搅拌30min后，搅拌下加入阳离子交换树脂中和，调节pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得38mg淡黄色粉末状目标产物T-02，收率77％。ESI-MSm/z:529.1[M+Na]+；1HNMR(400MHz,CD3OD)δ7.73(d,J＝2.0Hz,1H),7.65(dd,J＝8.5,2.1Hz,1H),6.94(d,J＝8.4Hz,1H),6.91(d,J＝2.2Hz,1H),6.69(d,J＝2.1Hz,1H),5.10(d,J＝7.5Hz,1H),3.97(d,J＝2.1Hz,1H),3.94(s,6H),3.79(s,3H),3.72–3.68(m,1H),3.61–3.55(m,1H),3.51(dd,J＝ 5.4,2.9Hz,2H),3.40–3.34(m,2H).Preparation step: The sample T-01 (90 mg, 0.097 mmol) synthesized in Example 10 was taken in a reaction flask, dissolved in 4 mL of methanol and 1 mL of dichloromethane, and sodium methoxide (0.41 M, 0.195 mmol) was slowly added, and stirred at room temperature for 30 min. The mixture was neutralized by stirring with a cation exchange resin, and the pH was adjusted to 5-6, and the filtrate was concentrated to dryness. The obtained residue was purified by silica gel column chromatography . ESI-MS m/z: 529.1 [M+Na] + ; 1 H NMR (400 MHz, CD 3 OD) δ 7.73 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.5, 2.1 Hz, 1H) , 6.94 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 2.2 Hz, 1H), 6.69 (d, J = 2.1 Hz, 1H), 5.10 (d, J = 7.5 Hz, 1H), 3.97 (d, J = 2.1 Hz, 1H), 3.94 (s, 6H), 3.79 (s, 3H), 3.72 - 3.68 (m, 1H), 3.61 - 3.55 (m, 1H), 3.51 (dd, J = 5.4) , 2.9 Hz, 2H), 3.40–3.34 (m, 2H).
实施例12：3,5,3'-三-乙氧基-4'-羟基-7-O-β-D-葡萄糖基-黄酮(T-03)Example 12: 3,5,3'-tris-ethoxy-4'-hydroxy-7-O-β-D-glucosyl-flavonoid (T-03)
Figure PCTCN2014086933-appb-000016
Figure PCTCN2014086933-appb-000016
反应试剂与条件：(i)KOH，TBAB，CHCl3-H2O，室温；(ii)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) KOH, TBAB, CHCl 3 -H 2 O, room temperature; (ii) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：(i)取M-06(200g，0.517mmol)和TBAB(33.4mg，0.103mmol)于反应瓶中，加入KOH水溶液(3.6mL，0.29M，1.04mmol)，室温搅拌15min，缓慢加入用氯仿(3.5mL)溶解的S-02(682.7mg，1.04mmol)，室温搅拌48h，所得反应液用稀盐酸调pH至2-3，乙酸乙酯萃取，有机层以水洗涤，无水硫酸镁干燥，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得98mg产物T-03；(ii)取上一步合成所得样品T-03(95mg，0.098mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.41M，0.197mmol)，室温搅拌30min后，搅拌下加入阳离子交换树脂调pH至5-6，过滤，滤液浓缩至干，得淡黄色粉末状T-04目标化合物，收率89％。ESI-MSm/z:571.2[M+Na]+；1HNMR(400MHz,DMSO-d6)δ9.69(s,1H),8.30(s,1H),7.66(d,J＝1.9Hz,1H),7.55(dd,J＝8.5,2.0Hz,1H),6.94(d,J＝8.5Hz,1H),6.83(d,J＝2.0Hz,1H),6.53(d,J＝1.9Hz,1H),5.39(d,J＝4.7Hz,1H),5.15(d,J＝4.5Hz,1H),5.08(d,J＝5.5Hz,1H),5.06(d,J＝7.6Hz,1H),4.65(t,J＝5.5Hz,1H),4.13–4.05(m,4H),3.96(q,J＝7.0Hz,2H),3.71(dd,J＝9.7,5.3Hz,1H),3.50–3.40(m,2H),3.29(dd,J＝8.7,4.5Hz,3H),3.18–3.07(m,1H),1.41–1.33(m,6H),1.23(t,J＝7.0Hz,3H).Preparation steps: (i) Take M-06 (200 g, 0.517 mmol) and TBAB (33.4 mg, 0.103 mmol) in a reaction flask, add KOH aqueous solution (3.6 mL, 0.29 M, 1.04 mmol), stir at room temperature for 15 min, slowly add S-02 (682.7 mg, 1.04 mmol), which was dissolved in chloroform (3.5 mL), and stirred at room temperature for 48 hr, the obtained mixture was adjusted to pH 2-3 with dilute hydrochloric acid, and ethyl acetate was evaporated. The magnesium was dried, and the ethyl acetate was evaporated to dryness. The residue obtained was purified by silica gel column chromatography to afford 98 mg of product T s; (ii) </ RTI> Add 4 mL of methanol and 1 mL of dichloromethane to dissolve, slowly add sodium methoxide (0.41 M, 0.197 mmol), stir at room temperature for 30 min, add cation exchange resin to pH to 5-6 with stirring, filter, and concentrate the filtrate to dryness. P-04 target compound in pale yellow powder, yield 89%. ESI-MSm / z: 571.2 [ M + Na] +; 1 HNMR (400MHz, DMSO-d6) δ9.69 (s, 1H), 8.30 (s, 1H), 7.66 (d, J = 1.9Hz, 1H) , 7.55 (dd, J = 8.5, 2.0 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.53 (d, J = 1.9 Hz, 1H) , 5.39 (d, J = 4.7 Hz, 1H), 5.15 (d, J = 4.5 Hz, 1H), 5.08 (d, J = 5.5 Hz, 1H), 5.06 (d, J = 7.6 Hz, 1H), 4.65 (t, J = 5.5 Hz, 1H), 4.13 - 4.05 (m, 4H), 3.96 (q, J = 7.0 Hz, 2H), 3.71 (dd, J = 9.7, 5.3 Hz, 1H), 3.50 - 3.40 ( m, 2H), 3.29 (dd, J = 8.7, 4.5 Hz, 3H), 3.18 - 3.07 (m, 1H), 1.41 - 1.33 (m, 6H), 1.23 (t, J = 7.0 Hz, 3H).
实施例13：3-甲氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-04) Example 13: 3-Methoxy-5-hydroxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid (T-04)
Figure PCTCN2014086933-appb-000017
Figure PCTCN2014086933-appb-000017
反应试剂与条件：(i)K2CO3，TBAB，CHCl3/DMF/H2O，45℃。Reagents and conditions: (i) K 2 CO 3 , TBAB, CHCl 3 /DMF/H 2 O, 45 ° C.
制备步骤：取M-11(0.2g，0.416mmol)、TBAB(14mg，0.042mmol)和碳酸钾(0.403g，2.91mmol)混合于反应瓶中，加入5mLDMF和5mL水，室温搅拌15min，缓慢加入用10mL氯仿溶解的S-02(1.1g，1.66mmol)，45℃搅拌48h。反应液用稀盐酸调pH至2-3，乙酸乙酯萃取，有机层以水洗涤，无水硫酸镁干燥，减压回收乙酸乙酯，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-04，收率71％。ESI-MSm/z:1081.2[M+Na]+；1HNMR(400MHz,CDCl3)δ12.60(s,1H),7.99–7.93(m,6H),7.90–7.86(m,2H),7.68–7.56(m,6H),7.55–7.50(m,2H),7.47(t,J＝7.4Hz,1H),7.43–7.30(m,13H),7.28–7.20(m,3H),6.96(d,J＝8.4Hz,1H),6.53(d,J＝2.2Hz,1H),6.50(d,J＝2.2Hz,1H),6.01(t,J＝9.2Hz,1H),5.81(dd,J＝9.1,7.3Hz,1H),5.76(d,J＝9.3Hz,1H),5.58(d,J＝7.3Hz,1H),4.86–4.66(m,1H),4.57–4.32(m,2H),3.85(s,3H)；13CNMR(101MHz,CDCl3)δ178.92,166.25,165.83,165.32,165.11,162.31,161.98,156.31,156.10,149.66,147.69,139.87,139.83,139.17,133.79,133.66,133.58,133.24,130.05,129.99,129.96,129.74,129.52,129.32,128.95,128.75,128.68,128.65,128.61,128.52,128.45,126.35,124.06,123.95,118.14,108.76,107.42,99.60,98.28,95.19,77.36,73.09,72.68,71.53,69.33,63.15,60.36。Preparation steps: M-11 (0.2 g, 0.416 mmol), TBAB (14 mg, 0.042 mmol) and potassium carbonate (0.403 g, 2.91 mmol) were mixed in a reaction flask, 5 mL DMF and 5 mL water were added, stirred at room temperature for 15 min, slowly added S-02 (1.1 g, 1.66 mmol) dissolved in 10 mL of chloroform was stirred at 45 ° C for 48 h. The reaction mixture was adjusted to pH 2-3 with dilute aqueous hydrochloric acid, and ethyl acetate was evaporated. Product T-04, yield 71%. ESI-MS m/z: 1081.2 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 12.60 (s, 1H), 7.79 - 7.93 (m, 6H), 7.90 - 7.86 (m, 2H), 7.68 –7.56(m,6H), 7.55–7.50(m,2H), 7.47(t,J=7.4Hz,1H), 7.43–7.30(m,13H), 7.28–7.20(m,3H),6.96(d , J = 8.4 Hz, 1H), 6.53 (d, J = 2.2 Hz, 1H), 6.50 (d, J = 2.2 Hz, 1H), 6.01 (t, J = 9.2 Hz, 1H), 5.81 (dd, J = 9.1, 7.3 Hz, 1H), 5.76 (d, J = 9.3 Hz, 1H), 5.58 (d, J = 7.3 Hz, 1H), 4.86 - 4.66 (m, 1H), 4.57 - 4.32 (m, 2H) , 3.85 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 178.92, 166.25, 165.83, 165.32, 165.11, 162.31, 161.98, 156.31, 156.10, 149.66, 147.69, 139.87, 139.83, 139.17, 133.79, 133.66, 133.58, 133.24,130.05,129.99,129.96,129.74,129.52,129.32,128.95,128.75,128.68,128.65,128.61,128.52,128.45,126.35,124.06,123.95,118.14,108.76,107.42,99.60,98.28,95.19,77.36,73.09, 72.68, 71.53, 69.33, 63.15, 60.36.
实施例14：3-甲氧基-5,3',4'-三羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-05)Example 14: 3-Methoxy-5,3',4'-trihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-05)
Figure PCTCN2014086933-appb-000018
Figure PCTCN2014086933-appb-000018
反应试剂与条件：(i)10％Pd/C，H2，CH3OH/THF/H2O，室温。Reaction reagents and conditions: (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
制备步骤：取T-04(554mg，0.523mmol)于反应瓶中，加入80mL甲醇、20mL四氢呋喃和1mL水溶解，加入10％Pd/C(500mg)，室温常压氢解反应48h，过滤去除钯碳，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得黄 色油状目标产物T-05，收率77％。ESI-MSm/z:917.2[M+Na]+；1HNMR(400MHz,CDCl3)δ12.49(s,1H),8.01–7.84(m,8H),7.77(d,J＝1.7Hz,1H),7.54–7.27(m,14H),7.00(d,J＝8.5Hz,1H),6.46(d,J＝3.1Hz,2H),6.02(t,J＝9.2Hz,1H),5.83–5.73(m,2H),5.53(d,J＝7.3Hz,1H),4.77–4.71(m,1H),4.53–4.40(m,2H),3.79(s,3H)。Preparation steps: Take T-04 (554mg, 0.523mmol) in a reaction flask, add 80mL methanol, 20mL tetrahydrofuran and 1mL water to dissolve, add 10% Pd / C (500mg), hydrogen sulfide reaction at room temperature for 48h, filter to remove palladium The residue was purified by silica gel column chromatography toiel ESI-MS m/z: 917.2 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 12.49 (s, 1H), 8.01 - 7.84 (m, 8H), 7.77 (d, J = 1.7 Hz, 1H) ), 7.54 - 7.27 (m, 14H), 7.00 (d, J = 8.5 Hz, 1H), 6.46 (d, J = 3.1 Hz, 2H), 6.02 (t, J = 9.2 Hz, 1H), 5.83 - 5.73 (m, 2H), 5.53 (d, J = 7.3 Hz, 1H), 4.77 - 4.71 (m, 1H), 4.53 - 4.40 (m, 2H), 3.79 (s, 3H).
实施例15：3-甲氧基-5,3',4'-三羟基-7-O-β-D-葡萄糖基-黄酮(T-06)Example 15: 3-Methoxy-5,3',4'-trihydroxy-7-O-β-D-glucosyl-flavonoid (T-06)
Figure PCTCN2014086933-appb-000019
Figure PCTCN2014086933-appb-000019
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-05(80mg，0.089mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.41M，0.27mmol)，室温搅拌30min。搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-06，收率83％。ESI-MSm/z:501.1[M+Na]+；1HNMR(400MHz,DMSO-d6)δ12.69(s,1H),8.16(s,1H),7.57(d,J＝2.2Hz,1H),7.45(dd,J＝8.5,2.2Hz,1H),6.91(d,J＝8.4Hz,1H),6.76(d,J＝2.1Hz,1H),6.42(d,J＝2.1Hz,1H),5.06(d,J＝7.4Hz,1H),3.78(s,3H),3.71–3.66(m,1H),3.50–3.41(m,2H),3.32–3.22(m,2H),3.16(t,J＝8.8Hz,1H)。Preparation: Take T-05 (80 mg, 0.089 mmol) in a reaction flask, dissolve 4 mL of methanol and 1 mL of dichloromethane, slowly add sodium methoxide (0.41 M, 0.27 mmol), and stir at room temperature for 30 min. The mixture was adjusted to pH 5-6 with stirring, and the mixture was filtered. ESI-MS m/z: 501.1 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.16 (s, 1H), 7.57 (d, J = 2.2 Hz, 1H) , 7.45 (dd, J = 8.5, 2.2 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 2.1 Hz, 1H), 6.42 (d, J = 2.1 Hz, 1H) , 5.06 (d, J = 7.4 Hz, 1H), 3.78 (s, 3H), 3.71 - 3.66 (m, 1H), 3.50 - 3.41 (m, 2H), 3.32 - 3.22 (m, 2H), 3.16 (t , J = 8.8 Hz, 1H).
实施例16：3-甲氧基-5,3',4'-三正戊氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-07)Example 16: 3-Methoxy-5,3',4'-tri-n-pentyloxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-07)
Figure PCTCN2014086933-appb-000020
Figure PCTCN2014086933-appb-000020
反应试剂与条件：(i)CH3(CH2)4Br，K2CO3，DMF，室温；Reaction reagents and conditions: (i) CH 3 (CH 2 ) 4 Br, K 2 CO 3 , DMF, room temperature;
制备步骤：取T-05(100mg，0.112mmol)于4mL无水DMF中溶解完全，加入无水碳酸钾(231mg，1.68mmol)，于氩气保护下，将溴戊烷(166μL，1.34mmol)注入反应瓶，室温搅拌反应12h，所得反应液以乙酸乙酯和水分散，萃取，有机层依次用稀盐酸和水洗涤，无水硫酸镁干燥，减压回收溶剂至干，所得 残留物经硅胶柱层析纯化，得淡黄色油状目标产物T-07，收率69％。ESI-MSm/z:1127.4[M+Na]+；1HNMR(400MHz,CDCl3)δ8.04–7.85(m,10H),7.64(d,J＝2.1Hz,1H),7.57–7.52(m,3H),7.50–7.44(m,1H),7.42–7.30(m,7H),7.18(t,J＝7.8Hz,2H),6.91(d,J＝8.7Hz,1H),6.64(d,J＝2.2Hz,1H),6.36(d,J＝2.2Hz,1H),6.02(t,J＝9.1Hz,1H),5.85–5.73(m,2H),5.63(d,J＝7.2Hz,1H),4.79–4.71(m,1H),4.55–4.44(m,2H),4.10–4.00(m,4H),3.98–3.86(m,2H),1.92–1.79(m,6H),1.55–1.32(m,13H),1.00–0.88(m,9H)。Preparation step: Take T-05 (100 mg, 0.112 mmol) in 4 mL of anhydrous DMF and dissolve completely, add anhydrous potassium carbonate (231 mg, 1.68 mmol), under argon, bromopentane (166 μL, 1.34 mmol) The reaction mixture was poured into a reaction flask, and the reaction mixture was stirred at room temperature for 12 hours. The obtained reaction mixture was evaporated to ethyl acetate and water, and the organic layer was washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated to dryness. Purification by column chromatography gave EtOAc (EtOAc) ESI-MS m/z: 1127.4 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.04 - 7.85 (m, 10H), 7.64 (d, J = 2.1 Hz, 1H), 7.57 - 7.52 (m) , 3H), 7.50 - 7.44 (m, 1H), 7.42 - 7.30 (m, 7H), 7.18 (t, J = 7.8 Hz, 2H), 6.91 (d, J = 8.7 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 6.36 (d, J = 2.2 Hz, 1H), 6.02 (t, J = 9.1 Hz, 1H), 5.85 - 5.73 (m, 2H), 5.63 (d, J = 7.2 Hz, 1H), 4.79–4.71 (m, 1H), 4.55–4.44 (m, 2H), 4.10–4.00 (m, 4H), 3.98–3.86 (m, 2H), 1.92–1.79 (m, 6H), 1.55– 1.32 (m, 13H), 1.00 - 0.88 (m, 9H).
实施例17：3-甲氧基-5,3',4'-三正戊氧基-7-O-β-D-葡萄糖基-黄酮(T-08)Example 17: 3-Methoxy-5,3',4'-tri-n-pentyloxy-7-O-β-D-glucosyl-flavonoid (T-08)
Figure PCTCN2014086933-appb-000021
Figure PCTCN2014086933-appb-000021
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-07(75mg，0.068mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.5ml，0.41M，0.20mmol)，室温搅拌30min后，搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-08，收率59％。ESI-MSm/z:711.3[M+Na]+；1HNMR(400MHz,DMSO-d6)δ7.63–7.58(m,2H),7.11(d,J＝8.4Hz,1H),6.84(d,J＝2.2Hz,1H),6.55(d,J＝2.2Hz,1H),5.40(d,J＝4.9Hz,1H),5.16(d,J＝4.7Hz,1H),5.09(d,J＝5.3Hz,1H),5.05(d,J＝7.4Hz,1H),4.65(t,J＝5.6Hz,1H),4.06–3.99(m,6H),3.72–3.69(m,1H),3.48–3.42(m,2H),3.34–3.23(m,3H),3.20–3.11(m,1H),1.81–1.68(m,6H),1.53–1.29(m,12H),0.93–0.86(m,9H)。Preparation step: Take T-07 (75mg, 0.068mmol) in a reaction flask, add 4mL methanol and 1mL dichloromethane to dissolve, slowly add sodium methoxide (0.5ml, 0.41M, 0.20mmol), stir at room temperature for 30min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated to dryness. ESI-MS m/z: 711.3 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.63 - 7.58 (m, 2H), 7.11 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 2.2 Hz, 1H), 6.55 (d, J = 2.2 Hz, 1H), 5.40 (d, J = 4.9 Hz, 1H), 5.16 (d, J = 4.7 Hz, 1H), 5.09 (d, J = 5.3 Hz, 1H), 5.05 (d, J = 7.4 Hz, 1H), 4.65 (t, J = 5.6 Hz, 1H), 4.06 - 3.99 (m, 6H), 3.72 - 3.69 (m, 1H), 3.48 - 3.42 (m, 2H), 3.34–3.23 (m, 3H), 3.20–3.11 (m, 1H), 1.81–1.68 (m, 6H), 1.53–1.29 (m, 12H), 0.93–0.86 (m, 9H) ).
实施例18：3,5-二甲氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-09)Example 18: 3,5-Dimethoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-09)
Figure PCTCN2014086933-appb-000022
Figure PCTCN2014086933-appb-000022
反应试剂与条件：(i)CH3I，K2CO3，DMF，室温；(ii)10％Pd/C，H2， CH3OH/THF/H2O；Reaction reagents and conditions: (i) CH 3 I, K 2 CO 3 , DMF, room temperature; (ii) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O;
制备步骤：(i)取T-04(773mg，0.73mmol)于8mL无水DMF中溶解完全，加入无水碳酸钾(403mg，2.92mmol)，于氩气保护下，将碘甲烷(182μL，2.92mmol)注入反应瓶，室温搅拌反应12h，将反应液以乙酸乙酯和水分散，萃取，有机层以水洗涤，无水硫酸镁干燥，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得淡黄色油状中间体T-09-M，收率70％；(ii)取T-09-M(530mg，0.49mmol)于反应瓶中，加入100mL甲醇、25mL四氢呋喃和1.25mL水溶解，加入530mg10％Pd/C，室温常压氢解反应48h，过滤去除钯碳，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-09，收率71％。ESI-MSm/z:931.2[M+Na]+；1HNMR(400MHz,DMSO-d6)δ8.30(s,3H),7.91–7.85(m,6H),7.76(dd,J＝8.3,1.2Hz,2H),7.67–7.54(m,4H),7.53–7.39(m,8H),7.37–7.29(m,3H),6.92(d,J＝2.2Hz,1H),6.88(d,J＝8.5Hz,1H),6.50(d,J＝2.2Hz,1H),6.32(d,J＝7.8Hz,1H),6.11(t,J＝9.5Hz,1H),5.79–5.69(m,2H),4.93–4.82(m,1H),4.63–4.45(m,2H),3.76(s,3H),3.72(s,3H)。The preparation steps were as follows: (i) T-04 (773 mg, 0.73 mmol) was dissolved in 8 mL of anhydrous DMF, and anhydrous potassium carbonate (403 mg, 2.92 mmol) was added. Under argon gas, iodomethane (182 μL, 2.92) was added. (mmol), the reaction mixture was poured into a reaction flask, and the reaction was stirred at room temperature for 12 h. The reaction mixture was taken with ethyl acetate and water, and then evaporated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. Purify to give the pale yellow oily intermediate T-09-M, yield 70%; (ii) take T-09-M (530 mg, 0.49 mmol) in a reaction flask, add 100 mL of methanol, 25 mL of tetrahydrofuran and 1.25 mL of water Dissolved, 530 mg of 10% Pd/C was added, and hydrogenation reaction was carried out at room temperature for 48 h, and the palladium carbon was removed by filtration. The solvent was evaporated to dryness. 71%. ESI-MS m/z: 931.2 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 3H), 7.91 - 7.85 (m, 6H), 7.76 (dd, J = 8.3, 1.2 Hz, 2H), 7.67–7.54 (m, 4H), 7.53–7.39 (m, 8H), 7.37–7.29 (m, 3H), 6.92 (d, J=2.2 Hz, 1H), 6.88 (d, J= 8.5 Hz, 1H), 6.50 (d, J = 2.2 Hz, 1H), 6.32 (d, J = 7.8 Hz, 1H), 6.11 (t, J = 9.5 Hz, 1H), 5.79 - 5.69 (m, 2H) , 4.93 - 4.82 (m, 1H), 4.63 - 4.45 (m, 2H), 3.76 (s, 3H), 3.72 (s, 3H).
实施例19：3,5-二甲氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮(T-10)Example 19: 3,5-Dimethoxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid (T-10)
Figure PCTCN2014086933-appb-000023
Figure PCTCN2014086933-appb-000023
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-09(100mg，0.11mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.8mL，0.41M，0.33mmol)，室温搅拌30min后，搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-10，收率73.3％。ESI-MSm/z:515.1[M+Na]+；1HNMR(400MHz,DMSO-d6)δ9.69(s,1H),9.32(s,1H),7.53(s,1H),7.39(d,J＝7.5Hz,1H),6.89(d,J＝7.8Hz,1H),6.81(s,1H),6.56(s,1H),5.43(s,1H),4.67(s,1H),3.84(s,3H),3.71(s,4H),3.45(s,2H),3.30(s,2H),3.16(s,1H)；13CNMR(101MHz,DMSO-d6)δ172.27,161.43,160.33,157.74,152.47,148.11,145.18,140.01,121.13,120.06,115.67,115.40,109.09,99.85,96.81,95.61, 77.30,76.58,73.21,69.75,60.73,59.26,56.15。Preparation steps: Take T-09 (100 mg, 0.11 mmol) in a reaction flask, add 4 mL of methanol and 1 mL of dichloromethane to dissolve, slowly add sodium methoxide (0.8 mL, 0.41 M, 0.33 mmol), stir at room temperature for 30 min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography toield ESI-MS m/z: 515.1 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.32 (s, 1H), 7.53 (s, 1H), 7.39 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.81 (s, 1H), 6.56 (s, 1H), 5.43 (s, 1H), 4.67 (s, 1H), 3.84 ( s, 3H), 3.71 (s, 4H), 3.45 (s, 2H), 3.30 (s, 2H), 3.16 (s, 1H); 13 CNMR (101 MHz, DMSO-d6) δ 172.27, 161.43, 160.33, 157.74, 152.47, 148.11, 145.18, 140.01, 121.13, 120.06, 115.67, 115.40, 109.09, 99.85, 96.81, 95.61, 77.30, 76.58, 73.21, 69.75, 60.73, 59.26, 56.15.
实施例20：3-甲氧基-5-乙氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-11)Example 20: 3-Methoxy-5-ethoxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid (T-11)
Figure PCTCN2014086933-appb-000024
Figure PCTCN2014086933-appb-000024
反应试剂与条件：(i)CH3CH2I，K2CO3，DMF，室温。Reaction reagents and conditions: (i) CH 3 CH 2 I, K 2 CO 3 , DMF, room temperature.
制备步骤：取T-04(620mg，0.58mmol)于8mL无水DMF中溶解完全，加入无水碳酸钾(243mg，1.76mmol)，于氩气保护下，将碘乙烷(141μL，1.76mmol)注入反应瓶，室温搅拌反应12h。将反应液加入乙酸乙酯和水分散，萃取，有机层以水洗涤，无水硫酸镁干燥，过滤，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得淡黄色油状目标产物T-11，收率78％。ESI-MSm/z:1109.3[M+Na]+；1HNMR(400MHz,CDCl3)δ8.00–7.93(m,4H),7.91–7.84(m,4H),7.63–7.57(m,5H),7.56–7.50(m,4H),7.50–7.45(m,1H),7.43–7.30(m,13H),7.22–7.15(m,1H),7.07(t,J＝7.6Hz,2H),6.93(d,J＝8.3Hz,1H),6.61(d,J＝2.2Hz,1H),6.35(d,J＝2.2Hz,1H),6.02(t,J＝9.2Hz,1H),5.82(dd,J＝9.1,7.3Hz,1H),5.75(t,J＝9.3Hz,1H),5.60(d,J＝7.3Hz,1H),4.75(t,J＝7.5Hz,1H),4.52–4.44(m,2H),4.07–3.97(m,2H),3.85(s,3H),1.46(t,J＝7.0Hz,3H)。Preparation step: T-04 (620 mg, 0.58 mmol) was dissolved in 8 mL of anhydrous DMF, and anhydrous potassium carbonate (243 mg, 1.76 mmol) was added. Under argon atmosphere, ethyl iodide (141 μL, 1.76 mmol) was added. The reaction flask was poured into the reaction flask, and the reaction was stirred at room temperature for 12 hours. The reaction mixture is added to ethyl acetate and water, and the mixture is evaporated. EtOAcjjjjjjjjjjj T-11, yield 78%. ESI-MS m/z: 1109.3 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 - 7.93 (m, 4H), 7.91 - 7.84 (m, 4H), 7.63 - 7.57 (m, 5H) , 7.56–7.50 (m, 4H), 7.50–7.45 (m, 1H), 7.43–7.30 (m, 13H), 7.22–7.15 (m, 1H), 7.07 (t, J=7.6 Hz, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 6.35 (d, J = 2.2 Hz, 1H), 6.02 (t, J = 9.2 Hz, 1H), 5.82 (dd , J = 9.1, 7.3 Hz, 1H), 5.75 (t, J = 9.3 Hz, 1H), 5.60 (d, J = 7.3 Hz, 1H), 4.75 (t, J = 7.5 Hz, 1H), 4.52 - 4.44 (m, 2H), 4.07 - 3.97 (m, 2H), 3.85 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H).
实施例21：3-甲氧基-5-乙氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-12)Example 21: 3-methoxy-5-ethoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-12)
Figure PCTCN2014086933-appb-000025
Figure PCTCN2014086933-appb-000025
反应试剂与条件：(i)10％Pd/C，H2，CH3OH/THF/H2O。Reaction reagents and conditions: (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O.
制备步骤：取T-11(480mg，0.44mmol)于反应瓶中，加入80mL甲醇、20mL四氢呋喃和1mL水溶解，加入10％Pd/C(480mg)，室温常压氢解反应48h，过滤去除钯碳，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得黄 色油状目标产物T--12，收率72％。ESI-MSm/z:945.2[M+Na]+；1HNMR(400MHz,CDCl3)δ8.02(s,1H),7.99–7.93(m,4H),7.92–7.85(m,4H),7.76(d,J＝2.0Hz,1H),7.55–7.44(m,3H),7.43–7.30(m,9H),7.18(t,J＝7.8Hz,2H),6.96(d,J＝8.5Hz,1H),6.64(d,J＝2.1Hz,1H),6.02(t,J＝9.1Hz,1H),5.81(dd,J＝9.0,7.3Hz,1H),5.78(t,J＝9.3Hz,1H),5.63(d,J＝7.2Hz,1H),4.73(dd,J＝11.9,2.7Hz,1H),4.59–4.43(m,2H),4.07–3.94(m,2H),3.75(s,3H),1.45(t,J＝6.9Hz,3H)。Preparation steps: Take T-11 (480 mg, 0.44 mmol) in a reaction flask, add 80 mL of methanol, 20 mL of tetrahydrofuran and 1 mL of water to dissolve, add 10% Pd/C (480 mg), hydrogenolysis at room temperature for 48 h, filter to remove palladium. The carbon was recovered under reduced pressure to dryness. ESI-MS m/z: 945.2 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (s, 1H), 7.99 - 7.93 (m, 4H), 7.92 - 7.85 (m, 4H), 7.76 (d, J = 2.0 Hz, 1H), 7.55 - 7.44 (m, 3H), 7.43 - 7.30 (m, 9H), 7.18 (t, J = 7.8 Hz, 2H), 6.96 (d, J = 8.5 Hz, 1H), 6.64 (d, J = 2.1 Hz, 1H), 6.02 (t, J = 9.1 Hz, 1H), 5.81 (dd, J = 9.0, 7.3 Hz, 1H), 5.78 (t, J = 9.3 Hz, 1H), 5.63 (d, J = 7.2 Hz, 1H), 4.73 (dd, J = 11.9, 2.7 Hz, 1H), 4.59 - 4.43 (m, 2H), 4.07 - 3.94 (m, 2H), 3.75 (s) , 3H), 1.45 (t, J = 6.9 Hz, 3H).
实施例22：3-甲氧基-5-乙氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮(T-13)Example 22: 3-methoxy-5-ethoxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid (T-13)
Figure PCTCN2014086933-appb-000026
Figure PCTCN2014086933-appb-000026
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-12(89mg，0.096mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(70μL，0.41M，0.029mmol)，室温搅拌30min。搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-13，收率73％。ESI-MSm/z:529.1[M+Na]+；1HNMR(400MHz,DMSO-d6)δ9.68(s,1H),9.32(s,1H),7.53(s,1H),7.40(d,J＝8.0Hz,1H),6.89(d,J＝8.2Hz,1H),6.79(s,1H),6.54(s,1H),5.42(s,1H),5.17(s,1H),5.10(s,2H),4.66(s,1H),4.10(d,J＝6.1Hz,2H),3.72(s,4H),3.48–3.45(m,2H),3.29(s,2H),3.17(s,1H),1.39(t,J＝6.4Hz,3H)；13CNMR(101MHz,DMSO-d6)δ172.25,161.34,159.60,157.75,152.32,148.05,145.16,139.99,121.15,120.01,115.65,115.37,109.15,99.82,97.48,95.52,77.26,76.55,73.18,69.71,64.47,60.69,59.29。Preparation: Take T-12 (89 mg, 0.096 mmol) in a reaction flask, dissolve 4 mL of methanol and 1 mL of dichloromethane, slowly add sodium methoxide (70 μL, 0.41 M, 0.029 mmol), and stir at room temperature for 30 min. The cation exchange resin was added thereto under stirring to adjust the pH to 5-6, and the filtrate was concentrated to dryness. ESI-MS m/z: 529.1 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.32 (s, 1H), 7.53 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.79 (s, 1H), 6.54 (s, 1H), 5.42 (s, 1H), 5.17 (s, 1H), 5.10 ( s, 2H), 4.66 (s, 1H), 4.10 (d, J = 6.1 Hz, 2H), 3.72 (s, 4H), 3.48 - 3.45 (m, 2H), 3.29 (s, 2H), 3.17 (s , 1H), 1.39 (t, J = 6.4 Hz, 3H); 13 CNMR (101 MHz, DMSO-d6) δ 172.25, 161.34, 159.60, 157.75, 152.32, 148.05, 145.16, 139.99, 121.15, 120.01, 115.65, 115.37, 109.15 , 99.82, 97.48, 95.52, 77.26, 76.55, 73.18, 69.71, 64.47, 60.69, 59.29.
实施例23：3-甲氧基-5-丙氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-14)Example 23: 3-Methoxy-5-propoxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid (T-14)
Figure PCTCN2014086933-appb-000027
Figure PCTCN2014086933-appb-000027
反应试剂与条件：(i)CH3CH2CH2I，K2CO3，DMF，室温。Reaction reagents and conditions: (i) CH 3 CH 2 CH 2 I, K 2 CO 3 , DMF, room temperature.
制备步骤：取T-04(300mg，0.283mmol)于8mL无水DMF中溶解完全，加入无水碳酸钾(156.6mg，1.13mmol)，于氩气保护下，将碘丙烷(119μL，1.13mmol)注入反应瓶，室温搅拌反应12h后，将反应液以乙酸乙酯和水分散，萃取，有机层以水洗涤，无水硫酸镁干燥，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得淡黄色油状目标产物T-14，收率78％。ESI-MSm/z:1123.3[M+Na]+；1HNMR(400MHz,CDCl3)δ8.00–7.92(m,4H),7.91–7.85(m,4H),7.64–7.57(m,5H),7.57–7.50(m,4H),7.50–7.45(m,1H),7.44–7.30(m,13H),7.20–7.15(m,1H),7.07(t,J＝7.6Hz,2H),6.93(d,J＝8.3Hz,1H),6.60(d,J＝2.2Hz,1H),6.35(d,J＝2.2Hz,1H),6.02(t,J＝9.2Hz,1H),5.82(dd,J＝9.1,7.3Hz,1H),5.76(t,J＝9.3Hz,1H),5.60(d,J＝7.3Hz,1H),4.77(q,J＝5.5Hz,1H),4.53–4.40(m,2H),3.95–3.86(m,2H),3.84(s,3H),1.92–1.81(m,2H),1.07(t,J＝7.4Hz,3H)；13CNMR(101MHz,CDCl3)δ173.73,166.07,165.65,165.18,165.03,160.73,160.27,158.07,152.54,148.82,147.37,141.13,139.88,139.79,133.64,133.55,133.43,133.05,132.39,130.03,129.87,129.83,129.78,129.37,129.29,129.06,128.78,128.56,128.48,128.46,128.37,128.33,128.24,128.16,126.20,124.40,123.16,117.66,110.88,108.43,98.09,97.82,95.23,72.91,72.44,71.41,70.97,69.25,63.00,59.98,22.17,10.49。Preparation steps: T-04 (300 mg, 0.283 mmol) was dissolved in 8 mL of anhydrous DMF, and anhydrous potassium carbonate (156.6 mg, 1.13 mmol) was added, and under argon, iodopropane (119 μL, 1.13 mmol) The reaction mixture was poured into a reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was crystallised eluted with ethyl acetate and water, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. Purification gave the desired product T-14 as a pale yellow oil, yield 78%. ESI-MS m/z: 1123.3 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 - 7.92 (m, 4H), 7.91 - 7.85 (m, 4H), 7.64 - 7.57 (m, 5H) , 7.57–7.50 (m, 4H), 7.50–7.45 (m, 1H), 7.44–7.30 (m, 13H), 7.20–7.15 (m, 1H), 7.07 (t, J=7.6 Hz, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 6.35 (d, J = 2.2 Hz, 1H), 6.02 (t, J = 9.2 Hz, 1H), 5.82 (dd , J=9.1, 7.3 Hz, 1H), 5.76 (t, J=9.3 Hz, 1H), 5.60 (d, J=7.3 Hz, 1H), 4.77 (q, J=5.5 Hz, 1H), 4.53–4.40 (m, 2H), 3.95 - 3.86 (m, 2H), 3.84 (s, 3H), 1.92 - 1.81 (m, 2H), 1.07 (t, J = 7.4 Hz, 3H); 13 CNMR (101 MHz, CDCl 3 ) δ173.73,166.07,165.65,165.18,165.03,160.73,160.27,158.07,152.54,148.82,147.37,141.13,139.88,139.79,133.64,133.55,133.43,133.05,132.39,130.03,129.87,129.83,129.78,129.37,129.29 , 129.06, 128.78, 128.56, 128.48, 128.46, 128.37, 128.33, 128.24, 128.16, 126.20, 124.40, 123.16, 117.66, 110.88, 108.43, 98.09, 97.82, 95.23, 72.91, 72.44, 71.41, 70.97, 69.25, 63.00, 59.98 , 22.17, 10.49.
实施例24：3-甲氧基-5-丙氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-15)Example 24: 3-methoxy-5-propoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-15)
Figure PCTCN2014086933-appb-000028
Figure PCTCN2014086933-appb-000028
反应试剂与条件：(i)10％Pd/C，H2，CH3OH/THF/H2O。Reaction reagents and conditions: (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O.
制备步骤：取T-14(190mg，0.172mmol)于反应瓶中，加入40mL甲醇、10mL四氢呋喃和0.5mL水溶解，加入10％Pd/C(190mg)，室温常压氢解反应48h，过滤去除钯碳，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-15，收率70％。ESI-MSm/z:959.3[M+Na]+；1HNMR(400MHz,CDCl3)δ8.00–7.92(m,4H),7.92–7.80(m,5H),7.56–7.43(m,3H),7.42– 7.29(m,8H),7.17(t,J＝7.7Hz,2H),6.96(d,J＝8.4Hz,1H),6.64(d,J＝1.9Hz,1H),6.33(d,J＝1.9Hz,1H),6.02(t,J＝9.1Hz,1H),5.81(dd,J＝9.0,7.1Hz,1H),5.79(t,J＝10.5Hz,2H),5.63(d,J＝7.1Hz,1H),4.74(dd,J＝11.9,2.6Hz,1H),4.56–4.44(m,2H),3.95–3.83(m,2H),3.72(s,3H),1.93–1.82(m,2H),1.05(t,J＝7.4Hz,3H)。Preparation steps: Take T-14 (190mg, 0.172mmol) in a reaction flask, add 40mL methanol, 10mL tetrahydrofuran and 0.5mL water to dissolve, add 10% Pd / C (190mg), hydrogenolysis reaction at room temperature for 48h, filter removal The palladium carbon was recovered under reduced pressure to dryness. ESI-MS m/z: 959.3 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 - 7.92 (m, 4H), 7.92 - 7.80 (m, 5H), 7.56 - 7.43 (m, 3H) , 7.42– 7.29 (m, 8H), 7.17 (t, J = 7.7 Hz, 2H), 6.96 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 6.33 (d, J = 1.9 Hz, 1H), 6.02 (t, J = 9.1 Hz, 1H), 5.81 (dd, J = 9.0, 7.1 Hz, 1H), 5.79 (t, J = 10.5 Hz, 2H), 5.63 (d, J=7.1 Hz, 1H), 4.74 (dd, J=11.9, 2.6 Hz, 1H), 4.56–4.44 (m, 2H), 3.95–3.83 (m, 2H), 3.72 (s, 3H), 1.93–1.82 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H).
实施例25：3-甲氧基-5-丙氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮(T-16)Example 25: 3-Methoxy-5-propoxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid (T-16)
Figure PCTCN2014086933-appb-000029
Figure PCTCN2014086933-appb-000029
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-15(102mg，0.11mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.8mL，0.41M，0.33mmol)，室温搅拌30min后，搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-16，收率73％。ESI-MSm/z:543.1[M+Na]+；1HNMR(400MHz,CD3OD)δ7.62(d,J＝1.5Hz,1H),7.53(dd,J＝8.4,1.6Hz,1H),6.89(d,J＝8.4Hz,1H),6.82(d,J＝1.3Hz,1H),6.63(s,1H),5.07(d,J＝5.7Hz,1H),4.04(t,J＝6.3Hz,2H),3.95(d,J＝12.0Hz,1H),3.70(dd,J＝12.0,5.9Hz,1H),3.60–3.46(m,3H),3.42–3.35(m,1H),1.96–1.84(m,2H),1.11(t,J＝7.4Hz,3H)；13CNMR(101MHz,CD3OD)δ176.09,163.57,161.63,159.73,155.72,149.57,146.38,141.73,122.92,122.09,116.34,110.76,101.76,98.77,97.05,78.53,77.88,74.76,72.00,71.42,62.57,60.24,23.18,10.88。Preparation step: Take T-15 (102 mg, 0.11 mmol) in a reaction flask, add 4 mL of methanol and 1 mL of dichloromethane to dissolve, slowly add sodium methoxide (0.8 mL, 0.41 M, 0.33 mmol), stir at room temperature for 30 min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography toield ESI-MS m/z: 543.1 [M+Na] + ; 1 H NMR (400 MHz, CD 3 OD) δ 7.62 (d, J = 1.5 Hz, 1H), 7.53 (dd, J = 8.4, 1.6 Hz, 1H) , 6.89 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 1.3 Hz, 1H), 6.63 (s, 1H), 5.07 (d, J = 5.7 Hz, 1H), 4.04 (t, J = 6.3 Hz, 2H), 3.95 (d, J = 12.0 Hz, 1H), 3.70 (dd, J = 12.00, 5.9 Hz, 1H), 3.60 - 3.46 (m, 3H), 3.42 - 3.35 (m, 1H), 1.96–1.84 (m, 2H), 1.11 (t, J = 7.4 Hz, 3H); 13 CNMR (101 MHz, CD 3 OD) δ 176.09, 163.57, 161.63, 159.73, 155.72, 149.57, 146.38, 141.73, 122.92, 122.09, 116.34, 110.76, 101.76, 98.77, 97.05, 78.53, 77.88, 74.76, 72.00, 71.42, 62.57, 60.24, 23.18, 10.88.
实施例26：3-甲氧基-5-乙氧羰基甲氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-17)Example 26: 3-methoxy-5-ethoxycarbonylmethoxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid (T -17)
Figure PCTCN2014086933-appb-000030
Figure PCTCN2014086933-appb-000030
反应试剂与条件：(i)ClCH2COOCH2CH3，K2CO3，DMF，室温。 Reaction reagents and conditions: (i) ClCH 2 COOCH 2 CH 3 , K 2 CO 3 , DMF, room temperature.
制备步骤：取T-04(200mg，0.189mmol)于4mL无水DMF中溶解完全，加入无水碳酸钾(104mg，0.755mmol)，于氩气保护下，将氯乙酸乙酯(80.5μL，0.755mmol)注入反应瓶，室温搅拌反应12h后，将反应液分散于乙酸乙酯和水中，萃取，有机层以水洗涤，无水硫酸镁干燥，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得淡黄色油状目标产物T-17，收率60％。ESI-MSm/z:1167.3[M+Na]+；1HNMR(400MHz,CDCl3)δ7.99–7.92(m,4H),7.91–7.84(m,4H),7.64–7.57(m,5H),7.56–7.50(m,4H),7.50–7.44(m,1H),7.42–7.36(m,10H),7.33(t,J＝7.8Hz,2H),7.22–7.15(m,1H),7.08(t,J＝7.6Hz,2H),6.93(d,J＝8.3Hz,1H),6.70(d,J＝2.2Hz,1H),6.34(d,J＝2.2Hz,1H),6.01(t,J＝9.2Hz,1H),5.81(dd,J＝9.1,7.4Hz,1H),5.75(t,J＝9.3Hz,1H),5.58(d,J＝7.3Hz,1H),4.76(t,J＝9.2Hz,1H),4.70(d,J＝2.6Hz,2H),4.52–4.43(m,2H),4.22–4.13(m,2H),3.86(s,3H),1.21(t,J＝7.1Hz,3H)。Preparation step: T-04 (200 mg, 0.189 mmol) was dissolved in 4 mL of anhydrous DMF, and anhydrous potassium carbonate (104 mg, 0.755 mmol) was added, and ethyl chloroacetate (80.5 μL, 0.755) was added under argon atmosphere. The reaction mixture was poured into a reaction flask, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated to ethyl acetate and water, and then evaporated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. Purification by chromatography gave the title product T-17 as a pale yellow oil. ESI-MS m/z: 1167.3 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 - 7.92 (m, 4H), 7.91 - 7.84 (m, 4H), 7.64 - 7.57 (m, 5H) , 7.56–7.50 (m, 4H), 7.50–7.44 (m, 1H), 7.42–7.36 (m, 10H), 7.33 (t, J = 7.8 Hz, 2H), 7.22–7.15 (m, 1H), 7.08 (t, J = 7.6 Hz, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), 6.34 (d, J = 2.2 Hz, 1H), 6.01 (t , J = 9.2 Hz, 1H), 5.81 (dd, J = 9.1, 7.4 Hz, 1H), 5.75 (t, J = 9.3 Hz, 1H), 5.58 (d, J = 7.3 Hz, 1H), 4.76 (t , J = 9.2 Hz, 1H), 4.70 (d, J = 2.6 Hz, 2H), 4.52 - 4.43 (m, 2H), 4.22 - 4.13 (m, 2H), 3.86 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H).
实施例27：3-甲氧基-5-乙氧羰基甲氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-18)Example 27: 3-Methoxy-5-ethoxycarbonylmethoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-18)
Figure PCTCN2014086933-appb-000031
Figure PCTCN2014086933-appb-000031
反应试剂与条件：(i)10％Pd/C，H2，CH3OH/THF/H2O。Reaction reagents and conditions: (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O.
制备步骤：取T-17(96mg，0.084mmol)于反应瓶中，加入40mL甲醇、10mL四氢呋喃和0.5mL水溶解，加入10％Pd/C(96mg)，室温常压氢解反应48h，过滤去除钯碳，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-18，收率70％。ESI-MSm/z:1003.3[M+Na]+；1HNMR(400MHz,CDCl3)δ8.00–7.85(m,9H),7.79(d,J＝1.5Hz,1H),7.55–7.43(m,4H),7.40–7.29(m,9H),7.18(t,J＝7.8Hz,3H),6.94(d,J＝8.5Hz,1H),6.72(d,J＝2.0Hz,1H),6.30(d,J＝2.0Hz,1H),6.02(t,J＝9.2Hz,1H),5.85–5.75(m,2H),5.63(d,J＝7.3Hz,1H),4.75(dd,J＝11.8,2.4Hz,1H),4.68(s,2H),4.56–4.44(m,2H),4.21–4.11(m,2H),3.73(s,3H),1.20(t,J＝7.1Hz,4H)。Preparation steps: Take T-17 (96mg, 0.084mmol) in a reaction flask, add 40mL methanol, 10mL tetrahydrofuran and 0.5mL water to dissolve, add 10% Pd/C (96mg), hydrogenolysis reaction at room temperature for 48h, filter and remove The palladium-carbon was recovered under reduced pressure to dryness. ESI-MS m/z: 1003.3 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 - 7.85 (m, 9H), 7.79 (d, J = 1.5 Hz, 1H), 7.55 - 7.43 (m) , 4H), 7.40 - 7.29 (m, 9H), 7.18 (t, J = 7.8 Hz, 3H), 6.94 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 6.30 (d, J = 2.0 Hz, 1H), 6.02 (t, J = 9.2 Hz, 1H), 5.85 - 5.75 (m, 2H), 5.63 (d, J = 7.3 Hz, 1H), 4.75 (dd, J = 11.8, 2.4 Hz, 1H), 4.68 (s, 2H), 4.56 - 4.44 (m, 2H), 4.21 - 4.11 (m, 2H), 3.73 (s, 3H), 1.20 (t, J = 7.1 Hz, 4H) ).
实施例28：3-甲氧基-5-羧甲氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮(T-19) Example 28: 3-methoxy-5-carboxymethoxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid (T-19)
Figure PCTCN2014086933-appb-000032
Figure PCTCN2014086933-appb-000032
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-18(102mg，0.109mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.8mL，0.41M，0.33mmol)，室温搅拌30min后，搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-19，收率61％。1HNMR(400MHz,DMSO-d6)δ7.95(s,2H),7.55(s,1H),7.42(d,J＝8.3Hz,1H),6.89(d,J＝8.3Hz,1H),6.81(s,1H),6.51(s,1H),5.03(d,J＝7.2Hz,1H),4.25(s,2H),3.77–3.69(m,4H),3.47(m,1H),3.28(m,2H),3.19–3.13(m,2H)；13CNMR(101MHz,DMSO-d6)δ173.41,169.78,166.10,162.40,161.48,159.34,157.68,153.14,148.74,145.41,139.78,120.66,120.19,115.79,115.43,109.64,108.95,99.93,98.23,95.55,77.26,76.53,73.13,69.83,69.27,60.78,59.29。Preparation steps: Take T-18 (102 mg, 0.109 mmol) in a reaction flask, add 4 mL of methanol and 1 mL of dichloromethane to dissolve, slowly add sodium methoxide (0.8 mL, 0.41 M, 0.33 mmol), stir at room temperature for 30 min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography. 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 2H), 7.55 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.81 (s, 1H), 6.51 (s, 1H), 5.03 (d, J = 7.2 Hz, 1H), 4.25 (s, 2H), 3.77 - 3.69 (m, 4H), 3.47 (m, 1H), 3.28 ( m, 2H), 3.19 - 3.13 (m, 2H); 13 CNMR (101MHz, DMSO-d6) δ 173.41, 169.78, 166.10, 162.40, 161.48, 159.34, 157.68, 153.14, 148.74, 145.41, 139.78, 120.66, 120.19, 115.79 , 115.43, 109.64, 108.95, 99.93, 98.23, 95.55, 77.26, 76.53, 73.13, 69.83, 69.27, 60.78, 59.29.
实施例29：3-乙氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-20)Example 29: 3-ethoxy-5-hydroxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid (T-20)
Figure PCTCN2014086933-appb-000033
Figure PCTCN2014086933-appb-000033
反应试剂与条件：(i)K2CO3，TBAI，CHCl3/DMF/H2O，45℃。Reagents and conditions: (i) K 2 CO 3 , TBAI, CHCl 3 /DMF/H 2 O, 45 ° C.
制备步骤：取M-20(182mg，0.368mmol)、TBAI(13.7mg，0.037mmol)和碳酸钾(356mg，2.58mmol)混合于反应瓶中，加入5mLDMF和5mL水，室温搅拌15min，缓慢加入用10mL氯仿溶解的S-02(971mg，1.47mmol)，45℃搅拌48h后，将反应液分散于乙酸乙酯和水中，萃取，有机层以水洗涤，无水硫酸镁干燥，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-20，收率63％。ESI-MSm/z:1095.3[M+Na]+；1HNMR(400MHz,CDCl3)δ12.65(s,1H),8.00–7.93(m,6H),7.90–7.85(m,2H),7.66(dd,J＝8.4, 1.8Hz,1H),7.62–7.57(m,5H),7.55–7.50(m,2H),7.47(t,J＝7.5Hz,1H),7.42–7.37(m,9H),7.36–7.29(m,4H),7.26–7.20(m,3H),7.19–7.13(m,2H),6.95(d,J＝8.4Hz,1H),6.53(d,J＝2.2Hz,1H),6.49(d,J＝2.2Hz,1H),6.00(t,J＝9.2Hz,1H),5.81(dd,J＝9.1,7.4Hz,1H),5.74(t,J＝9.3Hz,1H),5.57(d,J＝7.3Hz,1H),4.74(d,J＝9.7Hz,1H),4.50–4.40(m,2H),4.11–4.01(m,2H),1.33(t,J＝7.1Hz,3H)；13CNMR(101MHz,CDCl3)δ179.46,166.58,166.15,165.65,165.43,162.68,162.28,156.66,149.88,147.94,140.23,140.19,138.52,134.11,133.97,133.89,133.56,130.37,130.31,130.28,130.07,129.83,129.66,129.49,129.29,129.09,129.02,128.97,128.93,128.84,128.78,128.68,126.67,125.75,124.63,124.36,109.15,108.97,107.73,99.88,98.65,95.49,77.68,73.43,73.02,71.86,69.69,69.14,63.49。Preparation steps: Take M-20 (182 mg, 0.368 mmol), TBAI (13.7 mg, 0.037 mmol) and potassium carbonate (356 mg, 2.58 mmol) in a reaction flask, add 5 mL of DMF and 5 mL of water, stir at room temperature for 15 min, slowly add 10 mL of chloroform-dissolved S-02 (971 mg, 1.47 mmol), and stirred at 45 ° C for 48 h, the reaction mixture was taken in ethyl acetate and water, and the organic layer was washed with water, dried over anhydrous magnesium sulfate The ester was dried to dryness. ESI-MS m/z: 1095.3 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 12.65 (s, 1H), 8.00 - 7.93 (m, 6H), 7.90 - 7.85 (m, 2H), 7.66 (dd, J=8.4, 1.8 Hz, 1H), 7.62–7.57 (m, 5H), 7.55–7.50 (m, 2H), 7.47 (t, J=7.5 Hz, 1H), 7.42–7.37 (m, 9H) ), 7.36–7.29 (m, 4H), 7.26–7.20 (m, 3H), 7.19–7.13 (m, 2H), 6.95 (d, J=8.4 Hz, 1H), 6.53 (d, J=2.2 Hz, 1H), 6.49 (d, J = 2.2 Hz, 1H), 6.00 (t, J = 9.2 Hz, 1H), 5.81 (dd, J = 9.1, 7.4 Hz, 1H), 5.74 (t, J = 9.3 Hz, 1H), 5.57 (d, J = 7.3 Hz, 1H), 4.74 (d, J = 9.7 Hz, 1H), 4.50 - 4.40 (m, 2H), 4.11 - 4.01 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 179.46, 166.58, 166.15, 165.65, 165.43, 162.68, 162.28, 156.66, 149.88, 147.94, 140.23, 140.19, 138.52, 134.11, 133.97, 133.89, 133.56, 130.37 , 130.31, 130.28, 130.07, 129.83, 129.66, 129.49, 129.29, 129.09, 129.02, 128.97, 128.93, 128.84, 128.78, 128.68, 126.67, 125.75, 124.63, 124.36, 109.15, 108.97, 107.73, 99.88, 98.65, 95.49, 77.68 , 73.43, 73.02, 71.86, 69.69, 69.14, 63.49.
实施例30：3-乙氧基-5-羟基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-21)Example 30: 3-Ethoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-21)
Figure PCTCN2014086933-appb-000034
Figure PCTCN2014086933-appb-000034
反应试剂与条件：(i)10％Pd/C，H2，CH3OH/THF/H2O，室温。Reaction reagents and conditions: (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
制备步骤：取T-20(240mg，0.224mmol)于反应瓶中，加入60mL甲醇、15mL四氢呋喃和0.75mL水溶解，加入10％Pd/C(240mg)，室温常压氢解反应48h，过滤去除钯碳，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-21，收率51％。ESI-MSm/z:931.3[M+Na]+；1HNMR(400MHz,CDCl3)δ12.54(s,1H),7.92(ddd,J＝18.6,10.4,4.4Hz,8H),7.75(s,1H),7.55–7.41(m,5H),7.40–7.23(m,10H),7.02–6.94(m,1H),6.46(d,J＝1.9Hz,1H),6.45(d,J＝2.0Hz,1H),6.03(t,J＝9.2Hz,1H),5.81(dd,J＝8.9,7.3Hz,1H),5.77(t,J＝8.8Hz,1H),5.54(d,J＝7.3Hz,1H),4.74(dd,J＝12.0,2.5Hz,1H),4.50(dd,J＝12.0,6.4Hz,1H),4.46–4.40(m,1H),4.01(q,J＝6.9Hz,2H),1.28(t,J＝7.0Hz,3H)；13CNMR(101MHz,CDCl3)δ179.17,166.58,166.06,165.39,165.26,162.05,161.95,157.28,156.31,147.58,143.72,137.84,133.82,133.74,133.67,133.39,130.02,129.98,129.78,129.22,128.87,128.64,128.57,128.51,122.66,122.41,115.83,115.32,107.22,99.60,98.26,95.35,77.36,72.85,72.78,71.61,69.46,69.03,63.26。 Preparation steps: Take T-20 (240mg, 0.224mmol) in a reaction flask, add 60mL methanol, 15mL tetrahydrofuran and 0.75mL water to dissolve, add 10% Pd / C (240mg), hydrogen sulfide reaction at room temperature for 48h, filter to remove Palladium on carbon, and the solvent was evaporated to dryness. ESI-MS m/z: 931.3 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 12.54 (s, 1H), 7.92 (ddd, J = 18.6, 10.4, 4.4 Hz, 8H), 7.75 (s) , 1H), 7.55–7.41 (m, 5H), 7.40–7.23 (m, 10H), 7.02–6.94 (m, 1H), 6.46 (d, J=1.9 Hz, 1H), 6.45 (d, J=2.0) Hz, 1H), 6.03 (t, J = 9.2 Hz, 1H), 5.81 (dd, J = 8.9, 7.3 Hz, 1H), 5.77 (t, J = 8.8 Hz, 1H), 5.54 (d, J = 7.3) Hz, 1H), 4.74 (dd, J = 12.0, 2.5 Hz, 1H), 4.50 (dd, J = 12.00, 6.4 Hz, 1H), 4.46 - 4.40 (m, 1H), 4.01 (q, J = 6.9 Hz) , 2H), 1.28 (t, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ 179.17, 166.58, 166.06, 165.39, 165.26, 162.05, 161.95, 157.28, 156.31, 147.58, 143.72, 137.84, 133.82, 133.74, 133.67, 133.39, 130.02, 129.98, 129.78, 129.22, 128.87, 128.64, 128.57, 128.51, 122.66, 122.41, 115.83, 115.32, 107.22, 99.60, 98.26, 95.35, 77.36, 72.85, 72.78, 71.61, 69.46, 69.03, 63.26.
实施例31：3-乙氧基-5-羟基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮(T-22)Example 31: 3-Ethoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid (T-22)
Figure PCTCN2014086933-appb-000035
Figure PCTCN2014086933-appb-000035
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-21(88mg，0.097mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.41M，0.29mmol)，室温搅拌30min。搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-22，收率92％。ESI-MSm/z:515.2[M+Na]+；1HNMR(400MHz,DMSO-d6)δ9.83(s,1H),9.40(br,1H),8.29(br,1H),7.60(d,J＝2.2Hz,1H),7.47(dd,J＝8.5,2.2Hz,1H),6.90(d,J＝8.5Hz,1H),6.75(d,J＝2.1Hz,1H),6.42(d,J＝2.1Hz,1H),5.41(br,1H),5.13(br,1H),5.06(d,J＝7.3Hz,2H),4.61(br,1H),4.11(br,1H),4.01(q,J＝7.0Hz,2H),3.73–3.65(m,1H),3.49–3.45(m,1H),3.30–3.23(m,2H),3.17(s,1H),1.26(t,J＝7.0Hz,3H)；13CNMR(101MHz,DMSO-d6)δ178.33,162.90,160.95,156.60,156.03,148.86,145.21,136.85,120.91,120.79,115.73,115.67,105.84,99.86,99.21,94.48,79.21,77.18,76.42,73.15,69.57,67.81,60.65,48.66,15.37。The preparation steps: T-21 (88 mg, 0.097 mmol) was taken in a reaction flask, and 4 mL of methanol and 1 mL of dichloromethane were added to dissolve, and sodium methoxide (0.41 M, 0.29 mmol) was slowly added and stirred at room temperature for 30 min. The cation exchange resin was added to the mixture to adjust the pH to 5-6, and the residue was purified by silica gel column chromatography. ESI-MS m/z: 515.2 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 9.40 (br, 1H), 8.29 (br, 1H), 7.60 (d, J=2.2 Hz, 1H), 7.47 (dd, J=8.5, 2.2 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 6.75 (d, J=2.1 Hz, 1H), 6.42 (d, J=2.1 Hz, 1H), 5.41 (br, 1H), 5.13 (br, 1H), 5.06 (d, J = 7.3 Hz, 2H), 4.61 (br, 1H), 4.11 (br, 1H), 4.01 ( q, J = 7.0 Hz, 2H), 3.73 - 3.65 (m, 1H), 3.49 - 3.45 (m, 1H), 3.30 - 3.23 (m, 2H), 3.17 (s, 1H), 1.26 (t, J = 7.0 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 178.33, 162.90, 160.95, 156.60, 156.03, 148.86, 145.21, 136.85, 120.91, 120.79, 115.73, 115.67, 105.84, 99.86, 99.21, 94.48, 79.21, 77.18 , 76.42, 73.15, 69.57, 67.81, 60.65, 48.66, 15.37.
实施例32：3-丙氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-23)Example 32: 3-propoxy-5-hydroxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid (T-23)
Figure PCTCN2014086933-appb-000036
Figure PCTCN2014086933-appb-000036
反应试剂与条件：(i)K2CO3，TBAI，CHCl3/DMF/H2O，45℃。Reagents and conditions: (i) K 2 CO 3 , TBAI, CHCl 3 /DMF/H 2 O, 45 ° C.
制备步骤：取M-17(337mg，0.66mmol)、TBAI(24.4mg，0.066mmol)和碳酸钾(641mg，4.64mmol)混合于反应瓶中，加入7.5mLDMF和7.5mL水，室温搅拌15min，缓慢加入用15mL氯仿溶解的S-02(1.75g，2.65mmol)， 45℃搅拌48h后，反应液用乙酸乙酯和水分散，萃取，有机层以水洗涤，无水硫酸镁干燥，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-23，收率63％。ESI-MSm/z:1109.3[M+Na]+；1HNMR(400MHz,CDCl3)δ12.66(s,1H),7.99–7.93(m,6H),7.90–7.86(m,2H),7.65–7.57(m,6H),7.55–7.44(m,3H),7.42–7.37(m,9H),7.37–7.30(m,4H),7.25–7.21(m,2H),6.95(d,J＝8.3Hz,1H),6.53(d,J＝2.2Hz,1H),6.50(d,J＝2.2Hz,1H),6.01(t,J＝9.2Hz,1H),5.82(dd,J＝9.2,7.4Hz,1H),5.74(t,J＝9.4Hz,1H),5.57(d,J＝7.4Hz,1H),4.74(d,J＝9.5Hz,1H),4.50–4.40(m,2H),3.98–3.87(m,2H),1.79–1.68(m,2H),0.95(t,J＝7.4Hz,3H)；13CNMR(101MHz,CDCl3)δ178.93,166.08,165.66,165.16,164.94,162.20,161.78,156.18,149.37,147.41,139.73,139.70,138.22,133.62,133.47,133.40,133.07,129.88,129.82,129.79,129.59,129.33,129.18,128.80,128.60,128.53,128.48,128.44,128.37,128.34,128.29,126.19,124.08,123.90,108.79,108.46,107.29,99.37,98.17,95.00,74.55,72.94,72.53,71.37,69.20,63.01,23.30,10.38。Preparation steps: M-17 (337 mg, 0.66 mmol), TBAI (24.4 mg, 0.066 mmol) and potassium carbonate (641 mg, 4.64 mmol) were mixed in a reaction flask, and 7.5 mL of DMF and 7.5 mL of water were added, and stirred at room temperature for 15 min, slowly. After adding S-02 (1.75 g, 2.65 mmol) dissolved in 15 mL of chloroform, and stirring at 45 ° C for 48 h, the reaction mixture was taken with ethyl acetate and water. The ethyl acetate was evaporated to dryness. ESI-MS m/z: 1109.3 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 12.66 (s, 1H), 7.99 - 7.93 (m, 6H), 7.90 - 7.86 (m, 2H), 7.65 – 7.57 (m, 6H), 7.55–7.44 (m, 3H), 7.42–7.37 (m, 9H), 7.37–7.30 (m, 4H), 7.25–7.21 (m, 2H), 6.95 (d, J= 8.3 Hz, 1H), 6.53 (d, J = 2.2 Hz, 1H), 6.50 (d, J = 2.2 Hz, 1H), 6.01 (t, J = 9.2 Hz, 1H), 5.82 (dd, J = 9.2, 7.4 Hz, 1H), 5.74 (t, J = 9.4 Hz, 1H), 5.57 (d, J = 7.4 Hz, 1H), 4.74 (d, J = 9.5 Hz, 1H), 4.50 - 4.40 (m, 2H) , 3.98–3.87 (m, 2H), 1.79–1.68 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13 CNMR (101 MHz, CDCl 3 ) δ 178.93, 166.08, 165.66, 165.16, 164.94, 162.20 , 161.78, 156.18, 149.37, 147.41, 139.73, 139.70, 138.22, 133.62, 133.47, 133.40, 133.07, 129.88, 129.82, 129.79, 129.59, 129.33, 129.18, 128.80, 128.60, 128.53, 128.48, 128.44, 128.37, 128.34, 128.29 , 126.19, 124.08, 123.90, 108.79, 108.46, 107.29, 99.37, 98.17, 95.00, 74.55, 72.94, 72.53, 71.37, 69.20, 63.01, 23.30, 10.38.
实施例33：3-丙氧基-5-羟基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-24)Example 33: 3-propoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-24)
Figure PCTCN2014086933-appb-000037
Figure PCTCN2014086933-appb-000037
反应试剂与条件：(i)10％Pd/C，H2，CH3OH/THF/H2O，室温。Reaction reagents and conditions: (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
制备步骤：取T-23(219mg，0.20mmol)于反应瓶中，加入60mL甲醇、15mL四氢呋喃和0.75mL水溶解，加入10％Pd/C(219mg)，室温常压氢解反应48h后，过滤去除钯碳，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-24，收率48.9％。ESI-MSm/z:945.3[M+Na]+；1HNMR(400MHz,CDCl3)δ12.58(s,1H),7.99–7.86(m,8H),7.69(s,1H),7.54–7.48(m,3H),7.47–7.39(m,2H),7.38–7.27(m,8H),6.97(d,J＝8.4Hz,1H),6.44(s,2H),6.02(t,J＝9.2Hz,1H),5.81(dd,J＝8.8,7.2Hz,1H),5.79–5.74(m,1H),5.53(d,J＝7.3Hz,1H),4.74(dd,J＝12.0,2.6Hz,1H),4.50(dd,J＝12.0,6.4Hz,1H),4.46–4.38(m,1H),3.89(t,J＝6.9Hz,2H),1.75–1.65(m,2H),0.88(t,J＝7.4Hz,3H)。Preparation steps: Take T-23 (219mg, 0.20mmol) in a reaction flask, add 60mL methanol, 15mL tetrahydrofuran and 0.75mL water to dissolve, add 10% Pd / C (219mg), hydrogenolysis reaction at room temperature for 48h, filter The palladium on carbon was removed, and the solvent was evaporated to dryness. ESI-MS m/z: 945.3 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 12.58 (s, 1H), 7.99 - 7.86 (m, 8H), 7.69 (s, 1H), 7.54 - 7.48 (m, 3H), 7.47 - 7.39 (m, 2H), 7.38 - 7.27 (m, 8H), 6.97 (d, J = 8.4 Hz, 1H), 6.44 (s, 2H), 6.02 (t, J = 9.2 Hz, 1H), 5.81 (dd, J = 8.8, 7.2 Hz, 1H), 5.79 - 5.74 (m, 1H), 5.53 (d, J = 7.3 Hz, 1H), 4.74 (dd, J = 12.0, 2.6 Hz) , 1H), 4.50 (dd, J = 12.0, 6.4 Hz, 1H), 4.46 - 4.38 (m, 1H), 3.89 (t, J = 6.9 Hz, 2H), 1.75 - 1.65 (m, 2H), 0.88 ( t, J = 7.4 Hz, 3H).
实施例34：3-丙氧基-5-羟基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮(T-25) Example 34: 3-propoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid (T-25)
Figure PCTCN2014086933-appb-000038
Figure PCTCN2014086933-appb-000038
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-24(75mg，0.081mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.58mL，0.41M，0.24mmol)，室温搅拌30min。搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-25，收率63％。ESI-MSm/z:529.2[M+Na]+；1HNMR(400MHz,DMSO-d6)δ12.72(s,1H),8.29(s,1H),7.55(d,J＝2.2Hz,1H),7.45(dd,J＝8.5,2.2Hz,1H),6.89(d,J＝8.5Hz,1H),6.74(d,J＝1.9Hz,1H),6.42(d,J＝2.0Hz,1H),5.05(d,J＝7.4Hz,2H),4.63(s,1H),3.89(t,J＝6.6Hz,2H),3.72–3.64(m,1H),3.51–3.48(m,2H),3.29–3.22(m,2H),3.18–3.12(m,1H),1.65(h,J＝7.3Hz,2H),0.89(t,J＝7.4Hz,3H)；13CNMR(101MHz,DMSO-d6)δ178.29,162.91,160.98,156.68,156.07,148.88,145.24,137.06,120.88,115.84,115.64,105.91,99.89,99.24,94.51,79.23,77.20,76.44,73.73,73.17,69.61,60.67,48.69,22.85,10.46。Preparation: Take T-24 (75 mg, 0.081 mmol) in a reaction flask, add 4 mL of methanol and 1 mL of dichloromethane to dissolve, slowly add sodium methoxide (0.58 mL, 0.41 M, 0.24 mmol) and stir at room temperature for 30 min. The cation exchange resin was added thereto under stirring to adjust the pH to 5-6, and the filtrate was concentrated to dryness. ESI-MS m/z: 529.2 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 8.29 (s, 1H), 7.55 (d, J = 2.2 Hz, 1H) , 7.45 (dd, J = 8.5, 2.2 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 1.9 Hz, 1H), 6.42 (d, J = 2.0 Hz, 1H) , 5.05 (d, J = 7.4 Hz, 2H), 4.63 (s, 1H), 3.89 (t, J = 6.6 Hz, 2H), 3.72 - 3.64 (m, 1H), 3.51 - 3.48 (m, 2H), 3.29–3.22 (m, 2H), 3.18–3.12 (m, 1H), 1.65 (h, J = 7.3 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H); 13 CNMR (101 MHz, DMSO-d6) ) δ 178.29, 162.91, 160.98, 156.68, 156.07, 148.88, 145.24, 137.06, 120.88, 115.84, 115.64, 105.91, 99.89, 99.24, 94.51, 79.23, 77.20, 76.44, 73.73, 73.17, 69.61, 60.67, 48.69, 22.85, 10.46 .
实施例35：3-丙氧基-5-甲氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-26)Example 35: 3-propoxy-5-methoxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid (T-26)
Figure PCTCN2014086933-appb-000039
Figure PCTCN2014086933-appb-000039
反应试剂与条件：(i)CH3I，K2CO3，DMF，室温。Reaction reagents and conditions: (i) CH 3 I, K 2 CO 3 , DMF, room temperature.
制备步骤：取T-23(771mg，0.709mmol)和碳酸钾(147mg，1.06mmol)混合于反应瓶中，同时加入8mLDMF和CH3I(65μL，149mg，1.06mmol)，室温反应12h，所得反应液用乙酸乙酯和水分散，萃取，有机层以水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-26，收率70％。ESI-MSm/z:1123.2[M+Na]+；1HNMR(400 MHz,CDCl3)δ8.00–7.93(m,4H),7.91–7.85(m,4H),7.63–7.57(m,5H),7.56–7.50(m,3H),7.50–7.44(m,1H),7.44–7.36(m,10H),7.33(t,J＝7.8Hz,2H),7.21–7.16(m,1H),7.07(t,J＝7.7Hz,2H),6.92(d,J＝8.3Hz,1H),6.62(d,J＝2.2Hz,1H),6.37(d,J＝2.2Hz,1H),6.02(t,J＝9.2Hz,1H),5.83(dd,J＝9.1,7.3Hz,1H),5.76(t,J＝9.2Hz,1H),5.61(d,J＝7.3Hz,1H),4.80–4.73(m,1H),4.52–4.45(m,2H),4.02–3.88(m,2H),3.82(s,3H),1.79–1.69(m,2H),0.94(t,J＝7.4Hz,3H)；13CNMR(101MHz,CDCl3)δ173.81,166.01,165.58,165.11,164.95,161.10,160.18,158.00,152.64,148.67,147.20,140.29,139.81,139.74,133.58,133.49,133.36,133.00,129.96,129.80,129.76,129.71,129.30,129.20,128.99,128.70,128.49,128.42,128.40,128.30,128.25,128.09,126.14,124.46,123.25,117.52,110.67,108.53,108.24,98.01,96.87,95.36,77.12,73.89,72.86,72.38,71.34,69.18,62.94,56.36,23.28,10.31.。Preparation step: T-23 (771 mg, 0.709 mmol) and potassium carbonate (147 mg, 1.06 mmol) were mixed in a reaction flask, and 8 mL of DMF and CH 3 I (65 μL, 149 mg, 1.06 mmol) were added, and reacted at room temperature for 12 h. The liquid was dispersed with ethyl acetate and water, and the mixture was evaporated. EtOAcjjjjjjjjjjjjj -26, the yield is 70%. ESI-MS m/z: 1123.2 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 - 7.93 (m, 4H), 7.91 - 7.85 (m, 4H), 7.63 - 7.57 (m, 5H) ), 7.56–7.50 (m, 3H), 7.50–7.44 (m, 1H), 7.44–7.36 (m, 10H), 7.33 (t, J = 7.8 Hz, 2H), 7.21–7.16 (m, 1H), 7.07 (t, J = 7.7 Hz, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 2.2 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H), 6.02 ( t, J = 9.2 Hz, 1H), 5.83 (dd, J = 9.1, 7.3 Hz, 1H), 5.76 (t, J = 9.2 Hz, 1H), 5.61 (d, J = 7.3 Hz, 1H), 4.80 - 4.73 (m, 1H), 4.52 - 4.45 (m, 2H), 4.02 - 3.88 (m, 2H), 3.82 (s, 3H), 1.79 - 1.69 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13 CNMR (101MHz, CDCl 3 ) δ 173.81, 166.01, 165.58, 165.11, 164.95, 161.10, 160.18, 158.00, 152.64, 148.67, 147.20, 140.29, 139.81, 139.74, 133.58, 133.49, 133.36, 133.00, 129.96, 129.80 , 129.76, 129.71, 129.30, 129.20, 128.99, 128.70, 128.49, 128.42, 128.40, 128.30, 128.25, 128.09, 126.14, 124.46, 123.25, 117.52, 110.67, 108.53, 108.24, 98.01, 96.87, 95.36, 77.12, 73.89, 72.86 , 72.38, 71.34, 69.18, 62.94, 56.36, 23.28, 10.31.
实施例36：3-丙氧基-5-甲氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-27)Example 36: 3-propoxy-5-methoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-27)
Figure PCTCN2014086933-appb-000040
Figure PCTCN2014086933-appb-000040
反应试剂与条件：(i)10％Pd/C，H2，CH3OH/THF/H2O，室温。Reaction reagents and conditions: (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
制备步骤：取T-26(319mg，0.084mmol)于反应瓶中，加入90mL甲醇、22.5mL四氢呋喃和0.9mL水溶解，加入10％Pd/C(319mg)，室温常压氢解反应48h后，过滤去除钯碳，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-27，收率68％。ESI-MSm/z:959.3[M+Na]+；1HNMR(400MHz,CDCl3)δ8.00–7.86(m,9H),7.80(d,J＝2.1Hz,1H),7.56–7.44(m,3H),7.42(dd,J＝8.5,2.1Hz,1H),7.40–7.29(m,7H),7.17(dd,J＝10.8,4.9Hz,2H),7.09(d,J＝5.5Hz,1H),6.98(d,J＝8.5Hz,1H),6.66(d,J＝2.2Hz,1H),6.37(d,J＝2.2Hz,1H),6.03(t,J＝9.1Hz,1H),5.82(dd,J＝9.0,7.2Hz,1H),5.79(t,J＝9.9Hz,1H),5.63(d,J＝7.2Hz,1H),4.74(dd,J＝11.9,2.7Hz,1H),4.57–4.45(m,2H),3.88–3.83(m,2H),3.81(s,3H),1.68–1.56(m,2H),0.78(t,J＝7.4Hz,3H).Preparation steps: Take T-26 (319mg, 0.084mmol) in a reaction flask, add 90mL methanol, 22.5mL tetrahydrofuran and 0.9mL water to dissolve, add 10% Pd / C (319mg), room temperature atmospheric pressure hydrogenolysis reaction for 48h, The palladium carbon was removed by filtration, and the solvent was evaporated to dryness. ESI-MS m/z: 959.3 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 - 7.86 (m, 9H), 7.80 (d, J = 2.1 Hz, 1H), 7.56 - 7.44 (m) , 3H), 7.42 (dd, J = 8.5, 2.1 Hz, 1H), 7.40 - 7.29 (m, 7H), 7.17 (dd, J = 10.8, 4.9 Hz, 2H), 7.09 (d, J = 5.5 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.66 (d, J = 2.2 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H), 6.03 (t, J = 9.1 Hz, 1H) , 5.82 (dd, J = 9.0, 7.2 Hz, 1H), 5.79 (t, J = 9.9 Hz, 1H), 5.63 (d, J = 7.2 Hz, 1H), 4.74 (dd, J = 11.9, 2.7 Hz, 1H), 4.57–4.45 (m, 2H), 3.88–3.83 (m, 2H), 3.81 (s, 3H), 1.68–1.56 (m, 2H), 0.78 (t, J = 7.4 Hz, 3H).
实施例37：3-丙氧基-5-甲氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮(T-28) Example 37: 3-propoxy-5-methoxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid (T-28)
Figure PCTCN2014086933-appb-000041
Figure PCTCN2014086933-appb-000041
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-27(58mg，0.062mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.44mL，0.41M，0.18mmol)，室温搅拌30min后，搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-28，收率73％。ESI-MSm/z:543.2[M+Na]+；1HNMR(400MHz,CD3OD)δ7.59(d,J＝1.6Hz,1H),7.52(d,J＝8.4Hz,1H),6.88(d,J＝8.4Hz,1H),6.83(s,1H),6.66(s,1H),5.11–5.06(m,1H),4.60(s,2H),3.95(dd,J＝12.1,1.8Hz,1H),3.92(s,3H),3.85(t,J＝6.7Hz,2H),3.70(dd,J＝12.1,6.4Hz,1H),3.60–3.54(m,1H),3.54–3.50(m,2H),3.42–3.36(m,1H),1.79–1.68(m,2H),0.96(t,J＝7.4Hz,3H)；13CNMR(101MHz,CD3OD)δ176.15,163.57,162.04,159.69,156.16,149.46,146.25,140.82,123.10,122.33,116.58,116.19,110.58,101.77,97.97,97.25,78.52,77.88,75.21,74.76,71.44,62.58,56.66,24.29,10.86。Preparation step: Take T-27 (58mg, 0.062mmol) in a reaction flask, add 4mL methanol and 1mL dichloromethane to dissolve, slowly add sodium methoxide (0.44mL, 0.41M, 0.18mmol), stir at room temperature for 30min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated to dryness. ESI-MS m/z: 543.2 [M+Na] + ; 1 H NMR (400 MHz, CD 3 OD) δ 7.59 (d, J = 1.6 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 6.66 (s, 1H), 5.11 - 5.06 (m, 1H), 4.60 (s, 2H), 3.95 (dd, J = 12.1, 1.8) Hz, 1H), 3.92 (s, 3H), 3.85 (t, J = 6.7 Hz, 2H), 3.70 (dd, J = 12.1, 6.4 Hz, 1H), 3.60 - 3.54 (m, 1H), 3.54 - 3.50 (m, 2H), 3.42 - 3.36 (m, 1H), 1.79 - 1.68 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13 CNMR (101 MHz, CD 3 OD) δ 176.15, 163.57, 162.04 , 159.69, 156.16, 149.46, 146.25, 140.82, 123.10, 122.33, 116.58, 116.19, 110.58, 101.77, 97.97, 97.25, 78.52, 77.88, 75.21, 74.76, 71.44, 62.58, 56.66, 24.29, 10.86.
实施例38：3-丙氧基-5-甲氧基-3'-二羟基-4'-羟丙氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-29)Example 38: 3-propoxy-5-methoxy-3'-dihydroxy-4'-hydroxypropoxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-29)
Figure PCTCN2014086933-appb-000042
Figure PCTCN2014086933-appb-000042
反应试剂与条件：(i)BrCH2CH2CH2OH，K2CO3，DMF，室温；(ii)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) BrCH 2 CH 2 CH 2 OH, K 2 CO 3 , DMF, room temperature; (ii) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：(i)取T-27(127mg，0.135mmol)和碳酸钾(22mg，0.162mmol) 混合于反应瓶中，同时加入4mLDMF和BrCH2CH2CH2OH(22.6mg，0.162mmol)，室温反应15h，所得反应液用乙酸乙酯和水分散，萃取，所得有机层依次以稀盐酸、水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得黄色油状物T-29-M(85mg，收率63％)；(ii)取T-29-M(74mg，0.074mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.41M，0.15mmol)，室温搅拌30min。搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-30，收率70％。ESI-MSm/z:601.1[M+Na]+；1HNMR(400MHz,CD3OD)δ8.49(s,1H),7.88(s,1H),7.58(d,J＝1.9Hz,1H),7.51(dd,J＝8.4,2.0Hz,1H),6.90–6.80(m,2H),6.66(d,J＝2.0Hz,1H),5.09–5.05(m,1H),3.91(s,3H),3.84(t,J＝6.7Hz,2H),3.71–3.64(m,1H),3.58–3.52(m,1H),3.49(m,2H),3.40–3.33(m,2H),1.77–1.67(m,2H),0.94(t,J＝7.4Hz,3H)；13CNMR(101MHz,CD3OD)δ176.18,163.62,162.08,159.74,156.23,149.51,146.29,140.83,123.10,122.32,116.58,116.20,110.59,101.77,97.98,97.25,78.53,77.87,75.22,74.75,71.43,62.58,56.67,24.30,10.87。Preparation step: (i) T-27 (127 mg, 0.135 mmol) and potassium carbonate (22 mg, 0.162 mmol) were mixed in a reaction flask while 4 mL of DMF and BrCH 2 CH 2 CH 2 OH (22.6 mg, 0.162 mmol) were added. The reaction mixture was stirred at room temperature for 15 h. Purification by column chromatography gave EtOAc (EtOAc: EtOAc (EtOAc) Methane was dissolved, sodium methoxide (0.41 M, 0.15 mmol) was slowly added and stirred at room temperature for 30 min. The cation exchange resin was added thereto under stirring to adjust the pH to 5-6, and the filtrate was concentrated to dryness. ESI-MS m/z: 601.1 [M+Na] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.49 (s, 1H), 7.78 (s, 1H), 7.58 (d, J = 1.9 Hz, 1H) , 7.51 (dd, J = 8.4, 2.0 Hz, 1H), 6.90 - 6.80 (m, 2H), 6.66 (d, J = 2.0 Hz, 1H), 5.09 - 5.05 (m, 1H), 3.91 (s, 3H) ), 3.84 (t, J = 6.7 Hz, 2H), 3.71 - 3.64 (m, 1H), 3.58 - 3.52 (m, 1H), 3.49 (m, 2H), 3.40 - 3.33 (m, 2H), 1.77 - 1.67 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13 CNMR (101 MHz, CD 3 OD) δ 176.18, 163.62, 162.08, 159.74, 156.23, 149.51, 146.29, 140.83, 123.10, 122.32, 116.58, 116.20, 110.59, 101.77, 97.98, 97.25, 78.53, 77.87, 75.22, 74.75, 71.43, 62.58, 56.67, 24.30, 10.87.
实施例39：3-异丁氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-30)Example 39: 3-Isobutoxy-5-hydroxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid (T-30)
Figure PCTCN2014086933-appb-000043
Figure PCTCN2014086933-appb-000043
反应试剂与条件：(i)K2CO3，TBAI，CHCl3/DMF/H2O，45℃。Reagents and conditions: (i) K 2 CO 3 , TBAI, CHCl 3 /DMF/H 2 O, 45 ° C.
制备步骤：取前述合成中间体M--14(1.08g，2.07mmol)、TBAI(74mg，0.20mmol)和碳酸钾(2.0g，14mmol)混合于反应瓶中，加入DMF(25mL)和25mL水，室温搅拌15min，缓慢加入用50mL氯仿溶解的中间体S-02(5.54g，8.27mmol)，45℃搅拌48h后，反应液用乙酸乙酯和水分散，萃取，所得有机层水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-30，收率52％。ESI-MSm/z:1123.3[M+Na]+；1HNMR(500MHz,CDCl3)δ8.00–7.92(m,7H),7.90–7.84(m,2H), 7.61–7.44(m,10H),7.41–7.30(m,15H),7.24(s,2H),6.94(d,J＝10.0Hz,1H),6.53(s,1H),6.50(s,1H),6.00(t,J＝8.8Hz,1H),5.81(t,J＝7.6Hz,1H),5.74(t,J＝9.2Hz,1H),5.56(d,J＝6.2Hz,1H),4.73(d,J＝11.5Hz,1H),4.52–4.38(m,2H),3.80–3.63(m,2H),2.09–1.97(m,1H),0.96(d,J＝5.7Hz,6H)；13CNMR(125MHz,CDCl3)δ178.91,166.11,165.69,165.18,164.97,162.25,161.80,156.22,149.40,147.40,139.75,139.72,138.40,133.63,133.49,133.42,133.09,129.90,129.85,129.81,129.62,129.35,129.21,128.84,128.63,128.57,128.50,128.46,128.39,128.35,128.32,126.22,124.04,123.95,117.89,108.94,108.43,107.37,99.38,98.23,95.03,79.24,72.97,72.56,71.40,69.23,63.04,28.99,19.18。Preparation step: The above synthetic intermediate M--14 (1.08 g, 2.07 mmol), TBAI (74 mg, 0.20 mmol) and potassium carbonate (2.0 g, 14 mmol) were mixed in a reaction flask, and DMF (25 mL) and 25 mL of water were added. After stirring at room temperature for 15 min, the intermediate S-02 (5.54 g, 8.27 mmol) dissolved in 50 mL of chloroform was slowly added, and the mixture was stirred at 45 ° C for 48 h. The residue was purified by silica gel column chromatography eluting elut elut elut eluting ESI-MS m/z: 1123.3 [M+Na] + ; 1 H NMR (500 MHz, CDCl 3 ) δ 8.00 - 7.92 (m, 7H), 7.90 - 7.84 (m, 2H), 7.61 - 7.44 (m, 10H) , 7.41 - 7.30 (m, 15H), 7.24 (s, 2H), 6.94 (d, J = 10.0 Hz, 1H), 6.53 (s, 1H), 6.50 (s, 1H), 6.00 (t, J = 8.8 Hz, 1H), 5.81 (t, J = 7.6 Hz, 1H), 5.74 (t, J = 9.2 Hz, 1H), 5.56 (d, J = 6.2 Hz, 1H), 4.73 (d, J = 11.5 Hz, 1H), 4.52–4.38 (m, 2H), 3.80–3.63 (m, 2H), 2.09–1.97 (m, 1H), 0.96 (d, J=5.7 Hz, 6H); 13 CNMR (125 MHz, CDCl 3 ) Δ178.91,166.11,165.69,165.18,164.97,162.25,161.80,156.22,149.40,147.40,139.75,139.72,138.40,133.63,133.49,133.42,133.09,129.90,129.85,129.81,129.62,129.35,129.21,128.84,128.63, 128.57, 128.50, 128.46, 128.39, 128.35, 128.32, 126.22, 124.04, 123.95, 117.89, 108.94, 108.43, 107.37, 99.38, 98.23, 95.03, 79.24, 72.97, 72.56, 71.40, 69.23, 63.04, 28.99, 19.18.
实施例40：3-异丁氧基-5-羟基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-31)Example 40: 3-Isobutoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-31)
Figure PCTCN2014086933-appb-000044
Figure PCTCN2014086933-appb-000044
反应试剂与条件：(i)10％Pd/C，H2，CH3OH/THF/H2O，室温。Reaction reagents and conditions: (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
制备步骤：取T-30(700mg，0.63mmol)于反应瓶中，加入120mL甲醇、30mL四氢呋喃和1.5mL水溶解，加入10％Pd/C(720mg)，室温常压氢解反应48h，过滤去除钯碳，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T--31，收率84％。ESI-MSm/z:959.3[M+Na]+；1HNMR(400MHz,CDCl3)δ12.61(s,1H),8.01–7.91(m,6H),7.88(dd,J＝8.3,1.2Hz,2H),7.61(d,J＝1.9Hz,1H),7.55–7.47(m,3H),7.47–7.40(m,2H),7.39–7.32(m,5H),7.32–7.27(m,3H),6.96(d,J＝8.5Hz,1H),6.87(br,1H),6.65(br,1H),6.44(d,J＝2.2Hz,1H),6.42(d,J＝2.2Hz,1H),6.01(t,J＝9.2Hz,1H),5.81(dd,J＝9.2,7.5Hz,1H),5.76(t,J＝9.9Hz,1H),5.51(d,J＝7.4Hz,1H),4.74(dd,J＝12.1,2.8Hz,1H),4.50(dd,J＝12.1,6.4Hz,1H),4.45–4.35(m,1H),3.68(d,J＝6.6Hz,2H),2.04–1.95(m,1H),0.91(d,J＝6.7Hz,6H)。Preparation steps: Take T-30 (700mg, 0.63mmol) in a reaction flask, add 120mL methanol, 30mL tetrahydrofuran and 1.5mL water to dissolve, add 10% Pd / C (720mg), hydrogen sulfide reaction at room temperature for 48h, filter to remove Palladium on carbon, and the solvent was evaporated to dryness. ESI-MS m/z: 959.3 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 12.61 (s, 1H), 8.01 - 7.91 (m, 6H), 7.88 (dd, J = 8.3, 1.2 Hz , 2H), 7.61 (d, J = 1.9 Hz, 1H), 7.55 - 7.47 (m, 3H), 7.47 - 7.40 (m, 2H), 7.39 - 7.32 (m, 5H), 7.32 - 7.27 (m, 3H) ), 6.96 (d, J = 8.5 Hz, 1H), 6.87 (br, 1H), 6.65 (br, 1H), 6.44 (d, J = 2.2 Hz, 1H), 6.42 (d, J = 2.2 Hz, 1H) ), 6.01 (t, J = 9.2 Hz, 1H), 5.81 (dd, J = 9.2, 7.5 Hz, 1H), 5.76 (t, J = 9.9 Hz, 1H), 5.51 (d, J = 7.4 Hz, 1H) ), 4.74 (dd, J = 12.1, 2.8 Hz, 1H), 4.50 (dd, J = 12.1, 6.4 Hz, 1H), 4.45 - 4.35 (m, 1H), 3.68 (d, J = 6.6 Hz, 2H) , 2.04 - 1.95 (m, 1H), 0.91 (d, J = 6.7 Hz, 6H).
实施例41：3-异丁氧基-5-羟基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮(T-32) Example 41: 3-Isobutoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid (T-32)
Figure PCTCN2014086933-appb-000045
Figure PCTCN2014086933-appb-000045
反应试剂与条件：(i)CH3ONa，CH3OH-CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH-CH 2 Cl 2 , room temperature.
制备步骤：取T-31(100mg，0.107mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.78mL，0.41M，0.32mmol)，室温搅拌30min后，搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-32，收率68％。ESI-MSm/z:543.3[M+Na]+；1HNMR(400MHz,DMSO-d6)δ12.67(s,1H),7.45(d,J＝2.1Hz,1H),7.37(dd,J＝8.4,2.1Hz,1H),6.84(d,J＝8.4Hz,1H),6.69(d,J＝1.3Hz,1H),6.37(d,J＝1.5Hz,1H),5.40(br,1H),5.08(br,1H),5.00(d,J＝7.3Hz,2H),4.60(br,1H),3.64(d,J＝6.5Hz,3H),3.56(s,2H),3.28–3.16(m,3H),3.11(t,J＝8.8Hz,1H),1.96–1.80(m,1H),0.85(d,J＝6.7Hz,6H)。Preparation step: Take T-31 (100 mg, 0.107 mmol) in a reaction flask, add 4 mL of methanol and 1 mL of dichloromethane to dissolve, slowly add sodium methoxide (0.78 mL, 0.41 M, 0.32 mmol), stir at room temperature for 30 min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated to dryness. ESI-MS m/z: 543.3 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.37 (dd, J = 8.4, 2.1 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 1.3 Hz, 1H), 6.37 (d, J = 1.5 Hz, 1H), 5.40 (br, 1H) , 5.08 (br, 1H), 5.00 (d, J = 7.3 Hz, 2H), 4.60 (br, 1H), 3.64 (d, J = 6.5 Hz, 3H), 3.56 (s, 2H), 3.28 - 3.16 ( m, 3H), 3.11 (t, J = 8.8 Hz, 1H), 1.96 - 1.80 (m, 1H), 0.85 (d, J = 6.7 Hz, 6H).
实施例42：3-异丁氧基-5,3',4'-三甲氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-33)Example 42: 3-Isobutoxy-5,3',4'-trimethoxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-33)
Figure PCTCN2014086933-appb-000046
Figure PCTCN2014086933-appb-000046
反应试剂与条件：(i)CH3I，K2CO3，DMF，室温。Reaction reagents and conditions: (i) CH 3 I, K 2 CO 3 , DMF, room temperature.
制备步骤：取T-32(120mg，0.128mmol)和碳酸钾(177mg，1.28mmol)混合于反应瓶中，同时加入4mLDMF和CH3I(48μL，109mg，0.77mmol)，室温反应11h，反应液用乙酸乙酯和水分散，萃取，有机层依次以稀盐酸、水洗涤，无水硫酸镁干燥，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-33，收率47％。ESI-MSm/z:1001.3[M+Na]+；1HNMR(400MHz,CDCl3)δ8.00–7.93(m,4H),7.93–7.86(m,4H),7.63–7.57(m,2H),7.54(td,J＝7.5,1.2Hz,2H),7.50–7.45(m,1H),7.35(ddd,J＝13.4,11.4,6.7Hz,7H),7.18(t,J＝7.8Hz,2H),6.92(d,J＝8.6Hz,1H),6.66(d,J＝2.2Hz,1H),6.39(d,J＝2.2Hz,1H),6.03(t,J＝9.2Hz,1H),5.83(dd,J＝9.0,7.3Hz,1H),5.78(t,J＝9.4Hz,1H),4.80–4.72(m,1H),4.55–4.45(m,2H),3.96(s,3H),3.91(s,3H),3.83(s, 3H),3.80(dd,J＝8.8,6.7Hz,1H),3.73(dd,J＝8.8,6.7Hz,1H),2.11–1.99(m,1H),0.97(d,J＝2.1Hz,3H),0.95(d,J＝2.1Hz,3H)。Preparation step: T-32 (120 mg, 0.128 mmol) and potassium carbonate (177 mg, 1.28 mmol) were mixed in a reaction flask, and 4 mL of DMF and CH 3 I (48 μL, 109 mg, 0.77 mmol) were added, and the reaction was carried out for 11 h at room temperature. Dissolve with ethyl acetate and water, extract, and the organic layer is washed with EtOAc EtOAc. T-33, yield 47%. ESI-MS m/z: 1001.3 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 - 7.93 (m, 4H), 7.93 - 7.86 (m, 4H), 7.63 - 7.57 (m, 2H) , 7.54 (td, J = 7.5, 1.2 Hz, 2H), 7.50 - 7.45 (m, 1H), 7.35 (ddd, J = 13.4, 11.4, 6.7 Hz, 7H), 7.18 (t, J = 7.8 Hz, 2H) ), 6.92 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 2.2 Hz, 1H), 6.39 (d, J = 2.2 Hz, 1H), 6.03 (t, J = 9.2 Hz, 1H), 5.83 (dd, J=9.0, 7.3 Hz, 1H), 5.78 (t, J=9.4 Hz, 1H), 4.80–4.72 (m, 1H), 4.55–4.45 (m, 2H), 3.96 (s, 3H) , 3.91 (s, 3H), 3.83 (s, 3H), 3.80 (dd, J = 8.8, 6.7 Hz, 1H), 3.73 (dd, J = 8.8, 6.7 Hz, 1H), 2.11 - 1.99 (m, 1H) ), 0.97 (d, J = 2.1 Hz, 3H), 0.95 (d, J = 2.1 Hz, 3H).
实施例43：3-异丁氧基-5,3',4'-三甲氧基-7-O-β-D-葡萄糖基-黄酮(T-34)Example 43: 3-Isobutoxy-5,3',4'-trimethoxy-7-O-β-D-glucosyl-flavonoid (T-34)
Figure PCTCN2014086933-appb-000047
Figure PCTCN2014086933-appb-000047
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-33(49mg，0.050mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.41M，0.15mmol)，室温搅拌30min后，搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-34，收率78％。ESI-MSm/z:585.2[M+Na]+；1HNMR(400MHz,DMSO-d6)δ7.64(dd,J＝8.5,2.1Hz,1H),7.60(d,J＝2.1Hz,1H),7.11(d,J＝8.7Hz,1H),6.86(d,J＝2.2Hz,1H),6.57(d,J＝2.2Hz,1H),5.43(d,J＝4.8Hz,1H),5.18(d,J＝4.6Hz,1H),5.11(d,J＝5.3Hz,1H),5.07(d,J＝7.3Hz,1H),4.69(t,J＝5.5Hz,1H),3.84(s,3H),3.83(s,3H),3.81(s,3H),3.75–3.68(m,1H),3.65(d,J＝6.6Hz,2H),3.49–3.44(m,2H),3.32–3.24(m,2H),3.18–3.09(m,1H),2.00–1.86(m,1H),0.89(d,J＝6.7Hz,6H)；13CNMR(101MHz,DMSO-d6)δ172.29,161.47,160.33,157.77,152.05,150.70,148.31,139.69,122.65,121.64,111.42,111.35,109.17,100.02,96.80,95.96,77.95,77.47,76.65,73.21,69.86,60.79,56.13,55.67,55.61,30.77,28.68,19.20。Preparation step: Take T-33 (49mg, 0.050mmol) in a reaction flask, add 4mL methanol and 1mL dichloromethane to dissolve, slowly add sodium methoxide (0.41M, 0.15mmol), stir at room temperature for 30min, then add cation exchange with stirring The pH of the resin was adjusted to 5-6, and the filtrate was concentrated to dryness. ESI-MS m/z: 585.2 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (dd, J = 8.5, 2.1 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H) , 7.11 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.57 (d, J = 2.2 Hz, 1H), 5.43 (d, J = 4.8 Hz, 1H), 5.18 (d, J = 4.6 Hz, 1H), 5.11 (d, J = 5.3 Hz, 1H), 5.07 (d, J = 7.3 Hz, 1H), 4.69 (t, J = 5.5 Hz, 1H), 3.84 (s) , 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.75 - 3.68 (m, 1H), 3.65 (d, J = 6.6 Hz, 2H), 3.49 - 3.44 (m, 2H), 3.32 - 3.24 (m, 2H), 3.18 - 3.09 (m, 1H), 2.00 - 1.86 (m, 1H), 0.89 (d, J = 6.7 Hz, 6H); 13 CNMR (101 MHz, DMSO-d6) δ 172.29, 161.47, 160.33,157.77,152.05,150.70,148.31,139.69,122.65,121.64,111.42,111.35,109.17,100.02,96.80,95.96,77.95,77.47,76.65,73.21,69.86,60.79,56.13,55.67,55.61,30.77,28.68, 19.20.
实施例44：3-异丁氧基-5,3',4'-三正己氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-35)Example 44: 3-Isobutoxy-5,3',4'-tri-n-hexyloxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-35)
Figure PCTCN2014086933-appb-000048
Figure PCTCN2014086933-appb-000048
反应试剂与条件：(i)CH3CH2CH2CH2CH2CH2Br，K2CO3，DMF，室温。Reaction reagents and conditions: (i) CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 Br, K 2 CO 3 , DMF, room temperature.
制备步骤：取T-32(120mg，0.128mmol)和碳酸钾(124mg，0.90mmol)混 合于反应瓶中，同时加入4mLDMF和溴己烷(108μL，127mg，0.77mmol)，室温反应12h，反应液用乙酸乙酯和水分散，萃取，所得有机层依次以稀盐酸、水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-35，收率66％。ESI-MSm/z:1211.5[M+Na]+；1HNMR(400MHz,CDCl3)δ7.99–7.87(m,8H),7.61(d,J＝2.1Hz,1H),7.56–7.45(m,4H),7.41–7.31(m,7H),7.17(t,J＝7.8Hz,2H),6.89(d,J＝8.6Hz,1H),6.63(d,J＝2.2Hz,1H),6.36(d,J＝2.2Hz,1H),6.03(t,J＝9.2Hz,1H),5.82(dd,J＝9.1,7.3Hz,1H),5.77(t,J＝9.3Hz,1H),5.62(d,J＝7.3Hz,1H),4.74(dd,J＝11.5,2.3Hz,1H),4.54–4.43(m,2H),4.08–3.90(m,6H),3.78(dd,J＝8.8,6.8Hz,1H),3.69(dd,J＝8.8,6.8Hz,1H),2.10–1.98(m,1H),1.92–1.79(m,6H),1.54–1.41(m,6H),1.39–1.29(m,12H),0.95–0.87(m,15H)。Preparation steps: T-32 (120 mg, 0.128 mmol) and potassium carbonate (124 mg, 0.90 mmol) were mixed in a reaction flask, while 4 mL of DMF and bromohexane (108 μL, 127 mg, 0.77 mmol) were added, and reacted at room temperature for 12 h. Dissolve with ethyl acetate and water, and extract, and the organic layer is washed with EtOAc EtOAc. The oily target product T-35 was obtained in a yield of 66%. ESI-MS m/z: 1211.5 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 - 7.87 (m, 8H), 7.61 (d, J = 2.1 Hz, 1H), 7.56 - 7.45 (m) , 4H), 7.41 - 7.31 (m, 7H), 7.17 (t, J = 7.8 Hz, 2H), 6.89 (d, J = 8.6 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 6.36 (d, J = 2.2 Hz, 1H), 6.03 (t, J = 9.2 Hz, 1H), 5.82 (dd, J = 9.1, 7.3 Hz, 1H), 5.77 (t, J = 9.3 Hz, 1H), 5.62 (d, J = 7.3 Hz, 1H), 4.74 (dd, J = 11.5, 2.3 Hz, 1H), 4.54 - 4.43 (m, 2H), 4.08 - 3.90 (m, 6H), 3.78 (dd, J = 8.8 , 6.8 Hz, 1H), 3.69 (dd, J = 8.8, 6.8 Hz, 1H), 2.10–1.98 (m, 1H), 1.92–1.79 (m, 6H), 1.54–1.41 (m, 6H), 1.39– 1.29 (m, 12H), 0.95 - 0.87 (m, 15H).
实施例45：3-异丁氧基-5,3',4'-三正己氧氧基-7-O-β-D-葡萄糖基-黄酮(T-36)Example 45: 3-Isobutoxy-5,3',4'-tri-n-hexyloxy-7-O-β-D-glucosyl-flavonoid (T-36)
Figure PCTCN2014086933-appb-000049
Figure PCTCN2014086933-appb-000049
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-35(80mg，0.067mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.5mL，0.41M，0.20mmol)，室温搅拌30min后，搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-36，收率73％。ESI-MSm/z:795.4[M+Na]+；1HNMR(400MHz,DMSO-d6)δ7.61–7.55(m,2H),7.09(d,J＝8.5Hz,1H),6.81(d,J＝2.1Hz,1H),6.55(d,J＝2.2Hz,1H),5.41(d,J＝4.8Hz,1H),5.16(d,J＝4.7Hz,1H),5.09(d,J＝5.3Hz,1H),5.05(d,J＝7.3Hz,1H),4.65(t,J＝5.5Hz,1H),4.05–3.96(m,6H),3.70(dd,J＝9.7,5.3Hz,1H),3.65(d,J＝6.6Hz,2H),3.48–3.43(m,1H),3.32–3.24(m,3H),3.18–3.11(m,1H),1.98–1.86(m,1H),1.78–1.67(m,6H),1.51–1.39(m,6H),1.30(m,12H),0.99–0.74(m,15H)。Preparation steps: Take T-35 (80 mg, 0.067 mmol) in a reaction flask, add 4 mL of methanol and 1 mL of dichloromethane to dissolve, slowly add sodium methoxide (0.5 mL, 0.41 M, 0.20 mmol), stir at room temperature for 30 min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated to dryness. ESI-MS m/z: 795.4 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.61 - 7.55 (m, 2H), 7.09 (d, J = 8.5 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.55 (d, J = 2.2 Hz, 1H), 5.41 (d, J = 4.8 Hz, 1H), 5.16 (d, J = 4.7 Hz, 1H), 5.09 (d, J = 5.3 Hz, 1H), 5.05 (d, J = 7.3 Hz, 1H), 4.65 (t, J = 5.5 Hz, 1H), 4.05 - 3.96 (m, 6H), 3.70 (dd, J = 9.7, 5.3 Hz, 1H), 3.65 (d, J = 6.6 Hz, 2H), 3.48 - 3.43 (m, 1H), 3.32 - 3.24 (m, 3H), 3.18 - 3.11 (m, 1H), 1.98 - 1.86 (m, 1H) , 1.78–1.67 (m, 6H), 1.51–1.39 (m, 6H), 1.30 (m, 12H), 0.99–0.74 (m, 15H).
实施例46：3-异丁氧基-5,3',4'-三-(羟丙氧基)-7-O-β-D-苯甲酰基葡萄糖基-黄酮 (T-37)Example 46: 3-Isobutoxy-5,3',4'-tris-(hydroxypropoxy)-7-O-β-D-benzoyl glucosyl-flavonoid (T-37)
Figure PCTCN2014086933-appb-000050
Figure PCTCN2014086933-appb-000050
反应试剂与条件：(i)BrCH2CH2CH2OH，K2CO3，DMF，室温。Reaction reagents and conditions: (i) BrCH 2 CH 2 CH 2 OH, K 2 CO 3 , DMF, room temperature.
制备步骤：取T-32(120mg，0.128mmol)和碳酸钾(248mg，1.79mmol)混合于反应瓶中，同时加入4mLDMF和BrCH2CH2CH2OH(139μL，214mg，1.54mmol)，室温反应12h，反应液用乙酸乙酯和水分散，萃取，有机层依次以稀盐酸、水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，残留物经硅胶柱层析纯化，得黄色油状目标产物T-37，收率42％。ESI-MSm/z:1133.4[M+Na]+；1HNMR(400MHz,CDCl3)δ8.01–7.92(m,4H),7.89(d,J＝7.6Hz,4H),7.62–7.52(m,4H),7.48(t,J＝7.3Hz,1H),7.36(dt,J＝20.5,7.6Hz,7H),7.20(t,J＝7.6Hz,2H),6.93(d,J＝8.5Hz,1H),6.68(s,1H),6.37(s,1H),6.02(t,J＝9.0Hz,1H),5.85–5.75(m,2H),5.64(d,J＝7.0Hz,1H),4.82–4.73(m,1H),4.49(d,J＝9.6Hz,2H),4.31–4.15(m,4H),4.14–4.01(m,2H),3.96–3.82(m,6H),3.80–3.67(m,3H),2.13–2.05(m,6H),2.02–1.96(m,1H),0.93(d,J＝6.5Hz,6H)。Preparation step: T-32 (120 mg, 0.128 mmol) and potassium carbonate (248 mg, 1.79 mmol) were mixed in a reaction flask while 4 mL of DMF and BrCH 2 CH 2 CH 2 OH (139 μL, 214 mg, 1.54 mmol) were added and reacted at room temperature. After the reaction mixture was stirred with ethyl acetate and water, and the mixture was evaporated and evaporated. The title product T-37 was obtained as a yellow oil, yield 42%. ESI-MS m/z: 1133.4 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 - 7.92 (m, 4H), 7.89 (d, J = 7.6 Hz, 4H), 7.62 - 7.52 (m) , 4H), 7.48 (t, J = 7.3 Hz, 1H), 7.36 (dt, J = 20.5, 7.6 Hz, 7H), 7.20 (t, J = 7.6 Hz, 2H), 6.93 (d, J = 8.5 Hz) , 1H), 6.68 (s, 1H), 6.37 (s, 1H), 6.02 (t, J = 9.0 Hz, 1H), 5.85 - 5.75 (m, 2H), 5.64 (d, J = 7.0 Hz, 1H) , 4.82–4.73 (m, 1H), 4.49 (d, J=9.6 Hz, 2H), 4.31–4.15 (m, 4H), 4.14–4.01 (m, 2H), 3.96–3.82 (m, 6H), 3.80 -3.67 (m, 3H), 2.13 - 2.05 (m, 6H), 2.02 - 1.96 (m, 1H), 0.93 (d, J = 6.5 Hz, 6H).
实施例47：3-异丁氧基-5,3',4'-三-(羟丙氧基)-7-O-β-D-葡萄糖基-黄酮(T-38)Example 47: 3-Isobutoxy-5,3',4'-tris-(hydroxypropoxy)-7-O-β-D-glucosyl-flavonoid (T-38)
Figure PCTCN2014086933-appb-000051
Figure PCTCN2014086933-appb-000051
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-37(44mg，0.040mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.3mL，0.41M，0.12mmol)，室温搅拌30min后，搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-38，收率84％。ESI-MSm/z:717.2[M+Na]+；1HNMR(400MHz,DMSO-d6)δ7.64–7.59(m,2H),7.12(d,J＝9.2Hz,1H),6.85(d,J＝2.1Hz,1H),6.56(d,J＝2.1Hz,1H),5.41(br,1H),5.17 (br,1H),5.10(br,1H),5.07(d,J＝7.3Hz,1H),4.72(br,1H),4.68(br,1H),4.57(br,2H),4.17–4.04(m,6H),3.74–3.68(m,1H),3.70–3.62(m,4H),3.62–3.53(m,4H),3.32–3.23(m,5H),3.15(br,2H),1.98–1.81(m,7H),0.89(d,J＝6.7Hz,6H)。Preparation step: Take T-37 (44 mg, 0.040 mmol) in a reaction flask, add 4 mL of methanol and 1 mL of dichloromethane to dissolve, slowly add sodium methoxide (0.3 mL, 0.41 M, 0.12 mmol), stir at room temperature for 30 min, stir The cation exchange resin was added to adjust the pH to 5-6, and the filtrate was concentrated to dryness. ESI-MS m/z: 717.2 [M+Na] + ; 1 H NMR (400 MHz, DMSO-d6) δ 7.64 - 7.59 (m, 2H), 7.12 (d, J = 9.2 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.56 (d, J = 2.1 Hz, 1H), 5.41 (br, 1H), 5.17 (br, 1H), 5.10 (br, 1H), 5.07 (d, J = 7.3 Hz, 1H), 4.72 (br, 1H), 4.68 (br, 1H), 4.57 (br, 2H), 4.17 - 4.04 (m, 6H), 3.74 - 3.68 (m, 1H), 3.70 - 3.62 (m, 4H) , 3.62 - 3.53 (m, 4H), 3.32 - 3.23 (m, 5H), 3.15 (br, 2H), 1.98 - 1.81 (m, 7H), 0.89 (d, J = 6.7 Hz, 6H).
实施例48：3,5,3'-三甲氧基-4'-羟基-7-O-β-D-半乳糖基-黄酮(T-39)Example 48: 3,5,3'-Trimethoxy-4'-hydroxy-7-O-β-D-galactosyl-flavonoid (T-39)
Figure PCTCN2014086933-appb-000052
Figure PCTCN2014086933-appb-000052
反应试剂与条件：(i)KOH，TBAB，CHCl3/H2O，室温；(ii)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) KOH, TBAB, CHCl 3 /H 2 O, room temperature; (ii) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：(i)取M-04(100mg，0.29mmol)和TBAB(18.7mg，0.058mmol)于反应瓶中，加入KOH水溶液(0.29M，0.58mmol)，室温搅拌15min，缓慢加入用2mL氯仿溶解的S-04(383mg，0.58mmol)，室温搅拌48h后，反应液用稀盐酸调pH至2-3，加入乙酸乙酯和水分散，萃取，有机层以水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，即得中间体T-39-M(47mg)；(ii)取上一步粗品T-39-M(47mg，0.051mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.25mL，0.41M，0.10mmol)，室温搅拌30min后，搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-39，收率70％。1HNMR(400MHz,DMSO-d6)δ8.36(s,1H),7.60(d,J＝2.0Hz,1H),7.53(dd,J＝8.4,2.0Hz,1H),6.93(d,J＝8.4Hz,1H),6.87(d,J＝2.1Hz,1H),6.57(d,J＝2.1Hz,1H),5.02(d,J＝7.7Hz,1H),3.83(s,5H),3.74–3.72(m,2H),3.71–3.66(m,2H),3.64–3.57(m,3H),3.55–3.54(m,1H)；13CNMR(101MHz,DMSO-d6)δ172.41,161.70,160.38,157.83,152.41,147.59,140.15,121.82,115.71,111.81,109.11,100.74,96.95,95.99,79.28,76.13,73.43,70.31,68.39,60.71,59.38, 56.22,55.81,48.75.Preparation steps: (i) Take M-04 (100 mg, 0.29 mmol) and TBAB (18.7 mg, 0.058 mmol) in a reaction flask, add KOH aqueous solution (0.29 M, 0.58 mmol), stir at room temperature for 15 min, slowly add 2 mL of chloroform The solution was dissolved in water (MgSO4). The mixture was filtered, and the ethyl acetate was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 0.051mmol) was dissolved in 4mL of methanol and 1mL of dichloromethane in a reaction flask, slowly added sodium methoxide (0.25mL, 0.41M, 0.10mmol), stirred at room temperature for 30min, then added to the cation exchange resin to adjust the pH to 5-6 with stirring The filtrate was concentrated to dryness. 1 HNMR (400MHz, DMSO-d6 ) δ8.36 (s, 1H), 7.60 (d, J = 2.0Hz, 1H), 7.53 (dd, J = 8.4,2.0Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 2.1 Hz, 1H), 6.57 (d, J = 2.1 Hz, 1H), 5.02 (d, J = 7.7 Hz, 1H), 3.83 (s, 5H), 3.74 -3.72 (m, 2H), 3.71 - 3.66 (m, 2H), 3.64 - 3.57 (m, 3H), 3.55 - 3.54 (m, 1H); 13 CNMR (101 MHz, DMSO-d6) δ 172.41, 161.70, 160.38, 157.83, 152.41, 147.59, 140.15, 121.82, 115.71, 111.81, 109.11, 100.74, 96.95, 95.99, 79.28, 76.13, 73.43, 70.31, 68.39, 60.71, 59.38, 56.22, 55.81, 48.75.
实施例49：3,5,3'-三乙氧基-4'-羟基-7-O-β-D-半乳糖基-黄酮(T-40)Example 49: 3,5,3'-Triethoxy-4'-hydroxy-7-O-β-D-galactosyl-flavonoid (T-40)
Figure PCTCN2014086933-appb-000053
Figure PCTCN2014086933-appb-000053
反应试剂与条件：(i)KOH，TBAB，CHCl3/H2O，室温；(ii)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) KOH, TBAB, CHCl 3 /H 2 O, room temperature; (ii) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：(i)取M-04(100mg，0.26mmol)和TBAB(16mg，0.051mmol)于反应瓶中，加入KOH水溶液(0.29M，0.52mmol)，室温搅拌15min，缓慢加入用2mL氯仿溶解的S-04(345mg，0.52mmol)，室温搅拌48h。反应液用稀盐酸调pH至2-3，加入乙酸乙酯和水分散，萃取，有机层以水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，即得中间体T-40-M(105mg)；(ii)取中间体T-40-M(88mg，0.091mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.41M，0.18mmol)，室温搅拌30min。搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-40，收率57％。1HNMR(400MHz,DMSO-d6)δ9.72(s,1H),7.67(d,J＝2.1Hz,1H),7.55(dd,J＝8.5,2.1Hz,1H),6.95(d,J＝8.5Hz,1H),6.84(d,J＝2.1Hz,1H),6.55(d,J＝2.1Hz,1H),5.26(br,1H),5.02(d,J＝7.7Hz,1H),4.94(br,1H),4.74(br,1H),4.57(d,J＝3.7Hz,1H),4.14–4.05(m,5H),3.96(q,J＝7.0Hz,2H),3.74–3.66(m,2H),3.61(t,J＝8.5Hz,1H),3.54(s,2H),1.42–1.35(m,6H),1.23(t,J＝7.0Hz,3H)。Preparation steps: (i) Take M-04 (100 mg, 0.26 mmol) and TBAB (16 mg, 0.051 mmol) in a reaction flask, add KOH aqueous solution (0.29 M, 0.52 mmol), stir at room temperature for 15 min, slowly add 2 mL of chloroform to dissolve. S-04 (345 mg, 0.52 mmol) was stirred at room temperature for 48 h. The reaction mixture was adjusted to pH 2-3 with dilute aqueous hydrochloric acid, and ethyl acetate and water were evaporated and evaporated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated Column chromatography to obtain intermediate T-40-M (105 mg); (ii) Intermediate T-40-M (88 mg, 0.091 mmol) was taken in a reaction flask and dissolved in 4 mL of methanol and 1 mL of dichloromethane. Sodium methoxide (0.41 M, 0.18 mmol) was slowly added and stirred at room temperature for 30 min. The cation exchange resin was added thereto under stirring to adjust the pH to 5-6, and the filtrate was concentrated to dryness. 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.55 (dd, J = 8.5, 2.1 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 5.26 (br, 1H), 5.02 (d, J = 7.7 Hz, 1H), 4.94 (br, 1H), 4.74 (br, 1H), 4.57 (d, J = 3.7 Hz, 1H), 4.14 - 4.05 (m, 5H), 3.96 (q, J = 7.0 Hz, 2H), 3.74 - 3.66 ( m, 2H), 3.61 (t, J = 8.5 Hz, 1H), 3.54 (s, 2H), 1.42 - 1.35 (m, 6H), 1.23 (t, J = 7.0 Hz, 3H).
实施例50：3-甲氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基半乳糖基-黄酮(T-41) Example 50: 3-Methoxy-5-hydroxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoylgalactosyl-flavonoid (T-41)
Figure PCTCN2014086933-appb-000054
Figure PCTCN2014086933-appb-000054
反应试剂与条件：(i)K2CO3，TBAB，CHCl3/DMF/H2O，45℃。Reagents and conditions: (i) K 2 CO 3 , TBAB, CHCl 3 /DMF/H 2 O, 45 ° C.
制备步骤：取M-11(100mg，0.21mmol)、TBAB(6.8mg，0.021mmol)和碳酸钾(201mg，1.46mmol)混合于反应瓶中，加入4.5mLDMF和4.5mL水，室温搅拌15min，缓慢加入用9mL氯仿溶解的S-04(549mg，0.83mmol)，45℃搅拌48h。反应液用稀盐酸调pH至2-3，加入乙酸乙酯和水分散，萃取，有机层以水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-41，收率65％。1HNMR(400MHz,CDCl3)δ12.63(s,1H),8.14–8.10(m,2H),8.02–7.94(m,5H),7.82(dd,J＝8.3,1.2Hz,2H),7.65–7.57(m,8H),7.54–7.46(m,4H),7.43–7.33(m,10H),7.30–7.24(m,2H),6.97(d,J＝8.4Hz,1H),6.57(d,J＝2.2Hz,1H),6.55(d,J＝2.2Hz,1H),6.12–6.05(m,2H),5.72(dd,J＝10.3,3.4Hz,1H),5.53(d,J＝7.8Hz,1H),4.64–4.54(m,3H),3.85(s,3H)。Preparation steps: M-11 (100 mg, 0.21 mmol), TBAB (6.8 mg, 0.021 mmol) and potassium carbonate (201 mg, 1.46 mmol) were mixed in a reaction flask, and 4.5 mL of DMF and 4.5 mL of water were added, and stirred at room temperature for 15 min, slowly. S-04 (549 mg, 0.83 mmol) dissolved in 9 mL of chloroform was added, and stirred at 45 ° C for 48 h. The reaction mixture was adjusted to pH 2-3 with dilute aqueous hydrochloric acid, and ethyl acetate and water were evaporated and evaporated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated Purification by column chromatography gave the title compound T-41 as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 12.63 (s, 1H), 8.14 - 8.10 (m, 2H), 8.02 - 7.94 (m, 5H), 7.82 (dd, J = 8.3, 1.2 Hz, 2H), 7.65 –7.57(m,8H), 7.54–7.46(m,4H), 7.43–7.33(m,10H), 7.30–7.24(m,2H),6.97(d,J=8.4Hz,1H),6.57(d , J = 2.2 Hz, 1H), 6.55 (d, J = 2.2 Hz, 1H), 6.12 - 6.05 (m, 2H), 5.72 (dd, J = 10.3, 3.4 Hz, 1H), 5.53 (d, J = 7.8 Hz, 1H), 4.64 - 4.54 (m, 3H), 3.85 (s, 3H).
实施例51：3-甲氧基-5,3',4'-三羟基-7-O-β-D-苯甲酰基半乳糖基-黄酮(T-42)Example 51: 3-Methoxy-5,3',4'-trihydroxy-7-O-β-D-benzoylgalactosyl-flavonoid (T-42)
Figure PCTCN2014086933-appb-000055
Figure PCTCN2014086933-appb-000055
反应试剂与条件：(i)10％Pd/C，H2，CH3OH/THF/H2O，室温。Reaction reagents and conditions: (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
制备步骤：取T-41(130mg，0.123mmol)于反应瓶中，加入40mL甲醇、10mL四氢呋喃和0.5mL水溶解，加入10％Pd/C(130mg)，室温常压氢解反应48h，过滤去除钯碳，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-42，收率75％。1HNMR(400MHz,CDCl3)δ12.53(s,1H),8.12(d,J＝7.4Hz,2H),8.03–7.94(m,4H),7.82(d,J＝7.4Hz,2H),7.73(s,1H),7.64(t,J＝7.4Hz,1H),7.54–7.43(m,6H),7.40–7.27(m,7H),7.20–7.13(m,2H),6.98(d,J＝8.9Hz,1H),6.54(d,J＝1.8Hz,1H),6.50(d,J＝1.9Hz,1H),6.12–6.04(m,2H),5.74(dd,J＝10.3,3.3Hz,1H),5.51(d,J＝7.8Hz,1H),4.59–4.50(m, 2H),3.81(s,3H)。Preparation steps: Take T-41 (130mg, 0.123mmol) in a reaction flask, add 40mL methanol, 10mL tetrahydrofuran and 0.5mL water to dissolve, add 10% Pd / C (130mg), hydrogen sulfide reaction at room temperature for 48h, filter to remove Palladium on carbon, and the solvent was evaporated to dryness. 1 H NMR (400 MHz, CDCl 3 ) δ 12.53 (s, 1H), 8.12 (d, J = 7.4 Hz, 2H), 8.03 - 7.94 (m, 4H), 7.82 (d, J = 7.4 Hz, 2H), 7.73 (s, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.54 - 7.43 (m, 6H), 7.40 - 7.27 (m, 7H), 7.20 - 7.13 (m, 2H), 6.98 (d, J = 8.9 Hz, 1H), 6.54 (d, J = 1.8 Hz, 1H), 6.50 (d, J = 1.9 Hz, 1H), 6.12 - 6.04 (m, 2H), 5.74 (dd, J = 10.3, 3.3 Hz, 1H), 5.51 (d, J = 7.8 Hz, 1H), 4.59 - 4.50 (m, 2H), 3.81 (s, 3H).
实施例52：3-甲氧基-5,3',4'-三羟基-7-O-β-D-半乳糖基-黄酮(T-43)Example 52: 3-Methoxy-5,3',4'-trihydroxy-7-O-β-D-galactosyl-flavonoid (T-43)
Figure PCTCN2014086933-appb-000056
Figure PCTCN2014086933-appb-000056
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-42(69mg，0.77mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.41M，0.23mmol)，室温搅拌30min。搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-43，收率87％。1HNMR(400MHz,DMSO-d6)δ12.69(s,1H),7.56(s,1H),7.52(s,1H),7.45(d,J＝7.9Hz,1H),7.40(d,J＝7.9Hz,1H),6.89(d,J＝7.0Hz,2H),6.75(s,1H),6.42(s,1H),6.11(s,1H),5.95(s,1H),5.00(d,J＝7.6Hz,1H),4.87(d,J＝7.1Hz,1H),3.78(s,3H),3.72(s,3H),3.70(s,3H),3.60-3.41(m,5H)。Preparation: T-42 (69 mg, 0.77 mmol) was taken in a reaction flask, and 4 mL of methanol and 1 mL of dichloromethane were added to dissolve, and sodium methoxide (0.41 M, 0.23 mmol) was slowly added and stirred at room temperature for 30 min. The cation exchange resin was added thereto under stirring to adjust the pH to 5-6, and the filtrate was concentrated to dryness. 1 HNMR (400MHz, DMSO-d6 ) δ12.69 (s, 1H), 7.56 (s, 1H), 7.52 (s, 1H), 7.45 (d, J = 7.9Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 7.0 Hz, 2H), 6.75 (s, 1H), 6.42 (s, 1H), 6.11 (s, 1H), 5.95 (s, 1H), 5.00 (d, J = 7.6 Hz, 1H), 4.87 (d, J = 7.1 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 3.70 (s, 3H), 3.60-3.41 (m, 5H).
实施例53：3,5,3'-三甲氧基-7,4’-二-O-β-D-(2,3,4,6-四-O-苯甲酰基)-葡萄糖基-黄酮(T-44)Example 53: 3,5,3'-Trimethoxy-7,4'-di-O-β-D-(2,3,4,6-tetra-O-benzoyl)-glucosyl-flavonoid (T-44)
Figure PCTCN2014086933-appb-000057
Figure PCTCN2014086933-appb-000057
反应试剂与条件：(i)KOH，TBAB，CHCl3/H2O，室温。Reagents and conditions: (i) KOH, TBAB, CHCl 3 /H 2 O, room temperature.
制备步骤：取M-04(100mg，0.29mmol)和TBAB(18mg，0.058mmol)于反应瓶中，加入KOH水溶液(0.29M，0.87mmol)，室温搅拌15min，缓慢加入用3mL氯仿溶解的S-02(383mg，0.58mmol)，室温搅拌48h。反应液用稀盐酸调pH至2-3，加入乙酸乙酯和水分散，萃取，有机层以水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得淡 黄色油状目标产物T-44，收率40％。1HNMR(400MHz,CDCl3)δ8.05–8.00(m,4H),8.00–7.85(m,13H),7.57–7.51(m,5H),7.50–7.45(m,3H),7.45–7.36(m,12H),7.36–7.27(m,7H),7.16(t,J＝7.8Hz,2H),6.62(d,J＝2.2Hz,1H),6.39(d,J＝2.2Hz,1H),6.05–5.98(m,2H),5.89–5.73(m,4H),5.64(d,J＝7.0Hz,1H),5.37(d,J＝7.7Hz,1H),4.75(d,J＝9.2Hz,1H),4.70(dd,J＝12.1,3.2Hz,1H),4.59–4.44(m,3H),4.29(ddd,J＝9.4,5.9,3.2Hz,1H),3.83(s,3H),3.80(s,3H),3.45(s,3H)；13CNMR(101MHz,CDCl3)δ173.77,166.01,165.75,165.64,165.19,165.07,165.02,161.20,160.36,158.06,152.23,150.38,147.67,141.48,133.66,133.60,133.52,133.46,133.32,133.24,133.13,129.84,129.70,129.46,129.39,129.08,128.75,128.70,128.63,128.49,128.43,128.38,128.32,128.21,126.88,121.14,119.77,112.36,110.74,100.99,98.06,96.87,95.87,72.90,72.60,72.51,72.36,71.65,71.50,69.55,69.14,63.03,62.94,59.93,56.45,55.64.。Preparation step: Take M-04 (100 mg, 0.29 mmol) and TBAB (18 mg, 0.058 mmol) in a reaction flask, add KOH aqueous solution (0.29 M, 0.87 mmol), stir at room temperature for 15 min, slowly add S- dissolved in 3 mL of chloroform. 02 (383 mg, 0.58 mmol), stirred at room temperature for 48 h. The reaction mixture was adjusted to pH 2-3 with dilute aqueous hydrochloric acid, and ethyl acetate and water were evaporated and evaporated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated Purification by column chromatography gave the title compound T-44 as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 - 8.00 (m, 4H), 8.00 - 7.85 (m, 13H), 7.57 - 7.51 (m, 5H), 7.50 - 7.45 (m, 3H), 7.45 - 7.36 ( m, 12H), 7.36 - 7.27 (m, 7H), 7.16 (t, J = 7.8 Hz, 2H), 6.62 (d, J = 2.2 Hz, 1H), 6.39 (d, J = 2.2 Hz, 1H), 6.05–5.98 (m, 2H), 5.89–5.73 (m, 4H), 5.64 (d, J=7.0 Hz, 1H), 5.37 (d, J = 7.7 Hz, 1H), 4.75 (d, J = 9.2 Hz) , 1H), 4.70 (dd, J = 12.1, 3.2 Hz, 1H), 4.59 - 4.44 (m, 3H), 4.29 (ddd, J = 9.4, 5.9, 3.2 Hz, 1H), 3.83 (s, 3H), 3.80(s,3H), 3.45(s,3H); 13 CNMR(101MHz,CDCl 3 )δ173.77,166.01,165.75,165.64,165.19,165.07,165.02,161.20,160.36,158.06,152.23,150.38,147.67,141.48, 133.66,133.60,133.52,133.46,133.32,133.24,133.13,129.84,129.70,129.46,129.39,129.08,128.75,128.70,128.63,128.49,128.43,128.38,128.32,128.21,126.88,121.14,119.77,112.36,110.74, 100.99, 98.06, 96.87, 95.87, 72.90, 72.60, 72.51, 72.36, 71.65, 71.50, 69.55, 69.14, 63.03, 62.94, 59.93, 56.45, 55.64.
实施例54：3,5,3'-三甲氧基-7,4’-二-O-β-D-葡萄糖基-黄酮(T-45)Example 54: 3,5,3'-Trimethoxy-7,4'-di-O-β-D-glucosyl-flavonoid (T-45)
Figure PCTCN2014086933-appb-000058
Figure PCTCN2014086933-appb-000058
反应试剂与条件：(i)CH3ONa，CH3OH/CH2Cl2，室温。Reaction reagents and conditions: (i) CH 3 ONa, CH 3 OH/CH 2 Cl 2 , room temperature.
制备步骤：取T-44(125mg，0.083mmol)于反应瓶中，加入4mL甲醇和1mL二氯甲烷溶解，缓慢加入甲醇钠(0.41M，0.33mmol)，室温搅拌30min。搅拌下加入阳离子交换树脂调pH至5-6，过滤，浓缩滤液至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-45，收率68％。1HNMR(400MHz,DMSO-d6)δ7.68–7.64(m,1H),7.62(dd,J＝8.6,2.1Hz,1H),7.24(d,J＝8.8Hz,1H),6.90(d,J＝2.2Hz,1H),6.57(d,J＝2.2Hz,1H),5.41(d,J＝4.6Hz,1H),5.32(d,J＝4.5Hz,1H),5.15(d,J＝4.2Hz,1H),5.12–5.07(m,3H),5.06–5.01(m,2H),4.66(t,J＝5.3Hz,1H),4.56(t,J＝5.6Hz,1H),3.85(s,6H),3.75(s,3H),3.73–3.65(m,2H),3.50–3.41(m,4H),3.29(d,J＝2.6Hz,4H),3.20–3.11(m,2H)。Preparation: Take T-44 (125 mg, 0.083 mmol) in a reaction flask, dissolve 4 mL of methanol and 1 mL of dichloromethane, slowly add sodium methoxide (0.41 M, 0.33 mmol) and stir at room temperature for 30 min. The cation exchange resin was added thereto under stirring to adjust the pH to 5-6, and the filtrate was concentrated to dryness. 1 H NMR (400 MHz, DMSO-d6) δ 7.68 - 7.64 (m, 1H), 7.62 (dd, J = 8.6, 2.1 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 2.2 Hz, 1H), 6.57 (d, J = 2.2 Hz, 1H), 5.41 (d, J = 4.6 Hz, 1H), 5.32 (d, J = 4.5 Hz, 1H), 5.15 (d, J = 4.2 Hz, 1H), 5.12 - 5.07 (m, 3H), 5.06 - 5.01 (m, 2H), 4.66 (t, J = 5.3 Hz, 1H), 4.56 (t, J = 5.6 Hz, 1H), 3.85 ( s,6H),3.75(s,3H),3.73–3.65(m,2H),3.50–3.41(m,4H), 3.29(d,J=2.6Hz,4H), 3.20–3.11(m,2H) .
实施例55：3-甲氧基-5,3',4'-三-(乙酰氧基)-7-O-β-D-乙酰基葡萄糖基-黄酮(T-46) Example 55: 3-Methoxy-5,3',4'-tris-(acetoxy)-7-O-β-D-acetylglucosyl-flavonoid (T-46)
Figure PCTCN2014086933-appb-000059
Figure PCTCN2014086933-appb-000059
反应试剂与条件：(i)Ac2O，pyridine，室温。Reaction reagents and conditions: (i) Ac 2 O, pyridine, room temperature.
制备步骤：取T-06(47mg，0.098mmol)于反应瓶中，加入3mL吡啶溶解，冰水浴充分冷却下缓慢加入1.5mL乙酸酐，在滴加完毕后，室温搅拌10h，将反应液倒入乙酸乙酯和冰水混合物中，萃取，有机层依次用稀盐酸和水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得淡黄色粉末状目标产物T-46，收率85％。1HNMR(400MHz,CDCl3)δ7.99(dd,J＝8.6,2.1Hz,1H),7.92(d,J＝2.1Hz,1H),7.35(d,J＝8.6Hz,1H),7.27(s,1H),6.96(d,J＝2.4Hz,1H),6.68(dd,J＝6.1,2.4Hz,1H),5.36–5.27(m,2H),5.26–5.21(m,1H),5.20–5.13(m,1H),4.27(dd,J＝12.3,5.8Hz,1H),4.21(dd,J＝12.3,2.4Hz,1H),4.03–3.95(m,1H),3.83(s,3H),2.46(s,3H),2.35(s,3H),2.34(s,3H),2.08(s,3H),2.07(s,3H),2.06(s,3H),2.05(s,3H)。Preparation step: Take T-06 (47 mg, 0.098 mmol) in a reaction flask, add 3 mL of pyridine to dissolve, and slowly add 1.5 mL of acetic anhydride under ice cooling, and after stirring, stir at room temperature for 10 h, and pour the reaction solution. The mixture was extracted with ethyl acetate and EtOAc (EtOAc)EtOAc. Yellow powdery target product T-46, yield 85%. 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (dd, J = 8.6, 2.1 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.27 ( s, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.68 (dd, J = 6.1, 2.4 Hz, 1H), 5.36 - 5.27 (m, 2H), 5.26 - 5.21 (m, 1H), 5.20 –5.13(m,1H), 4.27 (dd, J=12.3, 5.8 Hz, 1H), 4.21 (dd, J=12.3, 2.4 Hz, 1H), 4.03–3.95 (m, 1H), 3.83 (s, 3H) ), 2.46 (s, 3H), 2.35 (s, 3H), 2.34 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H) .
实施例56：3-乙氧基-5-甲氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-47)Example 56: 3-Ethoxy-5-methoxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid (T-47)
Figure PCTCN2014086933-appb-000060
Figure PCTCN2014086933-appb-000060
反应试剂与条件：(i)CH3I，K2CO3，DMF，室温。Reaction reagents and conditions: (i) CH 3 I, K 2 CO 3 , DMF, room temperature.
制备步骤：取T-20(771mg，0.71mmol)和碳酸钾(147mg，1.06mmol)混合于反应瓶中，同时加入8mLDMF和CH3I(65μL，149mg，1.06mmol)，室温反应12h，所得反应液用乙酸乙酯和水分散，萃取，有机层以水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-47，收率68％。ESI-MSm/z:1123.21HNMR(400MHz,CDCl3)δ7.96(t,J＝7.4Hz,4H),7.91–7.84(m,4H),7.60(ddd,J＝6.9,5.2,1.8Hz,5H),7.57–7.50(m,3H),7.47(t,J＝7.5Hz,1H),7.44–7.29(m,12H),7.18(t,J＝7.4Hz,1H),7.07(t,J＝7.6Hz,2H),6.92(d,J＝8.3Hz,1H),6.62(d,J＝2.2Hz,1H),6.37 (d,J＝2.2Hz,1H),6.02(t,J＝9.2Hz,1H),5.82(dd,J＝9.1,7.3Hz,1H),5.76(t,J＝9.2Hz,1H),5.61(d,J＝7.3Hz,1H),4.84–4.69(m,1H),4.55–4.42(m,2H),4.19–3.98(m,2H),3.82(s,3H),1.33(t,J＝7.0Hz,3H).Preparation step: T-20 (771 mg, 0.71 mmol) and potassium carbonate (147 mg, 1.06 mmol) were mixed in a reaction flask, and 8 mL of DMF and CH 3 I (65 μL, 149 mg, 1.06 mmol) were added, and reacted at room temperature for 12 h. The liquid was dispersed with ethyl acetate and water, and the mixture was evaporated. EtOAcjjjjjjjjjjjjj -47, yield 68%. ESI-MS m/z: 1123.2 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (t, J = 7.4 Hz, 4H), 7.91 - 7.84 (m, 4H), 7.60 (ddd, J = 6.9, 5.2, 1.8 Hz , 5H), 7.57 - 7.50 (m, 3H), 7.47 (t, J = 7.5 Hz, 1H), 7.44 - 7.29 (m, 12H), 7.18 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 7.6 Hz, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 2.2 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H), 6.02 (t, J = 9.2 Hz, 1H), 5.82 (dd, J = 9.1, 7.3 Hz, 1H), 5.76 (t, J = 9.2 Hz, 1H), 5.61 (d, J = 7.3 Hz, 1H), 4.84 - 4.69 (m, 1H), 4.55–4.42 (m, 2H), 4.19–3.98 (m, 2H), 3.82 (s, 3H), 1.33 (t, J=7.0 Hz, 3H).
实施例57：3-乙氧基-5-甲氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-48)Example 57: 3-Ethoxy-5-methoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-48)
Figure PCTCN2014086933-appb-000061
Figure PCTCN2014086933-appb-000061
反应试剂与条件：(i)10％Pd/C，H2，CH3OH/THF/H2O，室温。Reaction reagents and conditions: (i) 10% Pd/C, H 2 , CH 3 OH/THF/H 2 O, room temperature.
制备步骤：取T-47(318mg，0.084mmol)于反应瓶中，加入90mL甲醇、22.5mL四氢呋喃和0.9mL水溶解，加入10％Pd/C(319mg)，室温常压氢解反应48h后，过滤去除钯碳，减压回收溶剂至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-48，收率68％。1HNMR(400MHz,CDCl3)δ8.05–7.82(m,9H),7.58–7.42(m,4H),7.41–7.31(m,7H),7.17(t,J＝7.6Hz,2H),6.98(d,J＝8.0Hz,1H),6.66(s,1H),6.36(s,1H),6.03(t,J＝9.1Hz,1H),4.74(d,J＝9.8Hz,1H),4.58–4.44(m,2H),4.03–3.92(m,2H),3.80(s,3H),1.20(t,J＝6.8Hz,3H)；13CNMR(101MHz,CDCl3)δ174.86,166.22,165.70,165.19,165.07,160.95,160.56,158.18,154.87,147.47,143.96,139.65,133.60,133.45,133.20,129.86,129.82,129.79,129.44,129.04,128.71,128.48,128.38,128.24,122.32,121.44,115.96,115.16,110.22,97.99,97.04,95.68,72.76,72.46,71.46,69.20,68.41,62.98,56.32,15.38。Preparation steps: Take T-47 (318mg, 0.084mmol) in a reaction flask, add 90mL methanol, 22.5mL tetrahydrofuran and 0.9mL water to dissolve, add 10% Pd / C (319mg), room temperature atmospheric pressure hydrogenolysis reaction for 48h, The palladium carbon was removed by filtration, and the solvent was evaporated to dryness. 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 - 7.82 (m, 9H), 7.58 - 7.42 (m, 4H), 7.41 - 7.31 (m, 7H), 7.17 (t, J = 7.6 Hz, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 6.36 (s, 1H), 6.03 (t, J = 9.1 Hz, 1H), 4.74 (d, J = 9.8 Hz, 1H), 4.58 -4.44 (m, 2H), 4.03 - 3.92 (m, 2H), 3.80 (s, 3H), 1.20 (t, J = 6.8 Hz, 3H); 13 CNMR (101 MHz, CDCl 3 ) δ 174.86, 166.22, 165.70, 165.19,165.07,160.95,160.56,158.18,154.87,147.47,143.96,139.65,133.60,133.45,133.20,129.86,129.82,129.79,129.44,129.04,128.71,128.48,128.38,128.24,122.32,121.44,115.96,115.16, 110.22, 97.99, 97.04, 95.68, 72.76, 72.46, 71.46, 69.20, 68.41, 62.98, 56.32, 15.38.
实施例58：3-甲氧基-5-乙氧基-3'-羟基-4'-苄氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-49)Example 58: 3-Methoxy-5-ethoxy-3'-hydroxy-4'-benzyloxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-49)
Figure PCTCN2014086933-appb-000062
Figure PCTCN2014086933-appb-000062
反应试剂与条件：(i)BnBr，K2CO3，DMF，室温。 Reaction reagents and conditions: (i) BnBr, K 2 CO 3 , DMF, room temperature.
制备步骤：称取T-12(93mg，0.1mmol)置于反应瓶中，加入5mL无水DMF，搅拌溶解后加入无水K2CO3(16.5mg，0.12mmol，1.2eq)和溴苄(13μL，0.11mmol，1.1eq)，室温反应过夜，所得反应液用乙酸乙酯和水分散、酸化，萃取，有机层以水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，即得目标产物T-49，收率81％。1HNMR(400MHz,DMSO-d6)δ7.89–7.83(m,6H),7.77–7.72(m,2H),7.66–7.53(m,4H),7.52–7.37(m,13H),7.31(ddd,J＝7.7,4.2,2.3Hz,3H),7.11(d,J＝8.8Hz,1H),6.88(d,J＝2.1Hz,1H),6.48(d,J＝2.1Hz,1H),6.29(d,J＝7.8Hz,1H),6.10(t,J＝9.5Hz,1H),5.76–5.70(m,4H),5.21(s,2H),4.90–4.83(m,1H),4.61–4.46(m,2H),3.99(ddd,J＝32.9,9.7,7.1Hz,2H),3.72(s,3H),1.28(t,J＝6.9Hz,3H)。Preparation steps: T-12 (93 mg, 0.1 mmol) was weighed into a reaction flask, 5 mL of anhydrous DMF was added, stirred and dissolved, and anhydrous K 2 CO 3 (16.5 mg, 0.12 mmol, 1.2 eq) and benzyl bromide were added. 13 μL, 0.11 mmol, 1.1 eq), and the reaction mixture was stirred at room temperature overnight. The obtained mixture was evaporated, evaporated, evaporated, evaporated The residue obtained was purified by silica gel column chromatography to give the desired product T-49, yield 81%. 1 H NMR (400 MHz, DMSO-d6) δ 7.89 - 7.83 (m, 6H), 7.77 - 7.72 (m, 2H), 7.66 - 7.53 (m, 4H), 7.52 - 7.37 (m, 13H), 7.31 (ddd , J = 7.7, 4.2, 2.3 Hz, 3H), 7.11 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.48 (d, J = 2.1 Hz, 1H), 6.29 (d, J = 7.8 Hz, 1H), 6.10 (t, J = 9.5 Hz, 1H), 5.76 - 5.70 (m, 4H), 5.21 (s, 2H), 4.90 - 4.83 (m, 1H), 4.61 - 4.46 (m, 2H), 3.99 (ddd, J = 32.9, 9.7, 7.1 Hz, 2H), 3.72 (s, 3H), 1.28 (t, J = 6.9 Hz, 3H).
实施例59：3-甲氧基-5,3'-二-羟基-4'-苄氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-50)Example 59: 3-Methoxy-5,3'-di-hydroxy-4'-benzyloxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-50)
Figure PCTCN2014086933-appb-000063
Figure PCTCN2014086933-appb-000063
反应试剂与条件：(i)BnBr，K2CO3，DMF，室温。Reaction reagents and conditions: (i) BnBr, K 2 CO 3 , DMF, room temperature.
制备步骤：称取T-05(180mg，0.2mmol)置于反应瓶中，加入8mL无水DMF，搅拌溶解后加入无水K2CO3(33mg，0.24mmol，1.2eq)和溴苄(26μL，0.22mmol，1.1eq)，室温反应过夜，所得反应液用乙酸乙酯和水分散、酸化，萃取，有机层以水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，即得目标产物T-50，收率78％。1HNMR(1MHz,CDCl3)δ12.61(s,1H),8.04–7.85(m,5H),7.67–7.22(m,12H),7.00(d,J＝8.5Hz,1H),6.54(s,1H),6.50(s,1H),6.00(t,J＝9.1Hz,1H),5.84–5.73(m,3H),5.58(d,J＝7.0Hz,1H),5.20(s,2H),4.73(d,J＝11.0Hz,1H),4.53–4.40(m,2H),3.86(s,3H)。Preparation step: T-05 (180 mg, 0.2 mmol) was weighed into a reaction flask, 8 mL of anhydrous DMF was added, stirred and dissolved, and then anhydrous K 2 CO 3 (33 mg, 0.24 mmol, 1.2 eq) and benzyl bromide (26 μL) were added. , 0.22 mmol, 1.1 eq), EtOAc (EtOAc) m. The obtained residue was purified by silica gel column chromatography toiel 1 H NMR (1MHz, CDCl 3 ) δ 12.61 (s, 1H), 8.04 - 7.85 (m, 5H), 7.67 - 7.22 (m, 12H), 7.00 (d, J = 8.5 Hz, 1H), 6.54 (s) , 1H), 6.50 (s, 1H), 6.00 (t, J = 9.1 Hz, 1H), 5.84 - 5.73 (m, 3H), 5.58 (d, J = 7.0 Hz, 1H), 5.20 (s, 2H) , 4.73 (d, J = 11.0 Hz, 1H), 4.53 - 4.40 (m, 2H), 3.86 (s, 3H).
实施例60：3-甲氧基-5,3'-二-丙氧基-4'-苄氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-51) Example 60: 3-Methoxy-5,3'-di-propoxy-4'-benzyloxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-51)
Figure PCTCN2014086933-appb-000064
Figure PCTCN2014086933-appb-000064
反应试剂与条件：(i)CH3CH2CH2I，K2CO3，DMF，室温。Reaction reagents and conditions: (i) CH 3 CH 2 CH 2 I, K 2 CO 3 , DMF, room temperature.
制备步骤：取T-50(99mg，0.10mmol)和碳酸钾(45mg，0.3mmol)混合于反应瓶中，同时加入4mLDMF和CH3CH2CH2I(29μL，0.3mmol)，室温反应过夜后，反应液用乙酸乙酯和水分散，萃取，有机层依次以稀盐酸、水洗涤，无水硫酸镁干燥，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，得黄色油状目标产物T-51，收率82％。1HNMR(400MHz,CDCl3)δ8.01–7.93(m,4H),7.89(d,J＝7.3Hz,4H),7.67(d,J＝2.0Hz,1H),7.56–7.51(m,2H),7.50–7.45(m,4H),7.42–7.29(m,11H),7.16(t,J＝7.8Hz,2H),6.94(d,J＝8.6Hz,1H),6.62(d,J＝2.1Hz,1H),6.36(d,J＝2.1Hz,1H),6.02(t,J＝9.1Hz,1H),5.84–5.74(m,2H),5.62(d,J＝7.2Hz,1H),5.23(s,2H),4.75(d,J＝9.4Hz,1H),4.55–4.44(m,2H),4.07–4.00(m,2H),3.94–3.87(m,2H),3.83(s,3H),1.88(dt,J＝14.4,7.1Hz,4H),1.11–1.03(m,6H)。Preparation step: T-50 (99 mg, 0.10 mmol) and potassium carbonate (45 mg, 0.3 mmol) were mixed in a reaction flask while 4 mL of DMF and CH 3 CH 2 CH 2 I (29 μL, 0.3 mmol) were added, and the reaction was carried out at room temperature overnight. The reaction mixture is separated with ethyl acetate and water, and the organic layer is washed with EtOAc EtOAc. Oily target product T-51, yield 82%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 - 7.93 (m, 4H), 7.89 (d, J = 7.3 Hz, 4H), 7.67 (d, J = 2.0 Hz, 1H), 7.56 - 7.51 (m, 2H) ), 7.50 - 7.45 (m, 4H), 7.42 - 7.29 (m, 11H), 7.16 (t, J = 7.8 Hz, 2H), 6.94 (d, J = 8.6 Hz, 1H), 6.62 (d, J = 2.1 Hz, 1H), 6.36 (d, J = 2.1 Hz, 1H), 6.02 (t, J = 9.1 Hz, 1H), 5.84 - 5.74 (m, 2H), 5.62 (d, J = 7.2 Hz, 1H) , 5.23 (s, 2H), 4.75 (d, J = 9.4 Hz, 1H), 4.55 - 4.44 (m, 2H), 4.07 - 4.00 (m, 2H), 3.94 - 3.87 (m, 2H), 3.83 (s , 3H), 1.88 (dt, J = 14.4, 7.1 Hz, 4H), 1.11 - 1.03 (m, 6H).
实施例61：3,5-二-甲氧基-3',4'-二-羟丙氧基7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-52)Example 61: 3,5-Di-methoxy-3',4'-di-hydroxypropoxy 7-O-β-D-benzoyl glucosyl-flavonoid (T-52)
Figure PCTCN2014086933-appb-000065
Figure PCTCN2014086933-appb-000065
反应试剂与条件：(i)BrCH2CH2OH，K2CO3，DMF，室温。Reaction reagents and conditions: (i) BrCH 2 CH 2 OH, K 2 CO 3 , DMF, room temperature.
制备步骤：取T-09(91mg，0.1mmol)和碳酸钾(46mg，0.31mmol)混合于反应瓶中，同时加入4mLDMF和BrCH2CH2OH(21μL，0.3mmol)，室温反应24h，反应液用乙酸乙酯和水分散，萃取，有机层水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，残留物经硅胶柱层析纯化，得黄色油状目标产物T-52，收率42％。1HNMR(400MHz,CDCl3)δ7.97(ddd,J＝12.0,8.4,1.2Hz,5H),7.91–7.88(m,4H),7.69–7.63(m,2H),7.56–7.45(m,4H),7.41–7.31(m,8H),7.19(t,J＝7.8Hz,2H),6.97(d,J＝8.6Hz,1H),6.66(d,J＝2.2Hz,1H),6.38(d,J＝ 2.2Hz,1H),6.03(t,J＝9.1Hz,1H),5.85–5.76(m,2H),5.66(d,J＝7.1Hz,1H),4.81–4.73(m,1H),4.56–4.46(m,2H),4.22–4.12(m,4H),4.02–3.95(m,4H),3.85(s,3H),3.83(s,3H)。Preparation step: T-09 (91 mg, 0.1 mmol) and potassium carbonate (46 mg, 0.31 mmol) were mixed in a reaction flask, and 4 mL of DMF and BrCH 2 CH 2 OH (21 μL, 0.3 mmol) were added thereto, and reacted at room temperature for 24 hours. The title product T-52 was obtained as a yellow oil, which was purified by silica gel column chromatography. The yield was 42%. 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (ddd, J = 12.0, 8.4, 1.2 Hz, 5H), 7.91 - 7.88 (m, 4H), 7.69 - 7.63 (m, 2H), 7.56 - 7.45 (m, 4H), 7.41 - 7.31 (m, 8H), 7.19 (t, J = 7.8 Hz, 2H), 6.97 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 2.2 Hz, 1H), 6.38 ( d, J = 2.2 Hz, 1H), 6.03 (t, J = 9.1 Hz, 1H), 5.85 - 5.76 (m, 2H), 5.66 (d, J = 7.1 Hz, 1H), 4.81 - 4.73 (m, 1H) ), 4.56 - 4.46 (m, 2H), 4.22 - 4.12 (m, 4H), 4.02 - 3.95 (m, 4H), 3.85 (s, 3H), 3.83 (s, 3H).
实施例62：3,5,3'-三-甲氧基-4'-苄氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮(T-53)Example 62: 3,5,3'-Tris-methoxy-4'-benzyloxy-7-O-β-D-benzoyl glucosyl-flavonoid (T-53)
Figure PCTCN2014086933-appb-000066
Figure PCTCN2014086933-appb-000066
反应试剂与条件：(i)BnBr，K2CO3，DMF，室温。Reaction reagents and conditions: (i) BnBr, K 2 CO 3 , DMF, room temperature.
制备步骤：称取T-01(93mg，0.1mmol)置于反应瓶中，加入5mL无水DMF，搅拌溶解后加入无水K2CO3(16.5mg，0.12mmol，1.2eq)和溴苄(13μL，0.11mmol，1.1eq)，室温反应过夜，所得反应液用乙酸乙酯和水分散，萃取，有机层以水洗涤，无水硫酸镁干燥，过滤，减压回收乙酸乙酯至干，所得残留物经硅胶柱层析纯化，即得目标产物T-53，收率85％。1HNMR(400MHz,CDCl3)δ7.96(dd,J＝12.6,4.9Hz,4H),7.91–7.86(m,4H),7.65(d,J＝2.0Hz,1H),7.57–7.45(m,6H),7.42–7.29(m,10H),7.15(t,J＝7.8Hz,2H),6.93(d,J＝8.7Hz,1H),6.64(d,J＝2.2Hz,1H),6.38(d,J＝2.2Hz,1H),6.02(t,J＝9.1Hz,1H),5.84–5.74(m,2H),5.63(d,J＝7.2Hz,1H),5.25(s,2H),4.79–4.73(m,1H),4.54–4.45(m,2H),3.92(s,3H),3.86(s,3H),3.83(s,3H)。 Preparation steps: T-01 (93 mg, 0.1 mmol) was weighed into a reaction flask, 5 mL of anhydrous DMF was added, stirred and dissolved, and anhydrous K 2 CO 3 (16.5 mg, 0.12 mmol, 1.2 eq) and benzyl bromide were added. 13 μL, 0.11 mmol, 1.1 eq), mp. The residue was purified by silica gel column chromatography to give the desired product T-53. 1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (dd, J = 12.6, 4.9 Hz, 4H), 7.91 - 7.86 (m, 4H), 7.65 (d, J = 2.0 Hz, 1H), 7.57 - 7.45 (m) , 6H), 7.42 - 7.29 (m, 10H), 7.15 (t, J = 7.8 Hz, 2H), 6.93 (d, J = 8.7 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 6.38 (d, J = 2.2 Hz, 1H), 6.02 (t, J = 9.1 Hz, 1H), 5.84 - 5.74 (m, 2H), 5.63 (d, J = 7.2 Hz, 1H), 5.25 (s, 2H) , 4.79 - 4.73 (m, 1H), 4.54 - 4.45 (m, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H).
(三)所合成的黄酮糖苷α--葡萄糖苷酶抑制活性测试(III) Test of flavonoid glycoside α-glucosidase inhibitory activity
具体采用《α-葡萄糖苷酶抑制剂微量筛选模型的正交法构建和筛选》(杨付梅，孙黔云，中国药理学通报，2009，245(8)：1113-6)中的方法。Specifically, the method of "orthogonal construction and screening of α-glucosidase inhibitor micro-screening model" (Yang Fumei, Sun Xiaoyun, Chinese Pharmacological Bulletin, 2009, 245(8): 1113-6) was used.
3.1 材料与仪器3.1 Materials and instruments
α-葡萄糖苷酶、牛血清白蛋白(BSA)购自Sigma公司；对硝基苯-α-葡萄糖昔(PNPG)购自F1uka公司；阿卡波糖为拜耳公司产品；其它试剂均为进口或国产分析纯；黄酮糖苷衍生物为本专利前述实施例所合成的目标化合物。550型酶标仪(美国Bio-Rad公司)；单道、多道移液器(德国Eppendorf公司)；96孔酶标板(德国Greiner公司)。Α-glucosidase, bovine serum albumin (BSA) was purchased from Sigma; p-nitrophenyl-α-glucose (PNPG) was purchased from F1uka; acarbose was manufactured by Bayer; other reagents were imported or Domestic analytically pure; flavonoid glycoside derivatives are the target compounds synthesized in the foregoing examples of the patent. 550 type microplate reader (Bio-Rad, USA); single-channel, multi-channel pipette (Eppendorf, Germany); 96-well microtiter plate (Greiner, Germany).
3.2 方法3.2 Methods
酶反应试液制备：α--葡萄糖苷酶：将酶冻干粉用pH7.4的0.1mol·L-1含0.1％BSA的磷酸盐缓冲液(phosphate buffer，PB)配制成溶液，分装，-20℃冻存备用。底物(PNPG)的配制：PNPG用pH7.4的0.1mol·L-1PB配制成10mmol·L-1的工作液。Preparation of enzyme reaction test solution: α--glucosidase: The enzyme lyophilized powder is prepared into a solution by using 0.1 mol·L -1 phosphate buffer (PB) containing 0.1% BSA at pH 7.4, and dispensing Store at -20 °C for later use. Preparation of substrate (PNPG): PNPG was prepared into a working solution of 10 mmol·L -1 with 0.1 mol·L -1 PB of pH 7.4.
待测样品试液的制备：取待测黄酮糖苷衍生物用DMSO溶解,浓度为1×10-2mol·L-1，用0.1mol·L-1PB稀释10倍备用。Preparation of test sample to be tested: The flavonoid glycoside derivative to be tested was dissolved in DMSO at a concentration of 1×10 -2 mol·L -1 and diluted 10 times with 0.1 mol·L -1 PB for use.
活性测定：取10μL稀释好的待测样品与50μLPB、20μL酶液混合，37℃孵育10min，然后加入20μL底物，37℃反应10min，加入反应终止剂后测定405nmOD值。阿卡波糖为阳性对照药物。Activity measurement: 10 μL of the diluted sample to be tested was mixed with 50 μL of LPB and 20 μL of the enzyme solution, incubated at 37 ° C for 10 min, then 20 μL of the substrate was added, reacted at 37 ° C for 10 min, and the 405 nm OD value was measured after the reaction terminator was added. Acarbose is a positive control drug.
3.3 筛选结果3.3 Screening results
以α-葡萄糖苷酶为酶源构建的筛选模型其信噪比为10.4。在所筛选的35个样品中,抑制率在20％～50％的样品有14个，抑制率在50％～80％的样品有5个，抑制率大于80％的样品有2个，其余为小于20％的样品。部分具有代表性的黄酮糖苷衍生物活性筛选结果见表1和表2，其中活性较好的T--24号样品的IC50值为1.93×10-5mol·L-1，阳性药物阿卡波糖的IC50值为2.47×10-9mol·L-1。本发明提供的黄酮糖苷衍生物显示出对α-葡萄糖苷酶具有较好抑制作用，从而使淀粉类分解为葡萄糖的速度减慢，从而减缓肠道内葡萄糖的吸收，降低餐后高血糖，可以用于制备治疗糖尿病的药物。 The screening model constructed with α-glucosidase as the enzyme source has a signal-to-noise ratio of 10.4. Among the 35 samples screened, there were 14 samples with inhibition rate of 20% to 50%, 5 samples with inhibition rate of 50% to 80%, and 2 samples with inhibition rate of more than 80%. Less than 20% of the sample. The screening results of some representative flavonoid glycoside derivatives are shown in Table 1 and Table 2. The better activity of the T--24 sample has an IC 50 value of 1.93×10 -5 mol·L -1 , and the positive drug Aka The IC 50 value of the wave sugar is 2.47 × 10 -9 mol·L -1 . The flavonoid glycoside derivative provided by the invention exhibits a good inhibitory effect on α-glucosidase, thereby slowing down the decomposition of starch into glucose, thereby slowing the absorption of glucose in the intestinal tract and reducing postprandial hyperglycemia. For the preparation of drugs for the treatment of diabetes.
表1 所合成的黄酮糖苷衍生物对α-葡萄糖苷酶抑制活性筛选结果(第一批次)Table 1 Screening results of α-glucosidase inhibitory activity of flavonoid glycoside derivatives synthesized (first batch)
Figure PCTCN2014086933-appb-000067
Figure PCTCN2014086933-appb-000067
注：1.阿卡波糖为阳性对照，其分子量为645.6；Note: 1. Acarbose is a positive control with a molecular weight of 645.6;
2.本实验样品每个浓度平行3次，重复实验2次，结果以M±SD表示。 2. Each concentration of the experimental sample was parallel 3 times, and the experiment was repeated twice, and the result was expressed by M±SD.
表2 所合成的黄酮糖苷衍生物对α-葡萄糖苷酶抑制活性筛选结果(第二批次)Table 2 Screening results of α-glucosidase inhibitory activity of flavonoid glycoside derivatives synthesized (Second batch)
Figure PCTCN2014086933-appb-000068
Figure PCTCN2014086933-appb-000068
注：1.阿卡波糖为阳性对照，其分子量为645.6；Note: 1. Acarbose is a positive control with a molecular weight of 645.6;
2.本实验样品每个浓度平行3次，重复实验2次，结果以M±SD表示。 2. Each concentration of the experimental sample was parallel 3 times, and the experiment was repeated twice, and the result was expressed by M±SD.

Claims (10)

  1. 一类黄酮糖苷衍生物，其特征在于：结构通式为下述通式I的化合物或其药学上可接受的盐或水合物，包括其消旋体、光学异构体及差向异构体：A flavonoid glycoside derivative characterized by having a compound of the formula I or a pharmaceutically acceptable salt or hydrate thereof, including racemates, optical isomers and epimers thereof :
    Figure PCTCN2014086933-appb-100001
    Figure PCTCN2014086933-appb-100001
    其中，RX为R1或R1′，R1代表β-D-吡喃葡萄糖基、β-D-吡喃半乳糖基、β-D-乳糖基或β-D-麦芽糖基；R1'代表2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖基、2,3,4,6-四-O-苯甲酰基-β-D-吡喃葡萄糖基、2,3,4,6-四-O-苯甲酰基-β-D-吡喃半乳糖基、2,3,6,2',3',4',6'-七-O-苯甲酰基-β-D-乳糖基或2,3,6,2',3',4',6'-七-O-苯甲酰基-β-D-麦芽糖基；R2代表氢、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH2CH2CH3、-CH(CH3)CH2CH3或-CH2CH(CH3)CH3；R3和R4分别选自氢、C1-C6直链或支链烷基、苄基、-COR、-CH2CH2OH、-CH2CH2CH2OH、-(CH2)nNRR'或-(CH2)nCOOH；R5选自氢、C1-C6直链或支链烷基、苄基、-COR、-CH2CH2OH、-CH2CH2CH2OH、-(CH2)nNRR'、-(CH2)nCOOH、β-D-吡喃葡萄糖基、β-D-吡喃半乳糖基；前述R、R'选自相同或不同的C1-C6直链或支链烷基，或C3-C7环烷基；n为1至4的整数。Wherein R X is R 1 or R 1 ', and R 1 represents β-D-glucopyranosyl, β-D-galactopyranosyl, β-D-lactosyl or β-D-maltosyl; R 1 'Represents 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl, 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl , 2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl, 2,3,6,2',3',4',6'-seven-O-benzene Formyl-β-D-lactosyl or 2,3,6,2',3',4',6'-hepta-O-benzoyl-β-D-maltosyl; R 2 represents hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 or -CH 2 CH ( CH 3 )CH 3 ; R 3 and R 4 are each independently selected from hydrogen, C1-C6 straight or branched alkyl, benzyl, -COR, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, - (CH 2 )nNRR' or -(CH 2 )nCOOH; R 5 is selected from hydrogen, C 1 -C 6 straight or branched alkyl, benzyl, -COR, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, —(CH 2 ) n NRR′, —(CH 2 ) n COOH, β-D-glucopyranosyl, β-D-galactopyranosyl; the foregoing R, R′ are selected from the same or Different C1-C6 linear or branched alkyl groups, or C3-C7 cycloalkyl groups; n is an integer from 1 to 4.
  2. 根据权利要求1所述的一类黄酮糖苷衍生物，其特征在于：所述烷基和环烷基可被1～2个羟基、硝基、卤代基、氰基或三氟甲基取代。A flavonoid glycoside derivative according to claim 1, wherein the alkyl group and the cycloalkyl group are substituted by 1 to 2 hydroxyl groups, a nitro group, a halogen group, a cyano group or a trifluoromethyl group.
  3. 根据权利要求1所述的一类黄酮糖苷衍生物，其特征在于：所述黄酮糖苷衍生物为3,5,3'-三甲氧基-4'-羟基-7-O-β-D-(2,3,4,6-四-O-苯甲酰基)-葡萄糖基-黄酮、3,5,3'-三甲氧基-4'-羟基-7-O-β-D-葡萄糖基-黄酮、3,5,3'-三-乙氧基-4'-羟基-7-O-β-D-葡萄糖基-黄酮、3-甲氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5,3',4'-三羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5,3',4'-三羟基-7-O-β-D-葡萄糖基-黄酮、3-甲氧基-5,3',4'-三正戊氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5,3',4'-三正戊氧基-7-O-β-D-葡萄糖基 -黄酮、3,5-二甲氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3,5-二甲氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-甲氧基-5-乙氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-乙氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-乙氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-甲氧基-5-丙氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-丙氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-丙氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-甲氧基-5-乙氧羰基甲氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-乙氧羰基甲氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-羧甲氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-乙氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-乙氧基-5-羟基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-乙氧基-5-羟基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-丙氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-丙氧基-5-羟基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-丙氧基-5-羟基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-丙氧基-5-甲氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-丙氧基-5-甲氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-丙氧基-5-甲氧基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-丙氧基-5-甲氧基-3'-二羟基-4'-羟丙氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-异丁氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-异丁氧基-5-羟基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-异丁氧基-5-羟基-3',4'-二羟基-7-O-β-D-葡萄糖基-黄酮、3-异丁氧基-5,3',4'-三甲氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-异丁氧基-5,3',4'-三甲氧基-7-O-β-D-葡萄糖基-黄酮、3-异丁氧基-5,3',4'-三正己氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-异丁氧基-5,3',4'-三正己氧基-7-O-β-D-葡萄糖基-黄酮、3-异丁氧基-5,3',4'-三-(羟丙氧基)-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-异丁氧基-5,3',4'-三-(羟丙氧基)-7-O-β-D-葡萄糖基-黄酮、3,5,3'-三甲氧基-4'-羟基-7-O-β-D-半乳糖基-黄酮、3,5,3'-三乙氧基-4'-羟基-7-O-β-D-半乳糖基-黄酮、3-甲氧基-5-羟基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基半乳糖基-黄酮、3-甲氧基-5,3',4'-三羟基-7-O-β-D-苯甲酰基半乳糖基-黄酮、3-甲氧基-5,3',4'-三羟基-7-O-β-D-半乳糖基-黄酮、3,5,3'-三甲氧基-7,4’-二-O-β-D-(2,3,4,6-四-O-苯甲酰基)-葡萄糖基-黄酮、3,5,3'- 三甲氧基-7,4’-二-O-β-D-葡萄糖基-黄酮、3-甲氧基-5,3',4'-三-(乙酰氧基)-7-O-β-D-乙酰基葡萄糖基-黄酮、3-乙氧基-5-甲氧基-3',4'-O-二苯基甲叉-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-乙氧基-5-甲氧基-3',4'-二羟基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5-乙氧基-3'-羟基-4'-苄氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5,3'-二-羟基-4'-苄氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3-甲氧基-5,3'-二-丙氧基-4'-苄氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮、3,5-二-甲氧基-3',4'-二-羟丙氧基7-O-β-D-苯甲酰基葡萄糖基-黄酮或3,5,3'-三-甲氧基-4'-苄氧基-7-O-β-D-苯甲酰基葡萄糖基-黄酮。A flavonoid glycoside derivative according to claim 1, wherein the flavonoid glycoside derivative is 3,5,3'-trimethoxy-4'-hydroxy-7-O-β-D- ( 2,3,4,6-tetra-O-benzoyl)-glucosyl-flavonoid, 3,5,3'-trimethoxy-4'-hydroxy-7-O-β-D-glucosyl-flavonoid ,3,5,3'-tris-ethoxy-4'-hydroxy-7-O-β-D-glucosyl-flavonoid, 3-methoxy-5-hydroxy-3',4'-O- Diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5,3',4'-trihydroxy-7-O-β-D-benzoyl Glucosyl-flavonoids, 3-methoxy-5,3',4'-trihydroxy-7-O-β-D-glucosyl-flavonoids, 3-methoxy-5,3',4'-three n-pentyloxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5,3',4'-tri-n-pentyloxy-7-O-β-D-glucose Base -Flavone, 3,5-dimethoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3,5-dimethoxy-3',4 '-Dihydroxy-7-O-β-D-glucosyl-flavonoid, 3-methoxy-5-ethoxy-3',4'-O-diphenylmethylidene-7-O-β- D-benzoyl glucosyl-flavonoid, 3-methoxy-5-ethoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methyl Oxy-5-ethoxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid, 3-methoxy-5-propoxy-3',4'-O -diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5-propoxy-3',4'-dihydroxy-7-O-β- D-benzoyl glucosyl-flavonoid, 3-methoxy-5-propoxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid, 3-methoxy- 5-ethoxycarbonylmethoxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5-ethoxycarbonyl Methoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5-carboxymethoxy-3',4'-dihydroxy -7-O-β-D-glucosyl-flavonoid, 3-ethoxy-5-hydroxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoylglucose Base-flavonoids, 3-ethoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-ethoxy-5-hydroxy-3', 4' -dihydroxy-7-O-β-D-glucosyl-flavonoid, 3-propoxy-5-hydroxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzene Formyl glucosyl-flavonoid, 3-propoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-propoxy-5- Hydroxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid, 3-propoxy-5-methoxy-3',4'-O-diphenylmethine- 7-O-β-D-benzoyl glucosyl-flavonoid, 3-propoxy-5-methoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl -Flavone, 3-propoxy-5-methoxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoid, 3-propoxy-5-methoxy-3 '-Dihydroxy-4'-hydroxypropoxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-isobutoxy-5-hydroxy-3',4'-O-diphenyl甲甲叉-7-O-β-D-benzoyl glucosyl-flavonoid, 3-isobutoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-benzoic acid Acylglucosyl-flavonoids, 3-isobutoxy-5-hydroxy-3',4'-dihydroxy-7-O-β-D-glucosyl-flavonoids, 3-isobutoxy-5,3' , 4'-three -7-O-β-D-benzoyl glucosyl-flavonoid, 3-isobutoxy-5,3',4'-trimethoxy-7-O-β-D-glucosyl-flavonoid, 3-isobutoxy-5,3',4'-tri-n-hexyloxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-isobutoxy-5,3',4' - Tri-n-hexyloxy-7-O-β-D-glucosyl-flavonoid, 3-isobutoxy-5,3',4'-tris-(hydroxypropoxy)-7-O-β-D -benzoylglucosyl-flavonoid, 3-isobutoxy-5,3',4'-tris-(hydroxypropoxy)-7-O-β-D-glucosyl-flavonoid, 3,5, 3'-Trimethoxy-4'-hydroxy-7-O-β-D-galactosyl-flavonoid, 3,5,3'-triethoxy-4'-hydroxy-7-O-β-D -galactosyl-flavonoid, 3-methoxy-5-hydroxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoylgalactosyl-flavonoid, 3- Methoxy-5,3',4'-trihydroxy-7-O-β-D-benzoylgalactosyl-flavonoid, 3-methoxy-5,3',4'-trihydroxy-7 -O-β-D-galactosyl-flavonoid, 3,5,3'-trimethoxy-7,4'-di-O-β-D-(2,3,4,6-tetra-O- Benzoyl)-glucosyl-flavonoids, 3,5,3'- Trimethoxy-7,4'-di-O-β-D-glucosyl-flavonoid, 3-methoxy-5,3',4'-tris-(acetoxy)-7-O-β- D-acetylglucosyl-flavonoid, 3-ethoxy-5-methoxy-3',4'-O-diphenylmethylidene-7-O-β-D-benzoyl glucosyl-flavonoid 3-ethoxy-5-methoxy-3',4'-dihydroxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5-ethoxy- 3'-Hydroxy-4'-benzyloxy-7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5,3'-di-hydroxy-4'-benzyloxy- 7-O-β-D-benzoyl glucosyl-flavonoid, 3-methoxy-5,3'-di-propoxy-4'-benzyloxy-7-O-β-D-benzoic acid Acylglucosyl-flavonoids, 3,5-di-methoxy-3',4'-di-hydroxypropoxy 7-O-β-D-benzoyl glucosyl-flavonoids or 3,5,3' Tris-methoxy-4'-benzyloxy-7-O-β-D-benzoyl glucosyl-flavonoid.
  4. 根据权利要求1～3任一项所述的一类黄酮糖苷衍生物，其特征在于：药学上可接受的盐为含有羧基的黄酮糖苷衍生物化合物与碱性物质反应得到或者含有氨基的黄酮糖苷衍生物化合物与酸性物质反应得到。A flavonoid glycoside derivative according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is a flavonoid glycoside obtained by reacting a flavonoid glycoside derivative compound containing a carboxyl group with a basic substance or containing an amino group. The derivative compound is obtained by reacting with an acidic substance.
  5. 根据权利要求4所述的一类黄酮糖苷衍生物，其特征在于：所述的碱性物质为碱金属或碱土金属的氢氧化物、碳酸盐、碳酸氢盐、三甲胺、三乙胺；所述的酸性物质为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、三氟甲磺酸、甲酸、乙酸、草酸或柠檬酸。The flavonoid glycoside derivative according to claim 4, wherein the basic substance is an alkali metal or alkaline earth metal hydroxide, carbonate, hydrogencarbonate, trimethylamine or triethylamine; The acidic substance is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, oxalic acid or citric acid.
  6. 如权利要求1～5任一项所述的黄酮糖苷衍生物的制备方法，其特征在于：按照以下合成路线I进行：以芦丁为原料经双苄基化得I-1，I-1经酸水解得I-2，I-2经烷基化得I-3，I-3经催化氢化得I-4，I-4经选择性糖基化反应得I-5，I-5经烷基化反应得I-6，I-6经甲醇钠处理脱酰基保护得I-7，The method for producing a flavonoid glycoside derivative according to any one of claims 1 to 5, which is characterized in that it is carried out according to the following Scheme I: bis-benzylation using rutin as a raw material to obtain I-1, I-1 Acid hydrolysis gives I-2, I-2 is alkylated to give I-3, I-3 is catalytically hydrogenated to give I-4, and I-4 is selectively glycosylated to give I-5, I-5 via alkane. The basic reaction gives I-6, and the I-6 is deacylated by sodium methoxide to obtain I-7.
    Figure PCTCN2014086933-appb-100002
    Figure PCTCN2014086933-appb-100002
    Figure PCTCN2014086933-appb-100003
    Figure PCTCN2014086933-appb-100003
    其中，Ry为芸香糖基，反应条件i为BnBr，DMF，K2CO3，室温；反应条件ii为HCl，MeOH，60℃；反应条件iii为R2I，DMF，K2CO3，室温；反应条件iv为H2，10％Pd/C，MeOH，室温；反应条件v为R1Br，四丁基溴化铵，CHCl3/H2O，K2CO3，室温；反应条件vi为R5I，DMF，K2CO3，室温；反应条件vii为NaOMe，MeOH，室温。Wherein Ry is a rutose group, reaction conditions i are BnBr, DMF, K 2 CO 3 , room temperature; reaction conditions ii are HCl, MeOH, 60 ° C; reaction conditions iii are R 2 I, DMF, K 2 CO 3 , room temperature ; reaction condition iv is H 2 , 10% Pd / C, MeOH, room temperature; reaction conditions v is R 1 Br, tetrabutylammonium bromide, CHCl 3 /H 2 O, K 2 CO 3 , room temperature; reaction conditions vi R 5 I, DMF, K 2 CO 3 , room temperature; reaction conditions vii is NaOMe, MeOH, room temperature.
  7. 如权利要求1～5任一项所述的一类黄酮糖苷衍生物的制备方法，其特征在于：按照以下合成路线II进行：以芦丁为原料经三苄基化得II-1，II-1经酸水解得II-2，II-2经烷基化得II-3，II-3经催化氢化得II-4，II-4与二苯基二氯甲烷反应得产物II-5，II-5经选择性糖基化反应得II-6，II-6经烷基化反应得II-7，II-7经催化氢化得得II-8，II-8经烷基化反应得II-9，II-9经烷基化反应得II-10，II-10经甲醇钠处理脱酰基保护得II-11，The method for preparing a flavonoid glycoside derivative according to any one of claims 1 to 5, which is characterized in that it is carried out according to the following Scheme II: tribenzylation with rutin as a raw material to obtain II-1,II- 1 by acid hydrolysis to obtain II-2, II-2 is alkylated to obtain II-3, II-3 is catalytically hydrogenated to obtain II-4, II-4 and diphenylmethylene chloride to obtain the product II-5, II -5 is selectively glycosylated to give II-6, II-6 is alkylated to give II-7, II-7 is catalytically hydrogenated to obtain II-8, II-8 is alkylated to give II- 9, II-9 is alkylated to give II-10, II-10 is deacylated by sodium methoxide treatment to obtain II-11,
    Figure PCTCN2014086933-appb-100004
    Figure PCTCN2014086933-appb-100004
    Figure PCTCN2014086933-appb-100005
    Figure PCTCN2014086933-appb-100005
    其中，Ry为芸香糖基，反应条件i为BnBr，DMF，K2CO3，室温；反应条件ii为HCl，MeOH，60℃；反应条件iii为R3I，DMF，K2CO3，室温；反应条件iv为H2，10％Pd/C，MeOH，室温；反应条件v为Ph2CCl2，Ph2O，180℃；反应条件vi为R1Br，四丁基溴化铵或四丁基碘化铵，CHCl3/H2O，K2CO3，室温；反应条件vii为R2I，DMF，K2CO3，室温；反应条件viii为H2，10％Pd/C，MeOH/THF，室温；反应条件ix为R5I，DMF，K2CO3，室温；反应条件x为R4I，DMF，K2CO3，室温；反应条件xi为NaOMe，MeOH，室温。Wherein Ry is a rutose group, reaction conditions i are BnBr, DMF, K 2 CO 3 , room temperature; reaction conditions ii are HCl, MeOH, 60 ° C; reaction conditions iii are R 3 I, DMF, K 2 CO 3 , room temperature ; reaction conditions iv is H 2 , 10% Pd / C, MeOH, room temperature; reaction conditions v is Ph 2 CCl 2 , Ph 2 O, 180 ° C; reaction conditions vi is R 1 Br, tetrabutylammonium bromide or four Butyl ammonium iodide, CHCl 3 /H 2 O, K 2 CO 3 , room temperature; reaction conditions vii is R 2 I, DMF, K 2 CO 3 , room temperature; reaction conditions viii is H 2 , 10% Pd/C, MeOH/THF, room temperature; reaction condition ix is R 5 I, DMF, K 2 CO 3 , room temperature; reaction condition x is R 4 I, DMF, K 2 CO 3 , room temperature; reaction condition xi is NaOMe, MeOH, room temperature.
  8. 如权利要求1～5任一项所述的黄酮糖苷衍生物在制备治疗糖尿病药物中的应用。The use of the flavonoid glycoside derivative according to any one of claims 1 to 5 for the preparation of a medicament for treating diabetes.
  9. 根据权利要求8所述的黄酮糖苷衍生物的应用，其特征在于：取黄酮糖苷衍生物，加入一种或多种药学上可接受的载体或赋形剂，制备成各种治疗糖尿病药物制剂。The use of the flavonoid glycoside derivative according to claim 8, wherein the flavonoid glycoside derivative is added, and one or more pharmaceutically acceptable carriers or excipients are added to prepare various therapeutic pharmaceutical preparations for diabetes.
  10. 根据权利要求8或9所述的黄酮糖苷衍生物的应用，其特征在于：所述的治疗糖尿病药物制剂为口服制剂：片剂、胶囊剂、口服液、混悬液；或者注射制剂：可注射的溶液、混悬液、粉针剂；或者外用制剂：软膏或溶液。 The use of the flavonoid glycoside derivative according to claim 8 or 9, wherein the therapeutic pharmaceutical preparation for diabetes is an oral preparation: a tablet, a capsule, an oral solution, a suspension; or an injection preparation: injectable Solution, suspension, powder injection; or external preparation: ointment or solution.
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