WO2022007765A1 - 一类五环三萜类碳苷化合物及其制备方法和用途 - Google Patents

一类五环三萜类碳苷化合物及其制备方法和用途 Download PDF

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WO2022007765A1
WO2022007765A1 PCT/CN2021/104599 CN2021104599W WO2022007765A1 WO 2022007765 A1 WO2022007765 A1 WO 2022007765A1 CN 2021104599 W CN2021104599 W CN 2021104599W WO 2022007765 A1 WO2022007765 A1 WO 2022007765A1
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substituted
unsubstituted
group
sulfonyl
acid
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PCT/CN2021/104599
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English (en)
French (fr)
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柳红
王江
刘怡楚
于常跃
王一冰
蒋华良
陈凯先
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中国科学院上海药物研究所
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Priority to CA3185288A priority Critical patent/CA3185288A1/en
Priority to EP21838780.1A priority patent/EP4180445A1/en
Priority to AU2021304754A priority patent/AU2021304754A1/en
Priority to JP2023501493A priority patent/JP2023533557A/ja
Priority to KR1020237004426A priority patent/KR20230043878A/ko
Publication of WO2022007765A1 publication Critical patent/WO2022007765A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the invention relates to the fields of medicinal chemistry and medicine, in particular to a class of pentacyclic triterpenoid carbon glycoside compounds, a preparation method thereof, and the effects of treating metabolic diseases and antiviral, in particular being prepared for the treatment of diabetes, influenza, and coronavirus caused by Medicinal uses for diseases such as pneumonia.
  • Diabetes Mellitus is a chronic, systemic and metabolic disease caused by the long-term combined action of genetic factors and environmental factors. It is characterized by increased plasma glucose levels, mainly due to insufficient insulin secretion or dysfunction in the body. A disease that affects normal physiological activities due to the disorder of sugar, fat, and protein metabolism caused by resistance).
  • the complications of diabetes can be divided into acute complications and chronic complications. Among them, acute complications include diabetic ketoacidosis, diabetic hyperosmolar coma, various acute infections and lactic acidosis.
  • hypoglycemia is also one of the most common acute complications; chronic complications include diabetic eye disease, diabetic nephropathy, diabetic psychiatric disease, diabetic heart, brain and limb macrovascular disease, diabetic foot and skin disease, etc.
  • the main clinical manifestations of diabetes are polydipsia, polyuria, polyphagia and weight loss.
  • Type II diabetes Diabetes is divided into insulin-dependent diabetes mellitus (Insulin-dependent diabetes mellitus, IDDM, namely type I diabetes) and non-insulin-dependent diabetes is the most common, accounting for more than 90% of diabetic patients.
  • IDDM insulin-dependent diabetes mellitus
  • non-insulin-dependent diabetes is the most common, accounting for more than 90% of diabetic patients.
  • the exact etiology and pathogenesis of type I diabetes are not very clear.
  • the etiology is a combination of genetic and environmental factors, mainly due to the damage of islet B cells in the body, resulting in the inability to produce insulin in the body.
  • Patients need daily insulin injections to control their blood levels. insulin levels.
  • Type 2 diabetes is a type of metabolic syndrome caused by the inability to control blood sugar levels in the body and is characterized by hyperglycemia, insulin resistance, and lack of insulin secretion.
  • the cause of type II diabetes is mainly due to insulin resistance, which makes the body unable to use insulin effectively, or the reduction of insulin secretion cannot meet the body's needs. Because these diabetic patients can secrete insulin, they generally do not need insulin therapy, and they can control blood sugar only with dietary adjustment or oral hypoglycemic drugs.
  • Pentacyclic triterpenoids are secondary plant metabolites found in a variety of plant organs, with some species present in amounts as high as 30% of their dry weight. Although the molecular mechanism remains unclear, triterpenoids are widely recognized as important components of plants' defense systems against pathogens and herbivores. It has been reported that some glycoside pentacyclic triterpenoids have in vitro anti-influenza virus activity comparable to or higher than oseltamivir. Mechanistic studies have shown that these compounds bind tightly to the hemagglutinin (HA) protein, thereby disrupting the interaction of hemagglutinin with sialic acid receptors and preventing virus entry into host cells, a process that is not susceptible to drug resistance.
  • HA hemagglutinin
  • oxyglycosides and nitrogen glycosides are easily oxidatively metabolized in the body, while carbon glycosides show good metabolic stability both in vivo and in vitro, which makes carbon glycosides widely concerned by scientists. Therefore, pentacyclic triterpenoid carbon glycosides have very bright prospects in the research and development of hypoglycemic drugs and antiviral drugs.
  • the object of the present invention is to provide a pentacyclic triterpene carboside derivative compound represented by general formula I or a pharmaceutically acceptable salt, racemate, R-isomer or S-isomer or their mixture.
  • the first aspect of the present invention provides a pentacyclic triterpene carbon glycoside derivative compound having the structure shown in the following general formula I, or its racemate, R-isomer, S-isomer, Pharmaceutically acceptable salts or mixtures thereof:
  • Ring A is selected from the group consisting of a 6-membered saturated carbocycle or an unsaturated carbocycle;
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl;
  • R 4 is selected from the group consisting of hydrogen, isopropenyl;
  • R 5 is selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, amino, nitro, hydroxyl, mercapto, aldehyde, carboxyl, sulfonyl, phosphate, substituted or unsubstituted C 1 -C 6 alkyl , substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen 5-7 membered heterocycle, substituted or unsubstituted C 1 -C 6 alkyl-phenyl, substituted or unsubstituted C 3 -C 12 cycloalkyl, substituted or unsubstituted C 2 -C 10 acyl, Substituted or unsubstituted C 2 -C 10 ester group, substituted or unsubstituted C 6 -C 10
  • Y is selected from the group :-( CH 2) m CHR 9 - , a carbonyl group, -CONH -, - COO-;
  • n 0 or 1
  • R 7 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted containing 1-3 selected from oxygen, sulfur 5-7-membered heterocycle, substituted or unsubstituted C 2 -C 10 ester group, substituted or unsubstituted C 5 -C 9 furanosyl group, substituted or unsubstituted C 5 - C 9 pyranosyl;
  • R 8 is selected from the group consisting of: hydrogen, deuterium, tritium, halo, cyano, amino, nitro, hydroxyl, mercapto group, aldehyde group, a carboxyl group, a sulfonyl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted or unsubstituted C1-C6 alkyl-phenyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C6-
  • R 9 is selected from the group consisting of: hydrogen, deuterium, tritium, halo, cyano, amino, nitro, hydroxy, mercapto;
  • R 6 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted containing 1-3 selected from oxygen, sulfur 5-7-membered heterocycle, substituted or unsubstituted C 5 -C 9 furanosyl, substituted or unsubstituted C 5 -C 9 pyranosyl with heteroatoms in nitrogen; the substitution refers to sugar
  • substituents selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, amino, nitro, mercapto, aldehyde, carboxyl, benzyl, substituted or unsubstituted C 1 -C 12 alkoxycarbonyl, substituted or unsubstituted C 2 -C 12 alkylaminocarbonyl, substituted or unsub
  • X is selected from the group consisting of: -CHR 9 -, a carbonyl group, S, -NHC (O) -R 8, -NHS (O) 2 -R 8, -NHC (O) NH-R 8, -NHC (S) NH -R 8 , -COO-, -OS(O) 2 -R 8 ;
  • n 1 or 2;
  • the substitution refers to the hydrogen atom on the corresponding group, or the hydroxyl group on the sugar ring is replaced by one or more substituents selected from the following group: deuterium, tritium, halogen, hydroxyl , carboxyl, mercapto, benzyl, C 1 -C 12 alkoxycarbonyl, C 1 -C 6 aldehyde, amino, C 1 -C 6 amido, nitro, cyano, unsubstituted or halogenated C 1 -C 6 alkyl, C 2 -C 10 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-amino, C 6 -C 10 aryl, five- or six-membered heteroaryl , five- or six-membered non-aromatic heterocyclic group, -O-(C 6 -C 10 aryl), -O-(five- or six-membered heteroaryl),
  • the compound of formula I has the structure shown in the following general formula II:
  • R 5 is selected from the group consisting of: hydrogen, deuterium, tritium, halo, cyano, amino, nitro, hydroxyl, mercapto group, aldehyde group, a carboxyl group, a sulfonyl group, a phosphoric acid group, a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroatoms containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen Ring, substituted or unsubstituted C1-C6 alkyl-phenyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C6-
  • X is selected from the group consisting of -CHR 9 -, carbonyl
  • R 6 is selected from the group consisting of substituted or unsubstituted C5-C9 furanosyl, substituted or unsubstituted C5-C9 pyranosyl; the substitution refers to that one or more hydrogens or hydroxyl groups on the sugar ring are selected Substituents substituted from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, amino, nitro, mercapto, aldehyde, carboxyl, benzyl, substituted or unsubstituted C1-C12 alkoxycarbonyl, substituted or unsubstituted C2-C12 alkylaminocarbonyl, substituted or unsubstituted C2-C10 acyl, sulfonyl, phosphoryl, C5-C9 furanosyl, C5-C9 pyranosyl;
  • R 9 is selected from the group consisting of: hydrogen, deuterium, tritium, halo, cyano, amino, nitro, hydroxy, mercapto;
  • Ring A is selected from the group consisting of a 6-membered saturated carbocycle or an unsaturated carbocycle;
  • n 1 or 2.
  • the compound of formula I has the structure shown in the following general formula III:
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl;
  • R 4 is selected from the group consisting of: hydrogen, isopropenyl
  • R 7 is selected from the group consisting of hydrogen, substituted or unsubstituted C5-C9 furanosyl, substituted or unsubstituted C5-C9 pyranosyl; the substitution refers to one or more hydrogens or hydroxyl groups on the sugar ring Substituted with a substituent selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, amino, nitro, mercapto, aldehyde, carboxyl, benzyl, substituted or unsubstituted C1-C12alkoxycarbonyl, substituted or Unsubstituted C1-C12 alkylaminocarbonyl, substituted or unsubstituted C2-C10 acyl, sulfonyl, phosphoryl, C5-C9 furanosyl, C5-C9 pyranosyl;
  • Y is selected from the group :-( CH 2) m CHR 9 - , a carbonyl group;
  • n 0, 1;
  • R 9 is selected from the group consisting of: hydrogen, deuterium, tritium, halo, cyano, amino, nitro, hydroxy, mercapto;
  • R 9 is selected from the group consisting of: hydrogen, halo, cyano, amino, nitro, hydroxy, mercapto;
  • X is selected from the group consisting of: -CHR 9 -, a carbonyl group, S, -NHC (O) -R 8, -NHS (O) 2 -R 8, -NHC (O) NH-R 8, -NHC (S) NH -R 8 , -COO-, -OS(O) 2 -R 8 ;
  • R 6 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted containing 1-3 selected from oxygen, sulfur 5-7-membered heterocycle, substituted or unsubstituted C 5 -C 9 furanosyl, substituted or unsubstituted C 5 -C 9 pyranosyl with heteroatoms in nitrogen; the substitution refers to sugar
  • substituents selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, amino, nitro, mercapto, aldehyde, carboxyl, benzyl, substituted or unsubstituted C 1 -C 12 alkoxycarbonyl, substituted or unsubstituted C 2 -C 12 alkylaminocarbonyl, substituted or unsub
  • Ring A is selected from the group consisting of a 6-membered saturated carbocycle or an unsaturated carbocycle;
  • n 1 or 2.
  • the compound of formula I has the structure shown in the following general formula IV, V or VI:
  • R 5 is selected from the following group: hydrogen, halogen, hydroxyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C10 acyl group, substituted or unsubstituted C2-C10 ester group, substituted or unsubstituted C1-C6 amide group.
  • R 9 is selected from the following group: hydrogen, hydroxyl, aldehyde group, mercapto group, or -XR 6 ;
  • X is selected from the group consisting of: -CHR 9 -, a carbonyl group, S, -NHC (O) -R 8, -NHS (O) 2 -R 8, -NHC (O) NH-R 8, -NHC (S) NH -R 8 , -COO-, -OS(O) 2 -R 8 ;
  • R 6 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted containing 1-3 selected from oxygen, sulfur and nitrogen 5-7-membered heterocyclic ring, substituted or unsubstituted C 5 -C 9 furanosyl group, substituted or unsubstituted C 5 -C 9 pyranosyl group of heteroatoms in One or more hydrogens or hydroxyl groups are substituted with substituents selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, amino, nitro, mercapto, aldehyde, carboxyl, benzyl, substituted or unsubstituted C 1- C 12 alkoxycarbonyl, substituted or unsubstituted C 2 -C 12 alkylaminocarbonyl, substituted or unsubstituted C 2 -
  • the pentacyclic triterpene carbon glycoside compound is the compound described in the embodiment:
  • the second aspect of the present invention provides a preparation method of the compound according to the first aspect of the present invention, characterized in that the preparation method comprises the following scheme 1 or scheme 2:
  • Step a compound IV and compound III are reacted to obtain the product of step a;
  • Step b reducing the product of step a to obtain the product of step b;
  • Step c performing an alkylation reaction on the product of step b to obtain the product of step c;
  • Step d use the product of step c to react with Dess-Martin reagent to obtain the compound of formula II;
  • the third aspect of the present invention provides a pharmaceutical composition
  • the pharmaceutical composition contains a therapeutically effective amount of the compound of formula I as described in the first aspect of the present invention, a pharmaceutically acceptable salt thereof, a racemate thereof , one or more of the R-isomer and the S-isomer, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, adjuvants and/or diluents.
  • the fourth aspect of the present invention provides a compound of formula I and formula II as described in the first aspect of the present invention, its racemate, R-isomer, S-isomer or pharmaceutically acceptable salt in Use in the preparation of a medicament for treating or preventing metabolic and viral diseases associated with diabetes; preferably, the diseases are selected from the group consisting of diabetes, influenza, obesity, liver fibrosis, metabolic diseases, and viral diseases.
  • Figure 1 shows the ICR mouse OGTT experimental data of A2, A4, A6, A10, A25, A43, A44, A47 and A67;
  • Figure 2 shows that A25 and A43 showed good hypoglycemic effect in vivo
  • Figure 3 shows the EC50 of A64 and the positive drug ANT777 and the effect of promoting GLP secretion in vitro;
  • Figure 4 shows that the compound of the present invention and the positive drug ribavirin show the same viral inhibition rate and low cytotoxicity, and the viral inhibition rate of the positive drug ribavirin is similar, but the cytotoxicity is lower than that of ribavirin;
  • Figure 5 shows the experimental data of A102, A104, A106, A108, A112, A114, A116, A117, A120, A121, A122, A123, A124, A125, A126, A127 and SARS-Cov-2N protein affinity;
  • Figure 6 shows the experimental data of the affinity of compounds A102, A114 and A116 with N protein
  • FIGS 7 and 8 show the experimental data of A102, A104, A114, A117, A118, A119, A120, A121, A122, A123, A124, A125, A126, A127, A128, A129 inhibiting SARS-Cov-2 virus replication
  • Figures 9 and 10 show the good in vivo PK properties of the A104 compound in mice.
  • the halogen is F, Cl, Br or I.
  • C1-C6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, propyl, isopropyl, butyl ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred.
  • C1-C6 alkoxy refers to a straight-chain or branched alkoxy having 1 to 6 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc.
  • C2-C6 alkenyl refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms containing one double bond, including non-limiting vinyl, propenyl, butenyl , isobutenyl, pentenyl and hexenyl, etc.
  • C2-C6alkynyl refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including, without limitation, ethynyl, propynyl, butyne base, isobutynyl, pentynyl and hexynyl, etc.
  • C3-C10 cycloalkyl refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, cycloheptyl, cyclooctyl and cyclodecyl, etc.
  • C3-C8 cycloalkyl “C3-C7 cycloalkyl”
  • C3-C6 cycloalkyl have similar meanings.
  • C3-C10 cycloalkenyl refers to a cyclic alkenyl having 3 to 10 carbon atoms in the ring, including, without limitation, cyclopropenyl, cyclobutenyl, cyclopentenyl , cyclohexenyl, cycloheptenyl, cyclooctenyl and cyclodecylene, etc.
  • C3-C7 cycloalkenyl has a similar meaning.
  • C1-C12 alkoxycarbonyl refers to an alkoxycarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including non-limitingly methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc.
  • C1-C12 alkylaminocarbonyl refers to an alkylaminocarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including, without limitation, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, Isopropylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, dimethylaminocarbonyl, etc.
  • C5-C9 furanosyl refers to a furanosyl group having 5 to 9 carbon atoms, wherein the 1-position of the sugar group is connected to the main chain, including non-limitingly ribofuranosyl, furan Deoxyribose, galactofuranosyl, etc.
  • C5-C9 pyranosyl refers to a pyranosyl group having 5 to 9 carbon atoms, wherein the 1-position of the sugar group is connected to the main chain, including, without limitation, glucopyranosyl group , Glucuropyranosyl, Rhamnopyranosyl, Galactopyranosyl, Mannopyranosyl, Xylopyranosyl, etc.
  • aromatic ring or “aryl” have the same meaning, preferably "aryl” is “C6-C12 aryl” or “C6-C10 aryl”.
  • C6-C12 aryl refers to an aromatic ring group having 6 to 12 carbon atoms, such as phenyl, naphthyl, and the like, without heteroatoms in the ring.
  • C6-C10 aryl has a similar meaning.
  • the terms "aromatic heterocycle” or “heteroaryl” have the same meaning and refer to a heteroaromatic group containing one to more heteroatoms.
  • the heteroatoms referred to herein include oxygen, sulfur and nitrogen.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • 3-12-membered heterocyclic group refers to a saturated or unsaturated 3-12-membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, such as Dioxolane, etc.
  • 3-7 membered heterocyclyl has a similar meaning.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position.
  • a cyclic substituent such as a heterocycloalkyl group, can be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, eg, the two rings have one carbon atom in common.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are for example (but not limited to): C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, Heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, C1-C12 alkoxycarbonyl, amino, alkoxy, C1-10 sulfonyl, etc. .
  • a pentacyclic triterpene carboside derivative compound having the structure shown in the following general formula I or general formula II, or its racemate, R-isomer, S-isomer , pharmaceutically acceptable salts or mixtures thereof:
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl;
  • R 4 is selected from the group consisting of hydrogen, isopropenyl;
  • R 5 is selected from the group consisting of: hydrogen, deuterium, tritium, halo, cyano, amino, nitro, hydroxyl, mercapto group, aldehyde group, a carboxyl group, a sulfonyl group, a phosphoric acid group, a substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heteroatoms containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen Ring, substituted or unsubstituted C1-C6 alkyl-phenyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C6-
  • R 6 is selected from the group consisting of substituted or unsubstituted C5-C9 furanosyl, substituted or unsubstituted C5-C9 pyranosyl; the substitution refers to that one or more hydrogens or hydroxyl groups on the sugar ring are selected Substituents substituted from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, amino, nitro, mercapto, aldehyde, carboxyl, benzyl, substituted or unsubstituted C1-C12 alkoxycarbonyl, substituted or unsubstituted C1-C12 alkylaminocarbonyl, substituted or unsubstituted C2-C10 acyl, sulfonyl, phosphoryl, C5-C9 furanosyl, C5-C9 pyranosyl;
  • X is selected from the group consisting of -CHR 9 -, carbonyl
  • R 9 is selected from the group consisting of: hydrogen, deuterium, tritium, halo, cyano, amino, nitro, hydroxy, mercapto;
  • Ring A is selected from the group consisting of a 6-membered saturated carbocycle or an unsaturated carbocycle;
  • n 1 or 2.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl;
  • R 4 is selected from the group consisting of hydrogen, isopropenyl;
  • R 7 is selected from the group consisting of: substituted or unsubstituted C5-C9 furanosyl, substituted or unsubstituted C5-C9 pyranosyl; said substitution means that one or more hydrogens or hydroxyl groups on the sugar ring are selected Substituents substituted from the group consisting of hydrogen, deuterium, tritium, halogen, cyano, amino, nitro, mercapto, aldehyde, carboxyl, benzyl, substituted or unsubstituted C1-C12 alkoxycarbonyl, substituted or unsubstituted C1-C12 alkylaminocarbonyl, substituted or unsubstituted C2-C10 acyl, sulfonyl, phosphoryl, C5-C9 furanosyl, C5-C9 pyranosyl;
  • Y is selected from the group :-( CH 2) mCHR 9 -, a carbonyl group;
  • m 0 or 1.
  • R 9 is selected from the group consisting of: hydrogen, deuterium, tritium, halo, cyano, amino, nitro, hydroxy, mercapto;
  • R 8 is selected from the group consisting of: hydrogen, deuterium, tritium, halo, cyano, amino, nitro, hydroxyl, mercapto group, aldehyde group, a carboxyl group, a sulfonyl group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heterocycle containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted or unsubstituted C1-C6 alkyl-phenyl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, substituted or unsubstituted C6-
  • Ring A is selected from the group consisting of a 6-membered saturated carbocycle or an unsaturated carbocycle;
  • n 1 or 2.
  • the compounds of general formula I and general formula II of the present invention are preferably the following specific compounds:
  • the compound of the present invention can be an acrylic acid derivative compound of the following general formula I or its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or mixture thereof:
  • the compounds of the present invention possess asymmetric centers, chiral axes and chiral planes, and may exist as racemates, R-isomers or S-isomers. Those skilled in the art can obtain the R-isomer and/or S-isomer from the racemate by conventional technical means.
  • the present invention provides pharmaceutically acceptable salts of compounds of general formula I and general formula II, specifically, the compounds of general formula I and general formula II react with inorganic or organic acids to form conventional pharmaceutically acceptable salts.
  • conventional pharmaceutically acceptable salts can be prepared by reacting compounds of general formula I and II with inorganic or organic acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid and phosphoric acid, etc.
  • the organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, apple acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid, etc.; or sodium, potassium, calcium, aluminum or ammonium salts formed by compounds of general formula I and II and inorganic bases; Or the methylamine salt, ethyl,
  • Another aspect of the present invention provides a preparation method of the compounds represented by the general formula I and the general formula II, and the preparation method is carried out according to the following scheme 1 and scheme 2.
  • Step a Compound IV and compound III were added to a redistilled tetrahydrofuran solution of 0.1 mol/L samarium diiodide at 0°C, and reacted under argon protection for 1 h.
  • Step b Dissolve the product of the previous step in a mixed solvent of ethyl acetate:methanol (1:1), add Pd/C, and react at 50° C. for 12 h in a hydrogen atmosphere.
  • Step c The previous step was dissolved CS 2, followed by addition of NaH (, 60% oil mixture) was stirred at room temperature for 2 hours. Then, CH 3 I was added to react overnight, then purified by column chromatography, dissolved in ultra-dry toluene, AIBN and tri-n-butyl tin hydride were added under stirring, and the mixture was stirred under reflux for 4 hours.
  • Step d Dissolve the product of the previous step in dichloromethane, add Dess Martin reagent, and stir for 2h.
  • compositions and methods of administration are provided.
  • the compound of the present invention Since the compound of the present invention has excellent hypoglycemic and influenza virus-inhibiting activities, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are
  • the pharmaceutical composition of the main active ingredient can be used for the treatment, prevention and alleviation of the related diseases caused by hyperglycemia and influenza virus.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that may be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 5 to 500 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the present invention provides a pentacyclic triterpene carboside derivative compound represented by general formula I or a pharmaceutically acceptable salt, racemate, R-isomer or S-isomer or a pharmaceutically acceptable salt thereof. mixture.
  • the present invention also provides a preparation method of the above compound.
  • the present invention also provides the above-mentioned pentacyclic triterpene carboside derivative compounds or their pharmaceutically acceptable salts, racemates, R-isomers or S-isomers or their mixtures in preparation for treatment Or use in drugs for preventing metabolic diseases such as diabetes and hyperlipidemia.
  • Example 60 (3R, 5S, 8R, 9R, 10S, 14R, 17R, 18S)-oleanolic acid-3-carbonyl-6"-deoxy-6"-fluoro- ⁇ -D-glucopyranoside (A60 )
  • Example 70 (3R, 5S, 8R, 9R, 10S, 14R, 17R, 18S, 19S, 20R)-ursolic acid-3-methyl- ⁇ -D-glucuronide (A70)
  • Example 104 (3S, 5S, 8R, 9R, 10S, 14R, 17R, 18S)-28-O-(pyrazol-1"-yl)methyloleanolic acid-3-(1'R)-( Hydroxy)methyl- ⁇ -D-glucuronide (A104)
  • Example 106 (3S, 5S, 8R, 9R, 10S, 14R, 17R, 18S)-28-O-(morpholin-4"-yl)methyloleanolic acid-3-(1'R)-( Hydroxy)methyl- ⁇ -D-glucuronide (A106)
  • Example 151 (3S, 5S, 8R, 9R, 10S, 14R, 17R, 18S)-oleanolic acid-17-(1'R)-(hydroxy)methyl- ⁇ -D-xylopyranoside (A151 )
  • Example 160 (5S, 8R, 9R, 10S, 14R, 17R, 18S)-3-carbonyl oleanolic acid-17-(1'R)-(hydroxy)methyl-2",3",4", 6"-O-Tetraacetyl- ⁇ -D-Galactopyranoside (A160)
  • Example 161 (5S, 8R, 9R, 10S, 14R, 17R, 18S)-3-carbonyloleanolic acid-17-methyl-2",3",4",6"-O-tetraacetyl- ⁇ -D-Galactopyranoside (A161)
  • Example 163 (5S, 8R, 9R, 10S, 14R, 17R, 18S)-3-carbonyl oleanolic acid-17-(2'R)-(hydroxy)ethyl-2",3",4", 6"-O-Tetraacetyl- ⁇ -D-Galactopyranoside (A163)
  • Example 164 (5S, 8R, 9R, 10S, 14R, 17R, 18S)-3-carbonylursolic acid-17-(2'R)-(hydroxy)ethyl-2",3",4",6 "-O-Tetraacetyl- ⁇ -D-galactopyranoside (A164)
  • Example 173 (5S, 8R, 9R, 10S, 14R, 17R, 18S)-3-carbonylursolic acid-17-(2'R)-(hydroxy)ethyl-2",3",4"-O -Triacetyl- ⁇ -L-rhamnopyranoside (A173)
  • Example 181 (5S, 8R, 9R, 10S, 14R, 17R, 18S)-3-carbonylursolic acid-17-(2'R)-(hydroxy)ethyl-2",3",4"-O -Triacetyl- ⁇ -D-glucuronide (A181)
  • Example 182 (5S, 8R, 9R, 10S, 14R, 17R, 18S)-3-carbonyl betulinic acid-17-(2'R)-(hydroxy)ethyl-2",3",4"-O -Triacetyl- ⁇ -D-glucuronide (A182)
  • Example 200 (5S, 8R, 9R, 10S, 14R, 17R, 18S)-3-carbonyl betulinic acid-17-(2'R)-(hydroxy)ethyl-2",3",4",6 "-O-Tetraacetyl- ⁇ -D-glucopyranoside (A200)
  • Example 202 (5S, 8R, 9R, 10S, 14R, 17R, 18S)-3-carbonylursolic acid-28- ⁇ -D-glucopyranoside (A202)
  • Example 204 (3S, 5S, 8R, 9R, 10S, 14R, 17R, 18S)-ursolic acid-17-(1'R)-(hydroxy)methyl- ⁇ -D-glucopyranoside (A204)
  • Example 205 (3S, 5S, 8R, 9R, 10S, 14R, 17R, 18S)-ursolic acid-28- ⁇ -D-glucopyranoside (A205)
  • Example 206 (3S, 5S, 8R, 9R, 10S, 14R, 17R, 18S)-oleanolic acid-28- ⁇ -D-glucopyranoside (A206)
  • Example 207 (3S, 5S, 8R, 9R, 10S, 13R, 14R, 17S, 18R, 19R)-betulinic acid-28- ⁇ -D-glucopyranoside (A207)
  • Example 208 (3S, 5S, 8R, 9R, 10S, 13R, 14R, 17S, 18R, 19R)-betulinic acid-17-(1'R)-(hydroxy)methyl- ⁇ -D-glucopyranose glycoside (A208)
  • Example 215 (3S, 5S, 8R, 9R, 10S, 13R, 14R, 17S, 18R, 19R)-betulinic acid-17-methyl- ⁇ -D-glucopyranoside (A215)
  • Example 217 (3R, 5S, 8R, 9R, 10S, 14R, 17R, 18S)-oleanolic acid-17-(1'R)-(hydroxy)methyl- ⁇ -D-glucopyranoside (A217 )
  • Example 1 Determination of in vivo hypoglycemic pharmacodynamic activity of the compounds of the present invention
  • the animals After the animals arrive at the WuXi AppTec facility, they are housed in an animal breeding room with strictly controlled environmental conditions.
  • the temperature in the breeding room is maintained at 20-24°C and the humidity is maintained at 30-70%.
  • the temperature and humidity in the breeding room were monitored in real time by a thermohygrometer, and the temperature and humidity were recorded twice a day (once in the morning and once in the afternoon).
  • the lighting in the animal breeding room is controlled by an electronic timed light-on system, with the lights on for 12 hours a day and off for 12 hours (on at 7:00 am and off at 19:00 in the afternoon).
  • the animals were housed in single cages, and the mice in each cage were provided with toys.
  • the animals had free access to food (growth/reproduction feed for rats and mice) and drinking water.
  • Oral glucose tolerance test 0.5 hours after the end of the animal administration, the animals were fed with sugar by gastric gavage, and the sugar feeding time was recorded as 0 minutes, and the oral dose of glucose was 5g/kg, 10ml/kg, and at Before, before, and at 15, 30, 60, 90, and 120 minutes after sugar administration, the animals were tested for blood glucose. Blood sugar will be tested with a blood glucose meter and supporting blood glucose test strips.
  • Detection tool HTRF kit
  • STC-1 cells were seeded at a certain density, and after the cells adhered overnight, the cells were starved with KRBH buffer, while BSA was used to maintain nutrition, and DPP4 inhibitor reduced the degradation of GLP-1. After 1 h, it was changed to KRBH buffer without glucose or with glucose The secretion of GLP-1 was stimulated, and a certain concentration of compounds was added at the same time. After 1 h of treatment, the supernatant was collected and the concentration of GLP-1 was detected by the HTRF kit. Simultaneous detection of LDH secretion indicates compound toxicity.
  • Example 3 Determination of in vitro anti-influenza virus pharmacodynamic activity of the compounds of the present invention
  • Compound stock solution configuration Compounds 1-7 were diluted to 10mM/L; screening concentration: 50 ⁇ M
  • MDCK cells were plated in a 96-well plate (1 ⁇ 10 4 /well), cultured in a 37° C., 5% CO 2 incubator for 24 hours, and then added with drugs.
  • I (inhibition rate) [1-(Xi-Xj)/(Yi-Yj)] ⁇ 100%
  • Xi the number of surviving cells without virus in the test group
  • Xj the number of surviving cells in the test group plus virus
  • Embodiment 4 In vitro affinity determination of the compound of the present invention and coronavirus N protein
  • Buffer 10 mM HEPES, pH 7.4, 150 mM NaCl, 3.0 mM EDTA, and 0.005% (v/v) surfactant P20, 5% DMSO.
  • N protein was first diluted to 20 ⁇ g/mL, and the full-length N protein was coupled to a CM5 chip using a standard amino coupling method, with a signal value of 10,000 signal units (RU).
  • the running buffer used was 10 mM HEPES, pH 7.4, 150 mM NaCl, 3.0 mM EDTA, and 0.005% (v/v) surfactant P20, 5% DMSO.
  • a 10 mM stock solution of the test compound in DMSO was diluted with running buffer in 7 gradient concentrations (1.56 ⁇ M-100 ⁇ M).
  • Embodiment 5 Determination of in vitro anti-SARS-Cov-2 virus pharmacodynamic activity of the compound of the present invention
  • Vero E6 cells (ATCC-1586) were plated in 48-well plates (50,000 cells/well), and 100 ⁇ L/well of medium containing graded compounds was added, followed by 2019-nCoV (nCoV-2019BetaCoV/Wuhan/WIV04/2019) , the multiplicity of infection (MOI) was 0.05. After co-incubating for 1 hour, the supernatant was aspirated, washed and re-added with 200 ⁇ L/well of medium containing graded compounds, and incubated at 37° C. for 24 hours. 24 hours later, the cell supernatant was collected, the viral RNA was extracted from the supernatant, and the viral copy number of the supernatant was detected by real-time quantitative PCR. The compound inhibition rate was calculated according to the viral copy number, and the EC 50 of the compound was calculated by prism 6.0.
  • Vero E6 cells (ATCC-1586) were plated in a 96-well plate (20,000 cells/well), and 100 ⁇ L/well of medium containing gradient compounds was added. After 24 hours, the CCK8 detection kit was used to detect the effect of compounds on cell viability. , the compound is calculated using the prism 6.0 CC 50.
  • Example 6 Determination of PK properties of the compounds of the present invention in mice
  • Feeding Animal house environmental control (target conditions: temperature 18 to 29°C, relative humidity 30 to 70%. Temperature and relative humidity are monitored daily. A 12 hour light/12 hour dark cycle is provided using an electronic time-controlled lighting system.

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Abstract

本发明提供了一类五环三萜碳苷类化合物及其制备方法和用途，具体地，本发明提供了一种如式I所示的化合物，其中，各基团的定义如说明书中所述。所述的化合物可以用于制备治疗糖尿病等代谢类疾病和流感病毒、冠状病毒等引起的病毒性疾病。

Description

一类五环三萜类碳苷化合物及其制备方法和用途 技术领域
本发明涉及药物化学和医药领域，具体涉及一类五环三萜碳苷化合物、其制备方法以及治疗代谢性疾病和抗病毒的作用，特别是制备用于治疗糖尿病、流行性感冒、冠状病毒引发的肺炎等疾病的药物用途。
背景技术
糖尿病(Diabetes Mellitus,DM)是一种遗传因素和环境因素长期共同作用所导致的慢性、全身性、代谢性疾病，以血浆葡萄糖水平增高为特征，主要是因体内胰岛素分泌不足或作用障碍(胰岛素抵抗)引起的糖、脂肪、蛋白质代谢紊乱而影响正常生理活动的一种疾病。糖尿病的并发症可分为急性并发症和慢性并发症，其中，急性并发症包括糖尿病酮症酸中毒、糖尿病高渗性昏迷、各种急性感染及乳酸酸中毒等，另外在糖尿病治疗过程中出现的低血糖症也是最常见的急性并发症之一；慢性并发症包括糖尿病眼病、糖尿病肾病、糖尿病精神病变、糖尿病心脑肢体大血管病变、糖尿病足部及皮肤病变等。糖尿病的主要临床表现为多饮、多尿、多食和体重下降等。
糖尿病分为胰岛素依赖型糖尿病(Insulin-dependent diabets mellitus,IDDM,即I型糖尿病)和非胰岛素依赖型糖尿病最为常见，占糖尿病病人的90％以上。I型糖尿病确切的病因及发病机制尚不十分清楚，其病因由遗传和环境因素的共同参与，主要是由于体内胰岛b细胞损伤，导致体内无法产生胰岛素，病人需要每天注射胰岛素以控制其血液中的胰岛素水平。II型糖尿病是一类由于不能控制体内血糖水平的代谢综合症，主要特征是高血糖、胰岛素抵抗和胰岛素分泌缺乏。II型糖尿病病因主要是由于胰岛素抵抗，使得机体不能有效的利用胰岛素，或胰岛素分泌的减少无法满足身体所需等。由于这类糖尿病患者能够分泌胰岛素，一般无需采用胰岛素治疗，仅用饮食调整或口服降糖药即可控制血糖。
五环三萜类化合物是在多种植物器官中发现的次生植物代谢物，一些物种的含量高达其干重的30％。尽管分子机制尚不清楚，但是三萜类化合物被普遍认为是植物抵抗病原体和食草动物的防御系统的重要组成部分。有报道指出一些糖苷类五环三萜化合物，它们在体外抗流感病毒活性与奥司他韦相当或更高。机理研究表明，这些化合物与血凝素(HA)蛋白紧密结合，从而破坏了血凝素与唾液酸受体的相互作用，阻止病毒进入宿主细胞，而这个过程是不易产生耐药性的。同时有研究表明，五环三萜类化合物可以与冠状病毒的N蛋白结合，阻止病毒的组装，达到抗冠状病毒的作用。同时冠状病毒的N蛋白具有高度的保守性，同时在免疫中发挥重要的作用，因此靶向N蛋白的化合物是很有潜力的抗病毒的小分子化合物。
对于糖类药物，氧苷和氮苷类药物在体内容易被氧化代谢，而碳苷类药物无论在体内还是体外都展现出良好的代谢稳定性，这使得碳苷类药物受到科学家们广泛关注。因此五环三萜碳苷类化合物在降糖药物和抗病毒药物的研发中具有十分光明的前景。
综上所述，本领域迫切需要开发新型的五环三萜碳苷类化合物。
发明内容
本发明的目的在于提供一种通式I所示的五环三萜碳苷衍生物类化合物或其药学上 可接受的盐、外消旋体、R-异构体或S-异构体或它们的混合物。
本发明的第一方面，提供了一种具有如下通式I所示结构的五环三萜碳苷衍生物类化合物，或者其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们的混合物：
Figure PCTCN2021104599-appb-000001
其中，
A环选自下组：6元饱和碳环或不饱和碳环；
R 1、R 2和R 3各自独立的选自下组：氢、甲基；R 4选自下组：氢、异丙烯基；
R 5选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、磷酸基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 6-C 10芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C 1-C 6烷基-苯基、取代或未取代的C 3-C 12环烷基、取代或未取代的C 2-C 10酰基、取代或未取代的C 2-C 10酯基、取代或未取代的C 6-C 10芳氧基、取代或未取代的C 1-C 6酰胺基，或Y-R 7；其中：
Y选自下组：-(CH 2) mCHR 9-、羰基、-CONH-、-COO-；
其中m为0或1；
R 7选自下组：氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C 2-C 10酯基、取代或未取代的C 5-C 9呋喃糖基、取代或未取代的C 5-C 9吡喃糖基；
Z选自下组：羰基、-CH(R 9) 2、C＝N-R 8、C＝N-NH-R 8，或-X-R 6；
R 8选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C1-C6烷基-苯基、取代或未取代的C3-C12环烷基、取代或未取代的C2-C10酰基、取代或未取代的C2-C10酯基、取代或未取代的C6-C10芳氧基、取代或未取代的C1-C6酰胺基；
R 9选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基；
R 6选自下组：氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C 5-C 9呋喃糖基、取代或未取代的C 5-C 9吡喃糖基；所述的取代指糖环上的一个或多个氢或羟基被选自下组的取代基取代：氢、氘、氚、卤素、氰基、氨基、硝基、巯基、醛基、羧基、苄基、取代或未取代的C 1-C 12烷氧羰基、取代或未取代的C 2-C 12烷氨基羰基、取代或未取代的C 2-C 10酰基、磺酰基、磷酰基、C 5-C 9呋喃糖基、C 5-C 9吡喃糖基；
X选自下组：-CHR 9-、羰基、S、-NHC(O)-R 8、-NHS(O) 2-R 8、-NHC(O)NH-R 8、-NHC(S)NH-R 8、-COO-、-O-S(O) 2-R 8；
n为1或2；
除非特别说明，上述各式中，所述的取代指对应基团上的氢原子，或者糖环上的羟基被一个或多个选自下组的取代基所取代：氘、氚、卤素、羟基、羧基、巯基、苄基、C 1-C 12烷氧基羰基、C 1-C 6醛基、氨基、C 1-C 6酰胺基、硝基、氰基、未取代或卤代的C 1-C 6烷基、C 2-C 10烯基、C 1-C 6烷氧基、C 1-C 6烷基-胺基、C 6-C 10芳基、五元或六元杂芳基、五元或六元非芳香性杂环基、-O-(C 6-C 10芳基)、-O-(五元或六元杂芳基)、C 1-C 12烷氨基羰基、取代或未取代的C 2-C 10酰基、磺酰基(-SO 2-OH)、磷酰基(-PO 3-OH)、C 5-C 9呋喃糖基、C 5-C 9吡喃糖基。
在另一优选例中，所述的式I化合物具有如下通式II所示的结构：
Figure PCTCN2021104599-appb-000002
其中：
R 5选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、磷酸基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C1-C6烷基-苯基、取代或未取代的C3-C12环烷基、取代或未取代的C2-C10酰基、取代或未取代的C2-C10酯基、取代或未取代的C6-C10芳氧基、取代或未取代的C1-C6酰胺基；
X选自下组：-CHR 9-、羰基；
R 6选自下组：取代或未取代的C5-C9呋喃糖基、取代或未取代的C5-C9吡喃糖基；所述的取代指糖环上的一个或多个氢或羟基被选自下组的取代基取代：氢、氘、氚、卤素、氰基、氨基、硝基、巯基、醛基、羧基、苄基、取代或未取代的C1-C12烷氧羰基、取代或未取代的C2-C12烷氨基羰基、取代或未取代的C2-C10酰基、磺酰基、磷酰基、C5-C9呋喃糖基、C5-C9吡喃糖基；
R 9选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基；
A环选自下组：6元饱和碳环或不饱和碳环；
n为1、2。
在另一优选例中，所述的式I化合物具有如下通式III所示的结构：
Figure PCTCN2021104599-appb-000003
Figure PCTCN2021104599-appb-000004
其中：
R 1、R 2和R 3各自独立的选自下组：氢、甲基；
R 4选自下组：氢、异丙烯基；
R 7选自下组：氢、取代或未取代的C5-C9呋喃糖基、取代或未取代的C5-C9吡喃糖基；所述的取代指糖环上的一个或多个氢或羟基被选自下组的取代基取代：氢、氘、氚、卤素、氰基、氨基、硝基、巯基、醛基、羧基、苄基、取代或未取代的C1-C12烷氧羰基、取代或未取代的C1-C12烷氨基羰基、取代或未取代的C2-C10酰基、磺酰基、磷酰基、C5-C9呋喃糖基、C5-C9吡喃糖基；
Y选自下组：-(CH 2) mCHR 9-、羰基；
m为0、1；
R 9选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基；
Z选自下组：羰基、-CH(R 9) 2、＝N-R 8，或-X-R 6；
R 9选自下组：氢、卤素、氰基、氨基、硝基、羟基、巯基；
X选自下组：-CHR 9-、羰基、S、-NHC(O)-R 8、-NHS(O) 2-R 8、-NHC(O)NH-R 8、-NHC(S)NH-R 8、-COO-、-O-S(O) 2-R 8；
R 6选自下组：氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C 5-C 9呋喃糖基、取代或未取代的C 5-C 9吡喃糖基；所述的取代指糖环上的一个或多个氢或羟基被选自下组的取代基取代：氢、氘、氚、卤素、氰基、氨基、硝基、巯基、醛基、羧基、苄基、取代或未取代的C 1-C 12烷氧羰基、取代或未取代的C 2-C 12烷氨基羰基、取代或未取代的C 2-C 10酰基、磺酰基、磷酰基、C 5-C 9呋喃糖基、C 5-C 9吡喃糖基；
A环选自下组：6元饱和碳环或不饱和碳环；
n为1、2。
在另一优选例中，所述的式I化合物具有如下通式IV、V或VI所示的结构：
Figure PCTCN2021104599-appb-000005
在另一优选例中，R 5选自下组：氢、卤素、羟基、羧基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C10酰基、取代或未取代的C2-C10酯基、取代或未取代的C1-C6酰胺基。
在另一优选例中，R 9选自下组：氢、羟基、醛基、巯基，或-X-R 6；
X选自下组：-CHR 9-、羰基、S、-NHC(O)-R 8、-NHS(O) 2-R 8、-NHC(O)NH-R 8、-NHC(S)NH-R 8、-COO-、-O-S(O) 2-R 8；
R 6选自下组：取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C 5-C 9 呋喃糖基、取代或未取代的C 5-C 9吡喃糖基；所述的取代指糖环上的一个或多个氢或羟基被选自下组的取代基取代：氢、氘、氚、卤素、氰基、氨基、硝基、巯基、醛基、羧基、苄基、取代或未取代的C 1-C 12烷氧羰基、取代或未取代的C 2-C 12烷氨基羰基、取代或未取代的C 2-C 10酰基、磺酰基、磷酰基、C 5-C 9呋喃糖基、C 5-C 9吡喃糖基。
在另一优选例中，所述五环三萜碳苷类化合物为实施例中所述的化合物：
本发明的第二方面，提供了一种如本发明第一方面所述的化合物的制备方法，其特征在于，所述制备方法包括如下方案1或方案2：
方案1：用式IIa化合物作为原料，经过步骤a和任选的步骤b、c或d，制备式II化合物：
Figure PCTCN2021104599-appb-000006
其中，各基团的定义如本发明第一方面中所述；
步骤a：化合物IV和化合物III进行反应，得到步骤a产物；
步骤b：将步骤a产物进行还原，得到步骤b产物；
步骤c：对步骤b产物进行烷基化反应，得到步骤c产物；
步骤d：用步骤c产物与戴斯马丁试剂进行反应，得到式II化合物；
其中化合物IV的结构为：
Figure PCTCN2021104599-appb-000007
方案2：用式IIIa化合物作为原料，经过步骤a和任选的步骤b、c或d，制备式III化合物：
Figure PCTCN2021104599-appb-000008
本发明的第三方面，提供了一种药物组合物，所述的药物组合物含有治疗有效量的如本发明第一方面所述的式I化合物、其可药用的盐、外消旋体、R-异构体和S-异构体中的一种或多种，以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
本发明的第四方面，提供了一种如本发明第一方面所述的式I和式II化合物、其外消旋体、R-异构体、S-异构体或可药用盐在制备治疗或预防与糖尿病相关的代谢性疾病和病毒性疾病的药物中的用途；优选地，所述疾病选自下组：糖尿病、流感、肥胖、肝纤维化、代谢性疾病、病毒性疾病。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了A2、A4、A6、A10、A25、A43、A44、A47和A67的ICR小鼠OGTT实验数据；
图2显示了A25、A43表现出良好的体内降糖效果；
图3显示了A64与阳性药ANT777的EC50和促进体外GLP分泌量效果；
图4显示了本发明化合物与阳性药利巴韦林表现出同等的病毒抑制率和低细胞毒性，与阳性药利巴韦林的病毒抑制率相近，但细胞毒性低于利巴韦林；
图5显示了A102、A104、A106、A108、A112、A114、A116、A117、A120、A121、A122、A123、A124、A125、A126、A127与SARS-Cov-2N蛋白亲和力实验数据；
图6显示了化合物A102、A114和A116与N蛋白的亲和力实验数据；
图7和图8显示了A102、A104、A114、A117、A118、A119、A120、A121、A122、A123、A124、A125、A126、A127、A128、A129抑制SARS-Cov-2病毒复制实验数据
图9、图10显示了A104化合物良好的小鼠体内的PK性质。
具体实施方式
本发明人通过广泛而深入的研究，首次意外地发现一类具有口服降糖活性或抗病毒活性的结构新颖、性能优异的五环三萜类碳苷。在此基础上完成了本发明。
术语
在本发明中，所述卤素为F、Cl、Br或I。
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等；优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中，术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中，术语“C2-C6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中，术语“C2-C6炔基”是指具有2至6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中，术语“C3-C10环烷基”是指在环上具有3至10个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。术语“C3-C8环烷基”、“C3-C7环烷基”、和“C3-C6环烷基”具有类似的含义。
在本发明中，术语“C3-C10环烯基”是指在环上具有3至10个碳原子的环状烯基，非限制性地包括环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基和环癸基烯等。术语“C3-C7环烯基”具有类似的含义。
在本发明中，术语“C1-C12烷氧羰基”是指在烷基链上具有1至12个碳原子的烷氧羰基，非限制性地包括甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、叔丁氧羰基、苄氧羰基等。
在本发明中，术语“C1-C12烷氨基羰基”是指在烷基链上具有1至12个碳原子的烷氨基羰基，非限制性地包括甲氨基羰基、乙氨基羰基、丙氨基羰基、异丙氨基羰基、叔丁氨基羰基、苄氨基羰基、二甲氨基羰基等。
在本发明中，术语“C5-C9呋喃糖基”是指在具有5至9个碳原子的呋喃糖基，其中糖基的1位与主链相连，非限制性地包括呋喃核糖基、呋喃脱氧核糖基、呋喃半乳糖基等。
在本发明中，术语“C5-C9吡喃糖基”是指具有5至9个碳原子的吡喃糖基，其中糖基的1位与主链相连，非限制性地包括吡喃葡萄糖基、吡喃葡萄糖醛酸糖基、吡喃鼠李糖基、吡喃半乳糖基、吡喃甘露糖基、吡喃木糖基等。
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选地“芳基”为“C6-C12芳基”或“C6-C10芳基”。术语“C6-C12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基，如苯基、萘基等。术语“C6-C10芳基”具有类似的含义。
在本发明中，术语“芳香杂环”或“杂芳基”具有相同的含义，指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂 芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中，术语“3-12元杂环基”是指在环上含有1～3个选自氧、硫和氮中的杂原子的饱和或不饱和的3-12元环基，例如二氧杂环戊基等。术语“3-7元杂环基”具有类似的含义。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环烷基，可以与另一个环相连，例如环烷基，从而形成螺二环系，例如，两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、C1-C12烷氧羰基、氨基、烷氧基、C1-10磺酰基等。
五环三萜碳苷类化合物
本发明中，提供了一种具有如下通式I或通式II所示结构的五环三萜碳苷衍生物类化合物，或者其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们的混合物：
Figure PCTCN2021104599-appb-000009
其中：
R 1、R 2和R 3各自独立的选自下组：氢、甲基；R 4选自下组：氢、异丙烯基；
R 5选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、磷酸基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C1-C6烷基-苯基、取代或未取代的C3-C12环烷基、取代或未取代的C2-C10酰基、取代或未取代的C2-C10酯基、取代或未取代的C6-C10芳氧基、取代或未取代的C1-C6酰胺基；
R 6选自下组：取代或未取代的C5-C9呋喃糖基、取代或未取代的C5-C9吡喃糖基；所述的取代指糖环上的一个或多个氢或羟基被选自下组的取代基取代：氢、氘、氚、卤素、氰基、氨基、硝基、巯基、醛基、羧基、苄基、取代或未取代的C1-C12烷氧羰基、取代或未取代的C1-C12烷氨基羰基、取代或未取代的C2-C10酰基、磺酰基、磷酰基、C5-C9呋喃糖基、C5-C9吡喃糖基；
X选自下组：-CHR 9-、羰基；
R 9选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基；
A环选自下组：6元饱和碳环或不饱和碳环；
n为1、2。
Figure PCTCN2021104599-appb-000010
其中：
R 1、R 2和R 3各自独立的选自下组：氢、甲基；R 4选自下组：氢、异丙烯基；
R 7选自下组：取代或未取代的C5-C9呋喃糖基、取代或未取代的C5-C9吡喃糖基；所述的取代指糖环上的一个或多个氢或羟基被选自下组的取代基取代：氢、氘、氚、卤素、氰基、氨基、硝基、巯基、醛基、羧基、苄基、取代或未取代的C1-C12烷氧羰基、取代或未取代的C1-C12烷氨基羰基、取代或未取代的C2-C10酰基、磺酰基、磷酰基、C5-C9呋喃糖基、C5-C9吡喃糖基；
Y选自下组：-(CH 2)mCHR 9-、羰基；
m为0、1。
R 9选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基；
Z选自下组：羰基、-CH(R 8)-、＝N-R 8；
R 8选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C1-C6烷基-苯基、取代或未取代的C3-C12环烷基、取代或未取代的C2-C10酰基、取代或未取代的C2-C10酯基、取代或未取代的C6-C10芳氧基、取代或未取代的C1-C6酰胺基；
A环选自下组：6元饱和碳环或不饱和碳环；
n为1、2。
在本发明更优选的实施方案中，本发明的通式I和通式II的化合物优选为如下具体化合物：
Figure PCTCN2021104599-appb-000011
Figure PCTCN2021104599-appb-000012
Figure PCTCN2021104599-appb-000013
Figure PCTCN2021104599-appb-000014
Figure PCTCN2021104599-appb-000015
Figure PCTCN2021104599-appb-000016
Figure PCTCN2021104599-appb-000017
Figure PCTCN2021104599-appb-000018
Figure PCTCN2021104599-appb-000019
Figure PCTCN2021104599-appb-000020
Figure PCTCN2021104599-appb-000021
Figure PCTCN2021104599-appb-000022
Figure PCTCN2021104599-appb-000023
Figure PCTCN2021104599-appb-000024
Figure PCTCN2021104599-appb-000025
Figure PCTCN2021104599-appb-000026
Figure PCTCN2021104599-appb-000027
Figure PCTCN2021104599-appb-000028
Figure PCTCN2021104599-appb-000029
Figure PCTCN2021104599-appb-000030
Figure PCTCN2021104599-appb-000031
Figure PCTCN2021104599-appb-000032
Figure PCTCN2021104599-appb-000033
Figure PCTCN2021104599-appb-000034
Figure PCTCN2021104599-appb-000035
Figure PCTCN2021104599-appb-000036
Figure PCTCN2021104599-appb-000037
Figure PCTCN2021104599-appb-000038
Figure PCTCN2021104599-appb-000039
Figure PCTCN2021104599-appb-000040
Figure PCTCN2021104599-appb-000041
活性成分
本发明化合物可以是如下通式I所示结构的丙烯酸衍生物类化合物或者其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们的混合物：
Figure PCTCN2021104599-appb-000042
各个基团的定义同前。
本发明的化合物具有不对称中心、手性轴和手性平面，并且可以以外消旋体、R-异构体或S-异构体的形式存在。本领域技术人员能够采用常规技术手段由外消旋体拆分获得R-异构体和/或S-异构体。
本发明提供了通式I及通式II化合物的可药用的盐，具体地为通式I及通式II化合物与无机酸或有机酸反应形成常规的可药用盐。例如，常规的可药用盐可通过通式I及通式II化合物与无机酸或有机酸反应制得，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者通式I及通式II化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式I及通式II化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐。
制备方法
本发明另一方面提供了一种通式I及通式II表示的化合物的制备方法，该制备方法按照如下方案1及方案2进行。
式(I)化合物可以通过以下方案1所示的方法制备
以下方案中使用的结构式和R基团标号仅在本部分使用。式(III)化合物、式(IV)化合物和式(V)化合物可市场上获得或可使用本领域的常规技术合成。
方案1：
Figure PCTCN2021104599-appb-000043
各个基团的定义同前。
步骤a：化合物IV和化合物III于0℃下加入0.1mol/L二碘化钐的重蒸四氢呋喃溶液中，氩气保护下反应1h。
步骤b：将前一步产物溶于乙酸乙酯:甲醇(1:1)的混合溶剂中，加入Pd/C，氢气环境中50℃反应12h。
步骤c：将前一步产物溶于CS 2，随后加入NaH(,60％油混合物)，室温下搅拌2小时。然后加入CH 3I反应过夜，随后经柱层析纯化后，溶于超干甲苯，搅拌下加入AIBN和三正丁基氢化锡，回流条件下搅拌4小时。
步骤d：将前一步产物溶于二氯甲烷，加入戴斯马丁试剂搅拌2h。
其中化合物IV的结构为：
Figure PCTCN2021104599-appb-000044
方案2：
Figure PCTCN2021104599-appb-000045
各个基团的定义同前。
步骤a、b、c、d的定义同方案1。
药物组合物和施用方法
由于本发明化合物具有优异的降糖和抑制流感病毒的活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与血糖偏高和流感病毒引起的相关疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2021104599-appb-000046
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体 剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、娇味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括如下：
本发明提供了一种通式I所示的五环三萜碳苷衍生物类化合物或其药学上可接受的盐、外消旋体、R-异构体或S-异构体或它们的混合物。
本发明还提供了上述化合物的制备方法。
本发明还提供了上述五环三萜碳苷衍生物类化合物或其药学上可接受的盐、外消旋体、R-异构体或S-异构体或它们的混合物在制备用于治疗或预防糖尿病、高脂血症等代谢类疾病的药物中的用途。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发 明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明，但不以任何方式限制本发明。
实施例1(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基齐墩果酸-3-(1’R)-(羟基)甲基-2”,3”,4”,6”-O-四苄基-β-D-吡喃葡萄糖苷(A1)
Figure PCTCN2021104599-appb-000047
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸(100.0mg,0.18mmol)和2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷(207.7mg,0.36mmol)溶解于重蒸过的15mL四氢呋喃中，氩气保护下，于0℃下加入0.1mol/L二碘化钐的四氢呋喃溶液(15mL,1.5mmol)，搅拌1小时，TLC监测反应完全后，加饱和氯化铵淬灭，二氯甲烷萃取，合并有机层，用饱和氯化钠溶液洗涤，有机层用无水硫酸钠干燥，浓缩，粗产物经柱层析得目标产物A1(152mg，78％)。 1H NMR(600MHz,CDCl 3)δ7.40–7.08(m,26H),5.29(t,J＝3.4Hz,1H),5.05(dt,J＝16.2,11.9Hz,3H),4.95(d,J＝11.0Hz,1H),4.83(dd,J＝19.7,11.0Hz,2H),4.74(d,J＝11.2Hz,1H),4.65–4.47(m,3H),4.01(d,J＝5.8Hz,1H),3.78(t,J＝8.9Hz,1H),3.68(s,1H),3.66–3.62(m,1H),3.58(t,J＝9.1Hz,1H),3.39(dt,J＝9.7,3.0Hz,1H),3.31(dd,J＝9.2,6.7Hz,1H),2.89(dd,J＝13.6,4.0Hz,1H),1.98(td,J＝13.5,3.9Hz,1H),1.87–1.76(m,2H),1.26(s,3H),1.12(s,3H),0.94(s,3H),0.91(d,J＝1.5Hz,4H),0.89(s,3H),0.85(s,3H),0.61(s,3H).LRMS(ESI):1083.66[M+H] +。
实施例2(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖苷(A2)
Figure PCTCN2021104599-appb-000048
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸(100.0mg,0.18mmol)和2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷(207.7mg,0.36mmol)溶解于重蒸过的15mL四氢呋喃中，氩气保护下，于0℃下加入0.1mol/L二碘化钐的四氢呋喃溶液(15mL,1.5mmol)，搅拌1小时，TLC监测反应完全后，加饱和氯化铵淬灭，二氯甲烷萃取，合并有机层，用饱和氯化钠溶液洗涤，有机层用无水硫酸钠干燥，浓缩，粗产物经 柱层析得152mg A1。随后将其溶于乙酸乙酯:甲醇(15mL:15mL)中，氢气环境中加入30mg Pd/C，50℃反应12h，随后经柱层析得目标产物A2(70mg,79％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):631.43[M-H] -。
实施例3(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基齐墩果酸-3-(1’R)-(羟基)甲基-2”,3”,4”,6”-O-四苄基-β-D-吡喃葡萄糖苷(A3)
将(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸，其余所需原料、试剂及制备方法同实施例1，得到A3(产率85％)。 1H NMR(600MHz,CDCl 3)δ7.40–7.08(m,26H),5.29(t,J＝3.4Hz,1H),5.05(dt,J＝16.2,11.9Hz,3H),4.95(d,J＝11.0Hz,1H),4.83(dd,J＝19.7,11.0Hz,2H),4.74(d,J＝11.2Hz,1H),4.65–4.47(m,3H),4.01(d,J＝5.8Hz,1H),3.78(t,J＝8.9Hz,1H),3.68(s,1H),3.66–3.62(m,1H),3.58(t,J＝9.1Hz,1H),3.39(dt,J＝9.7,3.0Hz,1H),3.31(dd,J＝9.2,6.7Hz,1H),2.89(dd,J＝13.6,4.0Hz,1H),1.98(td,J＝13.5,3.9Hz,1H),1.87–1.76(m,2H),1.26(s,3H),1.12(s,3H),0.94(s,3H),0.91(d,J＝1.5Hz,4H),0.89(s,3H),0.85(s,3H),0.61(s,3H).LRMS(ESI):1083.66[M+H] +。
实施例4(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖苷(A4)
将(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A4(产率74％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):631.43[M-H] -。
实施例5(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基齐墩果酸-3-甲基-2”,3”,4”,6”-O-四苄基-β-D-吡喃葡萄糖苷(A5)
Figure PCTCN2021104599-appb-000049
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸(66.7mg,0.12mmol)和2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷(138.5mg,0.24mmol)溶解于重蒸过的15mL四氢呋喃中，氩气保护下，于0℃下加入0.1mol/L二碘化钐的四氢呋喃溶液(15mL,1.5mmol)，搅拌1小时，TLC监测反应完全后，加饱和氯 化铵淬灭，二氯甲烷萃取，合并有机层，用饱和氯化钠溶液洗涤，有机层用无水硫酸钠干燥，浓缩，粗产物经柱层析得152mg A1。随后将其溶于10mL CS 2，随后加入NaH(15mg,0.37mmol,60％油混合物)，室温下搅拌2小时。然后加入CH 3I(31μL,0.50mmol)反应过夜，TLC监测反应完成后，加入饱和氯化铵淬灭反应，二氯甲烷萃取，合并有机层，饱和氯化钠洗涤，无水硫酸钠干燥，浓缩，粗产物经柱层析得中间体A。将中间体A和AIBN(23mg,0.14mmol)溶于20mL超干甲苯，搅拌下加入三正丁基氢化锡(0.12mL,0.45mmol)，回流条件下搅拌4小时，TLC监测反应完成，浓缩，经柱层析得目标产物A5(64mg,65％)。
1H NMR(600MHz,CDCl 3)δ7.40–7.08(m,26H),5.29(t,J＝3.4Hz,1H),5.05(dt,J＝16.2,11.9Hz,3H),4.95(d,J＝11.0Hz,1H),4.83(dd,J＝19.7,11.0Hz,2H),4.74(d,J＝11.2Hz,1H),4.65–4.47(m,3H),4.01(d,J＝5.8Hz,1H),3.78(t,J＝8.9Hz,1H),3.68(s,1H),3.66–3.62(m,1H),3.58(t,J＝9.1Hz,1H),3.39(dt,J＝9.7,3.0Hz,1H),3.31(dd,J＝9.2,6.7Hz,1H),2.89(dd,J＝13.6,4.0Hz,1H),1.98(td,J＝13.5,3.9Hz,1H),1.87–1.76(m,2H),1.26(s,3H),1.12(s,3H),0.94(s,3H),0.91(d,J＝1.5Hz,4H),0.89(s,3H),0.85(s,3H),0.61(s,3H).LRMS(ESI):1067.67[M+H] +。
实施例6(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-甲基-β-D-吡喃葡萄糖苷(A6)
Figure PCTCN2021104599-appb-000050
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸(66.7mg,0.12mmol)和2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷(138.5mg,0.24mmol)溶解于重蒸过的15mL四氢呋喃中，氩气保护下，于0℃下加入0.1mol/L二碘化钐的四氢呋喃溶液(15mL,1.5mmol)，搅拌1小时，TLC监测反应完全后，加饱和氯化铵淬灭，二氯甲烷萃取，合并有机层，用饱和氯化钠溶液洗涤，有机层用无水硫酸钠干燥，浓缩，粗产物经柱层析得A1。随后将其溶于10mL CS 2，随后加入NaH(15mg,0.37mmol,60％油混合物)，室温下搅拌2小时。然后加入CH 3I(31μL,0.50mmol)反应过夜，TLC监测反应完成后，加入饱和氯化铵淬灭反应，二氯甲烷萃取，合并有机层，饱和氯化钠洗涤，无水硫酸钠干燥，浓缩，粗产物经柱层析得中间体A。将中间体A和AIBN(23mg,0.14mmol)溶于20mL超干甲苯，搅拌下加入三正丁基氢化锡(0.12mL,0.45mmol)，回流条件下搅拌4小时，TLC监测反应完成，浓缩，经柱层析得64mg A5。随后将其溶于乙酸乙酯:甲醇(15mL:15mL)中，氢气环境中加入13mg Pd/C，50℃反应12h，随后经柱层析得目标产物A6(27mg,75％)。
1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.43[M-H] -。
实施例7(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基齐墩果酸-3-甲基- 2”,3”,4”,6”-O-四苄基-β-D-吡喃葡萄糖苷(A7)
将(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸，其余所需原料、试剂及制备方法同实施例5，得到A7(产率67％)。 1H NMR(600MHz,CDCl 3)δ7.40–7.08(m,26H),5.29(t,J＝3.4Hz,1H),5.05(dt,J＝16.2,11.9Hz,3H),4.95(d,J＝11.0Hz,1H),4.83(dd,J＝19.7,11.0Hz,2H),4.74(d,J＝11.2Hz,1H),4.65–4.47(m,3H),4.01(d,J＝5.8Hz,1H),3.78(t,J＝8.9Hz,1H),3.68(s,1H),3.66–3.62(m,1H),3.58(t,J＝9.1Hz,1H),3.39(dt,J＝9.7,3.0Hz,1H),3.31(dd,J＝9.2,6.7Hz,1H),2.89(dd,J＝13.6,4.0Hz,1H),1.98(td,J＝13.5,3.9Hz,1H),1.87–1.76(m,2H),1.26(s,3H),1.12(s,3H),0.94(s,3H),0.91(d,J＝1.5Hz,4H),0.89(s,3H),0.85(s,3H),0.61(s,3H).LRMS(ESI):1067.67[M+H] +。
实施例8(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-β-D-吡喃葡萄糖苷(A8)
将(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸，其余所需原料、试剂及制备方法同实施例6，得到A8(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.43[M-H] -。
实施例9(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基齐墩果酸-3-羰基-2”,3”,4”,6”-O-四苄基-β-D-吡喃葡萄糖苷(A9)
Figure PCTCN2021104599-appb-000051
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸(66.7mg,0.12mmol)和2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷(138.5mg,0.24mmol)溶解于重蒸过的15mL四氢呋喃中，氩气保护下，于0℃下加入0.1mol/L二碘化钐的四氢呋喃溶液(15mL,1.5mmol)，搅拌1小时，TLC监测反应完全后，加饱和氯化铵淬灭，二氯甲烷萃取，合并有机层，用饱和氯化钠溶液洗涤，有机层用无水硫酸钠干燥，浓缩，粗产物经柱层析得152mg A1。随后将其溶于10mL二氯甲烷，随后加入戴斯马丁试剂(76mg,0.18mmol)，室温下搅拌2小时。TLC监测反应完成后，加入饱和硫代硫酸钠淬灭反应，二氯甲烷萃取，合并有机层，饱和氯化钠洗涤，无水硫酸钠干燥，浓缩，粗产物经柱层析得目标产物A9(90mg,90％)。 1H NMR(600MHz,CDCl 3)δ7.40–7.08(m,26H),5.29(t,J＝3.4Hz,1H),5.05(dt,J＝16.2,11.9Hz,3H),4.95(d,J＝11.0Hz,1H),4.83(dd,J＝19.7,11.0Hz,2H),4.74(d,J＝11.2Hz,1H),4.65–4.47(m,3H),4.01(d,J＝5.8Hz,1H),3.78(t,J＝8.9Hz,1H),3.68(s,1H),3.66–3.62(m,1H),3.58(t,J＝9.1Hz,1H),3.39(dt,J＝9.7,3.0Hz,1H),3.31(dd,J＝9.2,6.7Hz,1H), 2.89(dd,J＝13.6,4.0Hz,1H),1.98(td,J＝13.5,3.9Hz,1H),1.87–1.76(m,2H),1.26(s,3H),1.12(s,3H),0.94(s,3H),0.91(d,J＝1.5Hz,4H),0.89(s,3H),0.85(s,3H),0.61(s,3H).LRMS(ESI):1081.65[M+H] +。
实施例10(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-β-D-吡喃葡萄糖苷(A10)
Figure PCTCN2021104599-appb-000052
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸(66.7mg,0.12mmol)和2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷(138.5mg,0.24mmol)溶解于重蒸过的15mL四氢呋喃中，氩气保护下，于0℃下加入0.1mol/L二碘化钐的四氢呋喃溶液(15mL,1.5mmol)，搅拌1小时，TLC监测反应完全后，加饱和氯化铵淬灭，二氯甲烷萃取，合并有机层，用饱和氯化钠溶液洗涤，有机层用无水硫酸钠干燥，浓缩，粗产物经柱层析得A1。随后将其溶于10mL二氯甲烷，随后加入戴斯马丁试剂(76mg,0.18mmol)，室温下搅拌2小时。TLC监测反应完成后，加入饱和硫代硫酸钠淬灭反应，二氯甲烷萃取，合并有机层，饱和氯化钠洗涤，无水硫酸钠干燥，浓缩，粗产物经柱层析得90mg A9。随后将其溶于乙酸乙酯:甲醇(15mL:15mL)中，氢气环境中加入13mg Pd/C，50℃反应12h，随后经柱层析得目标产物A10(38mg,73％)。
1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):629.41[M-H] -。
实施例11(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基齐墩果酸-3-羰基-2”,3”,4”,6”-O-四苄基-β-D-吡喃葡萄糖苷(A11)
将(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸，其余所需原料、试剂及制备方法同实施例9，得到A11(产率89％)。 1H NMR(600MHz,CDCl 3)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):1081.65[M+H] +。
实施例12(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-β-D-吡喃葡萄糖苷(A12)
将(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸，其余所需原料、试剂及制备方法同实施例10，得到A12(产率91％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):629.41[M-H] -。
实施例13(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃半乳糖苷(A13)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷。其余所需原料、试剂及制备方法同实施例2，得到A13(产率77％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):631.43[M-H] -。
实施例14(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃半乳糖苷(A14)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A14(产率74％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):631.43[M-H] -。
实施例15(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-β-D-吡喃半乳糖苷(A15)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，其余所需原料、试剂及制备方法同实施例6，得到A15(产率63％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.43[M-H] -。
实施例16(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-β-D-吡喃半乳糖苷(A16)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸，其余所需原料、试剂及制备方法同实施例6，得到A16(产率74％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.43[M-H] -。
实施例17(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-β-D-吡喃半乳糖苷(A17)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，其余所需原料、试剂及制备方法同实施例10，得到A17(产率81％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):629.41[M-H] -。
实施例18(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-β-D-吡喃半乳糖苷(A18)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸，其余所需原料、试剂及制备方法同实施例10，得到A18(产率86％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):629.41[M-H] -。
实施例19(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-(羟基)甲基-α-D-吡喃甘露糖苷(A19)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-α-D-吡喃甘露糖硫苷。其余所需原料、试剂及制备方法同实施例2，得到A19(产率73％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):631.43[M-H] -。
实施例20(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-(羟基)甲基-α-D-吡喃甘露糖苷(A20)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-α-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A20(产率62％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):631.43[M-H] -。
实施例21(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-α-D-吡喃甘露糖苷(A21)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-α-D-吡喃甘露糖硫苷，其余所需原料、试剂及制备方法同实施例6，得到A21(产率65％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.43[M-H] -。
实施例22(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-α-D-吡喃甘露糖苷(A22)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-α-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A22(产率64％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.43[M-H] -。
实施例23(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-α-D-吡喃甘露糖苷(A23)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-α-D-吡喃甘露糖硫苷，其余所需原料、试剂及制备方法同实施例10，得到A23(产率91％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):629.41[M-H] -。
实施例24(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-α-D-吡喃甘露糖苷(A24)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-α-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A24(产率86％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):629.41[M-H] -。
实施例25(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A25)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A25(产率77％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):645.41[M-H] -。
实施例26(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A26)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A26(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):645.41[M-H] -。
实施例27(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-β-D-吡喃葡萄糖醛酸苷(A27)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，其余所需原料、试剂及制备方法同实施例6，得到A27(产率65％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):629.41[M-H] -。
实施例28(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-β-D-吡喃葡萄糖醛酸苷(A28)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A28(产率65％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):629.41[M-H] -。
实施例29(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-β-D-吡喃葡萄糖醛酸苷(A29)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，其余所需原料、试剂及制备方法同实施例10，得到A29(产率89％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):643.39[M-H] -。
实施例30(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-β-D-吡喃葡萄糖醛酸苷(A30)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A30(产率88％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):643.39[M-H] -。
实施例31(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-脱氧-β-D-吡喃葡萄糖苷(A31)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-脱氧-β-D-吡喃葡萄糖硫苷。其余所需原料、试剂及制备方法同实施例2，得到A31(产率67％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.43[M-H] -。
实施例32(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-脱氧-β-D-吡喃葡萄糖苷(A32)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-脱氧-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A32(产率78％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.43[M-H] -。
实施例33(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-6”-脱氧-β-D-吡喃葡萄糖苷(A33)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-脱氧-β-D-吡喃葡萄糖硫苷，其余所需原料、试剂及制备方法同实施例6，得到A33(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):599.44[M-H] -。
实施例34(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-6”-脱氧-β-D-吡喃葡萄糖苷(A34)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-脱氧-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A34(产率65％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):599.44[M-H] -。
实施例35(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-6”-脱氧-β-D-吡喃葡萄糖苷(A35)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-脱氧-β-D-吡喃葡萄糖硫苷，其余所需原料、试剂及制备方法同实施例10，得到A35(产率86％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.42[M-H] -。
实施例36(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-6”-脱氧-β-D-吡喃葡萄糖苷(A36)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-脱氧-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A36(产率85％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.42[M-H] -。
实施例37(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃木糖苷(A37)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷。其余所需原料、试剂及制备方法同实施例2，得到A37(产率77％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):601.42[M-H] -。
实施例38(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃木糖苷(A38)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A38(产率78％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):601.42[M-H] -。
实施例39(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-β-D-吡喃木糖苷(A39)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，其余所需原料、试剂及制备方法同实施例6，得到A39(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):585.42[M-H] -。
实施例40(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-β-D-吡喃木糖苷(A40)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐 墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A40(产率66％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):585.42[M-H] -。
实施例41(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-β-D-吡喃木糖苷(A41)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，其余所需原料、试剂及制备方法同实施例10，得到A41(产率88％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):599.40[M-H] -。
实施例42(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-β-D-吡喃木糖苷(A42)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A42(产率81％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):599.40[M-H] -。
实施例43(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-(羟基)甲基-α-L-吡喃鼠李糖苷(A43)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-α-D-吡喃鼠李糖硫苷。其余所需原料、试剂及制备方法同实施例2，得到A43(产率75％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.43[M-H] -。
实施例44(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-(羟基)甲基-α-L-吡喃鼠李糖苷(A44)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-α-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A44(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H), 4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.43[M-H] -。
实施例45(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-甲基-α-L-吡喃鼠李糖苷(A45)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-α-D-吡喃鼠李糖硫苷，其余所需原料、试剂及制备方法同实施例6，得到A45(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):599.44[M-H] -。
实施例46(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-甲基-α-L-吡喃鼠李糖苷(A46)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-α-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A46(产率66％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):599.44[M-H] -。
实施例47(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-羰基-α-L-吡喃鼠李糖苷(A47)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-α-D-吡喃鼠李糖硫苷，其余所需原料、试剂及制备方法同实施例10，得到A47(产率84％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.42[M-H] -。
实施例48(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-羰基-α-L-吡喃鼠李糖苷(A48)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-α-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A48(产率87％)。 1H NMR(500MHz,MeOD)δ5.28(s, 1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.42[M-H] -。
实施例49(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-(羟基)甲基-α-L-吡喃岩藻糖苷(A49)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃岩藻糖硫苷。其余所需原料、试剂及制备方法同实施例2，得到A49(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.43[M-H] -。
实施例50(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-(羟基)甲基-α-L-吡喃岩藻糖苷(A50)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃岩藻糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A50(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.43[M-H] -。
实施例51(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-甲基-α-L-吡喃岩藻糖苷(A51)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃岩藻糖硫苷，其余所需原料、试剂及制备方法同实施例6，得到A51(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):599.44[M-H] -。
实施例52(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-甲基-α-L-吡喃岩藻糖苷(A52)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃岩藻糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A52(产率61％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H), 4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):599.44[M-H] -。
实施例53(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-羰基-α-L-吡喃岩藻糖苷(A53)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃岩藻糖硫苷，其余所需原料、试剂及制备方法同实施例10，得到A53(产率86％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.42[M-H] -。
实施例54(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’S)-羰基-α-L-吡喃岩藻糖苷(A54)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃岩藻糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A54(产率82％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.42[M-H] -。
实施例55(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A55)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷。其余所需原料、试剂及制备方法同实施例2，得到A55(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):633.42[M-H] -。
实施例56(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A56)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A56(产率68％)。 1H NMR(500MHz,MeOD) δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):633.42[M-H] -。
实施例57(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A57)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，其余所需原料、试剂及制备方法同实施例6，得到A57(产率65％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):617.43[M-H] -。
实施例58 3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A58)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A58(产率66％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):617.43[M-H] -。
实施例59(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A59)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，其余所需原料、试剂及制备方法同实施例10，得到A59(产率86％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):631.41[M-H] -。
实施例60(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A60)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A60(产率89％)。 1H NMR(500MHz,MeOD) δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):631.41[M-H] -。
实施例61(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃木糖(1→3)-β-D-吡喃葡萄糖醛酸苷(A61)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖(1→3)-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A61(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):777.45[M-H] -。
实施例62(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃木糖(1→3)-β-D-吡喃葡萄糖醛酸苷(A62)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖(1→3)-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A62(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):777.45[M-H] -。
实施例63(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-β-D-吡喃木糖(1→3)-β-D-吡喃葡萄糖醛酸苷(A63)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖(1→3)-β-D-吡喃葡萄糖醛酸硫苷，其余所需原料、试剂及制备方法同实施例6，得到A63(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):761.46[M-H]。
实施例64(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-甲基-β-D-吡喃木糖(1→3)-β-D-吡喃葡萄糖醛酸苷(A64)-
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖(1→3)-β-D-吡喃葡萄糖醛酸硫苷， (3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A64(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):761.46[M-H] -。
实施例65(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-β-D-吡喃木糖(1→3)-β-D-吡喃葡萄糖醛酸苷(A65)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖(1→3)-β-D-吡喃葡萄糖醛酸硫苷，其余所需原料、试剂及制备方法同实施例10，得到A65(产率86％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):775.43[M-H] -。
实施例66(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-羰基-β-D-吡喃木糖(1→3)-β-D-吡喃葡萄糖醛酸苷(A66)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖(1→3)-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A66(产率89％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):775.43[M-H] -。
实施例67(3S,5S,8R,9R,10S,14R,17R,18S,19S,20R)-熊果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A67)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S,19S,20R)-28-O-苄基-3-醛基熊果酸。其余所需原料、试剂及制备方法同实施例2，得到A67(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):645.41[M-H] -。
实施例68(3R,5S,8R,9R,10S,14R,17R,18S,19S,20R)-熊果酸-3-(1’R)-(羟基)甲基-β- D-吡喃葡萄糖醛酸苷(A68)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S,19S,20R)-28-O-苄基-3-醛基熊果酸。其余所需原料、试剂及制备方法同实施例2，得到A68(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):645.41[M-H] -。
实施例69(3S,5S,8R,9R,10S,14R,17R,18S,19S,20R)-熊果酸-3-甲基-β-D-吡喃葡萄糖醛酸苷(A69)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S,19S,20R)-28-O-苄基-3-醛基熊果酸。其余所需原料、试剂及制备方法同实施例6，得到A69(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.42[M-H] -。
实施例70(3R,5S,8R,9R,10S,14R,17R,18S,19S,20R)-熊果酸-3-甲基-β-D-吡喃葡萄糖醛酸苷(A70)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S,19S,20R)-28-O-苄基-3-醛基熊果酸。其余所需原料、试剂及制备方法同实施例6，得到A70(产率63％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.42[M-H] -。
实施例71(3S,5S,8R,9R,10S,14R,17R,18S,19S,20R)-熊果酸-3-羰基-β-D-吡喃葡萄糖醛酸苷(A71)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S,19S,20R)-28-O-苄基-3-醛基熊果酸。其余所需原料、试剂及制备方法同实施例10，得到A71(产率85％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz, 1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):627.40[M-H] -。
实施例72(3R,5S,8R,9R,10S,14R,17R,18S,19S,20R)-熊果酸-3-羰基-β-D-吡喃葡萄糖醛酸苷(A72)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,14R,17R,18S,19S,20R)-28-O-苄基-3-醛基熊果酸。其余所需原料、试剂及制备方法同实施例10，得到A72(产率89％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):627.40[M-H] -。
实施例73(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-白桦脂酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A73)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-28-O-苄基-3-醛基白桦脂酸。其余所需原料、试剂及制备方法同实施例2，得到A73(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):645.41[M-H] -。
实施例74(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-白桦脂酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A74)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,13R,14R,17S,18R,19R)-28-O-苄基-3-醛基白桦脂酸。其余所需原料、试剂及制备方法同实施例2，得到A74(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):645.41[M-H] -。
实施例75(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-白桦脂酸-3-甲基-β-D-吡喃葡萄糖醛酸苷(A75)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-28-O-苄基-3-醛基白桦脂酸。其余所需原料、试剂及制备方法同实施例6，得到A75(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.42[M-H] -。
实施例76(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-白桦脂酸-3-甲基-β-D-吡喃葡萄糖醛酸苷(A76)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,13R,14R,17S,18R,19R)-28-O-苄基-3-醛基白桦脂酸。其余所需原料、试剂及制备方法同实施例6，得到A76(产率65％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.42[M-H] -。
实施例77(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-白桦脂酸-3-羰基-β-D-吡喃葡萄糖醛酸苷(A77)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-28-O-苄基-3-醛基白桦脂酸。其余所需原料、试剂及制备方法同实施例10，得到A77(产率88％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):627.40[M-H] -。
实施例78(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-白桦脂酸-3-羰基-β-D-吡喃葡萄糖醛酸苷(A78)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R,5S,8R,9R,10S,13R,14R,17S,18R,19R)-28-O-苄基-3-醛基白桦脂酸。其余所需原料、试剂及制备方法同实施例10，得到A78(产率89％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):627.40[M-H] -。
实施例79(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-28-β-D-吡喃葡萄糖醛酸苷(A79)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A79(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.38[M-H] -。
实施例80(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A80)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A80(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.40[M-H] -。
实施例81(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-甲基-β-D-吡喃葡萄糖醛酸苷(A81)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A81(产率90％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):599.40[M-H] -。
实施例82(5S,8R,9R,10S,14R,17R,18S19S,20R)-3-羰基熊果酸-28-β-D-吡喃葡萄糖醛酸苷(A82)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S19S,20R)-3-羰基-17-醛基熊果酸。其余所需原料、试剂及制备方法同实施例2，得到A82(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.38[M-H] -。
实施例83(5S,8R,9R,10S,14R,17R,18S19S,20R)-3-羰基熊果酸-17-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A83)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S19S,20R)-3-羰基-17-醛基熊果酸。其余所需原料、试剂及制备方法同实施例6，得到A83(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.40[M-H] -。
实施例84(5S,8R,9R,10S,14R,17R,18S,19S,20R)-3-羰基熊果酸-17-甲基-β-D-吡喃葡萄糖醛酸苷(A84)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S19S,20R)-3-羰基-17-醛基熊果酸。其余所需原料、试剂及制备方法同实施例10，得到A84(产率86％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):599.40[M-H] -。
实施例85(5S,8R,9R,10S,13R,14R,17S,18R,19R)-3-羰基白桦脂酸-28-β-D-吡喃葡萄糖醛酸苷(A85)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,13R,14R,17S,18R,19R)-3-羰基-17-醛基白桦脂酸。其余所需原料、试剂及制备方法同实施例2，得到A85(产率74％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):613.38[M-H] -。
实施例86(5S,8R,9R,10S,13R,14R,17S,18R,19R)-3-羰基白桦脂酸-17-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A86)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,13R,14R,17S,18R,19R)-3-羰基-17-醛基白桦脂酸。其余所需原料、试剂及制备方法同实施例6，得到A86(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝ 20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):615.40[M-H] -。
实施例87(5S,8R,9R,10S,13R,14R,17S,18R,19R)-3-羰基白桦脂酸-17-甲基-β-D-吡喃葡萄糖醛酸苷(A87)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,13R,14R,17S,18R,19R)-3-羰基-17-醛基白桦脂酸。其余所需原料、试剂及制备方法同实施例10，得到A87(产率85％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):599.40[M-H] -。
实施例88(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-乙基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A88)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-乙基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A88(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):673.44[M-H] -。
实施例89(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-烯丙基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A89)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-烯丙基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A89(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):685.44[M-H] -。
实施例90(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(O-乙基)羧甲基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A90)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3- 醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(O-乙基)羧甲基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A90(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):731.44[M-H] -。
实施例91(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-乙酸基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A91)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-乙酸基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A91(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):703.41[M-H] -。
实施例92(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-羟乙基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A92)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-羟乙基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A92(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):689.43[M-H] -。
实施例93(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(N-甲基)氨乙基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A93)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(N-甲基)氨乙基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A93(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):702.47[M-H] -。
实施例94(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(N,N-二乙基)氨乙基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A94)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(N,N-二乙基)氨乙基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A94(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):744.51[M-H] -。
实施例95(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-羟丁-2”’-炔基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A95)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-羟丁-2”’-炔基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A95(产率62％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):713.43[M-H] -。
实施例96(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-环己基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A96)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-环己基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A96(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):727.49[M-H] -。
实施例97(3S,5S,8R,9R,10S,14R,17R,18S)-28-(O-甲基)羧甲氨基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A97)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(O-甲基)羧甲氨基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A97(产率73％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):716.45[M-H] -。
实施例98(3S,5S,8R,9R,10S,14R,17R,18S)-28-羧甲氨基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A98)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-羧甲氨基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A98(产率62％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):702.43[M-H] -。
实施例99(3S,5S,8R,9R,10S,14R,17R,18S)-28-(N,N-二乙基)氨丙氨基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A99)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(N,N-二乙基)氨丙氨基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A99(产率66％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):757.54[M-H] -。
实施例100(3S,5S,8R,9R,10S,14R,17R,18S)-28-(N-乙酰基)氨丙氨基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A100)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(N-乙酰基)氨丙氨基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A100(产率65％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):743.49[M-H] -。
实施例101(3S,5S,8R,9R,10S,14R,17R,18S)-28-(N,N-二乙基)氨己氨基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A101)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(N,N-二乙基)氨己氨基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A101(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝ 13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):799.59[M-H] -。
实施例102(3S,5S,8R,9R,10S,14R,17R,18S)-28-(N-乙酰基)氨己氨基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A102)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(N-乙酰基)氨己氨基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A102(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):785.54[M-H] -。
实施例103(3S,5S,8R,9R,10S,14R,17R,18S)-28-(N-乙基)氨己氨基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A103)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(N-乙基)氨己氨基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A103(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):771.56[M-H] -。
实施例104(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(吡唑-1”-基)甲基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A104)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(吡唑-1-基)甲基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A104(产率65％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):725.45[M-H] -。
实施例105(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(哌啶-1”-基)甲基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A105)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(哌啶-1-基)甲基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A105(产率70％)。 1H NMR(500MHz, MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):756.51[M-H] -。
实施例106(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(吗啉-4”-基)甲基齐墩果酸-3-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A106)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-(吗啉-4-基)甲基-3-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A106(产率67％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):758.49[M-H] -。
实施例107(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-氟代甲基-β-D-吡喃葡萄糖醛酸苷(A107)
Figure PCTCN2021104599-appb-000053
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，戴斯马丁试剂替换为DAST。其余所需原料、试剂及制备方法同实施例10，产物与得到A107(产率65％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):647.40[M-H] -。
实施例108(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-28-(1”R)-(羟基)甲基-β-D-二吡喃葡萄糖醛酸苷(A108)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷,(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-3,17-二醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A108(产率62％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,4H),3.46(dd,J＝20.4,9.3Hz,4H),3.38(s,2H),3.35–3.31(m,2H),3.23(d,J＝9.5Hz,2H),3.11(d,J＝9.5Hz,2H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):807.46[M-H] -。
实施例109(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-O-甲基-β-D-吡喃葡萄糖醛酸苷(A109)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-O-甲基-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A109(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):659.42[M-H] -。
实施例110(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-O-正丁基-β-D-吡喃葡萄糖醛酸苷(A110)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-O-正丁基-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A110(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):701.47[M-H] -。
实施例111(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-O-异丁基-β-D-吡喃葡萄糖醛酸苷(A111)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-O-异丁基-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A111(产率61％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):701.47[M-H] -。
实施例112(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-O-苄基-β-D-吡喃葡萄糖醛酸苷(A112)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-O-苄基-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A112(产率68％)。 1H NMR(500MHz,MeOD)δ7.32(m,5H),5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):735.46[M-H] -。
实施例113(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-O-(1-氟代乙酰基)-β-D-吡喃葡萄糖醛酸苷(A113)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6”-O-(1-氟代乙酰基)-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A113(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):658.44[M-H] -。
实施例114(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-甲氨基-β-D-吡喃葡萄糖醛酸苷(A114)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-甲氨基-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A114(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):658.44[M-H] -。
实施例115(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-正丁氨基-β-D-吡喃葡萄糖醛酸苷(A115)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-正丁氨基-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A115(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):600.49[M-H] -。
实施例116(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-异丁氨基-β-D-吡喃葡萄糖醛酸苷(A116)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-异丁氨基-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A116(产率80％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):700.49[M-H] -。
实施例117(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-苄氨 基-β-D-吡喃葡萄糖醛酸苷(A117)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-苄氨基-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A117(产率82％)。 1H NMR(500MHz,MeOD)δ7.33(m,5H),5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):734.47[M-H] -。
实施例118(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-二甲氨基-β-D-吡喃葡萄糖醛酸苷(A118)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-二甲氨基-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A118(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):672.46[M-H] -。
实施例119(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-6”-(1-氟代乙氨基)-β-D-吡喃葡萄糖醛酸苷(A119)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-6-(1-氟代乙氨基)-β-D-吡喃葡萄糖醛酸硫苷。其余所需原料、试剂及制备方法同实施例2，得到A119(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):672.46[M-H] -。
实施例120(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-3-(1’R)-(羟基)甲基-5”-氰基-β-D-吡喃木糖苷(A120)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-5-氰基-β-D-吡喃木糖硫苷。其余所需原料、试剂及制备方法同实施例2，得到A120(产率78％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):626.41[M-H] -。
实施例121(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’S)-(羟基)甲基-β-D- 吡喃甘露糖苷(A121)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A121(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):603.42[M+H] +。
实施例122(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A122)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羟基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A122(产率73％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):605.43[M+H] +。
实施例123(3S,5S,8R,9R,10S,14R,17R,18S)-3-甲氧基齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A123)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-甲氧基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A123(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):619.45[M+H] +。
实施例124(3S,5S,8R,9R,10S,14R,17R,18S)-3-(4-氟环己氧基)齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A124)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-(4-氟环己氧基)-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A124(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4, 9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):705.50[M+H] +。
实施例125(3S,5S,8R,9R,10S,14R,17R,18S)-3-乙酰氧基齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A125)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-乙酰氧基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A125(产率77％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):647.44[M+H] +。
实施例126(3S,5S,8R,9R,10S,14R,17R,18S)-3-氟乙酰氧基齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A126)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-氟乙酰氧基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A126(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):665.44[M+H] +。
实施例127(3S,5S,8R,9R,10S,14R,17R,18S)-3-(4-氟苯乙酰氧基)齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A127)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-(4-氟苯乙酰氧基)-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A127(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):727.45[M+H] +。
实施例128(3S,5S,8R,9R,10S,14R,17R,18S)-3-(4-三氟甲基苯磺酰氧基)齐墩果酸- 17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A128)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-(4-三氟甲基苯磺酰氧基)-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A128(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):813.41[M+H] +。
实施例129(3S,5S,8R,9R,10S,14R,17R,18S)-3-(2,3,5,6-四氟苯甲酰胺基)齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A129)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-(2,3,5,6-四氟苯甲酰胺基)-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A129(产率76％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):780.44[M+H] +。
实施例130(3S,5S,8R,9R,10S,14R,17R,18S)-3-(4-三氟甲基苯磺酰胺基)齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A130)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-(4-三氟甲基苯磺酰胺基)-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A130(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):812.43[M+H] +。
实施例131(5S,8R,9R,10S,14R,17R,18S)-3-肟基齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A131)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-肟基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A131(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3 Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):618.43[M+H] +。
实施例132(5S,8R,9R,10S,14R,17R,18S)-3-甲基腙基齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A132)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-甲基腙基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A132(产率79％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):631.46[M+H] +。
实施例133(5S,8R,9R,10S,14R,17R,18S)-3-苯腙基齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A133)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-苯腙基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A133(产率76％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):693.48[M+H] +。
实施例134(3S,5S,8R,9R,10S,14R,17R,18S)-3-(4-氟苯基脲基)齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A134)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-(4-氟苯基脲基)-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A134(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):741.48[M+H] +。
实施例135(3S,5S,8R,9R,10S,14R,17R,18S)-3-(4-氟苯基硫脲基)齐墩果酸-17-(1’S)- (羟基)甲基-β-D-吡喃甘露糖苷(A135)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-(4-氟苯基硫脲基)-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A135(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):757.45[M+H] +。
实施例136(3S,5S,8R,9R,10S,14R,17R,18S)-3-甲酰基齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A136)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-甲酰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A136(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):617.43[M+H] +。
实施例137(3S,5S,8R,9R,10S,14R,17R,18S)-3-(3-氟环丁基硫基)齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A137)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-(3-氟环丁基硫基)-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A137(产率73％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):693.45[M+H] +。
实施例138(3S,5S,8R,9R,10S,14R,17R,18S)-3-苯硫基齐墩果酸-17-(1’S)-(羟基)甲基-β-D-吡喃甘露糖苷(A138)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-苯硫基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A138(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3 Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):697.44[M+H] +。
实施例139(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-28-β-D-吡喃甘露糖苷(A139)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A139(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):601.40[M+H] +。
实施例140(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’S)-氟甲基-β-D-吡喃甘露糖苷(A140)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-氟甲基-17-醛基齐墩果酸，戴斯马丁试剂替换为DAST。其余所需原料、试剂及制备方法同实施例10，产物与得到A140(产率67％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):645.41[M+H] +。
实施例141(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-甲基-β-D-吡喃甘露糖苷(A141)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A141(产率80％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):587.42[M+H] +。
实施例142(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’S)-(羟基)甲基- 2”,3”,4”,6”-O-四乙酰基-β-D-吡喃甘露糖苷(A142)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A142(产率67％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):771.46[M+H] +。
实施例143(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-17-(1’S)-(羟基)甲基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃甘露糖苷(A143)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羟基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A143(产率66％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):773.48[M+H] +。
实施例144(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-甲基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃甘露糖苷(A144)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A144(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):755.47[M+H] +。
实施例145(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’S)-(羟基)乙基-β-D-吡喃甘露糖苷(A145)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A145(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4, 9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):617.43[M+H] +。
实施例146(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’S)-(羟基)乙基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃甘露糖苷(A146)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A146(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):685.48[M+H] +。
实施例147(5S,8R,9R,10S,14R,17R,18S)-3-羰基熊果酸-17-(2’S)-(羟基)乙基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃甘露糖苷(A147)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基熊果酸。其余所需原料、试剂及制备方法同实施例6，得到A147(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):685.48[M+H] +。
实施例148(5S,8R,9R,10S,14R,17R,18S)-3-羰基白桦脂酸-17-(2’S)-(羟基)乙基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃甘露糖苷(A148)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃甘露糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基白桦脂酸。其余所需原料、试剂及制备方法同实施例6，得到A148(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):685.48[M+H] +。
实施例149(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基-β-D- 吡喃木糖苷(A149)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A149(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):573.41[M+H] +。
实施例150(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17甲基-β-D-吡喃木糖苷(A150)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A150(产率77％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):557.41[M+H] +。
实施例151(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-17-(1’R)-(羟基)甲基-β-D-吡喃木糖苷(A151)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羟基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A151(产率73％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):575.42[M+H] +。
实施例152(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基-2”,3”,4”-O-三乙酰基-β-D-吡喃木糖苷(A152)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A152(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H), 3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):698.44[M+H] +。
实施例153(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-甲基-2”,3”,4”-O-三乙酰基-β-D-吡喃木糖苷(A153)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A153(产率74％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):683.44[M+H] +。
实施例154(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’R)-(羟基)乙基-2”,3”,4”-O-三乙酰基-β-D-吡喃木糖苷(A154)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A154(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):713.46[M+H] +。
实施例155(5S,8R,9R,10S,14R,17R,18S)-3-羰基熊果酸-17-(2’R)-(羟基)乙基-2”,3”,4”-O-三乙酰基-β-D-吡喃木糖苷(A155)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基熊果酸。其余所需原料、试剂及制备方法同实施例6，得到A155(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):713.46[M+H] +。
实施例156(5S,8R,9R,10S,14R,17R,18S)-3-羰基白桦脂酸-17-(2’R)-(羟基)乙基- 2”,3”,4”-O-三乙酰基-β-D-吡喃木糖苷(A156)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃木糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基白桦脂酸。其余所需原料、试剂及制备方法同实施例6，得到A156(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):713.46[M+H] +。
实施例157(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基-β-D-吡喃半乳糖苷(A157)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A157(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):603.42[M+H] +。
实施例158(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-甲基-β-D-吡喃半乳糖苷(A158)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A158(产率76％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):587.42[M+H] +。
实施例159(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-17-(1’R)-(羟基)甲基-β-D-吡喃半乳糖苷(A159)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羟基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A159(产率74％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3 Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,1H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):605.43[M+H] +。
实施例160(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃半乳糖苷(A160)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A160(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):771.46[M+H] +。
实施例161(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-甲基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃半乳糖苷(A161)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A161(产率74％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):755.47[M+H] +。
实施例162(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’R)-(羟基)乙基-β-D-吡喃半乳糖苷(A162)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A162(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):617.43[M+H] +。
实施例163(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’R)-(羟基)乙基- 2”,3”,4”,6”-O-四乙酰基-β-D-吡喃半乳糖苷(A163)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A163(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):785.48[M+H] +。
实施例164(5S,8R,9R,10S,14R,17R,18S)-3-羰基熊果酸-17-(2’R)-(羟基)乙基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃半乳糖苷(A164)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基熊果酸。其余所需原料、试剂及制备方法同实施例6，得到A164(产率68％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):785.48[M+H] +。
实施例165(5S,8R,9R,10S,14R,17R,18S)-3-羰基白桦脂酸-17-(2’R)-(羟基)乙基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃半乳糖苷(A165)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃半乳糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基白桦脂酸。其余所需原料、试剂及制备方法同实施例6，得到A165(产率74％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):785.48[M+H] +。
实施例166(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基-α-L-吡喃鼠李糖苷(A166)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A166(产率74％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H), 3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):587.42[M+H] +。
实施例167(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-甲基-α-L-吡喃鼠李糖苷(A167)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A167(产率74％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):571.43[M+H] +。
实施例168(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-17-(1’R)-(羟基)甲基-α-L-吡喃鼠李糖苷(A168)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羟基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A168(产率75％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,1H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):589.44[M+H] +。
实施例169(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基-2”,3”,4”-O-三乙酰基-α-L-吡喃鼠李糖苷(A169)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A169(产率73％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):713.46[M+H] +。
实施例170(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-甲基-2”,3”,4”-O-三 乙酰基-α-L-吡喃鼠李糖苷(A170)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A170(产率74％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):697.46[M+H] +。
实施例171(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’R)-(羟基)乙基-α-L-吡喃鼠李糖苷(A171)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A171(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):601.44[M+H] +。
实施例172(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’R)-(羟基)乙基-2”,3”,4”-O-三乙酰基-α-L-吡喃鼠李糖苷(A172)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A172(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):727.47[M+H] +。
实施例173(5S,8R,9R,10S,14R,17R,18S)-3-羰基熊果酸-17-(2’R)-(羟基)乙基-2”,3”,4”-O-三乙酰基-α-L-吡喃鼠李糖苷(A173)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基熊果酸。其余所需原料、试剂及制备方法同实施例6，得到A173(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3 Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):727.47[M+H] +。
实施例174(5S,8R,9R,10S,14R,17R,18S)-3-羰基白桦脂酸-17-(2’R)-(羟基)乙基-2”,3”,4”-O-三乙酰基-α-L-吡喃鼠李糖苷(A174)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基白桦脂酸。其余所需原料、试剂及制备方法同实施例6，得到A174(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):727.47[M+H] +。
实施例175(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-17-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖醛酸苷(A175)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羟基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A175(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,1H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):619.41[M+H] +。
实施例176(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-羰基-2”,3”,4”-O-三乙酰基-β-D-吡喃葡萄糖醛酸苷(A176)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A176(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,1H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):741.41[M+H] +。
实施例177(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基- 2”,3”,4”-O-三乙酰基-β-D-吡喃葡萄糖醛酸苷(A177)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A177(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):743.43[M+H] +。
实施例178(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-甲基-2”,3”,4”-O-三乙酰基-β-D-吡喃葡萄糖醛酸苷(A178)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A178(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):727.43[M+H] +。
实施例179(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’R)-(羟基)乙基-β-D-吡喃葡萄糖醛酸苷(A179)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A179(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):631.41[M+H] +。
实施例180(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’R)-(羟基)乙基-2”,3”,4”-O-三乙酰基-β-D-吡喃葡萄糖醛酸苷(A180)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A180(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4, 9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):757.44[M+H] +。
实施例181(5S,8R,9R,10S,14R,17R,18S)-3-羰基熊果酸-17-(2’R)-(羟基)乙基-2”,3”,4”-O-三乙酰基-β-D-吡喃葡萄糖醛酸苷(A181)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基熊果酸。其余所需原料、试剂及制备方法同实施例6，得到A181(产率77％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):757.44[M+H] +。
实施例182(5S,8R,9R,10S,14R,17R,18S)-3-羰基白桦脂酸-17-(2’R)-(羟基)乙基-2”,3”,4”-O-三乙酰基-β-D-吡喃葡萄糖醛酸苷(A182)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖醛酸硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基白桦脂酸。其余所需原料、试剂及制备方法同实施例6，得到A182(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):757.44[M+H] +。
实施例183(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A183)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A183(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):605.41[M+H] +。
实施例184(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17甲基-6”-脱氧-6”-氟- β-D-吡喃葡萄糖苷(A184)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A184(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):589.42[M+H] +。
实施例185(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-17-(1’R)-(羟基)甲基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A185)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羟基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A185(产率75％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,1H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):607.43[M+H] +。
实施例186(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基-2”,3”,4”-O-三乙酰基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A186)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A186(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):731.45[M+H] +。
实施例187(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-甲基-2”,3”,4”-O-三乙酰基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A187)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方 法同实施例10，得到A187(产率75％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):715.45[M+H] +。
实施例188(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’R)-(羟基)乙基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A188)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A188(产率76％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):619.43[M+H] +。
实施例189(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’R)-(羟基)乙基-2”,3”,4”-O-三乙酰基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A189)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A189(产率69％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):745.46[M+H] +。
实施例190(5S,8R,9R,10S,14R,17R,18S)-3-羰基熊果酸-17-(2’R)-(羟基)乙基-2”,3”,4”-O-三乙酰基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A190)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基熊果酸。其余所需原料、试剂及制备方法同实施例6，得到A190(产率67％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz, 1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):745.46[M+H] +。
实施例191(5S,8R,9R,10S,14R,17R,18S)-3-羰基白桦脂酸-17-(2’R)-(羟基)乙基-2”,3”,4”-O-三乙酰基-6”-脱氧-6”-氟-β-D-吡喃葡萄糖苷(A191)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三乙酰基-1-(吡啶-1-基)磺酰基-6-脱氧-6-氟-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基白桦脂酸。其余所需原料、试剂及制备方法同实施例6，得到A191(产率71％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):745.46[M+H] +。
实施例192(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖苷(A192)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A192(产率70％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):603.42[M+H] +。
实施例193(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17甲基--β-D-吡喃葡萄糖苷(A193)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A193(产率84％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):587.42[M+H] +。
实施例194(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-17-(1’R)-(羟基)甲基-β-D-吡 喃葡萄糖苷(A194)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羟基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A194(产率79％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,1H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):605.43[M+H] +。
实施例195(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃葡萄糖苷(A195)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A195(产率79％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):771.46[M+H] +。
实施例196(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-甲基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃葡萄糖苷(A196)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-醛基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A196(产率78％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):755.47[M+H] +。
实施例197(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’R)-(羟基)乙基-β-D-吡喃葡萄糖苷(A197)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A197(产率75％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4, 9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):617.43[M+H] +。
实施例198(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(2’R)-(羟基)乙基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃葡萄糖苷(A198)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A198(产率72％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):785.48[M+H] +。
实施例199(5S,8R,9R,10S,14R,17R,18S)-3-羰基熊果酸-17-(2’R)-(羟基)乙基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃葡萄糖苷(A199)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基熊果酸。其余所需原料、试剂及制备方法同实施例6，得到A199(产率79％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):785.48[M+H] +。
实施例200(5S,8R,9R,10S,14R,17R,18S)-3-羰基白桦脂酸-17-(2’R)-(羟基)乙基-2”,3”,4”,6”-O-四乙酰基-β-D-吡喃葡萄糖苷(A200)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4,6-O-四乙酰基-1-(吡啶-1-基)磺酰基-β-D-吡喃鼠李糖硫苷，(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰甲基白桦脂酸。其余所需原料、试剂及制备方法同实施例6，得到A200(产率77％)。 1H NMR(500MHz,MeOD)δ5.28(s,1H),4.16(s,1H),3.79(d,J＝2.0Hz,2H),3.46(dd,J＝20.4,9.3Hz,2H),3.38(s,1H),3.35–3.31(m,1H),3.23(d,J＝9.5Hz,1H),3.11(d,J＝9.5Hz,1H),2.88(dd,J＝13.5,3.0Hz,1H),2.03(dd,J＝13.5,10.3Hz,1H),1.93(d,J＝7.1Hz,2H),1.86–1.05(m,21H),1.06–0.93(m,12H),0.90–0.82(m,6H),0.81(d,J＝11.4Hz,1H).LRMS(ESI):785.48[M+H] +。
实施例201(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-28-β-D-吡喃葡萄糖苷 (A201)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A201(产率72％)。 1H NMR(500MHz,CDCl 3)δ5.48(d,J＝5.9Hz,1H),5.33(tdd,J＝5.1,1.8,1.1Hz,1H),5.07(d,J＝5.7Hz,1H),4.57(d,J＝6.3Hz,1H),4.44(dd,J＝8.8,2.6Hz,1H),4.19(t,J＝4.5Hz,1H),3.71–3.58(m,3H),3.58(dt,J＝7.7,3.5Hz,1H),3.58–3.49(m,1H),3.31(dddd,J＝8.5,7.8,5.8,1.8Hz,1H),2.48(ddd,J＝12.5,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.17(tq,J＝5.1,1.0Hz,1H),2.04(dddd,J＝12.6,6.4,5.1,1.0Hz,1H),1.95–1.87(m,1H),1.91–1.84(m,1H),1.86–1.81(m,1H),1.84–1.78(m,2H),1.72–1.59(m,6H),1.62–1.48(m,3H),1.51–1.41(m,1H),1.44–1.36(m,2H),1.40–1.33(m,1H),1.36–1.29(m,1H),1.15(s,2H),1.08(t,J＝1.6Hz,5H),0.99–0.92(m,6H),0.93(d,J＝6.6Hz,5H).LRMS(ESI)：601.4[M+H] +。
实施例202(5S,8R,9R,10S,14R,17R,18S)-3-羰基熊果酸-28-β-D-吡喃葡萄糖苷(A202)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基熊果酸。其余所需原料、试剂及制备方法同实施例10，得到A202(产率72％)。 1H NMR(500MHz,CDCl 3)δ5.53–5.46(m,2H),5.07(d,J＝5.7Hz,1H),4.57(d,J＝6.3Hz,1H),4.51(dd,J＝8.8,2.6Hz,1H),4.19(t,J＝4.5Hz,1H),3.71–3.58(m,3H),3.58(dt,J＝7.7,3.5Hz,1H),3.58–3.49(m,1H),3.31(dddd,J＝8.4,7.8,5.8,1.8Hz,1H),2.48(ddd,J＝12.5,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.28–2.22(m,1H),2.06–1.91(m,2H),1.89–1.78(m,4H),1.77(ddd,J＝12.5,7.7,5.2Hz,1H),1.73–1.57(m,5H),1.60–1.54(m,1H),1.57–1.51(m,1H),1.48–1.41(m,1H),1.44–1.38(m,2H),1.41–1.35(m,1H),1.35(dtd,J＝6.5,3.2,1.6Hz,1H),1.34–1.25(m,1H),1.20(s,2H),1.08(t,J＝1.6Hz,5H),0.99–0.90(m,9H),0.91(d,J＝2.0Hz,2H).LRMS(ESI)：601.4[M+H] +。
实施例203(5S,8R,9R,10S,14R,17R,18S)-3-羰基熊果酸-17-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖苷(A203)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基熊果酸。其余所需原料、试剂及制备方法同实施例2，得到A203(产率64％)。 1H NMR(500MHz,CDCl 3)δ5.47(tdd,J＝4.9,1.7,1.0Hz,1H),4.95(d,J＝5.3Hz,1H),4.81(dd,J＝11.0,5.7Hz,2H),4.61(d,J＝6.2Hz,1H),4.20(t,J＝4.5Hz,1H),4.00–3.88(m,2H),3.72(dddd,J＝8.8,7.9,6.1,2.8Hz,1H),3.70–3.65(m,1H),3.68–3.55(m,4H),2.48(ddd,J＝12.5,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.06–1.86(m,4H),1.84(ddd,J＝6.6,2.9,1.5Hz,1H),1.84–1.78(m,1H),1.71–1.64(m,1H),1.65(dd,J＝3.9,1.6Hz,1H),1.66–1.54(m,4H),1.57–1.51(m,1H),1.54–1.44(m,1H),1.47–1.39(m,2H),1.42–1.35(m,3H),1.37–1.32(m,1H),1.35–1.25(m,1H),1.11–1.05(m,8H),0.99–0.88(m,11H).LRMS(ESI)：603.4[M+H] +。
实施例204(3S,5S,8R,9R,10S,14R,17R,18S)-熊果酸-17-(1’R)-(羟基)甲基-β-D-吡喃 葡萄糖苷(A204)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-17-甲酰基熊果酸。其余所需原料、试剂及制备方法同实施例2，得到A204(产率50％)。 1H NMR(500MHz,CDCl 3)δ5.47(tdd,J＝4.9,1.7,1.0Hz,1H),4.95(d,J＝5.3Hz,1H),4.81(dd,J＝11.0,5.7Hz,2H),4.61(d,J＝6.2Hz,1H),4.20(t,J＝4.5Hz,1H),4.00–3.88(m,2H),3.76–3.55(m,6H),3.31–3.23(m,1H),3.00(d,J＝10.8Hz,1H),2.01–1.86(m,4H),1.74–1.25(m,19H),1.09(s,2H),0.97(d,J＝1.5Hz,3H),0.95–0.90(m,9H),0.93–0.87(m,6H).LRMS(ESI)：605.4[M+H] +。
实施例205(3S,5S,8R,9R,10S,14R,17R,18S)-熊果酸-28-β-D-吡喃葡萄糖苷(A205)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-17-甲酰基熊果酸。其余所需原料、试剂及制备方法同实施例10，得到A205(产率50％)。 1H NMR(500MHz,CDCl 3)δ5.53–5.46(m,2H),5.07(d,J＝5.7Hz,1H),4.57(d,J＝6.3Hz,1H),4.51(dd,J＝8.8,2.6Hz,1H),4.19(t,J＝4.5Hz,1H),3.71–3.49(m,5H),3.36–3.23(m,2H),3.00(d,J＝10.8Hz,1H),2.28–2.22(m,1H),2.01–1.93(m,1H),1.89–1.24(m,20H),1.20(s,2H),0.99–0.87(m,16H).LRMS(ESI)：603.4[M+H] +。
实施例206(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-28-β-D-吡喃葡萄糖苷(A206)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A206(产率50％)。 1H NMR(500MHz,CDCl 3)δ5.48(d,J＝5.9Hz,1H),5.33(tdd,J＝5.1,1.8,1.1Hz,1H),5.07(d,J＝5.7Hz,1H),4.57(d,J＝6.3Hz,1H),4.44(dd,J＝8.8,2.6Hz,1H),4.19(t,J＝4.5Hz,1H),3.71–3.58(m,3H),3.58(dt,J＝7.7,3.5Hz,1H),3.58–3.49(m,1H),3.36–3.23(m,2H),3.00(d,J＝10.8Hz,1H),2.17(tq,J＝5.1,1.0Hz,1H),2.05(dddd,J＝12.5,6.2,5.1,1.0Hz,1H),1.96–1.78(m,3H),1.74–1.39(m,15H),1.42–1.27(m,4H),1.15(s,2H),0.99–0.87(m,17H).LRMS(ESI)：603.4[M+H] +。
实施例207(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-白桦脂酸-28-β-D-吡喃葡萄糖苷(A207)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-17-甲酰基白桦脂酸。其余所需原料、试剂及制备方法同实施例10，得到A207(产率55％)。 1H NMR(500MHz,CDCl 3)δ5.48(d,J＝5.9Hz,1H),5.07(d,J＝5.7Hz,1H),4.83(h,J＝1.6Hz,1H),4.67(h,J＝1.5Hz,1H),4.57(d,J＝6.3Hz,1H),4.47(dd,J＝8.8,2.5Hz,1H),4.19(t,J＝4.5Hz,1H),3.72–3.49(m,5H),3.36–3.23(m,2H),3.04–2.96(m,2H),1.82–1.48(m,22H),1.51–1.47(m,1H),1.50–1.43(m,1H),1.45–1.35(m,1H),1.31(ddq,J＝6.8,4.0,1.5Hz,1H),1.18(ddp,J＝7.4,4.4,1.5Hz,1H),0.99–0.91(m,11H),0.82(t,J＝1.5Hz,3H)。LRMS(ESI)：603.4[M+H] +。
实施例208(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-白桦脂酸-17-(1’R)-(羟基)甲基 -β-D-吡喃葡萄糖苷(A208)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S,5S,8R,9R,10S,14R,17R,18S)-17-甲酰基白桦脂酸。其余所需原料、试剂及制备方法同实施例2，得到A208(产率56％)。 1H NMR(500MHz,CDCl 3)δ4.95(d,J＝5.1Hz,1H),4.84–4.79(m,2H),4.69(d,J＝5.3Hz,1H),4.65(h,J＝1.6Hz,1H),4.61(d,J＝6.2Hz,1H),4.20(t,J＝4.5Hz,1H),3.93(dddd,J＝8.6,7.6,5.9,1.8Hz,1H),3.85(ddd,J＝7.7,5.1,2.8Hz,1H),3.72(dddd,J＝8.8,7.5,6.0,2.9Hz,1H),3.71–3.64(m,1H),3.68–3.61(m,2H),3.64–3.58(m,1H),3.57(ddd,J＝12.3,4.6,3.3Hz,1H),3.31–3.23(m,1H),2.18–2.09(m,1H),1.76–1.27(m,25H),1.18(ddp,J＝7.4,4.4,1.5Hz,1H),0.99–0.90(m,11H),0.82(t,J＝1.5Hz,3H).LRMS(ESI)：605.4[M+H] +。
实施例209(5S,8R,9R,10S,13R,14R,17S,18R,19R)-3-羰基白桦脂酸-17-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖苷(A209)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基白桦脂酸。其余所需原料、试剂及制备方法同实施例2，得到A209(产率60％)。 1H NMR(500MHz,CDCl 3)δ4.84–4.79(m,1H),4.71–4.59(m,1H),3.76–3.53(m,2H),2.53–2.41(m,1H),1.86–1.76(m,1H),1.73(q,J＝1.4Hz,1H),1.63–1.28(m,7H),1.13–1.05(m,2H),0.97(d,J＝1.5Hz,1H),0.92(d,J＝1.5Hz,1H),0.85(t,J＝1.4Hz,1H).LRMS(ESI)：603.4[M+H] +。
实施例210(5S,8R,9R,10S,13R,14R,17S,18R,19R)-3-羰基白桦脂酸-28-β-D-吡喃葡萄糖苷(A210)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基白桦脂酸。其余所需原料、试剂及制备方法同实施例10，得到A210(产率51％)。 1H NMR(500MHz,CDCl 3)δ5.48(d,J＝5.9Hz,1H),5.07(d,J＝5.7Hz,1H),4.83(h,J＝1.6Hz,1H),4.67(h,J＝1.5Hz,1H),4.57(d,J＝6.3Hz,1H),4.47(dd,J＝8.8,2.5Hz,1H),4.19(t,J＝4.5Hz,1H),3.72–3.49(m,5H),3.31(dddd,J＝8.4,7.7,5.8,1.8Hz,1H),3.00(dddt,J＝10.3,5.0,3.3,1.6Hz,1H),2.53–2.41(m,2H),1.86–1.59(m,11H),1.62–1.57(m,1H),1.59–1.53(m,2H),1.51(ddddd,J＝12.4,7.7,6.5,2.6,1.4Hz,7H),1.50–1.40(m,3H),1.44–1.34(m,2H),1.13–1.05(m,7H),0.96(dd,J＝12.7,1.5Hz,6H),0.85(t,J＝1.4Hz,3H).LRMS(ESI)：601.4[M+H] +。
实施例211(5S,8R,9R,10S,13R,14R,17S,18R,19R)-3-羰基白桦脂酸-17-甲基-β-D-吡喃葡萄糖苷(A211)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基白桦脂酸。其余所需原料、试剂及制备方法同实施例6，得到A211(产率61％)。 1H NMR(500MHz,CDCl 3)δ4.85(d,J＝5.9Hz,1H),4.83–4.78(m,2H),4.65(h,J＝1.5Hz,1H),4.61(d,J＝6.4Hz,1H),4.23–4.16(m,1H),3.88(ddtd,J＝32.6,9.0,7.5,2.1Hz,2H),3.73(dddd,J＝8.8,7.7,6.2,2.2Hz,1H),3.70–3.63(m,2H),3.60–3.51(m,2H),2.53–2.41(m,2H),2.23(dtq,J＝7.0,5.3,1.7Hz,1H),1.96(dd,J＝13.8,7.2Hz,1H),1.83(ddd,J＝5.7,2.8,1.4Hz,1H),1.83–1.76(m, 1H),1.73(q,J＝1.5Hz,3H),1.70–1.60(m,1H),1.63–1.57(m,1H),1.59–1.54(m,1H),1.57–1.44(m,10H),1.47–1.42(m,1H),1.44–1.37(m,3H),1.40–1.33(m,1H),1.21(dd,J＝6.9,5.6Hz,1H),1.13–1.05(m,7H),0.97(d,J＝1.5Hz,3H),0.92(d,J＝1.3Hz,3H),0.85(t,J＝1.5Hz,3H).LRMS(ESI)：587.4[M+H] +。
实施例212(5S,8R,9R,10S,14R,17R,18S)-3-羰基熊果酸-17-甲基-β-D-吡喃葡萄糖苷(A212)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基熊果酸。其余所需原料、试剂及制备方法同实施例6，得到A212(产率57％)。 1H NMR(500MHz,CDCl 3)δ5.45(tdd,J＝4.9,1.8,1.1Hz,1H),4.85(d,J＝5.9Hz,1H),4.80(d,J＝5.7Hz,1H),4.61(d,J＝6.4Hz,1H),4.23–4.17(m,1H),3.96–3.88(m,1H),3.84(dtd,J＝9.3,7.0,2.3Hz,1H),3.73(dddd,J＝8.9,7.9,6.3,2.3Hz,1H),3.70–3.62(m,2H),3.62–3.51(m,2H),2.48(ddd,J＝12.5,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.07–2.01(m,1H),2.04–1.98(m,1H),1.96(dddd,J＝12.5,6.3,4.9,1.0Hz,1H),1.84(ddd,J＝6.6,2.9,1.5Hz,1H),1.84–1.78(m,1H),1.80–1.70(m,3H),1.70–1.20(m,15H),1.11–1.05(m,9H),0.97(d,J＝1.5Hz,3H),0.95–0.86(m,9H).LRMS(ESI)：587.4[M+H] +。
实施例213(3S,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-17-甲基-β-D-吡喃葡萄糖苷(A213)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S，5S,8R,9R,10S,14R,17R,18S)-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例6，得到A213(产率56％)。 1H NMR(500MHz,CDCl 3)δ5.26(tdd,J＝5.3,1.8,1.0Hz,1H),4.85(d,J＝5.9Hz,1H),4.80(d,J＝5.7Hz,1H),4.61(d,J＝6.4Hz,1H),4.23–4.17(m,1H),3.96–3.87(m,1H),3.84–3.70(m,2H),3.70–3.62(m,2H),3.62–3.51(m,2H),3.31–3.23(m,1H),3.00(d,J＝10.8Hz,1H),2.68(tq,J＝4.8,1.0Hz,1H),2.03(dd,J＝14.0,6.7Hz,1H),1.85(dddd,J＝12.7,6.4,5.2,1.0Hz,1H),1.76(dddd,J＝12.5,6.4,5.1,1.0Hz,1H),1.74–1.20(m,22H),1.09(s,2H),0.99–0.87(m,17H).LRMS(ESI)：589.4[M+H] +。
实施例214(3S,5S,8R,9R,10S,14R,17R,18S)-3-羰基熊果酸-17-甲基-β-D-吡喃葡萄糖苷(A214)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S，5S,8R,9R,10S,14R,17R,18S)-17-甲酰基熊果酸。其余所需原料、试剂及制备方法同实施例6，得到A214(产率56％)。 1H NMR(500MHz,CDCl 3)δ5.45(tdd,J＝5.0,1.8,1.1Hz,1H),4.85(d,J＝5.9Hz,1H),4.80(d,J＝5.7Hz,1H),4.61(d,J＝6.4Hz,1H),4.23–4.17(m,1H),3.96–3.88(m,1H),3.84(dtd,J＝9.3,7.0,2.3Hz,1H),3.73(dddd,J＝8.9,7.9,6.3,2.3Hz,1H),3.70–3.62(m,2H),3.62–3.51(m,2H),3.31–3.23(m,1H),3.00(d,J＝10.8Hz,1H),2.03(dd,J＝13.9,7.0Hz,1H),2.00–1.91(m,2H),1.80–1.20(m,23H),1.09(s,2H),0.97(d,J＝1.5Hz,3H),0.95–0.86(m,14H).LRMS(ESI)：589.4[M+H] +。
实施例215(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-白桦脂酸-17-甲基-β-D-吡喃葡 萄糖苷(A215)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3S，5S,8R,9R,10S,14R,17R,18S)-17-甲酰基白桦脂酸。其余所需原料、试剂及制备方法同实施例6，得到A215(产率48％)。 1H NMR(500MHz,CDCl 3)δ4.85(d,J＝5.9Hz,1H),4.83–4.78(m,2H),4.65(h,J＝1.5Hz,1H),4.61(d,J＝6.4Hz,1H),4.23–4.16(m,1H),3.88(ddtd,J＝32.6,9.0,7.5,2.1Hz,2H),3.73(dddd,J＝8.8,7.7,6.2,2.2Hz,1H),3.70–3.63(m,2H),3.60–3.51(m,2H),3.31–3.23(m,1H),3.00(d,J＝10.8Hz,1H),2.23(dtq,J＝7.0,5.3,1.7Hz,1H),1.96(dd,J＝13.8,7.2Hz,1H),1.76–1.33(m,24H),1.31(ddq,J＝6.8,4.1,1.5Hz,1H),1.24–1.15(m,2H),0.99–0.91(m,11H),0.82(t,J＝1.5Hz,3H).LRMS(ESI)：589.4[M+H] +。
实施例216(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-28-β-D-吡喃葡萄糖苷(A216)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R，5S,8R,9R,10S,14R,17R,18S)-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A216(产率55％)。 1H NMR(500MHz,CDCl 3)δ5.48(d,J＝5.9Hz,1H),5.33(tdd,J＝5.1,1.8,1.1Hz,1H),5.07(d,J＝5.7Hz,1H),4.57(d,J＝6.2Hz,1H),4.44(dd,J＝8.8,2.6Hz,1H),4.19(t,J＝4.5Hz,1H),3.67(ddd,J＝10.9,3.9,2.8Hz,1H),3.67–3.61(m,1H),3.64–3.49(m,3H),3.36–3.25(m,2H),3.00(d,J＝10.8Hz,1H),2.17(tq,J＝5.1,1.0Hz,1H),2.05(dddd,J＝12.5,6.2,5.1,1.0Hz,1H),1.96–1.79(m,3H),1.79–1.40(m,15H),1.43–1.27(m,4H),1.15(s,2H),0.99–0.88(m,17H).LRMS(ESI)：603.4[M+H] +。
实施例217(3R,5S,8R,9R,10S,14R,17R,18S)-齐墩果酸-17-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖苷(A217)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R，5S,8R,9R,10S,14R,17R,18S)-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A217(产率55％)。 1H NMR(500MHz,CDCl 3)δ5.24(tdd,J＝5.1,1.8,1.0Hz,1H),4.95(d,J＝5.2Hz,1H),4.82(d,J＝5.9Hz,1H),4.71(d,J＝5.7Hz,1H),4.61(d,J＝6.2Hz,1H),4.20(t,J＝4.5Hz,1H),3.98–3.88(m,2H),3.76–3.55(m,6H),3.29(ddd,J＝10.8,7.4,4.7Hz,1H),3.00(d,J＝10.8Hz,1H),2.23(tq,J＝4.6,1.1Hz,1H),1.95–1.81(m,2H),1.80–1.74(m,1H),1.77–1.72(m,1H),1.74–1.67(m,2H),1.70–1.61(m,1H),1.63–1.55(m,1H),1.58–1.52(m,2H),1.55–1.49(m,2H),1.50(dd,J＝5.3,1.6Hz,2H),1.49–1.44(m,3H),1.47–1.40(m,1H),1.44–1.26(m,4H),1.10(s,2H),0.99–0.88(m,17H).LRMS(ESI)：605.4[M+H] +
实施例218(3R,5S,8R,9R,10S,14R,17R,18S)-熊果酸-17-(1’R)-(羟基)甲基-β-D-吡喃葡萄糖苷(A218)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R，5S,8R,9R,10S,14R,17R,18S)-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A218(产率56％)。 1H NMR(500MHz,CDCl 3)δ5.47(tdd,J＝4.9,1.7,1.0Hz,1H),4.95(d,J＝5.3Hz,1H),4.81(dd,J＝11.0,5.7Hz,2H),4.61(d,J＝6.2Hz,1H),4.20(t,J＝4.5Hz,1H),3.96(ddd,J＝10.2,5.1,2.3Hz,1H),3.94–3.87(m,1H),3.76– 3.50(m,7H),3.29(ddd,J＝10.8,7.4,4.7Hz,1H),3.00(d,J＝10.8Hz,1H),2.06–1.24(m,25H),1.09(s,2H),0.97(d,J＝1.5Hz,3H),0.95(d,J＝1.5Hz,3H),0.93(d,J＝1.5Hz,3H),0.93–0.89(m,10H).LRMS(ESI)：605.4[M+H] +
实施例219(3R,5S,8R,9R,10S,14R,17R,18S)-熊果酸-28-β-D-吡喃葡萄糖苷(A219)
将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(3R，5S,8R,9R,10S,14R,17R,18S)-17-甲酰基熊果酸。其余所需原料、试剂及制备方法同实施例10，得到A219(产率56％)。 1H NMR(500MHz,CDCl 3)δ5.53–5.46(m,2H),5.07(d,J＝5.7Hz,1H),4.57(d,J＝6.3Hz,1H),4.51(dd,J＝8.8,2.6Hz,1H),4.19(t,J＝4.5Hz,1H),3.71–3.58(m,3H),3.58(dt,J＝7.7,3.5Hz,1H),3.58–3.49(m,1H),3.36–3.25(m,2H),3.00(d,J＝10.8Hz,1H),2.28–2.22(m,1H),2.01–1.93(m,1H),1.89–1.24(m,21H),1.20(s,2H),0.99–0.93(m,4H),0.96–0.90(m,8H),0.91(s,2H),0.91(d,J＝5.7Hz,1H),0.90(d,J＝1.5Hz,2H).LRMS(ESI)：603.4[M+H] +
实施例220(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-28-6”-O-甲基-β-D-吡喃葡萄糖醛酸苷
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-甲氧基-β-D-吡喃葡萄糖醛酸硫苷。将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A220(产率58％)。 1H NMR(500MHz,CDCl 3)δ5.42(d,J＝5.8Hz,1H),5.33(tdd,J＝5.1,1.8,1.1Hz,1H),4.89(d,J＝6.4Hz,1H),4.77(d,J＝6.3Hz,1H),4.50(dd,J＝8.7,2.7Hz,1H),4.39(d,J＝7.9Hz,1H),3.89–3.80(m,1H),3.73(s,2H),3.71–3.57(m,2H),2.48(ddd,J＝12.4,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.17(tq,J＝5.1,1.0Hz,1H),2.04(dddd,J＝12.7,6.4,5.1,1.0Hz,1H),1.95–1.87(m,1H),1.91–1.83(m,1H),1.83(dtt,J＝7.1,2.7,1.5Hz,2H),1.83–1.78(m,1H),1.72–1.65(m,2H),1.65(d,J＝1.6Hz,1H),1.66–1.62(m,1H),1.65–1.61(m,1H),1.64–1.52(m,3H),1.55–1.48(m,1H),1.51–1.29(m,5H),1.15(s,2H),1.08(t,J＝1.6Hz,5H),0.97(d,J＝1.5Hz,3H),0.95–0.90(m,8H).LRMS(ESI)：629.4[M+H] +。
实施例221(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-28-6”-O-乙基-β-D-吡喃葡萄糖醛酸苷(A221)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-乙氧基-β-D-吡喃葡萄糖醛酸硫苷。将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A221(产率53％)。 1H NMR(500MHz,CDCl 3)δ5.42(d,J＝5.8Hz,1H),5.33(tdd,J＝5.1,1.8,1.1Hz,1H),4.95(d,J＝6.4Hz,1H),4.77(d,J＝6.3Hz,1H),4.51(dd,J＝8.7,2.7Hz,1H),4.45(d,J＝8.2Hz,1H),4.21(qd,J＝6.3,2.5Hz,2H),3.85(tdd,J＝8.3,6.4,1.9Hz,1H),3.71–3.57(m,2H),2.48(ddd,J＝12.5,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.17(tq,J＝5.1,1.0Hz,1H),2.04(dddd,J＝ 12.6,6.4,5.1,1.0Hz,1H),1.95–1.87(m,1H),1.91–1.83(m,1H),1.86–1.80(m,2H),1.83–1.78(m,1H),1.72–1.29(m,14H),1.22–1.13(m,5H),1.08(t,J＝1.6Hz,5H),0.99–0.92(m,6H),0.93(d,J＝6.6Hz,5H).LRMS(ESI)：643.4[M+H] +。
实施例222(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-28-6”-O-2”’-氟乙基-β-D-吡喃葡萄糖醛酸苷(A222)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-2-氟乙基-β-D-吡喃葡萄糖醛酸硫苷。将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A222(产率53％)。 1H NMR(500MHz,CDCl 3)δ6.11(s,1H),6.02(s,1H),5.42(d,J＝5.8Hz,1H),5.33(tdd,J＝5.1,1.8,1.1Hz,1H),4.95(d,J＝6.3Hz,1H),4.77(d,J＝6.2Hz,1H),4.51(dd,J＝8.7,2.7Hz,1H),3.93(d,J＝8.2Hz,1H),3.85(tdd,J＝8.3,6.3,1.9Hz,1H),3.71–3.57(m,2H),2.48(ddd,J＝12.5,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.17(tq,J＝5.1,1.0Hz,1H),2.04(dddd,J＝12.6,6.4,5.1,1.0Hz,1H),1.95–1.87(m,1H),1.91–1.84(m,1H),1.86–1.81(m,1H),1.84–1.78(m,2H),1.72–1.66(m,1H),1.69–1.63(m,2H),1.66–1.62(m,1H),1.65–1.58(m,2H),1.62–1.51(m,2H),1.54–1.47(m,1H),1.50–1.41(m,1H),1.44–1.36(m,2H),1.36(ddd,J＝6.4,3.4,1.6Hz,1H),1.36–1.29(m,1H),1.15(s,2H),1.08(t,J＝1.6Hz,5H),0.97(d,J＝1.5Hz,3H),0.95–0.90(m,8H).LRMS(ESI)：647.4[M+H] +。
实施例223(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-17-(1’R)-(羟基)甲基-6”-O-甲基-β-D-吡喃葡萄糖醛酸苷(A223)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-甲氧基-β-D-吡喃葡萄糖醛酸硫苷。将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例2，得到A223(产率58％)。 1H NMR(500MHz,CDCl 3)δ5.24(tdd,J＝5.1,1.8,1.0Hz,1H),4.99(d,J＝5.3Hz,1H),4.87(d,J＝6.4Hz,1H),4.75(d,J＝5.7Hz,1H),4.62(d,J＝6.1Hz,1H),4.09(d,J＝7.5Hz,1H),3.93(ddd,J＝7.3,5.7,2.5Hz,1H),3.84(dddd,J＝8.3,7.5,6.4,1.8Hz,1H),3.77–3.69(m,1H),3.73(s,3H),3.68–3.60(m,1H),3.56(tdd,J＝8.3,6.1,2.6Hz,1H),2.48(ddd,J＝12.4,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.23(tq,J＝4.6,1.1Hz,1H),1.99(dddd,J＝12.6,6.4,5.2,1.0Hz,1H),1.95–1.86(m,1H),1.89–1.78(m,3H),1.78–1.59(m,4H),1.59–1.26(m,11H),1.11–1.05(m,8H),0.99–0.92(m,8H),0.90(s,2H).LRMS(ESI)：631.4[M+H] +。
实施例224(5S,8R,9R,10S,14R,17R,18S)-3-羰基熊果酸-28-6”-O-甲基-β-D-吡喃葡萄糖醛酸苷(A224)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-甲氧基-β-D-吡喃葡萄糖醛酸硫苷。将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基熊果酸。其余所需原料、试剂及制备方 法同实施例10，得到A224(产率62％)。 1H NMR(500MHz,CDCl 3)δ5.50(tdd,J＝4.9,1.8,0.9Hz,1H),5.42(d,J＝5.8Hz,1H),4.89(d,J＝6.4Hz,1H),4.77(d,J＝6.3Hz,1H),4.55(dd,J＝8.7,2.6Hz,1H),4.39(d,J＝7.9Hz,1H),3.89–3.80(m,1H),3.73(s,2H),3.71–3.57(m,2H),2.48(ddd,J＝12.5,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.28–2.22(m,1H),2.06–1.91(m,2H),1.89–1.78(m,4H),1.77(ddd,J＝12.5,7.7,5.2Hz,1H),1.73–1.57(m,5H),1.60–1.55(m,1H),1.57–1.51(m,1H),1.47–1.39(m,2H),1.40(td,J＝2.1,1.1Hz,1H),1.41–1.31(m,2H),1.34–1.25(m,1H),1.20(s,2H),1.08(t,J＝1.6Hz,5H),0.99–0.90(m,9H),0.91(d,J＝2.0Hz,2H).LRMS(ESI)：629.4[M+H] +。
实施例225(3S,5S,8R,9R,10S,13R,14R,17S,18R,19R)-白桦脂酸-28-6”-O-甲基-β-D-吡喃葡萄糖醛酸苷(A225)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-甲氧基-β-D-吡喃葡萄糖醛酸硫苷。将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基白桦脂酸。其余所需原料、试剂及制备方法同实施例10，得到A225(产率50％)。 1H NMR(500MHz,CDCl 3)δ5.42(d,J＝5.9Hz,1H),4.89(d,J＝6.4Hz,1H),4.83(h,J＝1.4Hz,1H),4.77(d,J＝6.3Hz,1H),4.67(h,J＝1.6Hz,1H),4.51(dd,J＝8.8,2.6Hz,1H),3.89–3.80(m,1H),3.73(s,2H),3.71–3.57(m,2H),3.00(dddt,J＝10.3,5.0,3.3,1.6Hz,1H),2.53–2.41(m,2H),1.86–1.34(m,26H),1.13–1.05(m,7H),0.96(dd,J＝12.7,1.5Hz,6H),0.85(t,J＝1.4Hz,3H).LRMS(ESI)：629.4[M+H] +。
实施例226(5S,8R,9R,10S,14R,17R,18S)-3-羰基白桦脂酸-17-(1’R)-(羟基)甲基-6”-O-甲基-β-D-吡喃葡萄糖醛酸苷(A226)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-甲氧基-β-D-吡喃葡萄糖醛酸硫苷。将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基白桦脂酸。其余所需原料、试剂及制备方法同实施例2，得到A226(产率53％)。1H NMR(500MHz,CDCl 3)δ4.99(d,J＝5.3Hz,1H),4.87(d,J＝6.4Hz,1H),4.81(h,J＝1.4Hz,1H),4.69(d,J＝5.3Hz,1H),4.67–4.60(m,2H),4.09(d,J＝7.5Hz,1H),3.91–3.80(m,2H),3.75–3.66(m,3H),3.66–3.52(m,2H),2.53–2.41(m,2H),2.13(dddd,J＝10.4,5.5,3.5,1.7Hz,1H),1.83(ddd,J＝5.7,2.8,1.4Hz,1H),1.83–1.76(m,1H),1.73(q,J＝1.4Hz,3H),1.63–1.28(m,20H),1.13–1.05(m,7H),0.97(d,J＝1.5Hz,3H),0.92(d,J＝1.5Hz,3H),0.85(t,J＝1.4Hz,3H).LRMS(ESI)：631.4[M+H] +。
实施例227(5S,8R,9R,10S,14R,17R,18S)-3-羰基白桦脂酸-17-(1’R)-(羟基)甲基-6”-O-甲基-β-D-吡喃葡萄糖醛酸苷(A227)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-异丙氧基-β-D-吡喃葡萄糖醛酸硫苷。将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为 (5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A227(产率53％)。 1H NMR(500MHz,CDCl 3)δ5.42(d,J＝5.9Hz,1H),5.33(tdd,J＝5.1,1.8,1.1Hz,1H),5.03(hept,J＝5.8Hz,1H),4.95(d,J＝6.4Hz,1H),4.77(d,J＝6.3Hz,1H),4.51(dd,J＝8.7,2.6Hz,1H),4.07(d,J＝7.9Hz,1H),3.86(tdd,J＝8.3,6.4,1.8Hz,1H),3.72–3.57(m,2H),2.48(ddd,J＝12.4,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.17(tq,J＝5.1,1.0Hz,1H),2.04(dddd,J＝12.7,6.4,5.1,1.0Hz,1H),1.95–1.87(m,1H),1.91–1.83(m,1H),1.83(dddd,J＝7.0,2.7,1.9,1.1Hz,2H),1.83–1.78(m,1H),1.72–1.29(m,14H),1.25(d,J＝5.7Hz,3H),1.20(d,J＝5.9Hz,3H),1.15(s,2H),1.08(t,J＝1.6Hz,5H),0.97(d,J＝1.5Hz,3H),0.95–0.90(m,8H).LRMS(ESI)：631.4[M+H] +。
实施例228(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-28-6”-O-环丙基甲基-β-D-吡喃葡萄糖醛酸苷(A228)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-环丙基甲氧基-β-D-吡喃葡萄糖醛酸硫苷。将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A228(产率54％)。 1H NMR(500MHz,CDCl 3)δ5.42(d,J＝5.8Hz,1H),5.33(tdd,J＝5.1,1.8,1.1Hz,1H),4.95(d,J＝6.4Hz,1H),4.77(d,J＝6.3Hz,1H),4.51(dd,J＝8.7,2.7Hz,1H),4.12–4.05(m,3H),3.85(tdd,J＝8.2,6.3,1.8Hz,1H),3.71–3.57(m,2H),2.48(ddd,J＝12.5,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.17(tq,J＝5.1,1.0Hz,1H),2.04(dddd,J＝12.6,6.4,5.1,1.0Hz,1H),1.95–1.83(m,2H),1.86–1.78(m,3H),1.72–1.66(m,1H),1.69–1.63(m,2H),1.66–1.62(m,1H),1.65–1.47(m,6H),1.50–1.41(m,1H),1.44–1.36(m,2H),1.36(ddd,J＝6.4,3.4,1.6Hz,1H),1.36–1.29(m,1H),1.15(s,2H),1.08(t,J＝1.6Hz,5H),0.97(d,J＝1.5Hz,3H),0.95–0.90(m,8H),0.58–0.44(m,4H).LRMS(ESI)：669.4[M+H] +。
实施例229(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-28-6”-N-乙基-β-D-吡喃葡萄糖醛酸苷(A229)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-乙胺基-β-D-吡喃葡萄糖醛酸硫苷。将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A229(产率58％)。 1H NMR(500MHz,CDCl 3)δ7.28(t,J＝3.9Hz,1H),5.46–5.39(m,1H),5.33(tdd,J＝5.1,1.8,1.1Hz,1H),4.89(d,J＝6.1Hz,1H),4.78–4.71(m,1H),4.50–4.43(m,1H),4.09(d,J＝7.5Hz,1H),3.81–3.72(m,1H),3.68–3.57(m,2H),3.23(qd,J＝6.2,3.9Hz,2H),2.48(ddd,J＝12.5,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.17(tq,J＝5.1,1.0Hz,1H),2.04(dddd,J＝12.6,6.4,5.1,1.0Hz,1H),1.95–1.84(m,2H),1.86–1.81(m,1H),1.84–1.78(m,2H),1.72–1.29(m,14H),1.21–1.13(m,5H),1.08(t,J＝1.6Hz,6H),0.99–0.92(m,6H),0.93(d,J＝6.6Hz,5H).LRMS(ESI)：642.4[M+H] +。
实施例230(5S,8R,9R,10S,14R,17R,18S)-3-羰基齐墩果酸-28-6”-N-2”’-氟乙基-β-D-吡喃葡萄糖醛酸苷(A230)
将2,3,4,6-O-四苄基-1-(吡啶-1-基)磺酰基-β-D-吡喃葡萄糖硫苷替换为2,3,4-O-三苄基-1-(吡啶-1-基)磺酰基-6-2-氟乙胺基-β-D-吡喃葡萄糖醛酸硫苷。将化合物(3S,5S,8R,9R,10S,14R,17R,18S)-28-O-苄基-3-醛基齐墩果酸替换为(5S,8R,9R,10S,14R,17R,18S)-3-羰基-17-甲酰基齐墩果酸。其余所需原料、试剂及制备方法同实施例10，得到A230(产率51％)。 1H NMR(500MHz,CDCl 3)δ7.80(t,J＝4.9Hz,1H),5.46–5.39(m,1H),5.33(tdd,J＝5.1,1.8,1.1Hz,1H),4.89(d,J＝6.1Hz,1H),4.78–4.71(m,1H),4.58(td,J＝3.4,2.3Hz,1H),4.53–4.43(m,2H),4.05(d,J＝7.4Hz,1H),3.81–3.72(m,1H),3.68–3.57(m,2H),3.44(dtd,J＝4.6,3.4,1.2Hz,1H),3.39(dtd,J＝4.8,3.4,1.1Hz,1H),2.48(ddd,J＝12.5,6.5,4.0Hz,1H),2.40(ddd,J＝12.5,6.6,4.0Hz,1H),2.17(tq,J＝5.1,1.0Hz,1H),2.04(dddd,J＝12.6,6.4,5.1,1.0Hz,1H),1.95–1.87(m,1H),1.91–1.84(m,1H),1.86–1.81(m,1H),1.84–1.78(m,2H),1.72–1.29(m,14H),1.15(s,2H),1.08(t,J＝1.6Hz,6H),0.99–0.92(m,6H),0.93(d,J＝6.6Hz,5H).LRMS(ESI)：650.4[M+H] +。
药理活性试验实施例
实施例1、本发明化合物体内降糖药效学活性的测定
一、化合物在ICR小鼠体内口服糖耐量的药效学实验
1.实验材料:
表6：动物的使用表
Figure PCTCN2021104599-appb-000054
动物到达药明康德设施后，将其饲养于严格控制环境条件的动物饲养间中，饲养间的温度维持在20～24℃，湿度维持在30～70％。通过温湿度计对饲养间的温度和湿度进行实时监控，并且每天对温度和湿度记录两次(上午和下午各1次)。动物饲养间的采光由一个电子定时开灯系统来控制，每天开灯12小时关灯12小时(上午7:00开，下午19:00关)。实验过程中，动物单笼饲养，并给每个笼中的小鼠提供玩具。实验过程中动物自由采食(大小鼠生长/繁殖饲料)和饮水。
动物到达后，适应环境1～2周，方可进行实验。
2.药物配制及给药:
表3：对照溶剂信息表
Figure PCTCN2021104599-appb-000055
1)药液的配制：各化合物在实验第一天进行配制，之后放在4℃冰箱中保存，便于第二天使用。
2)给药：分组结束后，各组动物在给糖前0.5时给药。
3)口服糖耐量实验：动物给药结束后0.5小时，对动物进行灌胃给糖操作，并将给糖时间记为0分钟，葡萄糖口服剂量为5g/kg,10ml/kg，并于给药前，给糖前，及给糖后15,30,60,90,120分钟分别对动物进行血糖检测。血糖将用血糖仪及配套血糖试纸进行检测。
3.实验结果:
结果表明口服五环三萜碳苷类化合物能有效降低ICR小鼠的餐后血糖水平(图1)，其中A25和A43的降糖活性最优,25mg/kg剂量下就有较明显的降糖效果，50mg/kg降糖效果进一步增强(图2)。
实施例2、本发明化合物体外促GLP-1分泌活性的测定
1.实验材料：
细胞系：肠道内分泌细胞系STC-1细胞
阴性对照：DMSO
阳性对照：INT777(TGR5受体激动剂)
检测工具：HTRF试剂盒
其它：KRBH缓冲液、BSA、DPP4抑制剂
2.实验方法：
STC-1细胞一定密度种板，细胞过夜贴壁后，用KRBH缓冲液饥饿细胞，同时用BSA维持营养，DPP4抑制剂减少GLP-1降解，1h后换为无葡萄糖或有葡萄糖的KRBH缓冲液刺激GLP-1分泌，同时加入一定浓度的化合物，处理1h后，收集上清利用HTRF试剂盒检测GLP-1浓度。同时检测LDH分泌指示化合物毒性。
3.实验结果：
实验结果表明：A64具有良好的体外促GLP-1分泌效果，其体外EC50为7.231μM，明显优于阳性化合物INT777(EC50＝22.82μM)(图3)。
实施例3、本发明化合物体外抗流感病毒药效学活性的测定
1.实验材料:
Cell lines:MDCK cell
Negative control:DMSO
Positive control:Zanamivir/Oseltamivir(50μM)
Figure PCTCN2021104599-appb-000056
Luminescent Cell Viability Assay
化合物母液配置：化合物1-7稀释至10mM/L；筛选浓度：50μM
2.实验方法:
MDCK细胞铺96孔板(1×10 4/孔)，37℃、5％CO 2孵箱培养24h后加药。
加药后将96孔板置于37℃、5％CO 2孵箱培养36h，酶标仪检测。
3.实验结果:
抑制率计算公式：I(抑制率)＝[1-(Xi-Xj)/(Yi-Yj)]×100％
Xi:待测组未加病毒存活细胞数；Xj：待测组加病毒存活细胞数
Yi:DMSO组未加病毒存活细胞数；Yj：DMSO组加病毒存活细胞数
结果表明五环三萜碳苷类化合物能产生有效的抗流感病毒的药理活性，其中A2与阳性药扎那米韦表现出同等的病毒抑制率和低细胞毒性，与阳性药利巴韦林的病毒抑制率相近，但细胞毒性低于利巴韦林(图4)。
实施例4、本发明化合物体外与冠状病毒N蛋白亲和力测定
1.实验材料：
N蛋白稀释液：20μg/mL
缓冲液：10mM HEPES,pH 7.4,150mM NaCl,3.0mM EDTA,和0.005％(v/v)surfactant P20，5％DMSO。
仪器：Biacore 8K(GE Healthcare)
2.试验方法：
使用Biacore 8K(GE Healthcare)采用表面等离子共振法(SPR)测试化合物与N蛋白的亲和力。在25℃条件下，首先将N蛋白稀释至20μg/mL，使用标准的氨基偶联法将全长N蛋白分别偶联至CM5芯片上，信号值10000信号单位(RU)。所用运行缓冲液为10mM HEPES,pH 7.4,150mM NaCl,3.0mM EDTA,and 0.005％(v/v)surfactant P20，5％DMSO。将10mM的待测化合物DMSO储存液使用运行缓冲液稀释7个梯度浓度(1.56μM-100μM)。测试时，使用运行缓冲液将仪器初始化运行3次后注射测试化合物并依次流经芯片，设置结合和解离时间100秒。一个循环结束后使用50％DMSO洗除残存于芯片上的化合物，并继续下一个循环。最后，使用含有4.5％-5.8％的运行缓冲液进行溶剂矫正。根据生成的图谱，扣减对照组数值并进行溶剂矫正，生成数据使用Biacore 8K数据处理软件采用静态亲和力模型按照固定Rmax值得方法计算KD值。
3.实验结论：
结果表明，五环三萜碳苷类化合物与N蛋白具有加强的亲和力，部分化合物的Ki<10μM。(图5、图6)
实施例5：本发明化合物体外抗SARS-Cov-2病毒药效学活性的测定
1.实验材料：
Vero E6细胞(ATCC-1586)
48孔板中(50000个细胞/孔)；96孔板中(20000个细胞/孔)
2019-nCoV(nCoV-2019BetaCoV/Wuhan/WIV04/2019)
2.实验方法：
Vero E6细胞(ATCC-1586)铺在48孔板中(50000个细胞/孔)，加入100μL/孔含梯度浓度化合物的培养基，随后加入2019-nCoV(nCoV-2019BetaCoV/Wuhan/WIV04/2019)，感染复数(MOI)为0.05。共孵育1小时后，吸走上清，清洗并重新加入200μL/孔含梯度浓度化合物的培养基，37℃培养24小时。24小时后，收集细胞上清，提取上清病毒RNA并利用实时荧光定量PCR的方法检测上清病毒拷贝数，根据病毒拷贝数算出化合物抑制率，利用prism 6.0计算化合物的EC 50。
Vero E6细胞(ATCC-1586)铺在96孔板中(20000个细胞/孔)，加入100μL/孔含梯度浓度化合物的培养基，24小时后利用CCK8检测试剂盒，检测化合物对细胞活性的影响，利用prism 6.0计算化合物的CC 50。
3.实验结论：
结果表明五环三萜碳苷类化合物能有效抑制SARS-Cov-2病毒的复制，其中A104与A114的EC50为3.6μM与4.6μM，同时部分化合物在10μM的水平上抑制率达100％(图7、图8)。
实施例6：本发明化合物小鼠PK性质测定
1.实验材料：
动物情况：
物种/品系：ICR(CD-1)小鼠
性别/鼠数：雄性(n＝6)
重量(g):雄性(20-24g)
饮食类型：标准啮齿动物饮食
水任意
给药前禁食12小时，并保持禁食2小时。
饲养：动物房环境控制(目标条件：温度18至29℃，相对湿度30至70％。每天监测温度和相对湿度。使用电子时间控制照明系统提供12小时光照/12小时黑暗循环。
2.试验方法：
给药剂量如下表：
Figure PCTCN2021104599-appb-000057
3.实验结论：
结果表明，本发明的五环三萜碳苷类化合物有较好的药代性质，具体结论见图9、图10。图9显示本发明化合物在经口和经肠给药后，均能够在实验时间内达到所需的药物暴露量。图10显示本发明化合物在给药后于8小时内迅速释放，并于24小时内释放完全。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种具有如下通式I所示结构的五环三萜碳苷衍生物类化合物，或者其外消旋体、R-异构体、S-异构体、药学上可接受的盐或它们的混合物：
    Figure PCTCN2021104599-appb-100001
    其中，
    A环选自下组：6元饱和碳环或不饱和碳环；
    R 1、R 2和R 3各自独立的选自下组：氢、甲基；R 4选自下组：氢、异丙烯基；
    R 5选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、磷酸基、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基、取代或未取代的C 6-C 10芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C 1-C 6烷基-苯基、取代或未取代的C 3-C 12环烷基、取代或未取代的C 2-C 10酰基、取代或未取代的C 2-C 10酯基、取代或未取代的C 6-C 10芳氧基、取代或未取代的C 1-C 6酰胺基，或Y-R 7；其中：
    Y选自下组：-(CH 2) mCHR 9-、羰基、-CONH-、-COO-；
    其中m为0或1；
    R 7选自下组：氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C 2-C 10酯基、取代或未取代的C 5-C 9呋喃糖基、取代或未取代的C 5-C 9吡喃糖基；
    Z选自下组：羰基、-CH(R 9) 2、C＝N-R 8、C＝N-NH-R 8，或-X-R 6；
    R 8选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C1-C6烷基-苯基、取代或未取代的C3-C12环烷基、取代或未取代的C2-C10酰基、取代或未取代的C2-C10酯基、取代或未取代的C6-C10芳氧基、取代或未取代的C1-C6酰胺基；
    R 9选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基；
    R 6选自下组：氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C 5-C 9呋喃糖基、取代或未取代的C 5-C 9吡喃糖基；所述的取代指糖环上的一个或多个氢或羟基被选自下组的取代基取代：氢、氘、氚、卤素、氰基、氨基、硝基、巯基、醛基、羧基、苄基、取代或未取代的C 1-C 12烷氧羰基、取代或未取代的C 2-C 12烷氨基羰基、取代或未取代的C 2-C 10酰基、磺酰基、磷酰基、C 5-C 9呋喃糖基、C 5-C 9吡喃糖基；
    X选自下组：-CHR 9-、羰基、S、-NHC(O)-R 8、-NHS(O) 2-R 8、-NHC(O)NH-R 8、- NHC(S)NH-R 8、-COO-、-O-S(O) 2-R 8；
    n为1或2；
    除非特别说明，上述各式中，所述的取代指对应基团上的氢原子，或者糖环上的羟基被一个或多个选自下组的取代基所取代：氘、氚、卤素、羟基、羧基、巯基、苄基、C 1-C 12烷氧基羰基、C 1-C 6醛基、氨基、C 1-C 6酰胺基、硝基、氰基、未取代或卤代的C 1-C 6烷基、C 2-C 10烯基、C 1-C 6烷氧基、C 1-C 6烷基-胺基、C 6-C 10芳基、五元或六元杂芳基、五元或六元非芳香性杂环基、-O-(C 6-C 10芳基)、-O-(五元或六元杂芳基)、C 1-C 12烷氨基羰基、取代或未取代的C 2-C 10酰基、磺酰基(-SO 2-OH)、磷酰基(-PO 3-OH)、C 5-C 9呋喃糖基、C 5-C 9吡喃糖基。
  2. 如权利要求1所述的化合物，或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物，其特征在于，所述的式I化合物具有如下通式II所示的结构：
    Figure PCTCN2021104599-appb-100002
    其中：
    R 5选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基、醛基、羧基、磺酰基、磷酸基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C6-C10芳基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C1-C6烷基-苯基、取代或未取代的C3-C12环烷基、取代或未取代的C2-C10酰基、取代或未取代的C2-C10酯基、取代或未取代的
    C6-C10芳氧基、取代或未取代的C1-C6酰胺基；
    X选自下组：-CHR 9-、羰基；
    R 6选自下组：取代或未取代的C5-C9呋喃糖基、取代或未取代的C5-C9吡喃糖基；所述的取代指糖环上的一个或多个氢或羟基被选自下组的取代基取代：氢、氘、氚、卤素、氰基、氨基、硝基、巯基、醛基、羧基、苄基、取代或未取代的C1-C12烷氧羰基、取代或未取代的C2-C12烷氨基羰基、取代或未取代的C2-C10酰基、磺酰基、磷酰基、C5-C9呋喃糖基、C5-C9吡喃糖基；
    R 9选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基；
    A环选自下组：6元饱和碳环或不饱和碳环；
    n为1、2。
  3. 如权利要求1所述的化合物，或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物，其特征在于，所述的式I化合物具有如下通式III所示的结构：
    Figure PCTCN2021104599-appb-100003
    其中：
    R 1、R 2和R 3各自独立的选自下组：氢、甲基；
    R 4选自下组：氢、异丙烯基；
    R 7选自下组：氢、取代或未取代的C5-C9呋喃糖基、取代或未取代的C5-C9吡喃糖基；所述的取代指糖环上的一个或多个氢或羟基被选自下组的取代基取代：氢、
    氘、氚、卤素、氰基、氨基、硝基、巯基、醛基、羧基、苄基、取代或未取代的C1-C12烷氧羰基、取代或未取代的C1-C12烷氨基羰基、取代或未取代的C2-C10酰基、磺酰基、磷酰基、C5-C9呋喃糖基、C5-C9吡喃糖基；
    Y选自下组：-(CH 2) mCHR 9-、羰基；
    m为0、1；
    R 9选自下组：氢、氘、氚、卤素、氰基、氨基、硝基、羟基、巯基；
    Z选自下组：羰基、-CH(R 9) 2、＝N-R 8，或-X-R 6；
    R 9选自下组：氢、卤素、氰基、氨基、硝基、羟基、巯基；
    X选自下组：-CHR 9-、羰基、S、-NHC(O)-R 8、-NHS(O) 2-R 8、-NHC(O)NH-R 8、-NHC(S)NH-R 8、-COO-、-O-S(O) 2-R 8；
    R 6选自下组：氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C 5-C 9呋喃糖基、取代或未取代的C 5-C 9吡喃糖基；所述的取代指糖环上的一个或多个氢或羟基被选自下组的取代基取代：氢、氘、氚、卤素、氰基、氨基、硝基、巯基、醛基、羧基、苄基、取代或未取代的C 1-C 12烷氧羰基、取代或未取代的C 2-C 12烷氨基羰基、取代或未取代的C 2-C 10酰基、磺酰基、磷酰基、C 5-C 9呋喃糖基、C 5-C 9吡喃糖基；
    A环选自下组：6元饱和碳环或不饱和碳环；
    n为1、2。
  4. 如权利要求1所述的化合物，或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物，其特征在于，所述的式I化合物具有如下通式IV、V或VI所示的结构：
    Figure PCTCN2021104599-appb-100004
  5. 如权利要求2所述的化合物，或者其外消旋体、R-异构体、S-异构体、可药用 盐或它们的混合物，其特征在于，R 5选自下组：氢、卤素、羟基、羧基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C10酰基、取代或未取代的C2-C10酯基、取代或未取代的C1-C6酰胺基。
  6. 如权利要求3所述的化合物，或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物，其特征在于，R 9选自下组：氢、羟基、醛基、巯基，或-X-R 6；
    X选自下组：-CHR 9-、羰基、S、-NHC(O)-R 8、-NHS(O) 2-R 8、-NHC(O)NH-R 8、-NHC(S)NH-R 8、-COO-、-O-S(O) 2-R 8；
    R 6选自下组：取代或未取代的C 1-C 6烷基、取代或未取代的C 2-C 6烯基、取代或未取代的含有1-3个选自氧、硫和氮中的杂原子的5-7元的杂环、取代或未取代的C 5-C 9呋喃糖基、取代或未取代的C 5-C 9吡喃糖基；所述的取代指糖环上的一个或多个氢或羟基被选自下组的取代基取代：氢、氘、氚、卤素、氰基、氨基、硝基、巯基、醛基、羧基、苄基、取代或未取代的C 1-C 12烷氧羰基、取代或未取代的C 2-C 12烷氨基羰基、取代或未取代的C 2-C 10酰基、磺酰基、磷酰基、C 5-C 9呋喃糖基、C 5-C 9吡喃糖基。
  7. 如权利要求1所述的化合物，或者其外消旋体、R-异构体、S-异构体、可药用盐或它们的混合物，其中，所述五环三萜碳苷类化合物选自如下化合物：
    Figure PCTCN2021104599-appb-100005
    Figure PCTCN2021104599-appb-100006
    Figure PCTCN2021104599-appb-100007
    Figure PCTCN2021104599-appb-100008
    Figure PCTCN2021104599-appb-100009
    Figure PCTCN2021104599-appb-100010
    Figure PCTCN2021104599-appb-100011
    Figure PCTCN2021104599-appb-100012
    Figure PCTCN2021104599-appb-100013
    Figure PCTCN2021104599-appb-100014
    Figure PCTCN2021104599-appb-100015
    Figure PCTCN2021104599-appb-100016
    Figure PCTCN2021104599-appb-100017
    Figure PCTCN2021104599-appb-100018
    Figure PCTCN2021104599-appb-100019
    Figure PCTCN2021104599-appb-100020
    Figure PCTCN2021104599-appb-100021
    Figure PCTCN2021104599-appb-100022
    Figure PCTCN2021104599-appb-100023
    Figure PCTCN2021104599-appb-100024
    Figure PCTCN2021104599-appb-100025
    Figure PCTCN2021104599-appb-100026
    Figure PCTCN2021104599-appb-100027
    Figure PCTCN2021104599-appb-100028
    Figure PCTCN2021104599-appb-100029
    Figure PCTCN2021104599-appb-100030
    Figure PCTCN2021104599-appb-100031
    Figure PCTCN2021104599-appb-100032
    Figure PCTCN2021104599-appb-100033
    Figure PCTCN2021104599-appb-100034
    Figure PCTCN2021104599-appb-100035
  8. 一种如权利要求1所述的化合物的制备方法，其特征在于，所述制备方法包括如下方案1或方案2：
    方案1：用式IIa化合物作为原料，经过步骤a和任选的步骤b、c或d，制备式II化合物：
    Figure PCTCN2021104599-appb-100036
    其中，各基团的定义如权利要求1中所述；
    步骤a：化合物IV和化合物III进行反应，得到步骤a产物；
    步骤b：将步骤a产物进行还原，得到步骤b产物；
    步骤c：对步骤b产物进行烷基化反应，得到步骤c产物；
    步骤d：用步骤c产物与戴斯马丁试剂进行反应，得到式II化合物；
    其中化合物IV的结构为：
    Figure PCTCN2021104599-appb-100037
    方案2：用式IIIa化合物作为原料，经过步骤a和任选的步骤b、c或d，制备式III化合物：
    Figure PCTCN2021104599-appb-100038
  9. 一种药物组合物，其特征在于，所述的药物组合物含有治疗有效量的如权利要求1所述的式I化合物、其可药用的盐、外消旋体、R-异构体和S-异构体中的一种或多种，以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
  10. 如权利要求1所述的式I和式II化合物、其外消旋体、R-异构体、S-异构体或可药用盐在制备治疗或预防与糖尿病相关的代谢性疾病和病毒性疾病的药物中的用途；优选地，所述疾病选自下组：糖尿病、流感、肥胖、肝纤维化、代谢性疾病、病毒性疾病。
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