WO2019184772A1 - 类赤霉素化合物、其制备方法、药物组合物及应用及其中间体 - Google Patents

类赤霉素化合物、其制备方法、药物组合物及应用及其中间体 Download PDF

Info

Publication number
WO2019184772A1
WO2019184772A1 PCT/CN2019/078805 CN2019078805W WO2019184772A1 WO 2019184772 A1 WO2019184772 A1 WO 2019184772A1 CN 2019078805 W CN2019078805 W CN 2019078805W WO 2019184772 A1 WO2019184772 A1 WO 2019184772A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
substituted
group
Prior art date
Application number
PCT/CN2019/078805
Other languages
English (en)
French (fr)
Inventor
张洪彬
吴明江
李艳
何严萍
陈静波
羊晓东
陈文�
龚雅潇
Original Assignee
云南大学
中国科学院昆明植物研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 云南大学, 中国科学院昆明植物研究所 filed Critical 云南大学
Publication of WO2019184772A1 publication Critical patent/WO2019184772A1/zh

Links

Classifications

    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
    • C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/86—Ring systems containing bridged rings containing four rings

Definitions

  • gibberellin is a class of tetracyclic diterpenoids having various biological activities, which are widely present in microorganisms and plants, and exhibit strong anticancer activity as biologically active groups.
  • gibberellin anticancer drugs have been found yet.
  • the present invention solves the above technical problems by the following technical solutions.
  • the present invention provides a gibberellin-like compound of the formula I, a tautomer thereof, an optical isomer, a hydrate, a solvate, a polymorph, a pharmaceutically acceptable salt, and a pharmaceutically acceptable Acceptable prodrugs or derivatives:
  • R 1 is H or halogen
  • R 6 is H or O
  • R 4 when in When represented by a single bond, R 4 is H; R 5 is a substituted or unsubstituted C 6 -C 20 aryl group, or a substituted or unsubstituted C 2 -C 20 heteroaryl group; said substituted or unsubstituted
  • the aryl group of C 6 -C 20 or the substituent in the substituted or unsubstituted C 2 -C 20 heteroaryl group is Wherein X is selected from C, N, S or O (for example C or N); R is H, halogen, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, or C 1 -C Alkoxy of 6 ; n is an integer from 1 to 5;
  • R 8 is OH, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group
  • the C 1 -C 6 alkyl group may be a C 1 -C 4 alkyl group such as methyl, ethyl, propyl, isopropyl and n-butyl.
  • the number of halogen substituents in the halogen-substituted C 1 -C 6 alkyl group may be one or more (2 or 3); the halogen may be fluorine.
  • the C 1 -C 6 alkoxy group may be a C 1 -C 4 alkoxy group such as a methoxy group, an ethoxy group and a propoxy group.
  • the R 4 when in Representing a double bond, the R 4 is O, in Representing a single bond, when R 6 is H, the R 5 may be a C 2 -C 6 alkoxy group;
  • the R 4 when in Representing a double bond, the R 4 is O, in Representing a double bond, when R 6 is O, the R 5 may be a C 1 -C 6 alkoxy group.
  • the Can be For example, the for Said for Said for
  • the compound of the formula I may be selected from any one of the compounds of the following formula II, formula III, formula IV or formula V:
  • R 9 , R 10 and R 11 are each independently
  • R 20 and R 21 are each independently H, Or methyl.
  • R 12 is a C 1 -C 6 alkyl group
  • the R 9 , R 10 and R 11 may each independently be For example, the for
  • R 1 is halogen
  • the R is halogen, or a halogen-substituted C 1 -C 6 alkyl group (eg, -CF 3 );
  • the R 2 is OH.
  • the R 1 may be hydrogen or a halogen such as hydrogen.
  • the R 2 may be OH or OTs, preferably OH.
  • the compounds of the formula III the R 2 is OH or OTs; said R 1 is hydrogen; R 10 is the For example, the for
  • the structure of the compound represented by the formula III can be:
  • the R 1 may be hydrogen.
  • the R 2 may be OH or OTs.
  • the R 2 is OH or OTs; the R 1 hydrogen; the R 11 is
  • the structure of the compound represented by the formula IV can be:
  • the R 1 may be a halogen such as fluorine.
  • the R 1 may be OH or OTs.
  • the R 12 may be a methyl group.
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 , R 20 and R 21 are each independently H or
  • R 20 and R 21 are each independently methyl; the remaining substituents are as defined above.
  • the gibberellin compound of formula I in a preferred embodiment of the invention, its tautomers, optical isomers, hydrates, solvates, polymorphs, pharmaceutically acceptable In a salt, a pharmaceutically acceptable prodrug or derivative,
  • the R 1 is H or halogen
  • the R 2 is H, OH or OTs
  • the R 3 is a methyl group
  • R 6 is O
  • R 4 when in Represents a double bond, R 4 is O, in Represents a single bond, when R 6 is H, R 5 is a C 2 -C 6 alkoxy group or a benzyloxy group;
  • R 4 when in Represents a double bond, R 4 is O, in Represents a double bond, when R 6 is O, R 5 is a C 1 -C 6 alkoxy group or a benzyloxy group;
  • R 7 is CH 2 or O
  • R 8 is OH or a C 1 -C 6 alkoxy group, for When R 8 is a C 1 -C 6 alkyl group, for
  • the gibberellin compound of formula I is a substituted or unsubstituted C 6 -C 10 aryl group; the substitution or not The substituted C 2 -C 20 heteroaryl group is a substituted or unsubstituted C 2 -C 10 heteroaryl group containing one aromatic heterocyclic ring, the hetero atom is nitrogen, and the number of the hetero atom is 1-3 Or the substituted or unsubstituted C 2 -C 20 heteroaryl group is a fused aromatic hetero group containing 2 rings; for The other groups and substituents are as defined above.
  • the gibberellin compound of formula I is a substituted or unsubstituted C 6 -C 10 aryl group; the substitution or not The substituted C 2 -C 20 heteroaryl group is a substituted or unsubstituted C 2 -C 10 heteroaryl group containing one aromatic heterocyclic ring, the hetero atom is nitrogen, and the number of the hetero atom is 1-3
  • the substituted or unsubstituted C 2 -C 20 heteroaryl group is a fused aromatic hetero group containing 2 rings; for Said for Said for Said for The other groups are defined as described above.
  • the gibberellin compound of formula I in a preferred embodiment of the invention, the gibberellin compound of formula I, its tautomers, optical isomers, hydrates, solvates, polymorphs, pharmaceutically acceptable
  • the substituted or unsubstituted C 6 -C 20 aryl group is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted naphthyl group
  • the substituted or unsubstituted C 2 -C 20 heteroaryl group is a substituted or unsubstituted pyrrole, a substituted or unsubstituted furan, a substituted or unsubstituted thiophene, a substituted or unsubstituted pyrazole, a substituted or unsubstituted imidazole.
  • the compound of the formula II may be selected from any of the following compounds:
  • the compound of the formula III may be selected from any of the following compounds:
  • the compound represented by the formula IV may be selected from any of the following compounds:
  • the compound represented by the formula V may be selected from any of the following compounds:
  • the present invention also provides a method for preparing a gibberellin derivative as shown in Formula I, which comprises the steps of:
  • Method 1 a compound represented by the formula VII represented by the formula VI is subjected to a cycloaddition reaction under the catalysis of copper to obtain a compound of the formula I;
  • the operation and method of the cycloaddition reaction can be referred to the conventional operations and methods in the art; for example, refer to VVRostovtsev, LG Green, VVFokin and KBSharpless, Angewandte Chemie, 2002, 41, 2596-2599. The procedures and methods are described (the contents of which are incorporated herein by reference).
  • preparation route 1 For example, preparation route 1:
  • gibberellin (GA 3 ) is used as a raw material to react with dimethyl sulfate, potassium carbonate and acetone to synthesize gibberellin (GA 3 ) methyl ester, and oxidized by Dess-Martin to obtain a carbonyl red Methyl methoxide, (for details, see J. Chen, Z. Sun, Y. Zhang, X. Zeng, C. Qing, J. Liu, L. Li and H.
  • gibberellin (GA 3 ) is used as a raw material, and reacted with 1.2 M hydrochloric acid at 65 ° C for 2.5 hours to obtain an aromatization product under the action of dimethyl sulfate, potassium carbonate and acetone.
  • preparation route 3 For example, preparation route 3:
  • the synthesized aromatization product 8 is protected with a tert-butyldimethylsilyl chloride to protect the phenolic hydroxyl group, lithium tetrahydrogenate to reduce the ester group, and p-toluenesulfonyl chloride to protect the primary hydroxyl group, tetra-n-butyl group.
  • the amine fluoride is deprotected by t-butyldimethylsilyl ether, the sodium sulfonate is azide, and finally the compound C 17 -C 24 is prepared by a copper-catalyzed azido-alkynyl Husigen cycloaddition reaction.
  • preparation route 4 For example, preparation route 4:
  • the synthesized azide compound 21 is reacted with N-bromosuccinimide, diisopropylamine and dichloromethane to obtain a brominated compound, followed by a copper-catalyzed azide-alkynyl group.
  • the Husigen cycloaddition reaction produces the compound C 25 -C 31 .
  • preparation route 5 For example, preparation route 5:
  • the synthesized sulfonate compound 10 is reacted with selenium dioxide, peroxybutanol and dichloromethane to obtain an allyl alcohol compound 23 and a ketone-containing compound 24; the allyl alcohol compound is subjected to azidation reaction.
  • the azide compound 25 is obtained, and then the copper-catalyzed azide-alkynyl Husigen cycloaddition reaction and Des-Martin oxidation are used to prepare the compound C 32 -C 39 ; likewise, the compound 24 undergoes azidation reaction and copper-catalyzed azide - alkynyl Husigen cycloaddition reaction to prepare C 48 -C 55 .
  • preparation route 6 For example, preparation route 6:
  • the synthetic silyl ether protected compound 17 is reacted with t-butoxide, selenium dioxide and dichloromethane to obtain an allyl alcohol compound 29, and the methyl ester is reduced with lithium tetrahydrogen aluminum, p-toluenesulfonyl chloride Activation of primary hydroxyl groups, sodium azide converts sulfonate to azide compound 32; azide compound undergoes copper-catalyzed azido-alkynyl Husigen cycloaddition reaction, Dess-Martin oxidation and tetra-n-butylammonium fluoride Protection with de-tert-butyldimethylsilyl ether gave compound C 40 -C 47 .
  • preparation route 7 For example, preparation route 7:
  • the synthesized phenolic compound 20 is reacted with selenium dioxide, t-butanol and methylene chloride to obtain a ketone compound 27, which is subjected to an azidation reaction and a copper-catalyzed azide-alkynyl Husigen cycloaddition.
  • the reaction was carried out to prepare C 56 -C 62 .
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a gibberellin derivative, a tautomer thereof, an optical isomer, a hydrate, a solvate, a polymorph as shown in Formula I.
  • the invention also provides the use of a gibberellin derivative as shown in Formula I for the preparation of a medicament for the treatment and/or prevention of an antitumor.
  • the anti-tumor drug may be an anti-breast cancer drug and/or an anti-cancer drug.
  • the invention also provides a method of treating a neoplastic disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a gibberellin-like compound, a tautomer thereof, an optical isomerism as described in Formula I above.
  • the tumor described therein is preferably breast cancer and/or intestinal cancer.
  • the invention also provides an intermediate of the gibberellin derivative of formula I shown below:
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt or solvate with an acid or a base.
  • pharmaceutically acceptable salts include, but are not limited to, salts formed with inorganic acids such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and the like.
  • Salt also includes salts with organic acids, such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, sulfonate, Tosylate, 2-hydroxyethyl sulfonate, benzoate, salicylate, stearate and alkanoate such as acetate, HOOC-(CH 2 ) n -COOH wherein n is a salt of 0-4, and the like.
  • pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • the "solvate” such as “hydrate” is formed by the interaction of a solvent and a compound.
  • the term “compound” shall include solvates of the compounds (including hydrates of the compounds).
  • “salts” also include solvates of salts (such as hydrates of salts). Suitable solvates are pharmaceutically acceptable, such as hydrates, which include monohydrates and hemihydrates.
  • the "prophylactically and/or therapeutically effective dose” means (i) the amount of the compound of the present invention which prevents and/or treats a specific disease or condition described herein, and (ii) weakens, improves or eliminates the present invention.
  • the invention relates to the amount of a compound of the invention for one or more symptoms of a particular disease or condition, or (iii) the invention for preventing or delaying the onset of one or more symptoms of a particular disease or condition described herein. The amount of the compound.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the disclosure of which is incorporated herein by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • the chemical formulae of the present invention may exhibit tautomerism, structural isomerism, and stereoisomerism.
  • the present invention includes any interconversion or structural or stereoisomeric forms thereof and mixtures thereof, and their ability is not limited to any one or a mixture thereof.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art.
  • the diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • the compounds of the invention are either by hand or Software naming, commercially available compounds using the supplier catalog name.
  • the positive progress of the present invention is that the gibberellin derivative of the present invention has good antitumor activity.
  • the preparation method is the same as the compound C 1 , and the phenylacetylene is changed to 4-bromophenylacetylene to obtain a white solid, that is, the compound C 2 , 41.3 mg, yield 58%, melting point: 118-121 ° C.
  • the preparation method is the same as the compound C 1 , and the phenylacetylene is changed to 4-methoxyphenylacetylene to obtain a white solid, that is, the compound C 3 , 42.1 mg, the yield is 64%, and the melting point is 112-113 ° C.
  • the preparation method is the same as the compound C 1 , and the phenylacetylene is changed to 4-trifluoromethylphenylacetylene to obtain a white solid, that is, the compound C 5 , 39.3 mg, yield 56%, melting point: 114-116 ° C.
  • the preparation method is the same as the compound C 1 , and the phenylacetylene is changed to 4-methylphenylacetylene to obtain a white solid, that is, the compound C 6 , 37.8 mg, yield 59%, melting point: 194-196 ° C.
  • the preparation method is the same as the compound C 1 , and the phenylacetylene is changed to 4-chlorophenylacetylene to obtain a white solid, that is, the compound C 7 , 36.4 mg, the yield is 55%, and the melting point is 112-115 ° C.
  • the preparation method is the same as the compound C 1 , and the phenylacetylene is changed to 4-fluorophenylacetylene to obtain a white solid, that is, the compound C 8 , 36.7 mg, yield 57%, melting point: 109-112 ° C.
  • the gibberellic acid (GA 3 ) (5.19 g, 15 mmol) and 1.2 M hydrochloric acid (30 mL) were mixed, and reacted under nitrogen for 6 h at 65 ° C. After the reaction was completed, 20 mL of ice water was added to cool, suction filtration, and washing with water. Drying gave a white solid, Compound 12, 2.81 g, yield 66%.
  • the preparation method is the same as the compound C 9 , and the phenylacetylene is changed to 4-bromophenylacetylene to obtain a white solid, that is, the compound C 10 , 28.6 mg, yield 60%, melting point: 233-236 ° C.
  • the preparation method is the same as the compound C 9 , and the phenylacetylene is changed to 4-methoxyphenylacetylene to obtain a white solid, that is, the compound C 11 , 29.1 mg, yield 68%, melting point: 199-200 ° C.
  • the preparation method is the same as the compound C 9 , and the phenylacetylene is changed to 4-trifluoromethylphenylacetylene to obtain a white solid, that is, compound C 13 , 28.4 mg, yield 62%, melting point: 224-226 ° C.
  • the preparation method is the same as the compound C 9 , and the phenylacetylene is changed to 4-methylphenylacetylene to obtain a white solid, that is, the compound C 14 , 26.8 mg, the yield is 65%, and the melting point is 200-204 ° C.
  • the preparation method is the same as the compound C 9 , and the phenylacetylene is changed to 4-chlorophenylacetylene to obtain a white solid, that is, the compound C 15 , 25.1 mg, the yield is 58%, and the melting point is 235-237 ° C.
  • the preparation method is the same as the compound C 9 , and the phenylacetylene is changed to 4-fluorophenylacetylene to obtain a white solid, that is, the compound C 16 , 24.9 mg, the yield is 60%, and the melting point is 211-213 ° C.
  • the preparation method is the same as the compound C 17 , and the phenylacetylene is changed to 4-bromophenylacetylene to obtain a white solid, that is, compound C 18 39.3 mg, yield 57%, melting point: 151-153 ° C.
  • the preparation method is the same as the compound C 17 , and the phenylacetylene is changed to 4-methoxyphenylacetylene to obtain a white solid, that is, the compound C 19 , 37.9 mg, yield 61%, melting point: 150-154 ° C.
  • the preparation method is the same as the compound C 17 , and the phenylacetylene is changed to 4-trifluoromethylphenylacetylene to obtain a white solid compound C 21 , 35.1 mg, yield 52%, melting point: 148-150 ° C.
  • the preparation method is the same as the compound C 17 , and the phenylacetylene is changed to 4-methylphenylacetylene to obtain a white solid compound C 22 , 31.1 mg, yield 52%, melting point: 143-147 ° C.
  • the preparation method is the same as the compound C 17 , and the phenylacetylene is changed to 4-chlorophenylacetylene to obtain a white solid, that is, the compound C 23 , 33.3 mg, yield 53%, melting point: 139-142 ° C.
  • the preparation method is the same as the compound C 17 , and the phenylacetylene is changed to 4-fluorophenylacetylene to obtain a white solid, that is, the compound C 24 , 29.0 mg, yield 48%. Melting point: 125-128 ° C.
  • the preparation method is the same as the compound C 25 , and the phenylacetylene is changed to 2-ethynyl pyridine.
  • the preparation method was the same as the compound C 25 , and the phenylacetylene was changed to 4-chlorophenylacetylene.
  • the preparation method was the same as the compound C 25 , and the phenylacetylene was changed to 4-fluorophenylacetylene.
  • the preparation method was the same as the compound C 48 , and the phenylacetylene was changed to 4-bromophenylacetylene.
  • the preparation method was the same as the compound C 48 , and the phenylacetylene was changed to 2-acetylpyrylpyridine.
  • the preparation method was the same as the compound C 48 , and the phenylacetylene was changed to 4-chlorophenylacetylene.
  • the preparation method was the same as the compound C 48 , and the phenylacetylene was changed to 4-fluorophenylacetylene.
  • the preparation method is the same as the compound C 56 , and the phenylacetylene is changed to 2-ethynylpyridine.
  • the preparation method was the same as the compound C 56 , and the phenylacetylene was changed to 4-fluorophenylacetylene.
  • the activity test of the present invention adopts the detection method of MTS, and MTS is an MTT analog, which is called 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H. -tetrazolium.
  • MTS is an MTT analog, which is called 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H. -tetrazolium.
  • This method can metabolize MTS by succinate dehydrogenase in living cell mitochondria to produce soluble formazan compound.
  • the optical density OD (490 nM) of the compound is proportional to the number of living cells, and the optical density OD is determined. The value is a measure of the antitumor activity of the compound.
  • the present invention selects five tumor cells: HL-60, A549, SMMC-7721, MCF-7 and SW480 for experiments, and cisplatin and paclitaxel are used as positive controls.
  • IC 50 value of the compound is determined by calculating the concentration effect of the growth curve.
  • the above activity data shows that the compounds C 21 , C 28 , C 30 and C 31 have general in vitro cytotoxic activity.
  • Compounds C 33 , C 34 , C 35 , C 37 , C 38 , C 39 have significant in vitro cytotoxic activity against breast cancer cells (MCF-7).
  • Compounds C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 have significant in vitro cytotoxic activity against colon cancer cells (SW480).
  • Compounds C 45 , C 46 , C 47 have a broad spectrum of in vitro anti-cancer activity.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种类赤霉素化合物、其制备方法、药物组合物、应用及其中间体，所述如式I所示的类赤霉素化合物具有较好的体外抗肿癌细胞毒活性，尤其对于乳腺癌细胞或结肠癌细胞具有显著的体外细胞毒活性。(I)

Description

类赤霉素化合物、其制备方法、药物组合物及应用及其中间体
本申请要求申请日为2018年3月29日的中国专利申请CN201810273045.4的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及类赤霉素化合物、其制备方法、药物组合物及应用及其中间体。
背景技术
癌症通常也叫恶性肿瘤，是严重威胁人类健康和生命的主要疾病之一，已成为危害人类健康的“第二杀手”(仅次于心血管疾病)。癌症作为一种全身性疾病，药物治疗是一种非常重要的治疗方法，但是目前常用的化疗药物多数具有大的副作用，抗瘤谱狭窄，从而限制了其应用。
例如，赤霉素是一类具有多种生物活性的四环二萜类化合物，广泛存在于微生物和植物体内，作为具有生物活性的基团表现出很强的抗癌活性。但是，目前还没有发现赤霉素类抗癌药物。
因此，寻找特异性高、毒副作用低甚至无毒的抗癌药物已成为药物研究中十分重要的课题。
发明内容
本发明所要解决的技术问题是为了克服现有技术中目前治疗癌症的药物多数具有副作用、抗瘤谱狭窄、从而限制其应用的问题，因而提供了一种类赤霉素化合物、其制备方法、药物组合物、应用及其中间体。本发明提供的类赤霉素化合物具有较好的体外抗肿癌细胞毒活性，尤其对于乳腺癌细胞或结肠癌即系具有显著的体外细胞毒活性。
本发明是通过下述技术方案来解决上述技术问题的。
本发明提供了一种如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物：
Figure PCTCN2019078805-appb-000001
其中，R 1为H或卤素；
R 2为H、OH或OTs(Ts为对甲苯磺酰基)；
R 3为甲基；
Figure PCTCN2019078805-appb-000002
代表单键或双键；
R 6为H或O；
当
Figure PCTCN2019078805-appb-000003
中
Figure PCTCN2019078805-appb-000004
代表单键时，R 6为H；
当
Figure PCTCN2019078805-appb-000005
中
Figure PCTCN2019078805-appb-000006
代表双键时，R 6为O；
当
Figure PCTCN2019078805-appb-000007
中
Figure PCTCN2019078805-appb-000008
代表单键时，R 4为H；R 5为取代或未取代的C 6-C 20的芳基，或取代或未取代的C 2-C 20的杂芳基；所述取代或未取代的C 6-C 20的芳基，或取代或未取代的C 2-C 20的杂芳基中的取代基为
Figure PCTCN2019078805-appb-000009
其中X选自C，N，S或O(例如C或N)；R为H、卤素、C 1-C 6的烷基、卤素取代的C 1-C 6的烷基，或C 1-C 6的烷氧基；n为1-5的整数；
当
Figure PCTCN2019078805-appb-000010
中
Figure PCTCN2019078805-appb-000011
代表双键，R 4为O，
Figure PCTCN2019078805-appb-000012
中
Figure PCTCN2019078805-appb-000013
代表单键，R 6为H时，R 5为C 2-C 6的烷氧基或苄氧基；
当
Figure PCTCN2019078805-appb-000014
中
Figure PCTCN2019078805-appb-000015
代表双键，R 4为O，
Figure PCTCN2019078805-appb-000016
中
Figure PCTCN2019078805-appb-000017
代表双键，R 6为O时，R 5为C 1-C 6的烷氧基或苄氧基；
R 7为CH 2或O；
R 8为OH、C 1-C 6的烷基或C 1-C 6的烷氧基；
且所述式I所示的化合物不为如下任一结构所示的化合物：
Figure PCTCN2019078805-appb-000018
本发明中，所述取代或未取代的C 6-C 20的芳基可为取代或未取代的C 6-C 10的芳基，例如取代或未取代的苯基，或取代或未取代的萘基。
本发明中，所述取代或未取代的C 2-C 20的杂芳基可为含有一个或多个(例如两个)芳杂环，杂原子为N、S或O(例如N)；所述杂原子的个数为1个或多个(例如2或3)的杂芳基，例如所述取代或未取代的C 2-C 20的杂芳基为含有一个芳杂环，杂原子为氮，所述杂原子的个数为1-3个的取代或未取代的C 2-C 10的杂芳基(例如为取代或未取代的吡咯，取代或未取代的呋喃，取代或未取代的噻吩，取代或未取代的吡唑，取代或未取代的咪唑，取代或未取代的噁唑，取代或未取代的噻唑，取代或未取代的异噁唑，取代或未取代的吡啶，取代或未取代的哒嗪，取代或未取代的嘧啶，取代或未取代的吡嗪、取代或未取代的1,2,4三氮唑
Figure PCTCN2019078805-appb-000019
或者取代或未取代的1,2,3三氮唑
Figure PCTCN2019078805-appb-000020
)；再例如所述取代或未取代的C 2-C 20的杂芳基为含有2个环的稠合芳杂基(例如取代或未取代的苯并吲哚，取代或未取代的苯并咪唑，取代或未取代的喹啉，取代或未取代的异喹啉。)
本发明中，所述卤素可为氟、氯、溴或碘，例如溴。
本发明中，所述C 1-C 6的烷基可为C 1-C 4的烷基，例如甲基，乙基，丙基，异丙基和正丁基。
本发明中，所述卤素取代的C 1-C 6的烷基中的卤素取代基的个数可为一个或多个(2个或三个)；所述卤素可为氟。
本发明中，所述C 1-C 6的烷氧基可为C 1-C 4的烷氧基，例如甲氧基，乙氧基和丙氧基。
本发明中，当
Figure PCTCN2019078805-appb-000021
中
Figure PCTCN2019078805-appb-000022
代表双键，所述R 4为O，
Figure PCTCN2019078805-appb-000023
中
Figure PCTCN2019078805-appb-000024
代表单键，所述R 6为H时，所述R 5可为C 2-C 6的烷氧基；
当
Figure PCTCN2019078805-appb-000025
中
Figure PCTCN2019078805-appb-000026
代表双键，所述R 4为O，
Figure PCTCN2019078805-appb-000027
中
Figure PCTCN2019078805-appb-000028
代表双键，所述R 6为O时，所述R 5可为C 1-C 6的烷氧基。
本发明中，所述
Figure PCTCN2019078805-appb-000029
中，所述n可为1；例如，所述
Figure PCTCN2019078805-appb-000030
为
Figure PCTCN2019078805-appb-000031
本发明中，所述R 8为OH或C 1-C 6的烷氧基时，所述
Figure PCTCN2019078805-appb-000032
可为
Figure PCTCN2019078805-appb-000033
所述R 8为C 1-C 6的烷基时，所述
Figure PCTCN2019078805-appb-000034
可为
Figure PCTCN2019078805-appb-000035
本发明中，所述
Figure PCTCN2019078805-appb-000036
可为
Figure PCTCN2019078805-appb-000037
例如，所述
Figure PCTCN2019078805-appb-000038
为
Figure PCTCN2019078805-appb-000039
所述
Figure PCTCN2019078805-appb-000040
为
Figure PCTCN2019078805-appb-000041
所述
Figure PCTCN2019078805-appb-000042
为
Figure PCTCN2019078805-appb-000043
本发明中，所述式I所示的化合物可选自如下式II、式III、式IV或式V所示的化合物中的任一种：
Figure PCTCN2019078805-appb-000044
其中，R 9、R 10和R 11各自独立地为
Figure PCTCN2019078805-appb-000045
Figure PCTCN2019078805-appb-000046
R 13、R 14、R 15、R 16、R 17、R 18和R 19各自独立地为H或
Figure PCTCN2019078805-appb-000047
R 20和R 21各自独立地为H、
Figure PCTCN2019078805-appb-000048
或甲基。
R 12为C 1-C 6的烷基；
R 1、R 2、X、R和C 1-C 6的烷基的定义均如前所述。
所述R 9、R 10和R 11可各自独立地为
Figure PCTCN2019078805-appb-000049
Figure PCTCN2019078805-appb-000050
例如，所述
Figure PCTCN2019078805-appb-000051
为
Figure PCTCN2019078805-appb-000052
较佳地，所述式II所示化合物中：
当所述R 1为卤素时，所述R为卤素，或者卤素取代的C 1-C 6的烷基(例如-CF 3)；
当所述R 1为H，所述R为卤素取代的C 1-C 6的烷基(例如-CF 3)。
较佳地，所述式II所示的化合物中，所述R 2为OH。
所述式II所示的化合物的结构可为：
Figure PCTCN2019078805-appb-000053
各取代基定义如前所述。
所述式III所示化合物中，所述R 1可为氢或卤素，例如氢。
所述式III所示化合物中，所述R 2可OH或OTs，优选OH。
在本发明一优选实施方式中，所述式III所示的化合物中，所述R 2为OH或OTs；所述R 1为氢；所述R 10为
Figure PCTCN2019078805-appb-000054
例如，所述
Figure PCTCN2019078805-appb-000055
为
Figure PCTCN2019078805-appb-000056
所述式III所示的化合物的结构可为：
Figure PCTCN2019078805-appb-000057
各取代基定义如前所述。
所述式IV所示的化合物中，所述R 1可为氢。
所述式IV所示的化合物中，所述R 2可为OH或OTs。
在本发明一优选实施方式中，所述式IV所示的化合物中，所述R 2为OH或OTs；所述R 1氢；所述R 11为
Figure PCTCN2019078805-appb-000058
所述式IV所示的化合物的结构可为：
Figure PCTCN2019078805-appb-000059
各取代基定义如前所述。
所述式V所示的化合物中，所述R 1可为卤素，例如氟。
所述式V所示的化合物中，所述R 1可为OH或OTs。
所述式V所示的化合物中，所述R 12可为甲基。
在本发明一优选实施方式中，所述式II、式III、式IV或式V所示的化合物中，所述R 9、R 10和R 11各自独立地为
Figure PCTCN2019078805-appb-000060
R 13、R 14、R 15、R 16、R 17、R 18和R 19、R 20和R 21各自独立地为H或
Figure PCTCN2019078805-appb-000061
R 20和R 21各自独立地为甲基；其余各取代基定义如前所述。
在本发明一优选实施方式中，所述式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物中，
所述R 1为H或卤素；
所述R 2为H、OH或OTs；
所述R 3为甲基；
Figure PCTCN2019078805-appb-000062
代表单键或双键；
当所述
Figure PCTCN2019078805-appb-000063
中
Figure PCTCN2019078805-appb-000064
代表单键时，所述R 6为H；
当所述
Figure PCTCN2019078805-appb-000065
中
Figure PCTCN2019078805-appb-000066
代表双键时，R 6为O；
当所述
Figure PCTCN2019078805-appb-000067
中
Figure PCTCN2019078805-appb-000068
代表单键时，R 4为H；R 5为取代或未取代的C 6-C 20的芳基，或取代或未取代的C 2-C 20的杂芳基；所述取代或未取代的C 6-C 20的芳基，和取代或未取代的C 2-C 20的杂芳基中的取代基为
Figure PCTCN2019078805-appb-000069
其中X选自C，N，S或O(例如C或N)；R选自H、卤素、C 1-C 6的烷基、卤素取代的C 1-C 6的烷基或C 1-C 6的烷氧基；n为1；
当
Figure PCTCN2019078805-appb-000070
中
Figure PCTCN2019078805-appb-000071
代表双键，R 4为O，
Figure PCTCN2019078805-appb-000072
中
Figure PCTCN2019078805-appb-000073
代表单键，R 6为H时，R 5为C 2-C 6的烷氧基或苄氧基；
当
Figure PCTCN2019078805-appb-000074
中
Figure PCTCN2019078805-appb-000075
代表双键，R 4为O，
Figure PCTCN2019078805-appb-000076
中
Figure PCTCN2019078805-appb-000077
代表双键，R 6为O时，R 5为C 1-C 6的烷氧基或苄氧基；
R 7为CH 2或O；
所述R 8为OH或C 1-C 6的烷氧基时，所述
Figure PCTCN2019078805-appb-000078
为
Figure PCTCN2019078805-appb-000079
所述R 8为C 1-C 6的烷基时，所述
Figure PCTCN2019078805-appb-000080
为
Figure PCTCN2019078805-appb-000081
在本发明一优选实施方式中，所述式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物中，所述取代或未取代的C 6-C 20的芳基为取代或未取代的C 6-C 10的芳基；所述取代或未取代的C 2-C 20的杂芳基为含有一个芳杂环，杂原子为氮，所述杂原子的个数为1-3个的取代或未取代的C 2-C 10的杂芳基，或者所述取代或未取代的C 2-C 20的杂芳基为含有2个环的稠合芳杂基；所述
Figure PCTCN2019078805-appb-000082
为
Figure PCTCN2019078805-appb-000083
Figure PCTCN2019078805-appb-000084
其他各基团及取代基定义如前所述。
在本发明一优选实施方式中，所述式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物中，所述取代或未取代的C 6-C 20的芳基为取代或未取代的C 6-C 10的芳基；所述取代或未取代的C 2-C 20的杂芳基为含有一个芳杂环，杂原子为氮，所述杂原子的个数为1-3个的取代或未取代的C 2-C 10的杂芳基，或者所述取代或未取代的C 2-C 20的杂芳基为含有2个环的稠合芳杂基；所述
Figure PCTCN2019078805-appb-000085
为
Figure PCTCN2019078805-appb-000086
Figure PCTCN2019078805-appb-000087
所述
Figure PCTCN2019078805-appb-000088
为
Figure PCTCN2019078805-appb-000089
所述
Figure PCTCN2019078805-appb-000090
为
Figure PCTCN2019078805-appb-000091
所述
Figure PCTCN2019078805-appb-000092
为
Figure PCTCN2019078805-appb-000093
其他各基团定义如前所述。
在本发明一优选实施方式中，所述式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物中，所述取代或未取代的C 6-C 20的芳基为取代或未取代的苯基，或取代或未取代的萘基；所述取代或未取代的C 2-C 20的杂芳基为取代或未取代的吡咯，取代或未取代的呋喃，取代或未取代的噻吩，取代或未取代的吡唑，取代或未取代的咪唑，取代或未取代的噁唑，取代或未取代的噻唑，取代或未取代的异噁唑，取代或未取代的吡啶，取代或未取代的哒嗪，取代或未取代的嘧啶，取代或未取代的吡嗪、取代或未取代的1,2,4三氮唑
Figure PCTCN2019078805-appb-000094
取代或未取代的1,2,3三氮唑
Figure PCTCN2019078805-appb-000095
取代或未取代的苯并吲哚，取代或未取代的苯并咪唑，取代或未取代的喹啉，或取代或未取代的异喹啉；所述R 8为OH或C 1-C 6的烷氧基时，所述
Figure PCTCN2019078805-appb-000096
为
Figure PCTCN2019078805-appb-000097
所述R 8为C 1-C 6的烷基时，所述
Figure PCTCN2019078805-appb-000098
为
Figure PCTCN2019078805-appb-000099
其他各基团定义如前所述。
在本发明一优选实施方式中，所述式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物中，所述取代或未取代的C 6-C 20的芳基为取代或未取代的苯基，或取代或未取代的萘基；所述取代或未取代的C 2-C 20的杂芳基为取代或未取代的吡咯，取代或未取代的呋喃，取代或未取代的噻吩，取代或未取代的吡唑，取代或未取代的咪唑，取代或未取代的噁唑，取代或未取代的噻唑，取代或未取代的异噁唑，取代或未取代的吡啶，取代或未取代的哒嗪，取代或未取代的嘧啶，取代或未取代的吡嗪、取代或未取代的1,2,4三氮唑
Figure PCTCN2019078805-appb-000100
取代或未取代的1,2,3三氮唑
Figure PCTCN2019078805-appb-000101
取代或未取代的苯并吲哚，取代或未取代的苯并咪唑，取代或未取代的喹啉，或取代或未取代的异喹啉；所述
Figure PCTCN2019078805-appb-000102
为
Figure PCTCN2019078805-appb-000103
所述
Figure PCTCN2019078805-appb-000104
为
Figure PCTCN2019078805-appb-000105
所述
Figure PCTCN2019078805-appb-000106
为
Figure PCTCN2019078805-appb-000107
所述
Figure PCTCN2019078805-appb-000108
为
Figure PCTCN2019078805-appb-000109
其他各基团定义如前所述。
本发明中，所述式II所示的化合物可选自下列任一化合物：
Figure PCTCN2019078805-appb-000110
Figure PCTCN2019078805-appb-000111
本发明中，所述式III所示的化合物可选自下列任一化合物：
Figure PCTCN2019078805-appb-000112
本发明中，所述式IV所示的化合物可选自下列任一化合物：
Figure PCTCN2019078805-appb-000113
本发明中，所述式V所示的化合物可选自下列任一化合物：
Figure PCTCN2019078805-appb-000114
本发明还提供了一种如式I所示的赤霉素衍生物制备方法，其包括以下步骤：
方法1：在铜的催化作用下，将式VI所示的化合物式VII所示的化合物进行环加成 反应，得到式I所示化合物即可；
Figure PCTCN2019078805-appb-000115
或方法2：
Figure PCTCN2019078805-appb-000116
各取代基定义如前所述。
所述方法1中，所述环加成反应的操作及方法可参考本领域的常规操作及方法；例如参照V.V.Rostovtsev,L.G.Green,V.V.Fokin and K.B.Sharpless,Angewandte Chemie,2002,41,2596-2599记载的操作及方法(该文献的内容通过引用的方式并入本文)。
例如，制备路线1：
Figure PCTCN2019078805-appb-000117
本发明一优选实施方式中，以赤霉素(GA 3)为原料，与硫酸二甲酯、碳酸钾和丙酮反应合成赤霉素(GA 3)甲酯，经过戴斯-马丁氧化得到羰基赤霉素甲酯，(具体操作可参考J.Chen,Z.Sun,Y.Zhang,X.Zeng,C.Qing,J.Liu,L.Li and H.Zhang,Bioorganic & medicinal chemistry letters,2009,19,5496-5499)(该文献的内容通过引用的方式并入本文)；然后与四三苯基膦钯、蒽醌-2-磺酸钠、二甲亚砜和水，在80℃反应12h得到芳构化产物，(具体操作可参考J.R.Annand,P.A.Bruno,A.K.Mapp and C.S.Schindler,Chemical communications,2015,51,8990-8993)(该文献的内容通过引用的方式并入本文)，四氢铝锂还原芳构化产物并用对甲苯磺酰氯保护伯羟基得到磺酸酯化合物，用叠氮化钠和N，N-二甲基甲酰胺在80℃下反应3h得到叠氮化合物，最后在抗坏血酸钠、醋酸铜、四氢呋喃和水的作用下，发生铜催化的叠氮-炔基Husigen环加成反应制备化合物C 1-C 8。
例如，制备路线2：
Figure PCTCN2019078805-appb-000118
本发明一优选实施方式中，以赤霉素(GA 3)为原料，与1.2M盐酸，在65℃下反应2.5h得到芳构化产物，在硫酸二甲酯、碳酸钾和丙酮的作用下得到芳构化的赤霉素(GA 3)甲酯化合物，通过四氢铝锂还原酯基和对甲苯磺酰氯保护伯羟基得到磺酸酯化合物，用叠氮化钠将磺酸酯叠氮化，最后经过铜催化的叠氮-炔基Husigen环加成反应制备化合物C 9-C 16。(具体操作可参考R.W.Huigens,3rd,K.C.Morrison,R.W.Hicklin,T.A.Flood,Jr.,M.F.Richter and P.J.Hergenrother,Nature chemistry,2013,5,195-202；和V.V.Rostovtsev,L.G.Green,V.V.Fokin and K.B.Sharpless,Angewandte Chemie,2002,41,2596-2599。)(该文献的内容通过引用的方式并入本文)
例如，制备路线3：
Figure PCTCN2019078805-appb-000119
本发明一优选实施方式中，合合成的芳构化产物8，用叔丁基二甲基氯硅烷保护酚羟基，四氢铝锂还原酯基，对甲苯磺酰氯保护伯羟基，四正丁基氟化胺脱去叔丁基二甲基硅醚保护，叠氮化钠将磺酸酯叠氮化，最后经过铜催化的叠氮-炔基Husigen环加成反应制备化合物C 17-C 24。
例如，制备路线4：
Figure PCTCN2019078805-appb-000120
本发明一优选实施方式中，合成的叠氮化合物21与N-溴代丁二酰亚胺、二异丙基胺和二氯甲烷反应得到溴代化合物，再经过铜催化的叠氮-炔基Husigen环加成反应制备化合物C 25-C 31。
例如，制备路线5：
Figure PCTCN2019078805-appb-000121
本发明一优选实施方式中，合成的磺酸酯化合物10与二氧化硒、过氧叔丁醇和二氯甲烷反应得到烯丙醇化合物23和含酮化合物24；烯丙醇化合物经叠氮化反应得到叠氮化合物25，再经过铜催化的叠氮-炔基Husigen环加成反应和戴斯-马丁氧化制备化合物C 32-C 39；同样，化合物24经过叠氮化反应和铜催化的叠氮-炔基Husigen环加成反应制备C 48-C 55。
例如，制备路线6：
Figure PCTCN2019078805-appb-000122
本发明一优选实施方式中，合成硅醚保护的化合物17与过氧叔丁醇、二氧化硒和二氯甲烷反应得到烯丙醇化合物29，用四氢铝锂还原甲酯，对甲苯磺酰氯活化伯羟基，叠氮化钠将磺酸酯转化为叠氮化合物32；叠氮化合物经过铜催化的叠氮-炔基Husigen环加成反应，戴斯-马丁氧化和四正丁基氟化胺脱去叔丁基二甲基硅醚保护得到化合物C 40-C 47。
例如，制备路线7：
Figure PCTCN2019078805-appb-000123
本发明一优选实施方式中，合成的酚类化合物20与二氧化硒、过氧叔丁醇和二氯甲烷反应得到酮化合物27，经过叠氮化反应和铜催化的叠氮-炔基Husigen环加成反应制备C 56-C 62。
根据本发明公开的上述制备方法，本领域技术人员可采用与之相同的原理和方法，制得本发明的通式化合物II、III、IV或V中涉及的各具体化合物。
本发明还提供了一种药物组合物，其包括治疗有效量的如式I所示的类赤霉素衍生物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，和一种或多种药学上可接受的载体或赋形剂。
本发明还提供了如式I所示的类赤霉素衍生物在制备治疗和/或预防抗肿瘤药物中的应用。
所述抗肿瘤药物可为抗乳腺癌药物和/或抗肠癌药物。
本发明还提供了一种治疗肿瘤疾病的方法，所述的方法包括给予需要其的个体治疗有效量的前述如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物。其中所述的肿瘤优选为乳腺癌和/或肠癌。
本发明还提供了如下所示的式I所示类赤霉素衍生物的中间体：
Figure PCTCN2019078805-appb-000124
Figure PCTCN2019078805-appb-000125
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：
本发明中，所述的确定了碳数范围的“C x1-C y1”的取代基(x1和y1为整数)、如“C x1-C y1”烷基、“C x1-C y1”的烷氧基、“C x1-C y1”芳基或“C x1-C y1”杂芳基，均表示未包含取代基的碳数，例如C 1-C 10烷基表示未包含取代基的C 1-C 10烷基。
关于任一基团包含一个或多个取代基，本领域一般技术人员均可理解，但不包括不切实际的高位阻、合成上不可行的和/或内在不稳定的取代基。
本发明中，所用的术语“药学上可接受的盐”指药学上可接受的与酸或与碱形成的盐和溶剂化物。这类药学上可接受的盐包括但不限于与无机酸形成的盐，如盐酸盐、磷酸盐、二磷酸盐、氢溴酸盐、硫酸盐、亚磺酸盐、硝酸盐、及其类似盐；也包括与有机酸形成的盐，如苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、醋酸盐、乳酸盐、磺酸盐、对甲苯磺酸盐、2-羟基乙基磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和链烷酸盐如醋酸盐，HOOC-(CH 2) n-COOH其中n为0-4的盐，及其类似盐。类似地，药学上可接受的阳离子包括但不限于钠、钾、钙、铝、锂和铵。本领域的成熟技术人员可识别各种可能用来制备无毒的药学上可接受的盐的合成方法。
本发明中，所述的“溶剂化物”如“水合物”，是由溶剂和化合物互相作用形成。术语“化合物”，应该包括了化合物的溶剂化物(包括化合物的水合物)。同样，“盐”也包括了盐的溶剂化物(如盐的水合物)。合适的溶剂化物是药学上可接受的，例如水合物，它包括了单水合物和半水合物。
本发明中，所述的“预防和/或治疗有效剂量”表示(i)预防和/或治疗本申请所述的具体疾病或病症的本发明化合物的量，(ii)削弱、改善或消除本申请所述的具体疾病或病症的一种或多种症状的本发明化合物的量，或(iii)预防或延迟本申请所述的具体疾病或病症的一种或多种症状的发作的本发明化合物的量。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。本发明的某些化合物可以以多晶或无定形形式存在。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams & Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120.1985年,62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明涉及的化学通式可以表现出互变异构、结构异构和立体异构现象。本发明包 括其任意互变或结构或立体异构形式及其混合物，他们的能力不限于任何一种异构或其混合物的形式。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的分步结晶法或色谱法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
除非另有规定，本发明所用试剂和原料均市售可得。
除非另有规定，本发明的化合物经手工或者
Figure PCTCN2019078805-appb-000126
软件命名，市售化合物采用供应商目录名称。
在不违背本领域常识的基础上，上述各优选条件，可任意组合在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明的积极进步效果在于：本发明的类赤霉素衍生物具有较好的抗肿瘤活性。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
C 1-C 8的制备反应式如下：
Figure PCTCN2019078805-appb-000127
上述制备方法步骤如下：
化合物5的合成：
将赤霉酸(GA 3)(5.19g,15mmol)溶于丙酮(80mL)中，在0℃下加入硫酸二甲酯(1.80g,14.3mmol)和无水碳酸钾(4.14g,30mmol)，加完后移除冰水浴，室温反应10h，TLC监测反应完毕后，减压蒸出反应液，加入50mL水，水相用乙酸乙酯(3×100mL)萃取，合并有机相，依次用水(40mL)、饱和食盐水(2×40mL)洗，用无水硫酸钠干燥有机相，减压蒸干得白色固体，即化合物5，5.31g，粗产物未经柱层析直接做下一步反应。
化合物6的合成：
将化合物5(5.31g,14.75mmol)溶于二氯甲烷(140mL)中，缓慢的加入戴斯-马丁氧化剂(6.88g,16.23mmol)，室温反应8h,反应完毕后，加入80mL水，碳酸氢钠(4eq)，硫代硫酸钠(4eq)，搅拌至溶液澄清。用二氯甲烷(3×100mL)萃取，合并有机相，依次用水(2×40mL)和饱和食盐水(2×40mL)洗，用无水硫酸钠干燥有机相，减压蒸干得白色固体即化合物6，4.14g。粗产物未经柱层析直接做下一步反应。
化合物8的合成：
在氮气保护下，将化合物6(4.14g,11.56mmol)、四三苯基膦钯(535mg,0.46mmol)、 蒽醌-2-磺酸钠(538mg,1.73mmol)、二甲亚砜(60ml)和水(20ml)混合，在80℃下反应16h，反应毕后，加入60mL水，水相用乙酸乙酯(3×120mL)萃取，合并有机相，依次用水(3×40mL)、饱和食盐水(3×40mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体2.31g。从赤霉酸(GA 3)为原料合成化合物8的三步总收率为49％。
1H NMR(400MHz,CDCl 3)δ:6.77(d,J＝7.9Hz,1H),6.62(d,J＝7.9Hz,1H),6.16(s,1H),5.17(t,J＝2.4Hz,1H),5.02(t,J＝1.9Hz,1H),3.66(s,3H),3.62(s,1H),3.33(dd,J＝8.4,2.5Hz,1H),2.73(dt,J＝16.3,3.0Hz,1H),2.54-2.22(m,2H),2.09(s,3H),2.04(dt,J＝6.4,4.1Hz,1H),1.92(ddt,J＝15.0,10.3,8.0Hz,1H),1.75(dtd,J＝20.0,10.5,9.3,6.5Hz,2H),1.60(dd,J＝10.7,2.6Hz,1H),1.56-1.45(m,1H). 13C NMR(100MHz,CDCl 3)δ:173.08,155.19,152.92,140.97,138.19,121.84,120.09,114.30,106.89,78.78,56.53,54.04,51.95,48.64,47.53,38.57,38.35,21.16,12.27.
化合物9的合成：
在氮气保护下，将化合物8(4.14g，13.18mmol)溶于无水的四氢呋喃(100mL)中，在冰水浴的条件下分批加入四氢铝锂(1.00g，26.36mmol)，加完后撤去冰水浴，在室温反应4h，反应结束，缓慢加入40mL冰水，水相用乙酸乙酯(3×110mL)萃取，合并有机相，依次用水(2×30mL)、饱和食盐水(2×30mL)洗，用无水硫酸钠干燥有机相，减压蒸干得白色固体3.53g，粗产物未经柱层析直接做下一步反应。
化合物10的合成：
将化合物9(3.53g，12.34mmol)溶于无水的二氯甲烷(100mL)中，分别加入二异丙基乙胺(3.98g，30.85mmol)、对甲苯磺酰氯(4.92g，25.91mmol)、4-二甲氨基吡啶(301mg，2.47)，在室温反应8h，反应结束，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物10，5.25g。两步的总收率为67％。
1H NMR(300MHz,CDCl 3)δ:7.77-7.65(m,2H),7.66-7.57(m,2H),7.31(dd,J＝10.9,8.1Hz,4H),6.84(s,2H),5.14(d,J＝2.4Hz,1H),5.00(s,1H),4.22-3.85(m,2H),3.04(d,J＝7.9Hz,1H),2.97(dd,J＝7.4,4.5Hz,1H),2.75(dt,J＝16.5,2.9Hz,1H),2.43(d,J＝8.6Hz,7H),2.21(s,1H),2.14-2.03(m,1H),1.84(s,3H),1.70-1.57(m,2H),1.46(d,J＝10.8Hz,1H),1.33(dd,J＝10.7,2.6Hz,1H),0.85(dq,J＝7.0,3.5,3.0Hz,1H). 13C NMR(75MHz,CDCl 3)δ:154.76,146.96,145.48,145.00,144.47,142.20,132.84,132.29,129.85,129.76,128.89,128.22,127.65,121.44,120.11,106.90,77.79,67.85,52.98,49.70,48.59,46.73,38.19,37.62,21.64,21.55,20.55,12.65.
化合物11的合成：
将化合物10(5.25g，8.82mmol)和叠氮化钠(1.72g，26.46mmol)溶于无水的N,N-二甲基甲酰胺(80mL)。在氮气保护下，80℃反应4h，反应毕后，加入50mL水，水相用乙酸乙酯(3×130mL)萃取，合并有机相，依次用水(3×40mL)、饱和食盐水(4×40mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物11，3.08g。产率为75％。
1H NMR(400MHz,CDCl 3)δ:7.70(d,J＝8.0Hz,2H),7.30(d,J＝8.0Hz,2H),6.86(t,J＝5.6Hz,2H),5.16(t,J＝2.3Hz,1H),5.06(s,1H),3.42(dd,J＝12.7,7.3Hz,1H),3.35(dd,J＝12.6,5.1Hz,1H),3.15(d,J＝8.1Hz,1H),2.86(dd,J＝7.2,5.2Hz,1H),2.79(dt,J＝16.3,3.0Hz,1H),2.51(d,J＝2.5Hz,1H),2.44(s,3H),2.17-2.06(m,1H),2.00(s,3H),1.97-1.83(m,2H),1.66(dd,J＝10.3,4.5Hz,2H),1.47(d,J＝10.8Hz,1H),1.38(dd,J＝10.8,2.7Hz,1H). 13C NMR(100MHz,CDCl 3)δ155.02,147.16,145.41,144.34,144.16,133.00,129.79,128.78,128.46,121.49,120.19,107.06,78.14,53.43,50.60,50.11,48.96,46.84,38.34,37.83,21.78,20.73,12.99。
化合物C 1的制备：
将化合物11(50mg，0.11mmol)、苯乙炔(22.4mg，0.22mmol)、醋酸铜(33.0mg，0.17mmol)、抗坏血酸钠(43.6mg，0.22mmol)、四氢呋喃(8mL)和水(2mL)混合，反应5h，反应结束，加入10mL水，水相用乙酸乙酯(3×20mL)萃取，合并有机相，依次用水(2×8mL)、饱和食盐水(2×8mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 1，38.4mg，收率61％。熔点:109-111℃。
IR ν max(cm -1):3418,2928,2859,1733,1597,1467,1369,1171,1093,814.87,715,553.HRMS(ESI)m/z calculated for C 33H 34O 4N 3S[M+H] +:568.2265,found:568.2264. 1H NMR(400MHz,CDCl 3)δ:7.75(d,J＝7.4Hz,2H),7.69(d,J＝8.1Hz,2H),7.38(t,J＝7.5Hz,2H),7.31(d,J＝7.3Hz,1H),7.27-7.24(m,2H),7.23(s,1H),6.83(d,J＝8.1Hz,1H),6.77(d,J＝8.1Hz,1H),5.16(d,J＝2.5Hz,1H),5.06(s,1H),4.62(dd,J＝14.2,6.0Hz,1H),4.51(dd,J＝14.2,5.8Hz,1H),3.34(t,J＝5.9Hz,1H),2.80-2.67(m,2H),2.66-2.56(m,1H),2.43(s,3H),2.05(dt,J＝15.2,4.4Hz,2H),1.95-1.81(m,4H),1.64(dt,J＝12.7,6.1Hz,2H),1.55(d,J＝10.8Hz,1H),1.41(dd,J＝10.8,2.6Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.54,147.77,147.24,145.42,144.65,143.74,133.23,130.35,129.82,129.21,128.81,128.27,128.18,125.73,121.48,120.61,120.51,107.37,78.06,53.70,50.99,49.49,49.29,46.55,38.23,37.39,21.71, 20.71,12.78.
化合物C 2的制备：
制备方法同化合物C 1，将苯乙炔改成4-溴苯乙炔，得白色固体即化合物C 2，41.3mg，收率58％，熔点:118-121℃。
IR ν max(cm -1):3416,2928,2861,1597,1468,1367,1195,1171,1045,834,554.HRMS(ESI)m/z calculated for C 33H 33O 4N 3Br S[M+H] +:646.1370,found:[M+H] +646.1372,[M+2+H] +648.1336. 1H NMR(400MHz,CDCl 3)δ:7.68(d,J＝8.2Hz,2H),7.67–7.57(m,2H),7.53–7.43(m,2H),7.31–7.27(m,3H),6.84(d,J＝8.1Hz,1H),6.76(d,J＝8.1Hz,1H),5.17(t,J＝2.3Hz,1H),5.05(d,J＝2.4Hz,1H),4.62(dd,J＝14.1,5.9Hz,1H),4.48(dd,J＝14.2,6.1Hz,1H),3.33(t,J＝6.0Hz,1H),2.71(dd,J＝18.9,5.1Hz,2H),2.61(dt,J＝16.1,2.9Hz,1H),2.44(s,3H),2.24(d,J＝3.5Hz,1H),2.07(dd,J＝9.2,5.8Hz,1H),1.99–1.87(m,1H),1.87(s,3H),1.64(dd,J＝10.8,4.8Hz,2H),1.56(d,J＝10.8Hz,1H),1.40(dd,J＝10.8,2.6Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.48,147.13,146.69,145.56,144.67,143.76,133.14,131.92,129.89,129.34,129.27,128.21,127.30,122.01,121.46,120.92,120.54,107.41,77.98,53.70,50.95,49.55,49.15,46.53,38.27,37.40,21.77,20.69,12.78.
化合物C 3的制备：
制备方法同化合物C 1，将苯乙炔改成4-甲氧基苯乙炔，得白色固体即化合物C 3，42.1mg，收率64％，熔点:112-113℃。
IR ν max(cm -1):3417,2929,1618,1500,1467,1368,1249,1171,1093,836,554.HRMS(ESI)m/z calculated for C 34H 36O 5N 3S[M+H] +:598.2370,found:598.2368. 1H NMR(400MHz,CDCl 3)δ:7.68(ddd,J＝8.5,5.2,2.4Hz,4H),7.28(d,J＝1.5Hz,2H),7.18(s,1H),6.96–6.86(m,2H),6.84(d,J＝8.2Hz,1H),6.78(d,J＝8.1Hz,1H),5.16(t,J＝2.4Hz,1H),5.04(d,J＝2.5Hz,1H),4.59(dd,J＝14.1,6.0Hz,1H),4.45(dd,J＝14.1,5.9Hz,1H),3.80(s,3H),3.33(t,J＝6.0Hz,1H),2.73(d,J＝8.5Hz,1H),2.70–2.64(m,1H),2.61(t,J＝2.9Hz,1H),2.43(s,3H),2.19(d,J＝4.6Hz,1H),2.05(dt,J＝9.0,4.2Hz,1H),1.96–1.87(m,1H),1.86(s,3H),1.70–1.60(m,2H),1.55(d,J＝10.9Hz,1H),1.39(dd,J＝11.1,2.6Hz,1H). 13C NMR(100MHz,CDCl 3)δ:159.63,154.63,147.62,147.19,145.49,144.69,143.91,133.20,129.87,129.22,128.29,127.06,123.14,121.45,120.50,119.88,114.26,107.34,78.01,55.38,53.73,51.00,49.42,49.22,46.54,38.28,37.39,21.76,20.71,12.75.
化合物C 4的制备：
制备方法同化合物C 1，将苯乙炔改成2-乙炔基吡啶，经柱层析(石油醚/乙酸乙酯＝ 1:2)得白色固体即化合物C 4，33.8mg，收率：54％，熔点:108-122℃。
IR ν max(cm -1):3416,2927,2857,1598,1470,1369,1195,1172,1044,836,784,554.HRMS(ESI)m/z calculated for C 32H 33O 4N 4S[M+H] +:569.2217,found:569.2215. 1H NMR(400MHz,CDCl 3)δ:8.53(dt,J＝4.8,1.3Hz,1H),8.14(d,J＝7.9Hz,1H),7.83(s,1H),7.80–7.70(m,3H),7.35–7.28(m,2H),7.22(ddd,J＝7.6,4.8,1.2Hz,1H),6.87(d,J＝8.2Hz,1H),6.82(d,J＝8.1Hz,1H),5.13(d,J＝2.6Hz,1H),5.01(d,J＝2.1Hz,1H),4.60(dd,J＝14.2,7.4Hz,1H),4.41(dd,J＝14.2,5.4Hz,1H),3.38(dd,J＝7.4,5.3Hz,1H),2.91(d,J＝8.0Hz,1H),2.63(dd,J＝16.2,2.7Hz,1H),2.48–2.38(m,4H),2.34(s,1H),2.10(dd,J＝14.8,4.4Hz,1H),1.97–1.77(m,4H),1.70–1.61(m,2H),1.53(d,J＝10.8Hz,1H),1.38(dd,J＝10.7,2.8Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.59,150.02,149.40,148.42,147.26,145.45,144.27,143.63,136.99,133.05,129.84,128.97,128.50,123.00,122.77,121.76,120.45,120.31,107.36,77.89,53.75,50.91,49.25,49.20,46.46,38.25,37.22,21.78,20.65,12.62.
化合物C 5的制备：
制备方法同化合物C 1，将苯乙炔改成4-三氟甲基苯乙炔，得白色固体即化合物C 5，39.3mg，收率56％，熔点:114-116℃。
IR ν max(cm -1):3420,2930,2862,1622,1468,1326,1171,1123,1064,850,554.HRMS(ESI)m/z calculated for C 34H 33O 4N 3F 3S[M+H] +:636.2138,found:636.2138. 1H NMR(400MHz,CDCl 3)δ:7.89(d,J＝8.1Hz,2H),7.75–7.67(m,2H),7.64(d,J＝8.2Hz,2H),7.40–7.18(m,3H),6.84(d,J＝8.1Hz,1H),6.77(d,J＝8.1Hz,1H),5.19(t,J＝2.5Hz,1H),5.10(s,1H),4.68(dd,J＝14.2,5.7Hz,1H),4.57(dd,J＝14.2,5.8Hz,1H),3.37(t,J＝5.8Hz,1H),2.83–2.74(m,1H),2.73–2.63(m,2H),2.45(s,3H),2.15–2.02(m,1H),1.94(s,3H),1.87(q,J＝7.1,5.7Hz,1H),1.66(dd,J＝10.6,4.6Hz,2H),1.58(d,J＝10.9Hz,1H),1.45(dd,J＝10.8,2.6Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.46,147.20,146.42,145.55,144.74,143.61,133.80,133.20,130.10,129.85,129.78,129.45,129.35,128.20,125.87,125.83,125.80,125.76,125.72,125.44,122.73,121.55,120.60,107.47,78.07,53.69,51.01,49.66,49.31,46.59,38.25,37.45,21.70,20.73,12.88.
化合物C 6的制备：
制备方法同化合物C 1，将苯乙炔改成4-甲基苯乙炔，得白色固体即化合物C 6，37.8mg，收率59％，熔点:194-196℃。
IR ν max(cm -1):3423,2920,1654,1378,1325,1171,1126,891,839,813,769,551.HRMS(ESI)m/z calculated for C 34H 36O 4N 3S[M+H] +:582.2421,found:582.2418. 1H NMR(400MHz, CDCl 3)δ:7.85–7.74(m,2H),7.73–7.64(m,2H),7.42–7.29(m,2H),7.26(t,J＝4.0Hz,3H),6.90(d,J＝8.2Hz,1H),6.85(d,J＝8.1Hz,1H),5.23(t,J＝2.4Hz,1H),5.12(d,J＝2.2Hz,1H),4.67(dd,J＝14.2,6.1Hz,1H),4.55(dd,J＝14.2,5.8Hz,1H),3.40(t,J＝5.9Hz,1H),2.87–2.72(m,2H),2.67(dt,J＝16.2,2.9Hz,1H),2.50(s,3H),2.42(s,3H),2.12(dt,J＝15.0,4.4Hz,1H),2.00(d,J＝13.5Hz,1H),1.95(s,3H),1.96–1.80(m,1H),1.78–1.66(m,2H),1.61(d,J＝10.9Hz,1H),1.47(dd,J＝10.7,2.7Hz,1H).
13C NMR(100MHz,CDCl 3)δ:154.67,147.91,147.29,145.50,144.72,143.88,138.10,133.29,129.90,129.56,129.26,128.37,127.64,125.71,121.56,120.56,120.30,107.43,78.11,53.78,51.06,49.50,49.37,46.60,38.31,37.45,21.81,21.36,20.78,12.82.
化合物C 7的制备：
制备方法同化合物C 1，将苯乙炔改成4-氯苯乙炔，得白色固体即化合物C 7，36.4mg，收率55％，熔点:112-115℃。
IR ν max(cm -1):3416,2927,2862,1597,1467,1369,1195,1171,1093,1045,836,554.HRMS(ESI)m/z calculated for C 33H 33O 4N 3ClS[M+H] +:602.1875,found:602.1877. 1H NMR(400MHz,CDCl 3)δ:7.82–7.60(m,4H),7.39–7.32(m,2H),7.29(d,J＝8.1Hz,2H),7.23(s,1H),6.85(d,J＝8.1Hz,1H),6.77(d,J＝8.1Hz,1H),5.18(t,J＝2.5Hz,1H),5.07(d,J＝2.2Hz,1H),4.64(dd,J＝14.1,5.9Hz,1H),4.51(dd,J＝14.2,5.9Hz,1H),3.35(t,J＝5.9Hz,1H),2.79–2.69(m,2H),2.68–2.59(m,1H),2.45(s,3H),2.11–2.02(m,1H),1.98–1.82(m,5H),1.72–1.61(m,2H),1.56(d,J＝10.9Hz,1H),1.43(dd,J＝10.9,2.6Hz,1H).
13C NMR(100MHz,CDCl 3)δ:154.57,147.26,146.82,145.60,144.75,143.79,133.95,133.28,129.94,129.37,129.06,128.97,128.30,127.08,121.58,120.88,120.62,107.50,78.12,53.79,51.06,49.63,49.34,46.64,38.33,37.50,21.82,20.80,12.89.
化合物C 8的制备：
制备方法同化合物C 1，将苯乙炔改成4-氟苯乙炔，得白色固体即化合物C 8，36.7mg，收率57％，熔点:109-112℃。
IR ν max(cm -1):3424,2929,2862,1597,1561,1497,1467,1368,1224,1171,1094,1045,841,554.HRMS(ESI)m/z calculated for C 33H 33O 4N 3FS[M+H] +:586.2170,found:586.2168. 1H NMR(400MHz,CDCl 3)δ:7.82–7.60(m,4H),7.28(d,J＝8.2Hz,2H),7.19(s,1H),7.12–6.97(m,2H),6.84(d,J＝8.1Hz,1H),6.76(d,J＝8.1Hz,1H),5.17(t,J＝2.4Hz,1H),5.07(d,J＝2.1Hz,1H),4.63(dd,J＝14.2,5.9Hz,1H),4.50(dd,J＝14.1,5.9Hz,1H),3.34(t,J＝5.9Hz,1H),2.80–2.68(m,2H),2.68–2.56(m,1H),2.44(s,3H),2.06(dt,J＝14.7,4.3Hz, 1H),2.02–1.73(m,5H),1.65(dd,J＝10.6,4.5Hz,2H),1.56(d,J＝10.8Hz,1H),1.42(dd,J＝10.7,2.7Hz,1H). 13C NMR(100MHz,CDCl 3)δ:163.87,161.42,154.52,147.18,146.93,145.51,144.67,143.74,133.20,129.85,129.30,128.23,127.52,127.44,126.61,121.48,120.53,120.45,115.86,115.64,107.42,78.05,53.71,50.99,49.52,49.29,46.56,38.25,37.42,21.73,20.71,12.81.
C 9-C 16的制备反应式如下：
Figure PCTCN2019078805-appb-000128
上述制备方法步骤如下：
化合物12的合成：
将赤霉酸(GA 3)(5.19g,15mmol)和1.2M的盐酸(30mL)混合，在氮气保护下，65℃反应3h，反应结束后，，加入20mL冰水冷却，抽滤，水洗，干燥得到白色固体，即化合物12，2.81g，收率66％，未经进一步处理直接做下一步反应。
化合物13的合成：
将化合物12(2.81g，9.89mmol)溶于丙酮(75mL)中，在冰水浴下加入硫酸二甲酯(1.18g,9.40mmol)和碳酸钾(2.73g,19.78mmol)，加完后撤去冰水浴，室温反应10h，反应完毕后，减压蒸出反应液，加入40mL水，水相用乙酸乙酯(3×80mL)萃取，合并有机相，依次用水(30mL)、饱和食盐水(2×40mL)洗，用无水硫酸钠干燥有 机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物13，2.42g，收率82％。
1H NMR(400MHz,CDCl 3)δ:7.14(t,J＝7.5Hz,1H),7.02(d,J＝7.6Hz,1H),6.94(d,J＝7.3Hz,1H),5.01(d,J＝2.6Hz,1H),4.78(d,J＝2.2Hz,1H),3.98(s,1H),3.78(s,3H),2.82(dd,J＝12.5,5.0Hz,1H),2.31–2.10(m,7H),2.05–1.87(m,3H),1.73(ddd,J＝11.9,4.8,2.3Hz,1H),1.60(qd,J＝12.8,5.2Hz,1H). 13C NMR(100MHz,CDCl 3)δ:171.94,154.42,144.47,138.36,135.06,129.04,127.52,119.79,103.37,80.61,77.47,77.16,76.84,54.83,53.47,52.14,51.89,48.83,39.46,34.28,22.08,19.80.
化合物14的合成：
在氮气保护下，将化合物13(2.41g，8.12mmol)溶于无水的四氢呋喃(65mL)中，在冰水浴的条件下，分批加入四氢铝锂(617mg，16.24mmol)，加完后移除冰水浴，在室温反应3.5h，反应结束，缓慢加入30mL冰水，水相用乙酸乙酯(3×90mL)萃取，合并有机相，依次用水(2×30mL)、饱和食盐水(2×30mL)洗，用无水硫酸钠干燥有机相，减压蒸干，得粗产物1.78g，粗产物未经柱层析直接做下一步反应。
化合物15的合成：
将化合物14(1.78g，6.59mmol)溶于无水的二氯甲烷(50mL)中，分别加入二异丙基乙胺(1.28g，12.75mmol)、对甲苯磺酰氯(1.50g，7.91mmol)、4-二甲氨基吡啶(160.8mg，1.32)，在室温反应7.5h，反应结束，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝3:1)得白色粉末即化合物15，2.31g。两步的总收率为67％。
1H NMR(400MHz,CDCl 3)δ:7.91–7.77(m,2H),7.35(d,J＝8.1Hz,2H),7.04(t,J＝7.4Hz,1H),6.87(dd,J＝7.5,4.5Hz,2H),5.04(d,J＝2.5Hz,1H),4.81(dd,J＝10.1,5.3Hz,1H),4.69(d,J＝1.9Hz,1H),4.22(dd,J＝10.1,8.7Hz,1H),3.36(dd,J＝8.6,5.3Hz,1H),2.64(dd,J＝12.5,5.0Hz,1H),2.49(d,J＝27.9Hz,1H),2.43(s,3H),2.30–2.10(m,5H),2.00–1.85(m,2H),1.84–1.74(m,2H),1.70(ddd,J＝12.0,5.2,2.6Hz,1H),1.46(qd,J＝12.7,5.3Hz,1H).
13C NMR(100MHz,CDCl 3)δ:154.24,145.02,144.96,138.77,133.60,132.43,129.91,129.35,127.90,127.01,120.00,103.51,79.78,68.84,53.08,51.30,49.02,47.68,39.19,31.30,21.80,21.57,20.64.
化合物16的合成：
将化合物15(2.31g，5.44mmol)和叠氮化钠(1.06g，16.32mmol)溶于无水的N,N-二甲基甲酰胺(40mL)。在氮气保护下，80℃反应3.8h，反应结束后，加入25mL水， 水相用乙酸乙酯(3×75mL)萃取，合并有机相，依次用水(3×20mL)、饱和食盐水(4×20mL)洗，有机相用无水硫酸钠干燥，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝4:1)得白色固体即化合物16，1.24g。产率为77％。
1H NMR(400MHz,CDCl 3)δ:7.11(t,J＝7.4Hz,1H),6.95(t,J＝8.4Hz,2H),5.06(d,J＝2.5Hz,1H),4.83(s,1H),4.22(dd,J＝12.7,5.3Hz,1H),3.63(dd,J＝12.6,8.8Hz,1H),3.31(dd,J＝8.8,5.5Hz,1H),2.72(dd,J＝12.6,5.0Hz,1H),2.41–2.30(m,5H),2.29–2.20(m,2H),2.05(s,1H),2.02–1.85(m,3H),1.80–1.71(m,1H),1.55(qd,J＝12.8,5.2Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.76,145.16,140.19,133.90,129.61,127.02,120.12,103.66,80.18,53.47,51.51,50.73,49.13,47.94,39.44,31.58,22.07,20.95.
化合物C 9的制备：
将化合物16(50mg，0.10mmol)、苯乙炔(20.4mg，0.22mmol)、醋酸铜(30.0mg，0.15mmol)、抗坏血酸钠(39.6mg，0.20mmol)、水(2mL)和四氢呋喃(8mL)混合，反应6h，反应结束，加入9mL水，水相用乙酸乙酯(3×18mL)萃取，合并有机相，依次用水(2×7mL)、饱和食盐水(2×7mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 9，25.0mg，收率63％，熔点:203-205℃。
IR ν max(cm -1):3507,2924,2865,1658,1463,1327,1219,1156,1083,899,762,693.HRMS(ESI)m/z calculated for C 26H 28ON 3[M+H] +:398.2227,found:398.2226. 1H NMR(400MHz,CDCl 3)δ:7.90(s,1H),7.83(d,J＝7.7Hz,2H),7.42(t,J＝7.5Hz,2H),7.33(t,J＝7.4Hz,1H),7.14(t,J＝7.5Hz,1H),6.98(t,J＝7.6Hz,2H),5.32(dd,J＝14.1,5.2Hz,1H),4.99(s,1H),4.86–4.67(m,2H),3.91(dd,J＝11.1,5.0Hz,1H),2.68(dt,J＝12.9,6.4Hz,2H),2.39(s,3H),2.20(dt,J＝12.0,5.3Hz,1H),1.96(d,J＝17.2Hz,1H),1.92–1.75(m,2H),1.66(dd,J＝12.4,4.9Hz,1H),1.53(dq,J＝9.0,5.6Hz,2H),0.76(d,J＝10.2Hz,1H).
13C NMR(100MHz,CDCl 3)δ:154.00,148.26,145.31,139.40,133.52,130.49,130.03,128.98,128.41,127.40,125.88,120.58,119.72,104.20,79.87,53.53,51.67,49.50,49.40,48.19,38.92,31.08,22.07,21.50.
化合物C 10的制备：
制备方法同化合物C 9，将苯乙炔改成4-溴苯乙炔，得白色固体即化合物C 10，28.6mg，收率60％，熔点:233-236℃。
IR ν max(cm -1):3509,2932,2850,1657,1452,1328,1083,971,897,793,508.
HRMS(ESI)m/z calculated for C 26H 27ON 3Br[M+H] +:476.1332,found:[M+H] + 476.1329,[M+2+H] +478.1298. 1H NMR(400MHz,CDCl 3)δ:7.89(s,1H),7.71(d,J＝8.2Hz,2H),7.55(d,J＝8.5Hz,2H),7.14(t,J＝7.5Hz,1H),6.98(t,J＝6.9Hz,2H),5.41–5.24(m,1H),4.99(d,J＝2.7Hz,1H),4.85–4.68(m,2H),3.91(dd,J＝11.1,5.0Hz,1H),2.78–2.62(m,2H),2.39(s,3H),2.21(dt,J＝12.0,5.2Hz,1H),2.01–1.93(m,1H),1.85(dt,J＝12.2,6.2Hz,1H),1.66(d,J＝12.6Hz,2H),1.54(tq,J＝12.4,7.1,6.4Hz,2H),0.73(dd,J＝10.3,2.4Hz,1H). 13C NMR(100MHz,CDCl 3)δ:153.97,147.30,145.27,139.29,133.52,132.17,130.10,129.46,127.51,127.41,127.37,122.36,120.65,119.77,104.27,79.91,53.55,51.72,49.61,49.44,48.28,38.97,31.11,22.10,21.53.
化合物C 11的制备：
制备方法同化合物C 9，将苯乙炔改成4-甲氧基苯乙炔，得白色固体即化合物C 11，29.1mg，收率68％，熔点:199-200℃。
IR ν max(cm -1):3406,2927,2859,1723,1657,1462,1332,1223,1055,894,764,694.513.HRMS(ESI)m/z calculated for C 27H 30O 2N 3[M+H] +:428.2333,found:428.2337. 1H NMR(400MHz,CDCl 3)δ:7.81(s,1H),7.75(d,J＝8.3Hz,2H),7.13(t,J＝7.6Hz,1H),7.04–6.79(m,4H),5.40–5.24(m,1H),4.99(s,1H),4.79(s,1H),4.77–4.61(m,1H),3.97–3.73(m,4H),2.67(d,J＝15.4Hz,2H),2.39(s,3H),2.19(dt,J＝12.0,5.3Hz,1H),1.99–1.79(m,3H),1.73–1.61(m,1H),1.53(d,J＝11.2Hz,2H),0.75(d,J＝10.3Hz,1H). 13C NMR(100MHz,CDCl 3)δ:159.80,154.05,148.12,145.32,139.44,133.52,130.00,127.36,127.17,123.21,120.55,118.94,114.38,104.15,79.85,55.45,53.51,51.65,49.44,49.38,48.14,38.92,31.05,22.07,21.48.
化合物C 12的制备：
制备方法同化合物C 9，将苯乙炔改成2-乙炔基吡啶，经柱层析(石油醚/乙酸乙酯＝1:2)得白色固体即化合物C 12，23.5mg，收率59％，熔点:107-110℃。
IR ν max(cm -1):3415,2930,2865,1734,1603,1461,1421,1248,1202,1088,1046,783,742,542.HRMS(ESI)m/z calculated for C 25H 27ON 4[M+H] +:399.2179,found:399.2177. 1H NMR(400MHz,CDCl 3)δ:8.44(s,1H),8.43–8.37(m,1H),7.88(d,J＝7.9Hz,1H),7.75(td,J＝7.7,1.8Hz,1H),7.27(ddd,J＝7.6,4.7,1.3Hz,1H),7.15(t,J＝7.5Hz,1H),6.99(dd,J＝7.4,5.2Hz,2H),5.40–5.26(m,1H),5.12(d,J＝2.6Hz,1H),4.90(s,1H),4.78(dd,J＝14.0,12.1Hz,1H),3.89(dd,J＝12.2,4.8Hz,1H),2.88–2.64(m,2H),2.41(s,3H),2.29–2.16(m,1H),2.13–1.98(m,2H),1.89(td,J＝12.3,5.1Hz,1H),1.77–1.67(m,1H),1.67–1.51(m,2H),0.86(dd,J＝10.2,2.2Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.73,149.30,148.90, 147.93,145.21,139.21,137.09,133.55,130.01,127.36,123.14,122.04,120.58,120.43,103.97,79.53,53.29,52.04,49.54,49.07,48.54,39.25,30.99,21.94,21.56.
化合物C 13的制备：
制备方法同化合物C 9，将苯乙炔改成4-三氟甲基苯乙炔，得白色固体即化合物C 13，28.4mg，收率62％，熔点:224-226℃。
IR ν max(cm -1):3512,2939,1620,1456,1326,1165,1127,1062,797.HRMS(ESI)m/z calculated for C 27H 27ON 3F 3[M+H] +:466.2101,found:466.2095. 1H NMR(400MHz,DMSO-d 6)δ:8.97(s,1H),8.09(d,J＝8.1Hz,2H),7.85(d,J＝8.1Hz,2H),7.10(t,J＝7.4Hz,1H),6.96(t,J＝8.1Hz,2H),5.38(dd,J＝14.2,5.1Hz,1H),4.91–4.62(m,4H),4.03–3.85(m,1H),2.74–2.55(m,2H),2.36(s,3H),2.23–2.06(m,1H),1.71(t,J＝15.5Hz,2H),1.54–1.41(m,1H),1.39–1.15(m,2H),0.61(d,J＝10.1Hz,1H). 13C NMR(100MHz,DMSO-d 6)δ:154.73,145.18,145.08,139.76,134.82,133.50,129.63,126.89,126.06,125.70,122.87,120.04,103.05,78.37,53.20,51.00,48.77,48.55,46.97,30.82,21.84,20.86.
化合物C 14的制备：
制备方法同化合物C 9，将苯乙炔改成4-甲基苯乙炔，得白色固体即化合物C 14，26.8mg，收率65％，熔点:200-204℃。
IR ν max(cm -1):3494,2928,2863,1739,1660,1500,1460,1326,1236,1090,1073,977,885,814,738,511.HRMS(ESI)m/z calculated for C 27H 30ON 3[M+H] +:412.2383,found:412.2388. 1H NMR(400MHz,CDCl 3)δ:7.86(s,1H),7.72(d,J＝7.8Hz,2H),7.21(d,J＝7.8Hz,2H),7.13(t,J＝7.5Hz,1H),6.97(t,J＝8.2Hz,2H),5.30(dd,J＝14.1,5.2Hz,1H),4.99(d,J＝2.6Hz,1H),4.79(d,J＝2.1Hz,1H),4.72(dd,J＝14.1,11.0Hz,1H),3.88(dd,J＝11.1,5.1Hz,1H),2.78–2.57(m,2H),2.37(d,J＝8.8Hz,6H),2.18(dtd,J＝10.5,5.4,2.8Hz,1H),2.05–1.90(m,2H),1.84(td,J＝12.2,5.1Hz,1H),1.71–1.59(m,1H),1.59–1.39(m,2H),0.75(dd,J＝10.2,2.3Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.02,148.29,145.31,139.43,138.26,133.50,129.98,129.62,127.66,127.34,125.77,120.53,119.42,104.15,79.83,53.50,51.62,49.43,49.36,48.11,38.90,31.04,22.05,21.47,21.38.
化合物C 15的制备：
制备方法同化合物C 9，将苯乙炔改成4-氯苯乙炔，得白色固体即化合物C 15，25.1mg，收率58％，熔点:235-237℃。
IR ν max(cm -1):3507,2936,2856,1657,1456,1326,1218,1156,1084,970,898,792,510.HRMS(ESI)m/z calculated for C 26H 27ON 3Cl[M+H] +:432.1837,found:432.1834. 1H NMR (400MHz,CDCl 3)δ:7.88(s,1H),7.82–7.67(m,2H),7.45–7.34(m,2H),7.14(t,J＝7.5Hz,1H),6.98(t,J＝6.9Hz,2H),5.39–5.30(m,1H),4.99(t,J＝2.6Hz,1H),4.84–4.68(m,2H),3.91(dd,J＝11.1,5.1Hz,1H),2.76–2.61(m,2H),2.39(s,3H),2.28–2.14(m,1H),1.97(dq,J＝17.2,2.3Hz,1H),1.86(td,J＝12.2,5.1Hz,1H),1.67(d,J＝12.7Hz,2H),1.61–1.44(m,2H),0.74(dd,J＝10.2,2.3Hz,1H). 13C NMR(100MHz,CDCl 3)δ:153.97,147.29,145.28,139.30,134.23,133.52,130.10,129.22,129.01,127.50,127.13,127.09,120.65,119.74,104.26,79.91,53.56,51.72,49.60,49.44,48.28,38.97,31.11,22.10,21.53.
化合物C 16的制备：
制备方法同化合物C 9，将苯乙炔改成4-氟苯乙炔，得白色固体即化合物C 16，24.9mg，收率60％，熔点:211-213℃。
IR ν max(cm -1):3506,2934,2855,1658,1558,1498,1459,1326,1223,1157,1083,899,843,791,521.HRMS(ESI)m/z calculated for C 26H 27ON 3F[M+H] +:416.2133,found:416.2137. 1H NMR(400MHz,DMSO-d 6)δ:8.77(s,1H),7.98–7.76(m,2H),7.40–7.24(m,2H),7.09(t,J＝7.4Hz,1H),6.95(t,J＝8.4Hz,2H),5.34(dd,J＝14.1,5.2Hz,1H),4.84(d,J＝10.4Hz,2H),4.79–4.66(m,2H),3.93(dd,J＝11.2,5.0Hz,1H),2.75–2.56(m,2H),2.36(s,3H),2.13(dt,J＝11.6,5.1Hz,1H),1.70(td,J＝14.2,12.6,3.8Hz,2H),1.55–1.42(m,1H),1.41–1.25(m,2H),0.72–0.52(m,1H). 13C NMR(101MHz,DMSO)δ163.06,160.63,154.75,145.72,145.11,139.81,133.50,129.63,127.47,127.44,127.25,127.17,126.87,121.47,120.03,116.05,115.84,103.03,78.39,53.21,51.00,48.67,48.57,46.96,40.05,30.81,21.86,20.88.
C 17-C 24的制备反应式如下：
Figure PCTCN2019078805-appb-000129
上述制备方法步骤如下：
化合物17的合成：
将化合物8(1.1g，3.50mmol)溶于二氯甲烷(30mL)中，依次加入咪唑(357.3mg，5.25mmol)和叔丁基二甲基氯硅烷(739.9mg，4.90mmol)，室温反应4h，反应结束，加入20mL水，水相用二氯甲烷(3×40mL)萃取，合并有机相，依次用水(20mL)、饱和食盐水(2×15mL)洗，有机相用无水硫酸钠干燥，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝6:1)得1.40g产物即化合物17。收率93％。
1H NMR(400MHz,CDCl 3)δ:6.82(d,J＝8.0Hz,1H),6.67(d,J＝8.0Hz,1H),5.16(t,J＝2.4Hz,1H),5.02(d,J＝2.1Hz,1H),3.63(d,J＝10.3Hz,4H),3.36(dd,J＝8.5,2.5Hz,1H),2.73(dt,J＝16.4,2.9Hz,1H),2.56–2.39(m,1H),2.10(s,5H),1.94(ddt,J＝15.0,10.3,7.9Hz,1H),1.83–1.65(m,2H),1.60(dd,J＝10.6,2.6Hz,1H),1.54(dd,J＝10.7,2.3Hz,1H),1.01(s,9H),0.21(d,J＝2.5Hz,6H). 13C NMR(100MHz,CDCl 3)δ:172.65,155.50,152.41,141.11,138.84,126.08,119.78,117.54,106.65,78.46,56.68,53.92,51.70,48.74,47.60,38.61,38.43,25.85,21.15,18.30,13.09,-4.15,-4.17.
化合物18的合成：
在氮气保护下，将化合物17(1.40g，3.26mmol)溶于无水的四氢呋喃(30mL)中， 在冰水浴的条件下，加入四氢铝锂(248.8mg，6.52mmol)，加完后移除冰水浴，在室温反应5h，反应完毕后，缓慢加入20mL冰水，水相用乙酸乙酯(3×80mL)萃取，合并有机相，依次用水(20mL)、饱和食盐水(2×15mL)洗，用无水硫酸钠干燥有机相，减压蒸干，得粗产物1.03g，未经柱层析直接做下一步反应。
化合物19的合成：
将化合物18(1.03g，2.57mmol)溶于无水的二氯甲烷(30mL)中，分别加入二异丙基乙胺(464.1mg，3.60mmol)、对甲苯磺酰氯(512.7mg，2.70mmol)、4-二甲氨基吡啶(62.7mg，0.514mmol)，在室温反应9h，反应结束，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝2:1)得白色粉末即化合物19，1.10g。两步的总收率为61％。
1H NMR(400MHz,CDCl 3)δ:7.66(d,J＝8.1Hz,2H),7.29(d,J＝8.0Hz,2H),6.75(d,J＝8.0Hz,1H),6.62(d,J＝8.0Hz,1H),5.12(d,J＝2.3Hz,1H),5.00(s,1H),4.03(qd,J＝10.2,6.3Hz,2H),3.10–2.92(m,2H),2.80(dt,J＝16.4,2.9Hz,1H),2.42-2.37(m,4H),2.14–2.01(m,2H),1.98(s,3H),1.87(ddt,J＝15.4,11.8,8.3Hz,1H),1.72–1.55(m,2H),1.48–1.34(m,2H),1.00(s,9H),0.19(d,J＝4.0Hz,6H). 13C NMR(100MHz,CDCl 3)δ:155.44,152.54,144.79,141.42,137.80,132.66,129.80,127.83,126.14,119.59,117.23,106.65,78.03,68.19,53.03,49.92,48.82,46.41,38.33,37.88,25.80,21.64,20.76,18.23,12.86,-4.18,-4.24.
化合物20的合成：
将化合物19(1.10g，1.98mmol)溶于无水的四氢呋喃，然后加入四正丁基氟化铵(517.3mg，1.98mmol)，室温反应1h,反应结束，加入25mL水，用乙酸乙酯(3×50mL)萃取，合并有机相，依次用水(18mL)、饱和食盐水(2×18mL)洗，有机相用无水硫酸钠干燥，减压蒸干，经柱层析(石油醚/乙酸乙酯＝2:1-1:1)得白色粉末即化合物20，750.9mg产物。收率86％。
1H NMR(400MHz,CDCl 3)δ:7.66(d,J＝8.0Hz,2H),7.29(d,J＝8.1Hz,2H),6.74(d,J＝7.9Hz,1H),6.61(d,J＝7.9Hz,1H),5.14(t,J＝2.3Hz,1H),5.03(d,J＝2.4Hz,1H),4.03(qd,J＝10.3,6.3Hz,2H),3.09–2.94(m,2H),2.81(dt,J＝16.5,3.0Hz,1H),2.40-2.45(m,4H),2.16–2.02(m,1H),1.97(s,3H),1.88(tt,J＝15.1,8.6Hz,1H),1.67(qd,J＝13.1,12.4,8.0Hz,2H),1.51–1.39(m,2H). 13C NMR(100MHz,CDCl 3)δ:155.32,153.03,145.04,141.49,137.31,132.53,129.93,127.92,121.75,120.02,113.86,106.95,78.46,68.39,53.20,49.86,48.92,46.48,38.36,37.95,21.75,20.91,12.04.
化合物21的合成：
将化合物20(750.9mg，1.70mmol)和叠氮化钠(331.5mg，5.10mmol)溶于无水的 N,N-二甲基甲酰胺(18mL)。在氮气保护下，80℃反应3h，反应结束后，加入20mL水，用乙酸乙酯(3×50mL)萃取，合并有机相，依次用水(3×15mL)、饱和食盐水(4×18mL)洗，有机相用无水硫酸钠干燥，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物21，423.0mg，产率为80％。
1H NMR(400MHz,CDCl 3)δ:6.79(d,J＝7.9Hz,1H),6.64(d,J＝7.9Hz,1H),5.87(s,1H),5.18(t,J＝2.1Hz,1H),5.09(s,1H),3.41(d,J＝6.4Hz,2H),3.10(d,J＝8.1Hz,1H),2.92(t,J＝6.4Hz,1H),2.83(dt,J＝16.2,3.0Hz,1H),2.51(d,J＝16.2Hz,1H),2.20(s,3H),2.17–2.08(m,2H),1.93(ddt,J＝15.3,11.4,8.2Hz,1H),1.80–1.62(m,2H),1.50(t,J＝2.7Hz,2H). 13C NMR(100MHz,CDCl 3)δ:155.29,153.00,143.58,137.12,121.63,119.95,113.70,107.04,78.73,53.52,50.87,50.09,49.03,46.49,38.40,38.02,20.95,12.29.
化合物C 17的制备：
将化合物21(44mg，0.14mmol)、苯乙炔(28.6mg，0.28mmol)、醋酸铜(42.0mg，0.21mmol)、抗坏血酸钠(55.4mg，0.28mmol)、水(2mL)和四氢呋喃(8mL)混合，反应8h，反应结束，加入9mL水，水相用乙酸乙酯(3×18mL)萃取，合并有机相，依次用水(2×6mL)、饱和食盐水(2×6mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 17，34.3mg，收率59％，熔点:141-142℃。
IR ν max(cm -1):3385,2929,2861,1639,1600,1465,1446,1356,1333,1262,1159,1054,895,822,764,695.HRMS(ESI)m/z calculated for C 26H 28O 2N 3[M+H] +:414.2176,found:414.2177. 1H NMR(400MHz,CDCl 3)δ:7.78–7.56(m,2H),7.33(dd,J＝8.3,6.6Hz,2H),7.28(s,1H),7.23(s,1H),6.72(q,J＝8.1Hz,3H),5.11(s,1H),4.98(s,1H),4.57(dd,J＝14.0,6.3Hz,1H),4.34(dd,J＝14.0,6.9Hz,1H),3.31(t,J＝6.7Hz,1H),2.80(d,J＝7.8Hz,1H),2.61–2.41(m,2H),2.29(s,1H),2.13–1.97(m,1H),1.92–1.68(m,1H),1.78(s,3H),1.62(dd,J＝10.9,7.0Hz,2H),1.49(d,J＝10.9Hz,1H),1.45–1.34(m,1H).
13C NMR(100MHz,CDCl 3)δ:154.85,153.48,147.83,143.22,136.85,130.31,128.98,128.37,125.88,122.12,120.78,120.30,114.11,107.33,78.37,53.94,50.99,50.02,49.18,46.31,38.38,37.49,20.95,11.79.
化合物C 18的制备：
制备方法同化合物C 17，将苯乙炔改成4-溴苯乙炔，得白色固体即化合物C 18 39.3mg，收率57％，熔点:151-153℃。
IR ν max(cm -1):3424,2927,2859,1638,1601,1451,1264,1120,1069,1011,823,514. HRMS(ESI)m/z calculated for C 26H 27O 2N 3Br[M+H] +:492.1281,found:[M+H] +492.1280,[M+2+H] +494.1256. 1H NMR(400MHz,CDCl 3)δ:7.58(d,J＝8.5Hz,2H),7.52–7.44(m,2H),7.28(s,1H),6.80(d,J＝8.0Hz,1H),6.72(d,J＝7.9Hz,1H),6.31(s,1H),5.16(d,J＝2.5Hz,1H),5.04(s,1H),4.63(dd,J＝13.9,6.2Hz,1H),4.39(dd,J＝14.0,7.0Hz,1H),3.35(t,J＝6.7Hz,1H),2.83(d,J＝8.0Hz,1H),2.67–2.47(m,2H),2.10(q,J＝6.5,5.9Hz,2H),1.90(d,J＝8.9Hz,2H),1.80(s,3H),1.66(t,J＝17.1Hz,1H),1.53(d,J＝10.9Hz,1H),1.46(dd,J＝10.7,2.2Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.83,153.36,146.85,143.22,137.03,132.13,129.34,127.38,122.26,122.03,120.82,120.40,114.10,107.40,78.37,53.99,51.01,50.10,49.25,46.36,38.41,37.54,20.99,11.75.
化合物C 19的制备：
制备方法同化合物C 17，将苯乙炔改成4-甲氧基苯乙炔，得白色固体即化合物C 19，37.9mg，收率61％，熔点:150-154℃。
IR ν max(cm -1):3415,2929,1658,1618,1500,1460,1249,1176,1054,1031,835,605,533.HRMS(ESI)m/z calculated for C 27H 30O 3N 3[M+H] +:444.2282,found:444.2285. 1H NMR(400MHz,CDCl 3)δ:7.61(d,J＝8.3Hz,2H),7.40(s,1H),7.24(s,1H),6.87(d,J＝8.4Hz,2H),6.73(s,2H),5.12(s,1H),4.98(s,1H),4.55(dd,J＝14.1,6.2Hz,1H),4.32(dd,J＝14.1,6.8Hz,1H),3.77(s,3H),3.38–3.24(m,1H),2.81(d,J＝7.5Hz,1H),2.50(q,J＝16.5Hz,3H),2.14–1.99(m,1H),1.85(s,1H),1.79(s,3H),1.61(d,J＝8.4Hz,2H),1.50(d,J＝10.8Hz,1H),1.42(d,J＝10.7Hz,1H). 13C NMR(100MHz,CDCl 3)δ:159.68,154.87,153.63,147.60,143.21,136.62,127.17,122.99,122.20,120.17,120.09,114.38,114.04,107.24,78.30,55.41,53.88,50.95,49.95,49.07,46.25,38.38,37.45,20.90,11.80.
化合物C 20的制备：
制备方法同化合物C 17，将苯乙炔改成2-乙炔基吡啶，粗产品经柱层析(石油醚/乙酸乙酯＝1:2)得白色固体化合物C 20，28.5mg，收率49％，熔点:144-147℃。
IR ν max(cm -1):3405,2927,2856,1734,1686,1601,1496,1422,1251,1121,1053,894,823,784.HRMS(ESI)m/z calculated for C 25H 27O 2N 4[M+H] +:415.2129,found:415.2128. 1H NMR(400MHz,CDCl 3)δ:8.50(d,J＝5.0Hz,1H),8.19(d,J＝7.9Hz,1H),8.00(s,1H),7.78(td,J＝7.7,1.8Hz,1H),7.22(dd,J＝7.5,5.0Hz,1H),6.74(d,J＝7.9Hz,1H),6.66(d,J＝7.9Hz,1H),5.12(t,J＝2.4Hz,1H),4.98(s,1H),4.61(dd,J＝14.1,7.2Hz,1H),4.36(dd,J＝14.1,6.0Hz,1H),3.34(t,J＝6.7Hz,1H),3.03–2.83(m,2H),2.56(d,J＝16.3Hz,1H),2.39(dt,J＝16.2,3.0Hz,1H),2.08(dd,J＝13.4,4.9Hz,1H),1.95–1.73(m,4H),1.63(dd,J＝11.0,6.5 Hz,2H),1.55–1.36(m,2H). 13C NMR(101MHz,CDCl 3)δ154.96,153.81,149.91,149.10,147.86,143.02,137.53,136.44,123.20,123.15,122.28,120.73,120.14,114.14,107.22,78.20,53.87,51.09,49.91,49.26,46.26,38.44,37.44,20.89,11.95.
化合物C 21的制备：
制备方法同化合物C 17，将苯乙炔改成4-三氟甲基苯乙炔，得白色固体化合物C 21，35.1mg，收率52％，熔点:148-150℃。
IR ν max(cm -1):3387,2929,2862,1623,1451,1326,1167,1123,1065,849,822,598.HRMS(ESI)m/z calculated for C 27H 27O 2N 3F 3[M+H] +:482.2050,found:482.2047. 1H NMR(400MHz,CDCl 3)δ:7.80(d,J＝8.1Hz,2H),7.60(d,J＝8.1Hz,2H),7.36(s,1H),6.78(d,J＝8.0Hz,1H),6.75–6.57(m,2H),5.15(t,J＝2.4Hz,1H),5.02(s,1H),4.63(dd,J＝14.0,6.1Hz,1H),4.40(dd,J＝14.0,7.0Hz,1H),3.35(t,J＝6.6Hz,1H),2.81(d,J＝7.8Hz,1H),2.66–2.46(m,2H),2.36(s,1H),2.21–1.99(m,1H),1.95–1.82(m,1H),1.78(s,3H),1.65(dd,J＝10.7,6.3Hz,2H),1.53(d,J＝10.9Hz,1H),1.48–1.38(m,1H). 13C NMR(100MHz,CDCl 3)δ:154.69,153.44,146.48,143.13,136.93,133.73,130.65,130.33,130.00,129.68,125.98,125.94,125.49,122.79,122.10,121.57,120.37,114.11,107.44,78.40,53.97,50.97,50.17,49.16,46.33,38.38,37.51,20.95,11.75.
化合物C 22的制备：
制备方法同化合物C 17，将苯乙炔改成4-甲基苯乙炔，得白色固体化合物C 22，31.1mg，收率52％，熔点:143-147℃。
IR ν max(cm -1):3406,2927,2861,1685,1600,1499,1450,1359,1263,1120,1054,895,822,517.HRMS(ESI)m/z calculated for C 27H 30O 2N 3[M+H] +:428.2333,found:428.2329. 1H NMR(400MHz,CDCl 3)δ:7.59(d,J＝7.8Hz,2H),7.28(s,1H),7.16(d,J＝7.8Hz,2H),7.12–6.86(m,1H),6.81–6.61(m,2H),5.13(s,1H),4.99(s,1H),4.56(dd,J＝14.1,6.3Hz,1H),4.33(dd,J＝14.0,6.8Hz,1H),3.31(t,J＝6.6Hz,1H),2.81(d,J＝7.7Hz,1H),2.64–2.13(m,3H),2.33(s,3H),2.14–1.97(m,1H),1.97–1.72(m,4H),1.74–1.55(m,2H),1.50(d,J＝11.0Hz,1H),1.43(d,J＝10.8Hz,1H). 13C NMR(100MHz,CDCl 3)δ154.86,153.55,147.87,143.20,138.22,136.73,129.64,127.45,125.78,122.15,120.47,120.23,114.10,107.28,78.36,53.91,50.98,49.98,49.13,46.28,38.37,37.46,21.36,20.93,11.79.
化合物C 23的制备：
制备方法同化合物C 17，将苯乙炔改成4-氯苯乙炔，得白色固体即化合物C 23，33.3mg，收率53％，熔点:139-142℃。
IR ν max(cm -1):3387,2928,2860,1660,1600,1485,1452,1358,1333,1264,1253,1093,1054,974,895,822,517.HRMS(ESI)m/z calculated for C 26H 27O 2N 3Cl[M+H] +:448.1786,found:448.1786. 1H NMR(400MHz,CDCl 3)δ:7.62(d,J＝8.1Hz,2H),7.38–7.28(m,3H),6.90(s,1H),6.83–6.60(m,2H),5.15(s,1H),5.02(s,1H),4.61(dd,J＝14.0,6.2Hz,1H),4.38(dd,J＝14.0,7.0Hz,1H),3.33(t,J＝6.6Hz,1H),2.82(d,J＝7.9Hz,1H),2.63–2.46(m,2H),2.44–2.22(m,1H),2.08(dd,J＝13.8,5.2Hz,1H),1.87(dd,J＝17.5,7.9Hz,1H),1.79(s,3H),1.65(dd,J＝10.7,6.6Hz,2H),1.52(d,J＝10.9Hz,1H),1.45(d,J＝10.9Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.79,153.52,146.78,143.15,136.81,134.07,129.15,128.84,127.10,122.11,120.87,120.31,114.08,107.36,78.35,53.94,50.98,50.08,49.15,46.32,38.40,37.51,20.95,11.77.
化合物C 24的制备：
制备方法同化合物C 17，将苯乙炔改成4-氟苯乙炔，得白色固体即化合物C 24，29.0mg，收率48％。熔点:125-128℃。
IR ν max(cm -1):3386,2929,2861,1773,1659,1600,1561,1498,1500,1229,1157,1054,841,599,526.HRMS(ESI)m/z calculated for C 26H 27O 2N 3F[M+H] +:432.2082,found:432.2085. 1H NMR(400MHz,CDCl 3)δ:7.66(dd,J＝8.6,5.4Hz,2H),7.28(s,1H),7.04(t,J＝8.6Hz,2H),6.86(s,1H),6.78(d,J＝8.1Hz,1H),6.73(d,J＝8.0Hz,1H),5.14(d,J＝2.5Hz,1H),5.02(s,1H),4.61(dd,J＝14.1,6.2Hz,1H),4.37(dd,J＝15.3,5.7Hz,1H),3.34(t,J＝6.7Hz,1H),2.84(d,J＝8.0Hz,1H),2.62–2.49(m,2H),2.40(s,1H),2.08(dq,J＝12.2,6.7,5.2Hz,1H),1.95–1.82(m,1H),1.79(s,3H),1.65(dd,J＝10.7,6.8Hz,2H),1.53(d,J＝11.0Hz,1H),1.49–1.40(m,1H). 13C NMR(101MHz,CDCl 3)δ164.01,161.55,154.78,153.50,146.99,143.19,136.81,127.68,127.60,126.49,122.14,120.62,120.30,116.07,115.85,114.07,107.36,78.37,53.96,50.98,50.07,49.14,46.32,38.40,37.51,20.95,11.76.
C 25-C 31的制备反应式如下：
Figure PCTCN2019078805-appb-000130
上述制备方法步骤如下：
化合物22的合成：
将化合物21(700.0mg，2.25mmol)和二异丙基胺(23mg，0.23mmol)溶于无水的二氯甲烷(15mL)，在冰水浴下，缓慢加入N-溴代琥珀酰亚胺(400.5mg，2.25mmol)的二氯甲烷(5mL)溶液，在该温度下反应1h，反应结束后，直接减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物22，570.3mg，收率65％。
1H NMR(400MHz,CDCl 3)δ:7.05(s,1H),5.55(s,1H),5.18(dd,J＝3.2,1.7Hz,1H),5.09(s,1H),3.68–3.30(m,2H),3.13(d,J＝8.1Hz,1H),2.91(t,J＝6.4Hz,1H),2.82(dt,J＝16.2,3.1Hz,1H),2.56–2.46(m,1H),2.27(s,3H),2.09(dd,J＝14.9,6.1Hz,1H),1.94(ddt,J＝15.4,11.4,8.2Hz,1H),1.86–1.60(m,4H),1.55–1.41(m,2H). 13C NMR(100MHz,CDCl 3)δ:155.18,149.20,143.37,138.45,123.23,122.76,108.92,107.13,78.30,53.48,50.82,50.02,49.18,46.56,38.38,37.95,20.97,13.32.
化合物C 25的制备：
将化合物22(45mg，0.12mmol)、苯乙炔(24.5mg，0.24mmol)、醋酸铜(36.0mg，0.18mmol)、抗坏血酸钠(47.5mg，0.24mmol)、水(2mL)和四氢呋喃(8mL)混合，反应10h，反应毕后，加入10mL水，水相用乙酸乙酯(3×18mL)萃取，合并有机相，依次用水(6mL)、饱和食盐水(2×7mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 25，36.6mg，收率62％。
IR ν max(cm -1):3504,2938,2846,1658,1617,1558,1498,1454,1327,1241,1178,1083,1036,899,843,792,640,525.HRMS(ESI)m/z calculated for C 26H 27O 2N 3Br[M+H] +:492.1281,found:[M+H] +492.1280，[M+2+H] +494.1247.
1H NMR(400MHz,CDCl 3)δ:7.88–7.60(m,2H),7.37(td,J＝15.9,15.5,7.5Hz,4H),7.07(s,1H),5.68(s,1H),5.16(t,J＝2.4Hz,1H),5.04(d,J＝2.1Hz,1H),4.62(dd,J＝14.0, 6.4Hz,1H),4.36(dd,J＝14.0,7.2Hz,1H),3.37(t,J＝6.8Hz,1H),2.92(d,J＝7.9Hz,1H),2.66–2.44(m,2H),2.14–1.98(m,2H),1.98–1.87(m,1H),1.87(s,3H),1.67(dd,J＝11.7,6.7Hz,2H),1.55(d,J＝10.9Hz,1H),1.44(dd,J＝10.9,2.4Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.56,149.32,147.96,143.12,138.34,130.44,128.96,128.34,125.85,123.71,123.11,120.46,109.20,107.51,78.09,53.94,50.90,49.66,49.18,46.26,38.24,37.39,20.91,12.68.
化合物C 26的制备：
制备方法同化合物C 25，将苯乙炔改成4-甲氧基苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 26，32.6mg，收率52％。熔点:152-154℃。
IR ν max(cm -1):3423,2928,2859,1774,1617,1561,1499,1459,1335,1250,1177,896,837,532.HRMS(ESI)m/z calculated for C 27H 29O 3N 3Br[M+H] +:522.1387,found:[M+H] +522.1386,[M+2+H] +524.1353. 1H NMR(400MHz,CDCl 3)δ:7.75–7.59(m,2H),7.28(s,1H),7.08(s,1H),6.97–6.87(m,2H),5.64(s,1H),5.16(t,J＝2.4Hz,1H),5.05(s,1H),4.61(dd,J＝14.0,6.4Hz,1H),4.35(dd,J＝14.1,7.3Hz,1H),3.83(s,3H),3.37(t,J＝6.8Hz,1H),2.93(d,J＝8.0Hz,1H),2.64–2.45(m,2H),2.08(dd,J＝15.2,5.6Hz,1H),1.99–1.88(m,2H),1.86(s,3H),1.68(dd,J＝11.7,6.7Hz,2H),1.55(d,J＝10.9Hz,1H),1.45(dd,J＝10.7,2.3Hz,1H). 13C NMR(101MHz,CDCl 3)δ159.81,154.59,149.31,147.87,143.17,138.35,127.18,123.72,123.11,119.72,114.42,109.18,107.52,78.13,55.47,53.97,50.91,49.65,49.20,46.28,38.25,37.40,20.93,12.67.
化合物C 27的制备：
制备方法同化合物C 25，将苯乙炔改成2-乙炔基吡啶，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 27，24.8mg，收率42％。熔点:149-153℃。
IR ν max(cm -1):3422,2927,2860,1732,1603,1461,1422,1331,1225,1121,1046,894,784.HRMS(ESI)m/z calculated for C 25H 26O 2N 4Br[M+H] +:493.1234,found:[M+H] +493.1233,[M+2+H] +495.1199. 1H NMR(400MHz,CDCl 3)δ:
8.58–8.46(m,1H),8.17(d,J＝8.0Hz,1H),7.94(s,1H),7.77(td,J＝7.8,1.8Hz,1H),7.22(ddd,J＝7.7,4.9,1.2Hz,1H),7.08(s,1H),5.82–5.63(m,1H),5.14(d,J＝2.5Hz,1H),5.02(d,J＝2.4Hz,1H),4.65(dd,J＝14.0,7.2Hz,1H),4.34(dd,J＝14.0,6.7Hz,1H),3.40(t,J＝7.0Hz,1H),3.05(d,J＝8.0Hz,1H),2.65–2.51(m,1H),2.43(dt,J＝16.3,3.0Hz,1H),2.11(dd,J＝14.7,5.7Hz,1H),2.05–1.79(m,4H),1.75–1.58(m,2H),1.58–1.49(m,1H),1.45(dd,J＝10.7,2.7Hz,1H),1.25(s,1H). 13C NMR(100MHz,CDCl 3)δ:154.64,150.12, 149.44,149.40,148.52,142.99,138.13,137.16,123.70,123.11,122.81,120.49,109.35,107.51,78.07,53.99,50.95,49.63,49.26,46.27,38.28,37.35,20.90,12.74。
化合物C 28的制备：
制备方法同化合物C 25，将苯乙炔改成4-三氟甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 28，30.9mg，收率46％。熔点:119-122℃。
IR ν max(cm -1):3405,2929,2861,1622,1461,1325,1190,1123,1064,849,798,597.HRMS(ESI)m/z calculated for C 27H 26O 2N 3BrF 3[M+H] +:560.1155,found:[M+H] +560.1160,[M+2+H] +562.1141. 1H NMR(400MHz,CDCl 3)δ:7.86(d,J＝8.0Hz,2H),7.66(d,J＝8.1Hz,2H),7.41(s,1H),7.09(s,1H),5.61(s,1H),5.18(t,J＝2.4Hz,1H),5.07(s,1H),4.67(dd,J＝14.0,6.2Hz,1H),4.41(dd,J＝14.0,7.2Hz,1H),3.40(t,J＝6.7Hz,1H),2.92(d,J＝8.0Hz,1H),2.69–2.50(m,2H),2.09(dd,J＝14.5,5.2Hz,1H),2.00–1.88(m,1H),1.86(s,3H),1.78(s,1H),1.69(dd,J＝11.5,6.7Hz,2H),1.57(d,J＝10.9Hz,1H),1.47(dd,J＝10.8,2.2Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.36,149.24,146.53,142.88,138.24,133.78,130.26,129.93,125.89,125.85,125.40,123.53,123.08,122.70,121.08,109.16,107.51,78.00,53.87,50.80,49.73,49.13,46.20,38.16,37.32,20.84,12.56.
化合物C 29的制备：
制备方法同化合物C 25，将苯乙炔改成4-甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 29，29.1mg，收率48％。熔点:169-171℃。
IR ν max(cm -1):3432,2929,2863,1719,1642,1561,1497,1452,1334,1223,1157,1052,912,865,796,765,527.HRMS(ESI)m/z calculated for C 27H 29O 2N 3Br[M+H] +:506.1438,found:[M+H] +506.1436,[M+2+H] +508.1403.
1H NMR(400MHz,CDCl 3)δ:7.64(d,J＝7.9Hz,2H),7.30(s,1H),7.22(d,J＝7.8Hz,2H),7.08(s,1H),5.57(s,1H),5.16(t,J＝2.4Hz,1H),5.05(d,J＝2.6Hz,1H),4.63(dd,J＝14.0,6.4Hz,1H),4.37(dd,J＝14.0,7.1Hz,1H),3.38(t,J＝6.7Hz,1H),2.92(d,J＝8.0Hz,1H),2.69–2.49(m,2H),2.37(s,3H),2.09(dd,J＝14.9,5.5Hz,1H),2.00–1.81(m,4H),1.80–1.60(m,3H),1.60–1.51(m,1H),1.46(dd,J＝10.8,2.4Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.53,149.19,147.97,143.07,138.25,138.11,129.53,127.57,125.65,123.57,122.98,119.93,109.06,107.39,78.02,53.85,50.82,49.52,49.17,46.18,38.14,37.29,21.27,20.84,12.57.
化合物C 30的制备：
制备方法同化合物C 25，将苯乙炔改成4-氯苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1) 得白色固体即化合物C 30，27.2mg，收率43％。熔点:166-169℃。
IR ν max(cm -1):3416,2927,2858,1726,1656,1485,1452,1333,1223,1092,1054,975,891,835,517.HRMS(ESI)m/z calculated for C 26H 26O 2N 3BrCl[M+H] +:526.0891,found:[M+H] +526.0896,[M+2+H] +528.0861. 1H NMR(400MHz,CDCl 3)δ:7.68(d,J＝8.3Hz,2H),7.38(d,J＝8.1Hz,2H),7.27(s,1H),7.09(s,1H),5.59(s,1H),5.17(t,J＝2.4Hz,1H),5.06(d,J＝2.6Hz,1H),4.65(dd,J＝14.0,6.3Hz,1H),4.38(dd,J＝14.0,7.1Hz,1H),3.38(t,J＝6.7Hz,1H),2.92(d,J＝8.0Hz,1H),2.72–2.45(m,2H),2.09(dd,J＝14.6,5.2Hz,1H),1.93(dq,J＝11.6,8.0,7.4Hz,1H),1.86(s,3H),1.79–1.62(m,3H),1.56(d,J＝10.8Hz,1H),1.46(dd,J＝10.8,2.3Hz,1H). 13C NMR(100MHz,CDCl 3)δ:154.42,149.22,146.86,142.95,138.24,134.01,129.07,128.87,126.97,123.53,123.03,120.35,109.12,107.47,78.01,53.86,50.81,49.63,49.15,46.19,38.15,37.31,20.84,12.56.
化合物C 31的制备：
制备方法同化合物C 25，将苯乙炔改成4-氟苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 31，27.5mg，收率45％。熔点:151-154℃。
IR ν max(cm -1):3415,2927,2861,1726,1655,1499,1459,1334,1222,1120,1054,889,820,793,517.HRMS(ESI)m/z calculated for C 26H 26O 2N 3BrF[M+H] +:510.1187,found:[M+H] +510.1189,[M+2+H] +512.1156. 1H NMR(400MHz,CDCl 3)δ:7.87–7.56(m,2H),7.31(s,1H),7.16–7.00(m,3H),5.64(s,1H),5.17(d,J＝2.5Hz,1H),5.05(d,J＝2.2Hz,1H),4.64(dd,J＝14.0,6.4Hz,1H),4.37(dd,J＝14.0,7.2Hz,1H),3.38(t,J＝6.8Hz,1H),2.93(d,J＝8.0Hz,1H),2.70–2.47(m,2H),2.09(dd,J＝14.4,5.2Hz,1H),1.99–1.77(m,5H),1.73–1.62(m,2H),1.56(dd,J＝11.0,2.3Hz,1H),1.46(dd,J＝10.9,2.4Hz,1H). 13C NMR(100MHz,CDCl 3)δ:163.93,161.47,154.44,149.22,147.04,142.99,138.24,127.53,127.45,126.59,126.56,123.57,123.02,120.10,115.96,115.74,109.11,107.44,78.00,53.86,50.81,49.60,49.11,46.18,38.16,37.31,20.83,12.56。
C 32-C 39和C 48-C 55的制备反应式如下：
Figure PCTCN2019078805-appb-000131
上述制备方法步骤如下：
化合物23和24的合成：
将化合物10(3.00g，5.04mmol)溶于二氯甲烷(35mL)中，依次加入二氧化硒(279.7mg，2.52mmol)和70％的过氧化叔丁醇水溶液(1.94g，15.12mmol)，室温反应4h，反应结束，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝4:1)得化合物24，1.35g，收率45％。经柱层析(石油醚/乙酸乙酯＝1:2)得化合物23，1.20g，收率39％。
化合物23的核磁数据：
1H NMR(400MHz,CDCl 3)δ:7.70(dd,J＝8.3,1.9Hz,2H),7.46(dd,J＝8.3,1.8Hz,2H),7.36–7.27(m,2H),7.24–7.11(m,2H),6.89–6.72(m,2H),5.38(s,1H),5.31(s,1H),4.36(s,1H),4.32(ddd,J＝10.0,5.3,1.6Hz,1H),4.28–4.16(m,1H),3.07(dd,J＝7.3,4.0Hz,2H),2.95(s,2H),2.42(d,J＝1.7Hz,3H),2.36(d,J＝1.6Hz,3H),2.09–1.99(m,1H),1.92(d,J＝11.0Hz,1H),1.76(d,J＝1.8Hz,3H),1.69(dd,J＝14.5,7.5Hz,1H),1.58(dd,J＝11.4,5.0Hz,2H),1.21–1.13(m,1H). 13C NMR(100MHz,CDCl 3)δ:159.09,147.06,145.55,145.04,144.02,142.37,132.96,131.98,129.88,128.99,128.27,127.64,121.39,120.25,112.34,77.20,75.47,68.61,57.99,47.85,44.68,44.58,37.94,21.73,21.60,20.73,12.84。
化合物24的核磁数据：
1H NMR(400MHz,CDCl 3)δ:7.67(dd,J＝16.2,8.0Hz,4H),7.30(dd,J＝8.0,5.1Hz,4H),6.79(s,2H),4.12(dd,J＝10.4,8.3Hz,1H),4.01(dd,J＝10.4,4.0Hz,1H),3.20–3.05 (m,2H),2.43(d,J＝7.5Hz,6H),2.16(dt,J＝13.7,5.0Hz,1H),2.08–1.97(m,2H),1.93–1.79(m,5H),1.62(dd,J＝12.9,5.1Hz,1H),1.53(td,J＝12.8,5.0Hz,1H),1.34(qd,J＝12.9,5.3Hz,1H),1.04(s,3H). 13C NMR(101MHz,CDCl 3)δ218.78,147.38,145.59,145.22,143.46,141.28,132.93,132.44,130.00,129.86,128.91,128.36,127.83,122.02,120.95,67.32,50.57,50.42,50.15,48.44,48.34,44.09,36.53,22.27,21.78,21.70,19.78,12.76.
化合物25的合成：
将化合物23(1.20g，1.96mmol)和叠氮化钠(383.0mg，5.89mmol)溶于无水的N,N-二甲基甲酰胺(20mL)。在氮气保护下，80℃反应3h，反应结束后，加入20mL水，水相用乙酸乙酯(3×65mL)萃取，合并有机相，依次用水(3×15mL)、饱和食盐水(4×15mL)洗，有机相用无水硫酸钠干燥，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝2:1-1:1)得白色固体即化合物25，670.8mg。产率为71％。
1H NMR(400MHz,CDCl 3)δ:7.73(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),7.00–6.72(m,2H),5.50(s,1H),5.43(s,1H),4.51(s,1H),3.65(dd,J＝12.6,8.5Hz,1H),3.51(dd,J＝12.6,4.5Hz,1H),3.16(t,J＝9.3Hz,2H),3.08(dd,J＝8.6,4.5Hz,1H),2.46(s,3H),2.13(dt,J＝15.0,4.0Hz,1H),2.04(s,3H),1.99(d,J＝10.9Hz,2H),1.87–1.75(m,1H),1.73–1.51(m,2H),1.23(d,J＝11.4Hz,1H). 13C NMR(100MHz,CDCl 3)δ:158.91,147.37,145.51,143.83,143.54,133.18,129.89,128.84,128.57,121.75,120.50,112.45,77.57,75.63,59.00,49.96,48.43,45.07,44.06,37.84,21.88,20.88,13.00.
化合物26的合成：
将化合物24(1.35g，2.27mmol)和叠氮化钠(442.4mg，6.81mmol)溶于无水的N,N-二甲基甲酰胺(22mL)。在氮气保护下，80℃反应3h，反应完毕后，加入22mL水，水相用乙酸乙酯(3×70mL)萃取，合并有机相，依次用水(3×15mL)、饱和食盐水(4×18mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝4:1)得白色固体即化合物26，730.0mg。产率为69％。
1H NMR(400MHz,CDCl 3)δ:7.70(d,J＝8.3Hz,2H),7.30(d,J＝8.1Hz,2H),6.83(s,2H),3.50(dd,J＝12.7,8.0Hz,1H),3.42(dd,J＝12.7,4.7Hz,1H),3.25(dd,J＝12.3,5.1Hz,1H),2.99(dd,J＝7.9,4.7Hz,1H),2.44(s,3H),2.24–2.15(m,1H),2.09–1.96(m,6H),1.93–1.85(m,1H),1.68–1.55(m,2H),1.44–1.32(m,1H),1.08(s,3H). 13C NMR(100MHz,CDCl 3)δ:218.97,147.48,145.47,143.31,133.04,129.82,128.63,128.47,121.94,120.95,50.88,50.54,50.44,50.25,48.57,48.50,44.26,36.70,22.36,21.77,19.85,12.97.
化合物C 32的制备：
将化合物25(70mg，0.15mmol)、苯乙炔(30.6mg，0.30mmol)、醋酸铜(36.0mg，0.23mmol)、抗坏血酸钠(59.4mg，0.30mmol)、水(2.5mL)和四氢呋喃(10mL)混合，反应10h，反应结束，加入12mL水，水相用乙酸乙酯(3×20mL)萃取，合并有机相，依次用水(6mL)、饱和食盐水(2×9mL)洗，用无水硫酸钠干燥有机相，减压蒸干，未经进一步纯化，粗产品溶于无水的二氯甲烷(8mL)，加入戴斯-马丁氧化剂(127.2mg，0.30mmol)，室温反应4h，反应完毕后，加入10mL水，水相用二氯甲烷(3×18mL)萃取，合并有机相，依次用水(8mL)、饱和食盐水(2×10mL)洗，用无水硫酸钠干燥，减压蒸干，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 32，33.2mg，两步收率38％。熔点:116-118℃。
IR ν max(cm -1):3428,2933,2868,1725,1643,1622,1468,1372,1326,1168,1123,1064,849,814,547.HRMS(ESI)m/z calculated for C 33H 32O 5N 3S[M+H] +:582.2057,found:582.2055. 1H NMR(400MHz,CDCl 3)δ:7.93(d,J＝8.0Hz,2H),7.78(s,1H),7.70(d,J＝7.7Hz,2H),7.65(d,J＝8.0Hz,2H),7.30(d,J＝8.0Hz,3H),6.97(s,2H),6.21(s,1H),5.65(s,1H),5.53(dd,J＝14.2,6.0Hz,1H),4.55(dd,J＝14.2,6.6Hz,1H),3.70(t,J＝6.2Hz,1H),3.42(d,J＝7.4Hz,1H),2.51(s,1H),2.45(s,3H),2.27(d,J＝12.7Hz,1H),1.96-1.74(m,5H),1.70(s,3H). 13C NMR(100MHz,CDCl 3)δ203.16,152.35,147.74,146.13,145.66,143.78,141.18,134.12,133.23,129.98,128.34,128.32,126.05,125.90,125.86,125.83,122.47,122.42,122.26,120.98,118.80,75.10,63.21,50.36,48.49,47.00,45.38,37.12,21.83,21.19,12.57,12.54.
化合物C 33的制备：
制备方法同化合物C 32，将苯乙炔改成4-溴苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 33，34.7mg，两步收率35％。熔点:139-141℃。
IR ν max(cm -1):3425,2932,2865,1724,1642,1597,1467,1454,1370,1194,1169,1094,1046,814,726,692,547.HRMS(ESI)m/z calculated for C 33H 31O 5N 3BrS[M+H] +:660.1162,found:660.1163,[M+2+H] +662.1144.
1H NMR(400MHz,CDCl 3)δ:7.80–7.59(m,5H),7.52(dd,J＝8.4,1.4Hz,2H),7.30(d,J＝7.9Hz,2H),6.97(d,J＝1.4Hz,2H),6.20(s,1H),5.64(s,1H),5.58–5.38(m,1H),4.65–4.35(m,1H),3.67(t,J＝6.4Hz,1H),3.42(d,J＝7.4Hz,1H),2.59(s,1H),2.45(s,3H),2.30–2.21(m,1H),2.06–1.78(m,4H),1.75(d,J＝11.7Hz,1H),1.67(d,J＝1.4Hz,3H). 13C NMR(100MHz,CDCl 3)δ:203.15,152.33,147.69,146.45,145.63,143.82,141.14,133.19,132.02,129.99,129.95,129.59,128.32,127.45,122.20,122.04,121.75,120.94,118.78,75.06, 63.20,50.35,48.42,46.96,45.32,37.07,21.86,21.16,12.48.
化合物C 34的制备：
制备方法同化合物C 32，将苯乙炔改成4-甲氧基苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 34，36.7mg，两步收率40％。熔点:141-144℃。
IR ν max(cm -1):3426,2931,2863,1724,1643,1618,1499,1467,1370,1249,1171,1093,1046,834,814,719,547.HRMS(ESI)m/z calculated for C 34H 34O 6N 3S[M+H] +:612.2163,found:612.2163. 1H NMR(400MHz,CDCl 3)δ:7.80-7.61(m,4H),7.55(d,J＝1.2Hz,1H),7.24(d,J＝2.2Hz,2H),6.94(d,J＝1.9Hz,2H),6.92-6.83(m,2H),6.14(s,1H),5.60(s,1H),5.48(dd,J＝14.1,5.7Hz,1H),4.44(dd,J＝14.2,7.1Hz,1H),3.78(d,J＝1.2Hz,3H),3.61(t,J＝6.5Hz,1H),3.39(d,J＝7.2Hz,1H),3.18(s,1H),2.40(s,3H),2.32-2.14(m,1H),2.06-1.76(m,4H),1.68(d,J＝11.3Hz,1H),1.56(s,3H). 13C NMR(100MHz,CDCl 3)δ:203.21,159.61,152.41,147.61,147.27,145.54,143.98,141.18,133.15,129.93,129.86,128.28,127.18,123.25,122.04,120.86,120.82,118.63,114.29,74.91,63.20,55.41,50.37,48.34,46.91,45.15,37.04,21.80,21.10,12.34.
化合物C 35的制备：
制备方法同化合物C 32，将苯乙炔改成2-乙炔吡啶，经柱层析(石油醚/乙酸乙酯＝1:2)得白色固体即化合物C 35，28.0mg，两步收率32％。熔点:127-128℃。
IR ν max(cm -1):3425,2930,2865,1723,1642,1598,1470,1421,1370,1222,1169,1093,1047,784,723,547.HRMS(ESI)m/z calculated for C 32H 31O 5N 4S[M+H] +:583.2010,found:583.2009. 1H NMR(400MHz,CDCl 3)δ:8.52(ddd,J＝4.9,1.8,0.9Hz,1H),8.08(d,J＝6.9Hz,2H),7.74(td,J＝7.7,1.8Hz,1H),7.71-7.65(m,2H),7.28(d,J＝8.0Hz,2H),7.19(ddd,J＝7.6,4.8,1.2Hz,1H),6.93(d,J＝1.5Hz,2H),6.16(s,1H),5.60(s,1H),5.50(dd,J＝14.2,6.1Hz,1H),4.50(dd,J＝14.1,6.6Hz,1H),3.67(t,J＝6.3Hz,1H),3.42(d,J＝7.4Hz,1H),3.13(s,1H),2.41(s,3H),2.23(ddd,J＝14.2,6.9,3.8Hz,1H),1.96-1.77(m,4H),1.72(d,J＝11.2Hz,1H),1.62(s,3H). 13C NMR(100MHz,CDCl 3)δ:203.05,152.38,150.22,149.40,147.90,147.74,145.52,143.75,141.11,136.99,133.12,129.92,129.77,128.38,123.82,122.91,122.18,120.83,120.38,118.67,74.96,63.11,50.19,48.38,46.92,45.23,37.11,21.82,21.16,12.41.
化合物C 36的制备：
制备方法同化合物C 32，将苯乙炔改成4-三氟甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 36，35.1mg，两步收率36％。熔点119-121℃。
IR ν max(cm -1):3416,2933,2866,1724,1643,1597,1467,1371,1194,1168,1093,1046,815,765,695,547.HRMS(ESI)m/z calculated for C 34H 31O 5N 3F 3S[M+H] +:650.1931,found:650.1934. 1H NMR(400MHz,CDCl 3)δ:7.84-7.76(m,2H),7.69(q,J＝5.2,4.0Hz,3H),7.40(t,J＝7.6Hz,2H),7.34-7.28(m,2H),6.99(q,J＝8.1Hz,2H),6.20(s,1H),5.63(s,1H),5.52(dd,J＝14.1,5.9Hz,1H),4.51(dd,J＝14.1,6.8Hz,1H),3.67(t,J＝6.3Hz,1H),3.42(d,J＝7.3Hz,1H),2.66(s,1H),2.43(s,3H),2.30-2.22(m,1H),1.96-1.71(m,5H),1.64(s,3H).
13C NMR(101MHz,CDCl 3)δ:203.16,152.43,147.74,147.47,145.55,143.92,141.16,133.26,130.65,129.96,129.90,128.91,128.35,128.33,128.20,125.91,122.20,121.59,120.91,118.66,75.07,63.21,50.44,48.38,47.00,45.33,37.09,21.83,21.20,12.44.
化合物C 37的制备：
制备方法同化合物C 32，将苯乙炔改成4-甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 37，4.0mg，两步收率38％。熔点:171-174℃。
IR ν max(cm -1):3424,2929,2865,1724,1643,1467,1195,1169,1093,1046,814,782,720,546.HRMS(ESI)m/z calculated for C 34H 34O 5N 3S[M+H] +:596.2214,found:596.2214. 1H NMR(400MHz,CDCl 3)δ:7.69(d,J＝2.6Hz,2H),7.67(d,J＝2.4Hz,2H),7.63(s,1H),7.27(d,J＝8.1Hz,2H),7.20(d,J＝7.9Hz,2H),6.98(q,J＝8.2Hz,2H),6.18(s,1H),5.62(s,1H),5.51(dd,J＝14.1,5.8Hz,1H),4.48(dd,J＝14.2,7.0Hz,1H),3.65(t,J＝6.4Hz,1H),3.42(d,J＝7.3Hz,1H),2.94(s,1H),2.42(s,3H),2.36(s,3H),2.30-2.22(m,1H),2.09-1.77(m,4H),1.72(d,J＝11.1Hz,1H),1.60(s,3H). 13C NMR(100MHz,CDCl 3)δ:203.20,152.40,147.67,147.50,145.54,143.96,141.15,138.02,133.20,129.94,129.87,129.56,128.31,127.75,125.80,122.12,121.24,120.88,118.65,74.99,63.21,50.41,48.35,46.95,45.23,37.05,21.82,21.37,21.15,12.36.
化合物C 38的制备：
制备方法同化合物C 32，将苯乙炔改成4-氯苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 38，32.3mg，两步收率35％。熔点:135-136℃。
IR ν max(cm -1):3424,2932,2865,1723,1642,1597,1484,1467,1370,1194,1169,1093,1046,833,814,718,547.HRMS(ESI)m/z calculated for C 34H 31O 5N 3ClS[M+H] +:616.1667,found:616.1667. 1H NMR(400MHz,CDCl 3)δ:7.92-7.57(m,5H),7.43-7.33(m,2H),7.29(d,J＝8.1Hz,2H),6.96(s,2H),6.19(s,1H),5.63(s,1H),5.51(dd,J＝14.2,6.0Hz,1H),4.49(dd,J＝14.2,6.7Hz,1H),3.67(t,J＝6.3Hz,1H),3.48-3.29(m,1H),2.61(s,1H),2.44(s,3H),2.33-2.15(m,1H),2.08-1.77(m,4H),1.74(d,J＝11.2Hz,1H),1.66(s,3H).
13C NMR(100MHz,CDCl 3)δ:203.16,152.33,147.69,146.43,145.63,143.83,141.15,133.89,133.19,129.98,129.96,129.14,129.08,128.32,127.17,122.20,121.73,120.94,118.77,75.06,63.21,50.36,48.42,46.97,45.32,37.08,21.86,21.16,12.48.
化合物C 39的制备：
制备方法同化合物C 32，将苯乙炔改成4-氟苯乙炔，经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物C 39，32.4mg，两步收率36％。熔点:184-186℃。
IR ν max(cm -1):3416,2933,2868,1723,1645,1598,1498,1468,1454,1373,1220,1170,1043,842,830,754,662,529.HRMS(ESI)m/z calculated for C 33H 31O 5N 3FS[M+H] +:600.1963,found:600.1962. 1H NMR(400MHz,CDCl 3)δ:7.86-7.72(m,2H),7.70(d,J＝8.3Hz,2H),7.64(s,1H),7.30(d,J＝8.1Hz,2H),7.09(t,J＝8.7Hz,2H),6.98(s,2H),6.21(s,1H),5.64(s,1H),5.53(dd,J＝14.1,5.9Hz,1H),4.50(dd,J＝14.2,6.8Hz,1H),3.68(t,J＝6.4Hz,1H),3.49-3.34(m,1H),2.44(s,4H),2.35-2.17(m,1H),2.10-1.80(m,4H),1.75(d,J＝11.2Hz,1H),1.66(s,3H). 13C NMR(100MHz,CDCl 3)δ:203.15,163.96,161.50,152.36,147.70,146.64,145.62,143.89,141.15,133.21,129.98,128.37,128.33,127.70,127.62,126.87,122.19,121.40,120.93,118.75,115.96,115.74,75.09,63.23,50.39,48.41,46.98,45.33,37.08,21.86,21.18,12.47.
化合物C 48的制备：
将化合物26(50mg，0.11mmol)、苯乙炔(22.4mg，0.22mmol)、醋酸铜(33.0mg，0.17mmol)、抗坏血酸钠(43.6mg，0.22mmol)、水(2.5mL)和四氢呋喃(10mL)混合，反应10h，反应结束，加入12mL水，用乙酸乙酯(3×20mL)萃取，合并有机相，依次用水(6mL)、饱和食盐水(2×10mL)洗，用无水硫酸钠干燥，减压蒸干，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 48，36.2mg，收率58％。熔点:223-226℃。
IR ν max(cm -1):2957,2931,1739,1598,1469,1404,1364,1164,1095,1050,890,854,829,751,694,663,593,538.HRMS(ESI)m/z calculated for C 33H 34O 4N 3S[M+H] +:568.2265,found:568.2264. 1H NMR(400MHz,CDCl 3)δ:7.82-7.76(m,2H),7.73-7.66(m,2H),7.51-7.36(m,2H),7.35-7.31(m,1H),7.30(s,1H),7.28(s,1H),7.26(s,1H),6.77(q,J＝8.1Hz,2H),4.71(dd,J＝14.2,6.4Hz,1H),4.60(dd,J＝14.2,5.3Hz,1H),3.51(t,J＝5.9Hz,1H),2.83(dd,J＝12.3,5.1Hz,1H),2.44(s,3H),2.27(dd,J＝11.4,3.5Hz,1H),2.20-2.04(m,2H),1.99(s,1H),1.96(s,3H),1.91-1.84(m,1H),1.71-1.52(m,2H),1.35(qd,J＝12.6,5.9Hz,1H),1.07(s,3H). 13C NMR(100MHz,CDCl 3)δ:218.52,147.91,147.60,145.59,143.71,143.04,133.19,130.42,129.93,129.15,128.92,128.36,128.32,125.79,122.01,121.34,120.68,51.28, 51.07,50.67,49.30,48.76,48.33,43.50,36.58,22.39,21.82,19.82,12.94.
化合物C 49的制备：
制备方法同化合物C 48，将苯乙炔改成4-溴苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 49，37.7mg，收率53％。熔点:119-123℃。
IR ν max(cm -1):2925,2868,1739,1597,1456,1370,1197,1177,1093,1046,839,814,728,552.HRMS(ESI)m/z calculated for C 33H 33O 4N 3BrS[M+H] +:646.1370,found:[M+H] +646.1374,[M+2+H] +648.1379. 1H NMR(400MHz,CDCl 3)δ:7.77-7.62(m,4H),7.55-7.45(m,2H),7.29(dd,J＝8.7,2.8Hz,3H),6.90-6.71(m,2H),4.72(dd,J＝14.2,6.3Hz,1H),4.59(dd,J＝14.2,5.5Hz,1H),3.51(t,J＝5.9Hz,1H),2.84(dd,J＝12.3,5.2Hz,1H),2.46(s,3H),2.26(dd,J＝11.3,3.5Hz,1H),2.17-2.06(m,2H),2.00(s,1H),1.95(s,3H),1.92-1.83(m,1H),1.74-1.51(m,2H),1.36(qd,J＝12.7,5.9Hz,1H),1.08(s,3H). 13C NMR(100MHz,CDCl 3)δ:218.38,147.52,146.87,145.66,143.68,142.99,133.16,132.01,129.95,129.36,129.20,128.29,127.34,122.14,122.01,121.36,120.89,51.27,51.04,50.65,49.36,48.69,48.33,43.50,36.56,22.37,21.82,19.80,12.94。
化合物C 50的制备：
制备方法同化合物C 48，将苯乙炔改成4-甲氧基苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 50，40.1mg，收率61％。熔点:179-180℃。
IR ν max(cm -1):2924,2848,1736,1618,1597,1561,1500,1457,1367,1248,1198,1093,1032,888,838,721,664,551.HRMS(ESI)m/z calculated for C 34H 36O 5N 3S[M+H] +:598.2370,found:598.2372. 1H NMR(400MHz,CDCl 3)δ:7.68(dd,J＝8.6,3.2Hz,4H),7.27(s,1H),7.25(s,1H),7.21(s,1H),7.01-6.85(m,2H),6.84-6.66(m,2H),4.66(dd,J＝14.2,6.5Hz,1H),4.52(dd,J＝14.2,5.5Hz,1H),3.79(s,3H),3.48(t,J＝6.0Hz,1H),2.84(dd,J＝12.2,5.1Hz,1H),2.42(s,3H),2.22(dd,J＝11.4,3.5Hz,1H),2.16-1.97(m,2H),1.96(s,1H),1.91(s,3H),1.88-1.75(m,1H),1.66-1.47(m,2H),1.46-1.26(m,1H),1.04(s,3H).
13C NMR(100MHz,CDCl 3)δ:218.51,159.70,147.73,147.52,145.57,143.66,143.11,133.15,129.90,129.09,128.32,127.06,123.11,121.94,121.28,119.85,114.28,55.39,51.25,51.02,50.60,49.19,48.67,48.25,43.44,36.55,22.36,21.79,19.78,12.85.
化合物C 51的制备：
制备方法同化合物C 48，将苯乙炔改成2-乙炔吡啶，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C 51，30.7mg，收率49％。熔点:238-240℃。
IR ν max(cm -1):2955,2927,1739,1601,1473,1367,1165,1095,1046,853,811,751,664, 538.HRMS(ESI)m/z calculated for C 32H 33O 4N 4S[M+H] +:569.2217,found:569.2218. 1H NMR(400MHz,CDCl 3)δ:8.53(ddd,J＝4.9,1.7,0.9Hz,1H),8.13(dt,J＝7.9,1.1Hz,1H),7.85(s,1H),7.77(dd,J＝7.7,1.8Hz,1H),7.75-7.68(m,2H),7.28(d,J＝8.0Hz,2H),7.22(ddd,J＝7.6,4.8,1.2Hz,1H),6.80(d,J＝2.0Hz,2H),4.69(dd,J＝14.2,8.0Hz,1H),4.45(dd,J＝14.2,4.9Hz,1H),3.56(dd,J＝8.0,4.9Hz,1H),3.02(dd,J＝12.2,5.2Hz,1H),2.42(s,3H),2.26-1.98(m,3H),1.95(s,1H),1.91(s,3H),1.73-1.49(m,3H),1.36(qd,J＝12.6,5.8Hz,1H),1.00(s,3H). 13C NMR(100MHz,CDCl 3)δ:218.47,150.02,149.50,148.62,147.60,145.55,143.33,142.79,137.01,133.03,129.88,128.82,128.54,123.08,122.65,122.30,121.30,120.32,51.23,50.99,50.54,49.07,48.63,48.17,43.40,36.60,22.40,21.82,19.78,12.72.
化合物C 52的制备：
制备方法同化合物C 48，将苯乙炔改成4-三氟甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 52，40.1mg，收率58％。熔点:139-141℃。
IR ν max(cm -1):2928,1741,1622,1469,1372,1326,1166,1124,1064,888,849,719,552.HRMS(ESI)m/z calculated for C 34H 33O 4N 3F 3S[M+H] +:636.2138,found:636.2136. 1H NMR(400MHz,CDCl 3)δ:7.89(d,J＝8.1Hz,2H),7.70-7.65(m,2H),7.62(d,J＝8.2Hz,2H),7.37(s,1H),7.27(d,J＝6.4Hz,2H),6.78(d,J＝8.1Hz,1H),6.74(s,1H),4.74(dd,J＝14.2,6.2Hz,1H),4.62(dd,J＝14.2,5.5Hz,1H),3.51(t,J＝5.8Hz,1H),2.81(dd,J＝12.3,5.1Hz,1H),2.43(s,3H),2.27(dd,J＝11.3,3.6Hz,1H),2.11(dt,J＝18.8,3.5Hz,2H),1.99(s,1H),1.96(s,3H),1.90(dd,J＝11.3,1.5Hz,1H),1.71-1.50(m,2H),1.34(qd,J＝12.6,6.0Hz,1H),1.07(s,3H). 13C NMR(100MHz,CDCl 3)δ:218.33,147.55,146.54,145.71,143.73,142.95,133.86,133.16,130.19,129.94,129.87,129.26,128.27,128.21,125.95,125.92,125.88,125.84,125.80,125.50,122.80,122.05,121.66,121.40,51.29,51.05,50.68,49.45,48.72,48.38,43.52,36.56,22.36,21.78,19.79,12.99.
化合物C 53的制备：
制备方法同化合物C 48，将苯乙炔改成4-甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 53，41.0mg，收率64％。熔点:141-143℃。
IR ν max(cm -1):2925,2868,1740,1597,1467,1370,1177,1093,1047,841,814,720,552.HRMS(ESI)m/z calculated for C 34H 36O 4N 3S[M+H] +:582.2421,found:582.2420. 1H NMR(400MHz,CDCl 3)δ:7.68(dd,J＝10.9,8.0Hz,4H),7.30-7.27(m,3H),7.21(d,J＝7.9Hz,2H),6.93-6.54(m,2H),4.69(dd,J＝14.2,6.5Hz,1H),4.56(ddd,J＝14.0,5.5,1.6Hz,1H),3.51(t,J＝5.9Hz,1H),2.85(dd,J＝12.3,5.1Hz,1H),2.44(s,3H),2.36(s,3H),2.31-2.19(m, 1H),2.11(ddd,J＝18.6,11.9,4.2Hz,2H),1.98(s,1H),1.93(d,J＝1.6Hz,3H),1.85(d,J＝11.3Hz,1H),1.69-1.51(m,2H),1.46-1.28(m,1H),1.06(s,3H). 13C NMR(100MHz,CDCl 3)δ:218.53,147.95,147.55,145.56,143.66,143.08,138.15,133.17,129.90,129.56,129.08,128.35,127.58,125.68,121.98,121.29,120.29,51.26,51.04,50.62,49.22,48.70,48.27,43.45,36.56,22.38,21.80,21.35,19.79,12.86.
化合物C 54的制备：
制备方法同化合物C 48，将苯乙炔改成4-氯苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 54，41.1mg，收率62％。熔点:117-119℃。
IR ν max(cm -1):2926,2868,1740,1597,1456,1370,1178,1093,1047,839,814,663,552.HRMS(ESI)m/z calculated for C 33H 33O 4N 3ClS[M+H] +:602.1875,found:602.1873. 1H NMR(400MHz,CDCl 3)δ:7.82-7.57(m,4H),7.35(d,J＝8.5Hz,2H),7.29(dd,J＝7.8,3.2Hz,3H),6.80(d,J＝8.1Hz,1H),6.75(d,J＝8.1Hz,1H),4.72(dd,J＝14.2,6.4Hz,1H),4.59(dd,J＝14.2,5.6Hz,1H),3.51(t,J＝5.9Hz,1H),2.85(dd,J＝12.3,5.2Hz,1H),2.45(s,3H),2.26(dd,J＝11.3,3.6Hz,1H),2.20-2.06(m,2H),2.00(s,1H),1.95(s,3H),1.89(dd,J＝11.4,1.5Hz,1H),1.74-1.53(m,2H),1.36(qd,J＝12.7,5.9Hz,1H),1.08(s,3H). 13C NMR(100MHz,CDCl 3)δ:218.39,147.52,146.85,145.66,143.68,143.00,133.98,133.16,129.94,129.20,129.06,128.92,128.28,127.05,122.00,121.35,120.86,51.27,51.03,50.65,49.35,48.69,48.33,43.49,36.56,22.36,21.81,19.80,12.93。
化合物C 55的制备：
制备方法同化合物C 48，将苯乙炔改成4-氟苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 55，40.6mg，收率63％。熔点:180-182℃。
IR ν max(cm -1):2926,2868,1740,1597,1561,1497,1467,1370,1223,1178,1094,1046,888,841,771,716,813,552.HRMS(ESI)m/z calculated for C 33H 33O 4N 3FS[M+H] +:586.2170,found:586.2169. 1H NMR(400MHz,CDCl 3)δ:7.98-7.73(m,2H),7.69(d,J＝8.2Hz,2H),7.30(d,J＝7.8Hz,3H),7.08(t,J＝8.7Hz,2H),6.80(d,J＝8.1Hz,1H),6.75(d,J＝8.1Hz,1H),4.72(dd,J＝14.2,6.4Hz,1H),4.58(dd,J＝14.2,5.5Hz,1H),3.52(t,J＝6.0Hz,1H),2.86(dd,J＝12.2,5.1Hz,1H),2.45(s,3H),2.26(dd,J＝11.4,3.5Hz,1H),2.19-2.05(m,2H),2.00(s,1H),1.95(s,3H),1.91-1.84(m,1H),1.72-1.54(m,2H),1.36(qd,J＝12.7,6.0Hz,1H),1.07(s,3H). 13C NMR(101MHz,CDCl 3)δ:218.41,163.92,161.46,147.50,147.01,145.64,143.66,143.03,133.13,129.92,129.17,128.27,127.55,127.47,126.64,126.61,121.95,121.31,120.51,115.92,115.71,51.25,51.01,50.62,49.28,48.66,48.29,43.46,36.54,22.34,21.78, 19.77,12.89.
C 40-C 47的制备反应式如下：
Figure PCTCN2019078805-appb-000132
上述制备步骤如下：
化合物29的合成：
将化合物17(3.50g，8.16mmol)溶于二氯甲烷(45mL)中，依次加入二氧化硒(452.9mg，4.08mmol)和70％的过氧化叔丁醇水溶液(3.15g，24.48mmol)，室温反应4h，反应结束，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝4:1)得白色固体即化合物29，2.83g，收率78％。
1H NMR(400MHz,CDCl 3)δ:6.81(d,J＝8.0Hz,1H),6.67(d,J＝8.0Hz,1H),5.45(s,1H),5.41(d,J＝1.3Hz,1H),4.53(s,1H),3.76(s,1H),3.63(s,4H),3.35(d,J＝7.7Hz,1H),3.06(s,1H),2.14(s,3H),2.11–2.03(m,1H),2.03–1.97(m,1H),1.85–1.60(m,3H),1.44–1.33(m,1H),1.01(s,9H),0.21(d,J＝1.4Hz,6H). 13C NMR(100MHz,CDCl 3)δ:173.56,159.06,152.58,140.52,138.05,126.69,119.84,117.57,112.34,77.64,76.32,59.79,54.16,52.12,45.22,44.42,37.81,25.88,21.06,18.35,13.21,-4.13.
化合物30的合成：
在氮气保护下，将化合物29(2.83g，6.36mmol)溶于无水的四氢呋喃(45mL)中，在冰水浴的条件下分批加入四氢铝锂(483.3mg，12.72mmol)，加完后移除冰水浴，在室温反应4h，反应结束，缓慢加入30mL冰水，水相用乙酸乙酯(3×60mL)萃取，合并有机相，依次用水(2×20mL)、饱和食盐水(2×20mL)洗，用无水硫酸钠干燥有机相， 减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝4:1)得白色固体即化合物30，2.33g，收率88％。
1H NMR(400MHz,CDCl 3)δ:6.77(d,J＝8.0Hz,1H),6.61(d,J＝7.9Hz,1H),5.80(s,1H),5.46(s,1H),5.38(d,J＝16.8Hz,2H),4.56(s,1H),4.05(s,1H),3.70(t,J＝10.8Hz,1H),3.56(d,J＝10.7Hz,1H),3.16(dd,J＝10.6,2.8Hz,1H),3.07(d,J＝7.5Hz,1H),2.15(s,3H),2.13–2.06(m,1H),2.02–1.88(m,1H),1.82–1.57(m,3H),1.33(d,J＝10.8Hz,1H),1.02(s,9H),0.21(d,J＝3.6Hz,6H). 13C NMR(100MHz,CDCl 3)δ:158.10,152.70,142.71,136.65,125.96,119.57,116.85,112.69,77.80,76.20,59.81,58.83,51.94,45.14,44.02,37.79,25.91,20.68,18.35,12.87,-4.09,-4.11.
化合物31的合成：
将化合物30(2.33g，5.59mmol)溶于无水的二氯甲烷(40mL)中，分别加入二异丙基乙胺(1.08g，8.39mmol)、对甲苯磺酰氯(1.06g，5.59mmol)、4-二甲氨基吡啶(136.4mg，1.12)，在室温反应10h，反应结束，减压蒸干，粗产物经柱层析(石油醚/乙酸乙酯＝2:1)得白色固体即化合物31，2.68g。收率为84％。
1H NMR(400MHz,CDCl 3)δ:7.58–7.52(m,2H),7.23(dd,J＝8.5,2.3Hz,2H),6.76(d,J＝8.0Hz,1H),6.62(d,J＝8.0Hz,1H),5.41(d,J＝2.0Hz,1H),5.34(s,1H),4.41(d,J＝1.8Hz,1H),4.29(qd,J＝9.9,5.7Hz,2H),3.14(dd,J＝11.2,5.4Hz,3H),3.04(d,J＝7.8Hz,1H),2.40(d,J＝2.0Hz,3H),2.10–2.00(m,1H),1.96(d,J＝11.2Hz,1H),1.92(s,3H),1.78–1.53(m,3H),1.26(dd,J＝10.7,1.9Hz,1H),1.01(s,9H),0.20(d,J＝11.2Hz,6H). 13C NMR(100MHz,CDCl 3)δ:159.21,152.61,144.83,141.49,137.28,132.28,129.80,127.82,126.31,119.76,117.23,112.26,77.36,75.71,68.90,58.21,47.90,44.80,44.17,37.99,25.86,21.68,20.91,18.29,13.04,-4.08,-4.23.
化合物32的合成：
将化合物31(2.68g，4.69mmol)和叠氮化钠(914.6mg，14.07mmol)溶于无水的N,N-二甲基甲酰胺(50mL)。在氮气保护下，80℃反应3h，反应结束后，加入50mL水，水相用乙酸乙酯(3×90mL)萃取，合并有机相，依次用水(3×18mL)、饱和食盐水(4×25mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物32，1.49g。产率为72％。
1H NMR(400MHz,CDCl 3)δ:6.80(d,J＝8.0Hz,1H),6.65(d,J＝8.0Hz,1H),5.45(s,1H),5.39(s,1H),4.47(s,1H),3.77(d,J＝2.9Hz,1H),3.66(dd,J＝12.5,8.4Hz,1H),3.52(dd,J＝12.5,4.6Hz,1H),3.33(s,1H),3.17–2.99(m,2H),2.18(s,3H),2.15–2.04(m,1H), 2.03–1.95(m,1H),1.86–1.55(m,3H),1.27(dd,J＝10.8,1.8Hz,1H),1.02(s,9H),0.21(d,J＝5.2Hz,6H). 13C NMR(100MHz,CDCl 3)δ:158.60,152.75,143.09,136.89,125.86,119.82,117.22,112.43,77.40,75.75,58.81,50.27,48.46,44.81,43.75,37.91,25.86,20.88,18.30,13.07,-4.11,-4.20.
化合物C 40的制备：
将化合物32(70mg，0.16mmol)、苯乙炔(32.6mg，0.32mmol)、醋酸铜(48.0mg，0.24mmol)、抗坏血酸钠(63.4mg，0.32mmol)、水(2mL)和四氢呋喃(10mL)混合，室温反应11h，反应结束，加入14mL水，水相用乙酸乙酯(3×24mL)萃取，合并有机相，依次用水(8mL)、饱和食盐水(2×12mL)洗，用无水硫酸钠干燥，减压蒸干，未经进一步纯化，粗产品溶于无水的二氯甲烷(10mL)，加入戴斯-马丁氧化剂(135.7mg，0.32mmol)，室温反应4.5h，反应完毕后，加入11mL水，用二氯甲烷(3×24mL)萃取，合并有机相，依次用水(10mL)、饱和食盐水(2×10mL)洗，用无水硫酸钠干燥，减压蒸干，未经进一步纯化，溶于无水的四氢呋喃(10mL)中，加入三水合四丁基氟化铵(55.6mg，0.18mmol)，室温反应1h，反应结束，加入10mL水，用乙酸乙酯(3×25mL)萃取，合并有机相，依次用水(8mL)、饱和食盐水(3×12mL)洗，用无水硫酸钠干燥，减压蒸干，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C 40，2.0mg，三步总收率45％。熔点:165-167℃。
IR ν max(cm -1):3387,2932,2864,1722,1642,1601,1464,1264,1081,1054,821,765,694.HRMS(ESI)m/z calculated for C 26H 26O 3N 3[M+H] +:428.1969,found:428.1969. 1H NMR(400MHz,MeOD)δ:7.95(d,J＝2.4Hz,1H),7.72(d,J＝7.5Hz,2H),7.39(td,J＝7.6,1.7Hz,2H),7.35–7.19(m,1H),6.90(d,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),6.17(s,1H),5.58(s,1H),5.54(d,J＝5.5Hz,1H),4.62(ddd,J＝14.5,8.9,2.2Hz,1H),3.68(dd,J＝8.9,5.4Hz,1H),3.48(d,J＝6.8Hz,1H),2.45–2.23(m,1H),1.88–1.76(m,4H),1.67(d,J＝11.1Hz,1H),1.50(s,3H). 13C NMR(100MHz,MeOD)δ:205.02,155.80,154.52,148.54,144.27,134.05,131.60,129.93,129.27,126.63,124.06,123.65,121.52,118.09,114.59,75.63,65.21,51.06,50.05,47.76,45.76,38.26,21.96,11.64.
化合物C 41的制备：
制备方法同化合物C 40，将苯乙炔改成4-溴苯乙炔，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C 41，34.8mg，三步总收率43％。熔点:157-160℃。
IR ν max(cm -1):3405,2931,2864,1722,1642,1602,1454,1336,1263,1179,1070,1010,972,821,652,514.HRMS(ESI)m/z calculated for C 26H 25O 3N 3Br[M+H] +:506.1074,found: [M+H] +506.1072,[M+2+H] +508.1059. 1H NMR(400MHz,MeOD)δ:8.00(s,1H),7.65(d,J＝8.4Hz,2H),7.55(d,J＝8.3Hz,2H),6.90(d,J＝8.0Hz,1H),6.68(d,J＝8.0Hz,1H),6.17(s,1H),5.68–5.50(m,2H),4.62(dd,J＝14.1,8.8Hz,1H),3.68(dd,J＝8.7,5.5Hz,1H),3.48(d,J＝7.1Hz,1H),2.32(dd,J＝11.5,3.9Hz,1H),1.83(tt,J＝9.4,4.1Hz,4H),1.67(d,J＝11.1Hz,1H),1.51(s,3H). 13C NMR(100MHz,MeOD)δ:205.03,155.82,154.54,147.42,144.23,134.06,133.08,130.84,128.32,124.02,123.90,122.92,121.54,118.10,114.62,75.64,65.21,51.04,50.10,47.78,45.77,38.28,21.97,11.65.
化合物C 42的制备：
制备方法同化合物C 40，将苯乙炔改成4-甲氧基苯乙炔，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C 42，34.4mg，三步总收率47％。熔点：157-158℃。
IR ν max(cm -1):3394,2933,2864,1722,1642,1618,1500,1457,1249,1176,836,732,534.HRMS(ESI)m/z calculated for C 27H 28O 4N 3[M+H] +:458.2074,found:458.2076. 1H NMR(400MHz,CDCl 3)δ:7.65(d,J＝8.7Hz,2H),7.59(s,1H),6.97–6.85(m,2H),6.81(d,J＝8.0Hz,1H),6.77–6.70(m,2H),6.16(s,1H),5.61(s,1H),5.53(dd,J＝14.0,5.7Hz,1H),4.44(dd,J＝14.1,7.5Hz,1H),3.80(s,3H),3.60(t,J＝6.7Hz,1H),3.39(d,J＝5.7Hz,1H),2.21(d,J＝7.8Hz,1H),1.96–1.71(m,6H),1.63(s,3H). 13C NMR(100MHz,CDCl 3)δ:203.99,159.67,154.02,152.67,147.24,143.12,133.47,127.24,123.12,122.83,121.07,120.64,118.44,114.50,114.40,75.27,63.76,55.46,50.36,48.94,46.88,45.29,37.13,21.28,11.56.
化合物C 43的制备：
制备方法同化合物C 40，将苯乙炔改成2-乙炔吡啶，经柱层析(石油醚/乙酸乙酯＝1:2)得白色固体即化合物C 43，27.8mg，三步总收率38％。熔点:164-166℃。
IR ν max(cm -1):3404,2932,2864,1722,1642,1602,1473,1422,1264,1054,997,822,784,742.HRMS(ESI)m/z calculated for C 25H 25O 3N 4[M+H] +:429.1921,found:429.1922.
1H NMR(400MHz,MeOD)δ:8.53(d,J＝4.9Hz,1H),8.21(s,1H),8.05(d,J＝7.9Hz,1H),7.90(td,J＝7.8,1.7Hz,1H),7.40–7.28(m,1H),6.90(d,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),6.18(s,1H),5.64–5.53(m,2H),4.71(dd,J＝14.1,8.4Hz,1H),3.72(dd,J＝8.4,5.6Hz,1H),3.50(d,J＝6.9Hz,1H),3.36(s,1H),2.38–2.26(m,1H),1.91–1.79(m,4H),1.69(d,J＝11.1Hz,1H),1.57(s,3H). 13C NMR(100MHz,MeOD)δ:205.01,155.84,154.55,150.95,150.32,148.24,144.13,138.89,134.06,125.57,124.42,123.94,121.51,121.45,118.07,114.63,75.64,65.13,51.05,50.14,47.80,45.81,38.29,21.96,11.70.
化合物C 44的制备：
制备方法同化合物C 40，将苯乙炔改成4-三氟甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C 44，29.4mg，三步总收率37％。熔点：160-161℃。
IR ν max(cm -1):3397,2934,2866,1724,1663,1325,1265,1167,1123,1065,849,822,733.HRMS(ESI)m/z calculated for C 27H 25O 3N 3F 3[M+H] +:496.1843,found:496.1847. 1H NMR(400MHz,MeOD)δ:8.13(s,1H),7.92(d,J＝8.0Hz,2H),7.70(d,J＝8.1Hz,2H),6.91(d,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),6.17(s,1H),5.57(q,J＝6.5,5.5Hz,2H),4.66(dd,J＝9.2,5.1Hz,1H),3.70(dd,J＝8.7,5.7Hz,1H),3.49(d,J＝7.0Hz,1H),2.42–2.24(m,1H),2.00–1.73(m,5H),1.67(d,J＝11.0Hz,1H),1.52(s,3H). 13C NMR(101MHz,MeOD)δ:205.03,155.85,154.53,147.03,144.21,135.54,134.07,131.35,131.02,130.70,130.38,126.96,126.91,126.87,126.83,124.70,124.25,124.01,121.57,118.13,114.64,75.66,65.22,51.02,50.15,47.79,45.77,38.28,21.96,11.66.
化合物C 45的制备：
制备方法同化合物C 40，将苯乙炔改成4-甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C 45，29.7mg，三步总收率42％。熔点:154-156℃。
IR ν max(cm -1):3404,2931,2865,1723,1642,1601,1453,1264,1183,1081,1054,820,519.HRMS(ESI)m/z calculated for C 27H 28O 3N 3[M+H] +:442.2125,found:442.2126. 1H NMR(400MHz,MeOD)δ:7.90(s,1H),7.60(d,J＝8.0Hz,2H),7.21(d,J＝7.9Hz,2H),6.90(d,J＝8.0Hz,1H),6.68(d,J＝8.0Hz,1H),6.17(s,1H),5.67–5.49(m,2H),4.60(dd,J＝14.1,8.9Hz,1H),3.67(dd,J＝8.9,5.4Hz,1H),3.48(d,J＝7.0Hz,1H),2.30-2.35(s,4H),1.85(ddt,J＝25.4,9.6,5.8Hz,4H),1.66(d,J＝11.1Hz,1H),1.49(s,3H). 13C NMR(100MHz,MeOD)δ:205.04,155.81,154.57,148.65,144.31,139.31,134.05,130.53,128.79,126.59,124.09,123.30,121.51,118.06,114.58,75.64,65.24,51.09,50.04,47.78,45.78,38.28,21.97,21.30,11.62.
化合物C 46的制备：
制备方法同化合物C 40，将苯乙炔改成4-氯苯乙炔，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C 46，28.8mg，三步总收率39％。熔点:162-165℃。
IR ν max(cm -1):3374,2931,2863,1722,1642,1601,1455,1336,1263,1092,1054,820,653,517.HRMS(ESI)m/z calculated for C 26H 25O 3N 3Cl[M+H] +:462.1579,found:462.1581. 1H NMR(400MHz,MeOD)δ:7.98(s,1H),7.70(d,J＝8.4Hz,2H),7.39(d,J＝8.3Hz,2H),6.90(d,J＝8.0Hz,1H),6.68(d,J＝8.0Hz,1H),6.16(s,1H),5.65–5.48(m,2H),4.61(dd,J＝14.1,8.7Hz,1H),3.68(dd,J＝8.7,5.5Hz,1H),3.47(d,J＝7.0Hz,1H),2.32(dt,J＝12.0, 2.7Hz,1H),1.96–1.73(m,4H),1.67(d,J＝11.0Hz,1H),1.51(s,3H). 13C NMR(100MHz,MeOD)δ:205.02,155.81,154.52,147.39,144.22,134.90,134.05,130.41,130.07,128.05,124.02,123.87,121.54,118.10,114.61,79.42,65.19,51.02,50.08,47.77,45.75,38.26,21.96,11.65.
化合物C 47的制备：
制备方法同化合物C 40，将苯乙炔改成4-氟苯乙炔，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C 47，25.6mg，三步总收率36％。熔点:161-163℃。
IR ν max(cm -1):3405,2933,2865,1723,1643,1602,1498,1458,1337,1264,1226,1157,1055,841,815,526.HRMS(ESI)m/z calculated for C 26H 25O 3N 3F[M+H] +:446.1874,found:446.1873. 1H NMR(400MHz,MeOD)δ:7.85(s,1H),7.70–7.56(m,2H),7.03(t,J＝8.7Hz,2H),6.80(d,J＝8.0Hz,1H),6.58(d,J＝8.0Hz,1H),6.06(s,1H),5.67–5.33(m,2H),4.51(dd,J＝14.0,8.7Hz,1H),3.57(dd,J＝8.8,5.5Hz,1H),3.38(d,J＝7.0Hz,1H),3.20(p,J＝1.6Hz,1H),2.22(dt,J＝12.4,2.7Hz,1H),1.82–1.64(m,4H),1.56(d,J＝11.1Hz,1H),1.39(s,3H). 13C NMR(100MHz,MeOD)δ:205.04,165.27,162.82,155.83,154.56,147.65,144.28,134.07,128.63,128.55,128.11,128.08,124.07,123.57,121.54,118.09,116.86,116.64,114.61,75.65,65.24,51.07,50.08,47.78,45.78,38.29,21.97,11.62.
C 56-C 62的制备反应式如下：
Figure PCTCN2019078805-appb-000133
上述制备方法步骤如下：
化合物27的合成：
将化合物20(2.00g，4.54mmol)溶于二氯甲烷(35mL)中，依次加入二氧化硒(252.0mg，2.27mmol)和70％的过氧化叔丁醇水溶液(1.75g，13.62mmol)，室温反应4h，反应结束，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝4:1)得白色固体 即化合物27，1.42g，收率71％。
1H NMR(400MHz,CDCl 3)δ:7.68(d,J＝8.2Hz,2H),7.30(d,J＝8.2Hz,2H),6.65(t,J＝8.5Hz,1H),6.58(t,J＝7.5Hz,1H),4.17–4.08(m,1H),4.04(dd,J＝10.4,3.9Hz,1H),3.17–3.05(m,2H),2.42(s,3H),2.15(dd,J＝12.9,5.1Hz,1H),2.09–1.99(m,2H),1.95(s,3H),1.92–1.86(m,2H),1.58(dtd,J＝17.8,12.7,5.1Hz,2H),1.38–1.25(m,1H),1.23(s,1H),1.05(s,3H). 13C NMR(101MHz,CDCl 3)δ:221.23,153.50,145.16,140.36,136.09,132.46,129.96,127.90,121.51,120.63,114.26,67.86,50.66,50.51,50.12,48.47,48.02,44.20,36.80,25.83,22.57,21.67,19.79,11.90.
化合物28的合成：
将化合物27(1.42g，3.22mmol)和叠氮化钠(627.9mg，9.66mmol)溶于无水的N,N-二甲基甲酰胺(24mL)。在氮气保护下，80℃反应2.5h，反应结束后，加入30mL水，水相用乙酸乙酯(3×65mL)萃取，合并有机相，依次用水(3×15mL)、饱和食盐水(4×20mL)洗，用无水硫酸钠干燥有机相，减压蒸干，粗产品经柱层析(石油醚/乙酸乙酯＝4:1)得白色固体即化合物28，741.1mg。产率为74％。
1H NMR(400MHz,CDCl 3)δ:6.72(d,J＝7.9Hz,1H),6.60(d,J＝7.9Hz,1H),6.05(s,1H),3.54–3.40(m,2H),3.19(dd,J＝12.4,5.2Hz,1H),3.03(t,J＝6.6Hz,1H),2.24-2.19(m,4H),2.12(dd,J＝6.6,2.6Hz,1H),2.09–2.05(m,1H),2.00(dd,J＝11.4,3.6Hz,1H),1.93(d,J＝18.8Hz,1H),1.73–1.58(m,2H),1.36(qd,J＝12.8,5.9Hz,1H),1.12(s,3H). 13C NMR(100MHz,CDCl 3)δ:221.48,153.40,153.37,142.60,136.17,136.13,121.29,121.27,120.66,114.11,50.89,50.83,50.48,50.39,48.75,48.13,44.42,37.01,22.70,19.93,12.19.
化合物C 56的制备：
将化合物28(50mg，0.16mmol)、苯乙炔(32.6mg，0.32mmol)、醋酸铜(48.0mg，0.24mmol)、抗坏血酸钠(63.4mg，0.32mmol)、水(2mL)和四氢呋喃(8mL)混合，反应12h，反应结束，加入8mL水，用乙酸乙酯(3×24mL)萃取，合并有机相，依次用水(6mL)、饱和食盐水(2×10mL)洗，用无水硫酸钠干燥，减压蒸干，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 56，46.4mg，收率70％，熔点:151-154℃。
IR ν max(cm -1):3367,2925,2867,1736,1599,1458,1361,1265,1054,972,912,817,765,729,695.HRMS(ESI)m/z calculated for C 26H 28O 2N 3[M+H] +:414.2176,found:414.2177. 1H NMR(400MHz,CDCl 3)δ:7.73(dd,J＝7.1,1.7Hz,2H),7.43-7.35(m,3H),7.33-7.29(m,1H),7.23(s,1H),6.72(s,2H),4.70(dd,J＝14.0,6.9Hz,1H),4.45(dd,J＝14.0,6.3Hz,1H),3.52(t,J＝6.6Hz,1H),2.93(dd,J＝12.2,5.2Hz,1H),2.28-2.01(m,3H),1.95(s,1H),1.90(s, 3H),1.75(d,J＝11.4Hz,1H),1.57(ddt,J＝25.5,12.8,6.3Hz,2H),1.32(qd,J＝16.0,14.4,4.1Hz,1H),1.02(s,3H). 13C NMR(100MHz,CDCl 3)δ:220.19,153.91,147.87,142.25,135.84,130.18,128.98,128.42,125.83,121.71,121.02,120.71,114.50,51.22,50.89,50.71,49.78,48.66,47.97,43.49,36.86,22.72,19.83,11.83.
化合物C 57的制备：
制备方法同化合物C 56，将苯乙炔改成4-甲氧基苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 57，56.1mg，收率79％。熔点:165-167℃。
IR ν max(cm -1):3383,2925,1738,1661,1617,1562,1500,1457,1362,1250,1175,1031,835,726,534.HRMS(ESI)m/z calculated for C 27H 30O 3N 3[M+H] +:444.2282,found:444.2281. 1H NMR(400MHz,CDCl 3)δ:7.65(d,J＝8.7Hz,2H),7.31(s,1H),7.15(s,1H),6.90(d,J＝8.8Hz,2H),6.72(s,2H),4.68(dd,J＝14.0,7.0Hz,1H),4.43(dd,J＝14.0,6.3Hz,1H),3.80(s,3H),3.51(t,J＝6.6Hz,1H),2.93(dd,J＝12.7,5.6Hz,1H),2.28-2.01(m,3H),1.92(d,J＝20.8Hz,4H),1.74(d,J＝11.3Hz,1H),1.66-1.50(m,2H),1.32(ddd,J＝25.6,12.8,5.6Hz,1H),1.02(s,3H). 13C NMR(100MHz,CDCl 3)δ:220.04,159.77,153.93,147.76,142.35,135.90,127.17,122.96,121.72,121.04,119.89,114.48,114.40,55.43,51.24,50.95,50.70,49.73,48.69,48.01,43.52,36.88,22.74,19.85,11.83.
化合物C 58的制备：
制备方法同化合物C 56，将苯乙炔改成2-乙炔基吡啶，经柱层析(石油醚/乙酸乙酯＝1:1)得白色固体即化合物C 58，40.5mg，收率61％。熔点:142-145℃。
IR ν max(cm -1):3377,2925,2867,1736,1600,1473,1422,1365,1266,1096,1052,911,785,731.HRMS(ESI)m/z calculated for C 25H 27O 2N 4[M+H] +:415.2129,found:415.2130. 1H NMR(400MHz,CDCl 3)δ:8.67–8.40(m,1H),8.33–8.11(m,1H),7.99(s,1H),7.87–7.69(m,2H),7.26–7.21(m,1H),6.71(d,J＝7.9Hz,1H),6.64(d,J＝7.9Hz,1H),4.74(dd,J＝14.1,7.6Hz,1H),4.49(dd,J＝14.1,5.3Hz,1H),3.54(dd,J＝7.6,5.4Hz,1H),3.02–2.91(m,1H),2.26–2.06(m,3H),1.99(s,3H),1.91(d,J＝18.8Hz,1H),1.70(d,J＝11.4Hz,1H),1.65–1.48(m,2H),1.34(qd,J＝12.7,5.9Hz,1H),1.00(s,3H). 13C NMR(100MHz,CDCl 3)δ:219.73,154.13,149.88,149.15,147.97,142.10,137.57,135.81,123.26,123.02,121.71,121.02,120.72,114.56,51.20,51.10,50.70,49.75,48.81,48.05,43.56,36.87,22.76,19.87,11.99。
化合物C 59的制备：
制备方法同化合物C 56，将苯乙炔改成4-三氟甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 59，60.2mg，收率78％。熔点:148-152℃。
IR ν max(cm -1):3412,2927,1736,1622,1458,1326,1166,1124,1064,849,728,598.HRMS(ESI)m/z calculated for C 27H 27O 2N 3F 3[M+H] +:482.2050,found:482.2053. 1H NMR(400MHz,CDCl 3)δ:7.83(d,J＝8.1Hz,2H),7.62(d,J＝8.1Hz,2H),7.43(s,1H),6.82-6.62(m,3H),4.74(dd,J＝14.0,6.8Hz,1H),4.49(dd,J＝14.0,6.4Hz,1H),3.53(t,J＝6.6Hz,1H),2.92(dd,J＝12.2,5.2Hz,1H),2.30-2.03(m,3H),1.94(d,J＝19.6Hz,1H),1.87(s,3H),1.79(d,J＝10.9Hz,1H),1.59(ddt,J＝25.5,12.8,6.3Hz,2H),1.33(qd,J＝12.8,5.7Hz,1H),1.04(s,3H). 13C NMR(100MHz,CDCl 3)δ:220.07,153.79,146.56,142.23,136.05,133.70,130.68,130.36,130.04,129.71,126.00,125.97,125.92,125.46,122.76,121.67,121.44,121.15,114.53,51.30,50.92,50.78,49.93,48.68,48.05,43.56,36.88,22.73,19.83,11.80.
化合物C 60的制备：
制备方法同化合物C 56，将苯乙炔改成4-甲基苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 60，52.0mg，收率76％。熔点:156-158℃。
IR ν max(cm -1):3374,2925,2867,1736,1599,1499,1456,1361,1266,1223,1054,910,818,727,518.HRMS(ESI)m/z calculated for C 27H 30O 2N 3[M+H] +:428.2333,found:428.2333. 1H NMR(400MHz,CDCl 3)δ:7.63(d,J＝7.9Hz,2H),7.37(s,1H),7.19(d,J＝7.9Hz,2H),6.72(s,2H),4.69(dd,J＝14.0,7.0Hz,1H),4.44(dd,J＝14.0,6.3Hz,1H),3.52(t,J＝6.6Hz,1H),2.93(dd,J＝12.2,5.2Hz,1H),2.35(s,3H),2.25–1.98(m,4H),1.96(d,J＝10.1Hz,1H),1.90(s,3H),1.74(d,J＝11.3Hz,1H),1.58(dtd,J＝17.8,12.8,5.1Hz,2H),1.43–1.24(m,1H),1.02(s,3H). 13C NMR(100MHz,CDCl 3)δ:220.14,153.91,147.95,142.29,138.31,135.86,129.65,127.37,125.75,121.70,121.01,120.35,114.49,51.23,50.92,50.70,49.75,48.68,47.98,43.50,36.87,22.73,21.36,19.84,11.82.
化合物C 61的制备：
制备方法同化合物C 56，将苯乙炔改成4-氯苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 61，53.8mg，收率75％。熔点:153-156℃。IR ν max(cm -1):3397,2925,2868,1735,1600,1484,1456,1361,1266,1093,1054,973,835,730,517.HRMS(ESI)m/z calculated for C 26H 27O 2N 3Cl[M+H] +:448.1786,found:448.1788. 1H NMR(400MHz,CDCl 3)δ:7.78-7.56(m,2H),7.38-7.31(m,3H),6.86(s,1H),6.79-6.60(m,2H),4.71(dd,J＝14.0,6.8Hz,1H),4.45(dd,J＝14.0,6.4Hz,1H),3.51(t,J＝6.6Hz,1H),2.93(dt,J＝12.2,6.2Hz,1H),2.19-2.05(m,3H),1.93(d,J＝18.9Hz,1H),1.86(s,3H),1.77(d,J＝11.3Hz,1H),1.58(ddt,J＝25.5,12.8,6.4Hz,2H),1.43-1.25(m,1H),1.03(s,3H). 13C NMR(100MHz,CDCl 3)δ:220.04,153.79,146.87,142.26,135.99,134.15,129.18,128.75,127.08,121.67, 121.10,120.74,114.50,51.27,50.92,50.74,49.85,48.67,48.03,43.54,36.88,22.73,19.85,11.80.
化合物C 62的制备：
制备方法同化合物C 56，将苯乙炔改成4-氟苯乙炔，经柱层析(石油醚/乙酸乙酯＝3:1)得白色固体即化合物C 62，47.7mg，收率69％。熔点:146-147℃。
IR ν max(cm -1):3393,2926,2868,1736,1599,1561,1498,1458,1362,1266,1224,1157,1097,1054,841,815,728,526.HRMS(ESI)m/z calculated for C 26H 27O 2N 3F[M+H] +:432.2082,found:432.2084. 1H NMR(400MHz,CDCl 3)δ:7.78-7.55(m,2H),7.33(s,1H),7.06(t,J＝8.6Hz,2H),6.85(s,1H),6.79-6.61(m,2H),4.72(dd,J＝14.0,6.9Hz,1H),4.46(dd,J＝14.0,6.4Hz,1H),3.52(t,J＝6.6Hz,1H),2.99-2.90(m,1H),2.29-2.01(m,3H),1.94(d,J＝19.0Hz,1H),1.88(s,3H),1.77(d,J＝11.3Hz,1H),1.59(ddt,J＝25.4,12.8,6.3Hz,2H),1.41-1.22(m,1H),1.03(s,3H). 13C NMR(101MHz,CDCl 3)δ:220.01,164.02,161.56,153.81,147.08,142.31,136.01,127.65,127.57,126.51,126.48,121.67,121.10,120.42,116.09,115.87,114.49,51.28,50.95,50.75,49.82,48.69,48.05,43.56,36.89,22.75,19.86,11.81.
效果实施例
本发明的活性测试采用了MTS的检测方法，MTS为MTT类似物，全称为3-(4，5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium。此方法通过活细胞线粒体中琥珀酸脱氢酶能够代谢还原MTS，生成可溶性的甲臜(Formazan)化合物，该化合物的光密度OD(490nM)值与活细胞数目成正比，通过光密度OD的测定值来衡量化合物的抗肿瘤活性。本发明挑选五种肿瘤细胞：HL-60,A549,SMMC-7721,MCF-7和SW480进行实验，检测以顺铂和紫杉醇作为阳性对照。化合物的IC 50值通过浓度效应生长曲线计算确定。
MTS具体的检测方法参照(该文献的内容通过引用的方式并入本文)：
[1]D.K.Kim,D.H.Ryu,J.Y.Lee,N.Lee,Y.W.Kim,J.S.Kim,K.Chang,G.J.Im,T.K.Kim and W.S.Choi,Journal of medicinal chemistry,2001,44,1594-1602；
[2]R.Cao,Q.Chen,X.Hou,H.Chen,H.Guan,Y.Ma,W.Peng and A.Xu,Bioorganic & medicinal chemistry,2004,12,4613-4623。
部分化合物按照MTT方法进行了白血病、肝癌、肺癌、乳腺癌和结肠癌5种细胞株的抗肿瘤细胞毒活性筛选，其半数抑制剂量(IC 50值，μM)测定结果与已商品化的抗癌药物——顺铂(DDP)和紫杉醇相比较于下表1和表2中。
表1 化合物C 1-C 32,C 36,B 1,B 2的细胞毒活性数据
Figure PCTCN2019078805-appb-000134
Figure PCTCN2019078805-appb-000135
表2 化合物C 33-C 62,B 3的细胞毒活性数据
Figure PCTCN2019078805-appb-000136
Figure PCTCN2019078805-appb-000137
以上活性数据显示化合物C 21，C 28，C 30，C 31具有一般的体外细胞毒活性。化合物C 33，C 34，C 35，C 37，C 38，C 39对乳腺癌细胞(MCF-7)具有显著的体外细胞毒活性。化合物C 40，C 41，C 42，C 43，C 44，C 45，C 46，C 47对结肠癌细胞(SW480)具有显著的体外细胞毒活性。化合物C 45，C 46，C 47具有广谱的体外抗癌细胞毒活性。
化合物B 1、B 2和B 3的结构如下所示：
Figure PCTCN2019078805-appb-000138
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (20)

  1. 一种如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物：
    Figure PCTCN2019078805-appb-100001
    其中，R 1为H或卤素；
    R 2为H、OH或OTs；
    R 3为甲基；
    Figure PCTCN2019078805-appb-100002
    代表单键或双键；
    R 6为H或O；
    当
    Figure PCTCN2019078805-appb-100003
    中
    Figure PCTCN2019078805-appb-100004
    代表单键时，R 6为H；
    当
    Figure PCTCN2019078805-appb-100005
    中
    Figure PCTCN2019078805-appb-100006
    代表双键时，R 6为O；
    当
    Figure PCTCN2019078805-appb-100007
    中
    Figure PCTCN2019078805-appb-100008
    代表单键时，R 4为H；
    R 5为取代或未取代的C 6-C 20的芳基，或取代或未取代的C 2-C 20的杂芳基；所述取代或未取代的C 6-C 20的芳基，和取代或未取代的C 2-C 20的杂芳基中的取代基为
    Figure PCTCN2019078805-appb-100009
    其中X选自C，N，S或O；R为H、卤素、C 1-C 6的烷基、卤素取代的C 1-C 6的烷基，或C 1-C 6的烷氧基；n为1-5的整数；
    当
    Figure PCTCN2019078805-appb-100010
    中
    Figure PCTCN2019078805-appb-100011
    代表双键，R 4为O，
    Figure PCTCN2019078805-appb-100012
    中
    Figure PCTCN2019078805-appb-100013
    代表单键，R 6为H时，R 5为C 2-C 6的烷氧基或苄氧基；
    当
    Figure PCTCN2019078805-appb-100014
    中
    Figure PCTCN2019078805-appb-100015
    代表双键，R 4为O，
    Figure PCTCN2019078805-appb-100016
    中
    Figure PCTCN2019078805-appb-100017
    代表双键，R 6为O时，R 5为C 1-C 6的烷氧基或苄氧基；
    R 7为CH 2或O；
    R 8为OH、C 1-C 6的烷基或C 1-C 6的烷氧基；
    且所述式I所示的化合物不为如下所示任一化合物：
    Figure PCTCN2019078805-appb-100018
  2. 如权利要求1所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，其特征在于，其中，
    所述取代或未取代的C 6-C 20的芳基为取代或未取代的C 6-C 10的芳基；
    和/或，所述取代或未取代的C 2-C 20的杂芳基为含有一个或多个芳杂环，杂原子为N、S或O；所述杂原子的个数为1个或多个的杂芳基；
    和/或，所述卤素为氟、氯、溴或碘；
    和/或，所述C 1-C 6的烷基为C 1-C 4的烷基；
    和/或，所述卤素取代的C 1-C 6的烷基中的卤素取代基的个数为一个或多个；
    和/或，所述C 1-C 6的烷氧基为C 1-C 4的烷氧基；
    和/或，当
    Figure PCTCN2019078805-appb-100019
    中
    Figure PCTCN2019078805-appb-100020
    代表双键，所述R 4为O，
    Figure PCTCN2019078805-appb-100021
    中
    Figure PCTCN2019078805-appb-100022
    代表单键，所述R 6为H时，所述R 5为C 2-C 6的烷氧基；
    当
    Figure PCTCN2019078805-appb-100023
    中
    Figure PCTCN2019078805-appb-100024
    代表双键，所述R 4为O，
    Figure PCTCN2019078805-appb-100025
    中
    Figure PCTCN2019078805-appb-100026
    代表双键，所述R 6为O时，所述R 5为C 1-C 6的烷氧基；
    和/或，所述
    Figure PCTCN2019078805-appb-100027
    中，所述n为1；
    和/或，所述R 8为OH或C 1-C 6的烷氧基时，所述
    Figure PCTCN2019078805-appb-100028
    为
    Figure PCTCN2019078805-appb-100029
    所述R 8为C 1-C 6的烷基时，所述
    Figure PCTCN2019078805-appb-100030
    为
    Figure PCTCN2019078805-appb-100031
  3. 如权利要求1或2所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，其特征在于，其中，
    所述取代或未取代的C 6-C 20的芳基为取代或未取代的苯基，或取代或未取代的萘基；
    和/或，所述取代或未取代的C 2-C 20的杂芳基为含有一个芳杂环，杂原子为氮，所述杂原子的个数为1-3个的取代或未取代的C 2-C 10的杂芳基，或者所述取代或未取代的C 2-C 20的杂芳基为含有2个环的稠合芳杂基；
    和/或，所述C 1-C 6的烷基为甲基，乙基，丙基，异丙基或正丁基；
    和/或，所述卤素取代的C 1-C 6的烷基中的卤素取代基的个数为一个或多个；所述卤素为氟；
    和/或，所述
    Figure PCTCN2019078805-appb-100032
    为
    Figure PCTCN2019078805-appb-100033
    和/或，所述C 1-C 6的烷氧基为甲氧基，乙氧基或丙氧基；
    和/或，所述
    Figure PCTCN2019078805-appb-100034
    为
    Figure PCTCN2019078805-appb-100035
  4. 如权利要求1～3中至少一项所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，其特征在于，所述
    Figure PCTCN2019078805-appb-100036
    为
    Figure PCTCN2019078805-appb-100037
    Figure PCTCN2019078805-appb-100038
    其中，所述
    Figure PCTCN2019078805-appb-100039
    为
    Figure PCTCN2019078805-appb-100040
    所述
    Figure PCTCN2019078805-appb-100041
    为
    Figure PCTCN2019078805-appb-100042
    所述
    Figure PCTCN2019078805-appb-100043
    为
    Figure PCTCN2019078805-appb-100044
  5. 如权利要求1～4中至少一项所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，其特征在于，如式I所示的类赤霉素化合物化合物选自如下式II、式III、式IV或式V所示的化合物中的任一种：
    Figure PCTCN2019078805-appb-100045
    其中，R 9、R 10和R 11各自独立地为
    Figure PCTCN2019078805-appb-100046
    Figure PCTCN2019078805-appb-100047
    R 13、R 14、R 15、R 16、R 17、R 18和R 19各自独立地为H或
    Figure PCTCN2019078805-appb-100048
    R 20和R 21各自独立地为H、
    Figure PCTCN2019078805-appb-100049
    或甲基；
    R 12为C 1-C 6的烷基；其他基团的定义如权利要求1-4中至少一项所述。
  6. 如权利要求5所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，其特征在于，如式II、式III、式IV或式V所示的化合物中，所述R 9、R 10和R 11各自独立地为
    Figure PCTCN2019078805-appb-100050
    较佳地，所述
    Figure PCTCN2019078805-appb-100051
    为
    Figure PCTCN2019078805-appb-100052
  7. 如权利要求5或6所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍 生物，其特征在于，如式II所示的化合物中，
    当所述R 1为卤素时，所述R为卤素，或者卤素取代的C 1-C 6的烷基；
    当所述R 1为H时，所述R为卤素取代的C 1-C 6的烷基；
    和/或，所述R 2为OH。
  8. 如权利要求5或6所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，其特征在于，所述的如式III所示的化合物中，
    所述R 1为氢或卤素；
    和/或，所述R 2为OH或OTs。
  9. 如权利要求5、6或8中至少一项所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，其特征在于，所述的如式III所示的化合物中，
    所述R 2为OH或OTs；所述R 1氢；所述R 10为
    Figure PCTCN2019078805-appb-100053
    Figure PCTCN2019078805-appb-100054
    较佳地，所述
    Figure PCTCN2019078805-appb-100055
    为
    Figure PCTCN2019078805-appb-100056
  10. 如权利要求5或6所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，其特征在于，所述式IV所示的化合物中，
    所述R 1为氢；
    和/或，所述R 2为OH或OTs。
  11. 如权利要求5、6或10中至少一项所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，其特征在于，所述式IV所示的化合物中，
    所述R 2为OH或OTs；所述R 1氢；所述R 11为
    Figure PCTCN2019078805-appb-100057
  12. 如权利要求5或6所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，其特征在于，所述式V所示的化合物中，
    所述R 1为卤素、OH或OTs；
    和/或，所述R 12为甲基。
  13. 如权利要求5～12中至少一项所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，其特征在于，所述如式II所示的化合物结构为：
    Figure PCTCN2019078805-appb-100058
    所述的式III所示的化合物结构为：
    Figure PCTCN2019078805-appb-100059
    所述的式IV所示的化合物结构为：
    Figure PCTCN2019078805-appb-100060
  14. 如权利要求1～13中至少一项所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，其特征在于，所述的如式I所示的类赤霉素化合物选自下列任一化合物：
    Figure PCTCN2019078805-appb-100061
    Figure PCTCN2019078805-appb-100062
    Figure PCTCN2019078805-appb-100063
    Figure PCTCN2019078805-appb-100064
  15. 一种如式I所示的类赤霉素化合物的制备方法，其包括以下步骤：
    方法1：在铜的催化作用下，将式VI所示的化合物式VII所示的化合物进行环加成反应，即可；
    Figure PCTCN2019078805-appb-100065
    或方法2：
    Figure PCTCN2019078805-appb-100066
    各取代基定义均如权利要求1-14中至少一项所述。
  16. 一种药物组合物，其特征在于，其包括治疗有效量的如权利要求1-14中至少一项所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物，和一种或多种药学上可接受的载体或赋形剂。
  17. 一种如权利要求1-14中至少一项所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物在制备治疗和/或预防抗肿瘤药物中的应用。
  18. 如权利要求17所述的应用，其中，所述抗肿瘤药物为抗乳腺癌药物和/或抗肠癌药物。
  19. 如下所示的如式I所示类赤霉素化合物的中间体：
    Figure PCTCN2019078805-appb-100067
    Figure PCTCN2019078805-appb-100068
  20. 一种治疗肿瘤疾病的方法，所述的方法包括给予需要其的个体治疗有效量的如权利要求1～14中至少一项所述的如式I所示的类赤霉素化合物、其互变异构体、光学异构体、水合物、溶剂化物、多晶型物、药学上可接受的盐、药学上可接受的前体药物或衍生物。
PCT/CN2019/078805 2018-03-29 2019-03-20 类赤霉素化合物、其制备方法、药物组合物及应用及其中间体 WO2019184772A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810273045.4 2018-03-29
CN201810273045.4A CN110317179B (zh) 2018-03-29 2018-03-29 类赤霉素化合物、其制备方法、药物组合物及应用及其中间体

Publications (1)

Publication Number Publication Date
WO2019184772A1 true WO2019184772A1 (zh) 2019-10-03

Family

ID=68059274

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/078805 WO2019184772A1 (zh) 2018-03-29 2019-03-20 类赤霉素化合物、其制备方法、药物组合物及应用及其中间体

Country Status (2)

Country Link
CN (1) CN110317179B (zh)
WO (1) WO2019184772A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1560044A (zh) * 2004-02-27 2005-01-05 云南大学 3,15-二羰基赤霉酸类化合物及其酯和盐
CN101068764A (zh) * 2004-11-01 2007-11-07 默克公司 雌激素受体调节剂
CN102108075A (zh) * 2009-12-28 2011-06-29 中国药科大学 由赤霉素ga3合成新颖衍生物的合成方法及其应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010062372A2 (en) * 2008-11-03 2010-06-03 President And Fellows Of Harvard College Methods for modulating nf-kb using gibberellins
WO2013142873A2 (en) * 2012-03-23 2013-09-26 The Board Of Trustees Of The University Of Illinois Complex and structurally diverse compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1560044A (zh) * 2004-02-27 2005-01-05 云南大学 3,15-二羰基赤霉酸类化合物及其酯和盐
CN101068764A (zh) * 2004-11-01 2007-11-07 默克公司 雌激素受体调节剂
CN102108075A (zh) * 2009-12-28 2011-06-29 中国药科大学 由赤霉素ga3合成新颖衍生物的合成方法及其应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANNAND, J. R.: "Synthesis and biological evaluation of pharbinilic Chemi- cal Communications", CHEMICAL COMMUNICATIONS, 21 April 2015 (2015-04-21), XP055639943, ISSN: 1359-7345 *
WU, MINGJIANG ET AL.: "Synthesis and anti-proliferative activity of allogibberic acid derivatives containing 1, 2, 3-triazole pharmacophore", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 18 May 2018 (2018-05-18), ISSN: 0960-894X *

Also Published As

Publication number Publication date
CN110317179A (zh) 2019-10-11
CN110317179B (zh) 2023-01-24

Similar Documents

Publication Publication Date Title
JP5676656B2 (ja) 重水素化ω−ジフェニル尿素の合成及び生産の方法並びにプロセス
EP3305769B1 (en) Method for preparation of (7-phenoxy-4-hydroxy-1-methyl-isoquinoline-3-carbonyl)-glycine (roxedustat) and its intermediates based on simultaneous opening of oxazolic ring, fission of ether and creation of imine
KR102266680B1 (ko) 벨리노스테트의 다형태 및 이의 제조 방법
WO1996032384A1 (fr) Nouveaux derives 4,6-diarylpyrimidine et leurs sels
WO2023088441A1 (zh) Kif18a抑制剂
CA2690337A1 (fr) Derives de 7-alkynyl-1,8-naphthyridones, leur preparation et leur application en therapeutique
WO2019184772A1 (zh) 类赤霉素化合物、其制备方法、药物组合物及应用及其中间体
CN110511197B (zh) 一种n-呋喃酮基芳基磺酰腙类化合物及其合成方法和应用
EP0842924B1 (en) Pyridine intermediates, useful in the synthesis of beta-adrenergic receptor agonists
JPH07242670A (ja) ピロロ［３，２−ｅ］ピラゾロ［１，５−ａ］ピリミジン誘導体及びこれを含有する循環器系疾患治療剤
CN110172062B (zh) 一种单氟代螺环化合物的合成方法及其中间体
JP7553927B2 (ja) ビリベルジン又はその誘導体の製造方法
JPH0533230B2 (zh)
FR2479194A1 (fr) Nouveau derive d'alcool benzylique, procede pour le preparer et application a des compositions pharmaceutiques
JP3432880B2 (ja) 光学活性アザスピロ化合物の製法
JPS5910358B2 (ja) 新規エルゴリン誘導体
JP2564141B2 (ja) アルキルベンゾチアゾール類の製造方法
JP2662607B2 (ja) ビシクロ［８．３．０］トリデカ―９，１３―ジエン―２，７―ジイン誘導体
JP3495774B2 (ja) １−ヒドロキシインドール類の製法
CN116514708A (zh) 一种吡啶-酰胺类化合物及其制备方法与应用
CN115925720A (zh) 喹啉并环丁烷类化合物及其合成方法
KR20230072437A (ko) 아이속사졸 유도체의 제조 방법 및 그의 중간체
WO2011078302A1 (ja) Ｎ－アルキル－β－バリエナミン類縁体の製造方法
WO2014136807A1 (ja) 細胞死抑制剤及び新規化合物
JPS6019755B2 (ja) ウラシル誘導体の製法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19775290

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19775290

Country of ref document: EP

Kind code of ref document: A1