WO2021244199A1 - 一种β-内酰胺化合物、其用途及其制备方法 - Google Patents

一种β-内酰胺化合物、其用途及其制备方法 Download PDF

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WO2021244199A1
WO2021244199A1 PCT/CN2021/091320 CN2021091320W WO2021244199A1 WO 2021244199 A1 WO2021244199 A1 WO 2021244199A1 CN 2021091320 W CN2021091320 W CN 2021091320W WO 2021244199 A1 WO2021244199 A1 WO 2021244199A1
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compound
group
general formula
formula
linear
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PCT/CN2021/091320
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English (en)
French (fr)
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宋丹青
唐胜
游雪甫
李志文
汪燕翔
卢曦
李迎红
胡辛欣
郭志浩
王秀坤
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中国医学科学院医药生物技术研究所
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Priority to EP21818212.9A priority Critical patent/EP4159733A4/en
Priority to US18/000,444 priority patent/US20230227444A1/en
Priority to JP2022574453A priority patent/JP2023527917A/ja
Publication of WO2021244199A1 publication Critical patent/WO2021244199A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a novel ⁇ -lactam compound and a preparation method thereof.
  • the ⁇ -lactam compound has good antibacterial properties against bacteria, especially gram-negative bacteria, and has extremely low drug resistance, and is suitable for preparing antibacterial agents with excellent performance.
  • ⁇ -lactams such as aztreonam represented by the following formula
  • aztreonam represented by the following formula
  • the antibacterial activity of aztreonam against some bacteria, especially gram-negative bacteria is not ideal.
  • the synthesis and research of aztreonam derivatives have appeared one after another.
  • the following patent documents 1 to 3 disclose related derivatives of aztreonam.
  • the currently obtained aztreonam derivatives still have great room for improvement in terms of drug resistance.
  • Patent Document 1 CN106164072A
  • Patent Document 2 US4816582A
  • Patent Document 3 International Publication No. WO2017/050218A1
  • the technical problem of the present invention is to provide a novel ⁇ -lactam compound with low drug resistance against gram-negative bacteria and excellent antibacterial activity, its use and a preparation method thereof.
  • the present invention is as follows.
  • R 1 and R 2 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group optionally having substituents, or both together form a ring with a carbon number of 3-8 Cycloalkyl;
  • R 3 and R 4 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group optionally having a substituent, a C6-12 aryl group optionally having a substituent, or both Together to form a cycloalkyl group with a carbon number of 3 to 8;
  • X represents C or N;
  • Y represents a linear or branched alkenyl or alkynyl group with a carbon number of 2 to 6 optionally substituted, or a carboxyl group .
  • R 1 , R 2 , R 3 , R 4 , and X are as defined above.
  • R 1 , R 2 , R 3 , and R 4 are as defined above.
  • R 5 represents an alkenyl or alkynyl group having 3 to 7 carbon atoms that may have a substituent
  • X is as defined above.
  • R 5 has the same definition as above.
  • the compound represented by the formula (3) is produced by reacting the compound represented by the following formula (1) with the compound represented by the formula (2);
  • PG represents a protecting group
  • R 1 and R 2 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group optionally having substituents, or the two together form a ring with a carbon number of 3 to 8 cycloalkyl
  • R 3 and R 4 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group that may have a substituent, and a C6-12 aryl group that may have a substituent , Or the two together form a cycloalkyl group with a ring carbon number of 3-8
  • X represents C or N
  • Y represents an optionally substituted linear or branched alkenyl or alkyne with a carbon number of 2-6 Group, or carboxyl group
  • Step b
  • the compound represented by the general formula (I) is prepared by reacting the above formula (3) with trifluoroacetic acid and triethylsilane to remove the protective group,
  • R 1 , R 2 , R 3 , R 4 , X, and Y are as defined above.
  • R 1 and R 2 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group optionally having substituents, or both together form a ring with a carbon number of 3-8 Cycloalkyl;
  • R 3 and R 4 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group optionally having a substituent, a C6-12 aryl group optionally having a substituent, or both Together to form a cycloalkyl group with a carbon number of 3 to 8;
  • X represents C or N;
  • Y represents a linear or branched alkenyl or alkynyl group with a carbon number of 2 to 6 optionally substituted, or a carboxyl group .
  • the compounds of the present invention are effective against gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter cloacae, Enterobacter aerogenes, Salmonella typhi, mucilage Serratia, Citronella freudenii, Prufeidenobacter regius, Proteus vulgaris, Proteus mirabilis, Pseudomonas maltophilus, Shigella flexneri, etc. have excellent antibacterial activity, and Low drug resistance.
  • gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter cloacae, Enterobacter aerogenes, Salmonella typhi, mucilage Serratia, Citronella freudenii, Prufeideno
  • Halogen or "halo” can be fluorine, chlorine, bromine or iodine
  • C1 ⁇ X (e.g. C1-10) alkyl group means a straight or branched chain alkyl group having 1 to X (e.g. 1-10) carbon atoms; examples include methyl, ethyl, propyl, iso Propyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, butyl, tert-butyl, pentyl and hexyl, etc., which can be interpreted as including C1,
  • the alkyl groups of various morphological structures including C2, C3, C4, C5, C6, C7, C8, ... CX (e.g., C10) are not limited to the examples listed above;
  • alkyl groups refer to various possible groups including straight or branched chains, such as butyl, including n-butyl, isobutyl, and tert-butyl.
  • C3-X (e.g. C3-8) cycloalkyl means a cycloalkyl group having 3 to X (e.g. 3-8) ring-forming carbon atoms; examples include cyclopropyl, cyclobutyl, and cyclopentyl , Cyclohexyl, cycloheptyl, etc., which can be interpreted as cycloalkyls of various morphological structures including C3, C4, C5, C6, ... CX (such as C8), and are not limited to the above-listed examples;
  • C6-X (e.g. C6-12) aryl group means an aryl group having 6 to X (e.g. 6-12) carbon atoms; it can be interpreted as including C6, C7, C8, ... CX (e.g. C12)
  • the aryl groups in the various morphological structures are not limited to the examples listed above;
  • C2-X (e.g. C2-6) alkenyl group means a straight or branched chain alkenyl group having 2 to X (e.g. 2-6) carbon atoms; it can be interpreted as including C2, C3, ... CX(
  • the alkenyl groups of various morphological structures including C6) are not limited to the examples listed above;
  • C2 ⁇ X (e.g. C2 ⁇ 6) alkynyl group means a straight or branched chain alkynyl group having 2 to X (e.g. 2-6) carbon atoms; it can be interpreted as including C2, C3, ... CX(
  • the alkynyl groups of various morphological structures including C6) are not limited to the examples listed above;
  • Carboxy refers to the group -COOH
  • the substituents in the present invention are selected from C1-C6 alkoxy groups optionally having one or more halogen atoms, C1-C6 alkyl groups optionally having one or more halogen atoms, and C1-C6 alkyl groups optionally having one or more halogen atoms.
  • optical isomers and geometric isomers when there are optical isomers and geometric isomers in the compound of the present invention, it includes all isomer classes.
  • R 1 and R 2 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group optionally having substituents, or both together form a ring with a carbon number of 3-8 Cycloalkyl;
  • R 3 and R 4 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group optionally having a substituent, a C6-12 aryl group optionally having a substituent, or both Together to form a cycloalkyl group with a carbon number of 3 to 8;
  • X represents C or N;
  • Y represents a linear or branched alkenyl or alkynyl group with a carbon number of 2 to 6 optionally substituted, or a carboxyl group .
  • R 1 and R 2 each independently represent:
  • R 3 and R 4 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group that may have a substituent, a C6-12 aryl group that may have a substituent, or the two together form a ring Cycloalkyl having 3 to 8 carbon atoms; preferably represents a hydrogen atom, a C1 to 6 linear or branched alkyl group optionally having substituents, or both together form a cycloalkane having 3 to 6 carbon atoms More preferably, it represents a hydrogen atom, a C1-6 linear or branched alkyl group optionally having substituents, or the two together form a cycloalkyl group having 3 to 6 ring carbon atoms; particularly preferably each is a hydrogen atom , Isopropyl group, or both together form a cycloalkyl group having 3 to 6 ring carbon atoms.
  • Y represents a linear or branched alkenyl or alkynyl group with 2-6 carbons, or a carboxyl group, optionally substituted; preferably a linear or branched chain with 2 to 4 carbons, optionally substituted
  • An alkenyl or alkynyl group, or a carboxyl group particularly preferably represents a vinyl group optionally having a substituent, or an ethynyl group optionally having a substituent, or a carboxyl group.
  • Examples of the form of the compound of the present invention include the following.
  • R 1 , R 2 , R 3 , R 4 , and X are as defined above.
  • Y represents a compound having an alkenyl or alkynyl group having 2 to 6 carbon atoms, which is represented by the following general formula (I-2) Compound:
  • R 5 represents an alkenyl or alkynyl group having 3 to 7 carbon atoms that may have a substituent
  • X is as defined above.
  • R 1 and R 2 each independently represent a hydrogen atom, a methyl group or an ethyl group, ring A represents a cycloalkyl group having 3 to 6 ring carbon atoms, and X represents C or N.
  • R 1 and R 2 each independently represent a hydrogen atom, a methyl group, or an ethyl group
  • R 3 represents an ethyl group, an isopropyl group, a phenyl group, or the number of ring carbon atoms is 3 to 6.
  • X represents C or N.
  • ring A represents a cycloalkyl group having 3 to 6 ring carbon atoms
  • ring B represents a cycloalkyl group having 3 to 6 ring carbon atoms
  • X represents C or N.
  • R 1 and R 2 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group optionally having substituents, or both together form a ring with a carbon number of 3-8 Cycloalkyl;
  • R 3 and R 4 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group optionally having a substituent, a C6-12 aryl group optionally having a substituent, or both Together, they form a cycloalkyl group having 3 to 8 ring carbon atoms.
  • R 5 represents an alkenyl or alkynyl group having 3 to 7 carbon atoms which may have a substituent.
  • the compound represented by the formula (3) is produced by reacting the compound represented by the following formula (1) with the compound represented by the formula (2);
  • PG represents a protecting group
  • R 1 and R 2 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group optionally having substituents, or the two together form a cycloalkyl group having 3 to 8 ring carbon atoms;
  • R 3 , R 4 each independently represents a hydrogen atom, a C1-10 linear or branched alkyl group that may have a substituent, a C6-12 aryl group that may have a substituent, or both together form a ring carbon number Is a cycloalkyl group of 3 to 8;
  • X represents C or N;
  • Y represents an optionally substituted linear or branched alkenyl or alkynyl group with a carbon number of 2-6, or a carboxyl group;
  • Step b
  • the compound represented by the general formula (I) is prepared by reacting the above formula (3) with trifluoroacetic acid and triethylsilane to remove the protective group,
  • R 1 , R 2 , R 3 , R 4 , X, and Y are as defined above.
  • R 1 and R 2 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group optionally having substituents, or the two together form a ring with 3 to 8 carbon atoms Alkyl;
  • R 3 and R 4 each independently represent a hydrogen atom, a C1-10 linear or branched alkyl group that may have a substituent, a C6-12 aryl group that may have a substituent, or both together
  • a cycloalkyl group having 3 to 8 ring carbon atoms is formed;
  • PG1 and PG2 represent protecting groups.
  • step 1a compound 7a is dissolved in a solvent, triethylamine is added, triphenylchloromethane is added in batches, and the reaction is carried out at room temperature. After the reaction is complete, intermediate compound 7b is obtained.
  • organic solvent used in the reaction of step 1a above for example, dichloromethane, chloroform, toluene, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, methanol, ethanol, isopropanol, and their mixture.
  • step 1b compound 7b is dissolved in 1,4-dioxane/water (50:50), sodium hydroxide is added, and the reaction is continued with stirring until the raw material disappears.
  • the 1,4-dioxane was distilled off under reduced pressure, the pH was adjusted to 2-3, stirred, filtered, and the filter cake was washed with water until the filtrate was neutral, and the filter cake was collected and dried to obtain compound 7c.
  • step 1 disperse compound 1, diphenyl bromide in an organic solvent, and stir at room temperature, add DBU (1,8-diazabicyclo-undec-7-ene ), the temperature is raised to 70-80°C, and the reaction is stirred until the raw material no longer decreases, and then the temperature is lowered to room temperature.
  • the reaction solution was extracted, the organic phases were combined, dried, and concentrated to obtain a residue, which was separated by column chromatography to obtain compound 2.
  • organic solvent used in the reaction of the said step for example, dichloromethane, toluene, tetrahydrofuran, N,N-dimethylformamide, etc. can be mentioned.
  • step 2 disperse compound 2 and diphenylphosphohydroxyl amide in an organic solvent, exhaust nitrogen for 3-4 times, stir at 0°C, then add sodium tert-butoxide, and stir at constant temperature to react until When the reactant is completely converted, a saturated sodium chloride solution is added to the reaction solution, stirred and filtered to remove insoluble matter, to obtain compound 3.
  • organic solvent used in the reaction of the said step 2 for example, dichloromethane, toluene, tetrahydrofuran, N,N-dimethylformamide, etc. can be mentioned.
  • step 3 compound 7c is dispersed in an organic solvent, and the methanol solution of compound 3 is added under stirring at room temperature, and the reaction is stirred at constant temperature until the conversion of the raw materials is complete, and compound 4 is obtained by column chromatography.
  • Examples of the organic solvent used in the reaction of the above step 3 include methanol, ethanol, isopropanol, N,N-dimethylformamide, and the like.
  • step 4 compound 4 is dispersed in an organic solvent, and HATU (2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate), NaHCO 3 , compound 8, and the reaction is stirred at room temperature until the conversion of the raw materials is complete, and compound 5 is obtained by column chromatography.
  • step 5 dissolve compound 5 in an organic solvent, stir at -5 ⁇ -10°C, add triethylsilane and trifluoroacetic acid to it, react at a constant temperature until the reaction is complete, and evaporate at room temperature under reduced pressure. The solvent is removed, and the target product, that is, the compound represented by the general formula (A), is isolated.
  • organic solvent used in the reaction of the above step 5 for example, anhydrous dichloromethane, toluene, tetrahydrofuran, N,N-dimethylformamide, and the like can be cited.
  • R 5 represents an alkenyl or alkynyl group having 3 to 7 carbon atoms which may have a substituent
  • PG2 represents a protecting group
  • step 1 above compound 7 is dissolved in an organic solvent, triethylamine is added, triphenylchloromethane is added in batches, and the reaction is stirred at room temperature until the reaction is complete, followed by extraction, drying and concentration to obtain compound 8.
  • Examples of the organic solvent used in the reaction of the above step 1 include dichloromethane, toluene, tetrahydrofuran, N,N-dimethylformamide, and the like.
  • step 2 compound 8 is dissolved in an organic solvent, K 2 CO 3 is added, allyl bromide is added, and the reaction is stirred at room temperature until the reaction is complete, and then extracted, dried and concentrated to obtain compound 9.
  • organic solvent used in the reaction of the said step 2 for example, dichloromethane, toluene, tetrahydrofuran, N,N-dimethylformamide, etc. can be mentioned.
  • step 3 dissolve compound 9 in 1,4-dioxane/water (50:50), stir at room temperature, add sodium hydroxide, continue to stir the reaction until the raw material disappears, and evaporate under reduced pressure. 1,4-dioxane is extracted, the pH is adjusted to 2-3, stirred, filtered, and washed with water until the filtrate is neutral to obtain compound 10.
  • step 4 compound 10 is dispersed in an organic solvent, and HATU (2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea Hexafluorophosphate), NaHCO 3 , and compound 8, and the reaction is stirred at room temperature until the conversion of the raw materials is complete, and compound 11 is obtained by column chromatography.
  • step 5 dissolve compound 11 in an organic solvent, stir at -5 ⁇ -10°C, add triethylsilane and trifluoroacetic acid to it, react at a constant temperature until the reaction is complete, and evaporate at room temperature under reduced pressure. The solvent is removed, and the target product, that is, the compound represented by the general formula (B), is isolated.
  • organic solvent used in the reaction of the above step 5 for example, anhydrous dichloromethane, toluene, tetrahydrofuran, N,N-dimethylformamide, and the like can be cited.
  • R 1 to R 4 in the general formula (I) are all hydrogen atoms, Y is a carboxyl group, and X is a C atom;
  • R 1 to R 4 in the general formula (I) are all methyl groups, Y is a carboxyl group, and X is a C atom;
  • R 1 and R 2 in the general formula (I) are both methyl groups, R 3 is a hydrogen atom, R 4 is a butyl group, Y is a carboxyl group, and X is a C atom;
  • R 1 and R 2 are both methyl groups, R 3 and R 4 are both pentyl groups, Y is a carboxyl group, and X is a compound with a C atom;
  • R 1 and R 2 in the general formula (I) are both methyl, R 3 and R 4 together form a cyclopropyl group, Y is a carboxyl group, and X is a C atom;
  • R 1 and R 2 are both methyl groups, R 3 and R 4 together form a cyclobutyl group, Y is a carboxyl group, and X is a compound with a C atom;
  • R 1 and R 2 are both methyl, R 3 and R 4 together form a cyclopentyl group, Y is a carboxyl group, and X is a compound with a C atom;
  • R 1 and R 2 in the general formula (I) are both methyl, R 3 and R 4 together form a cyclohexyl group, Y is a carboxyl group, and X is a C atom;
  • R 1 and R 2 are both methyl, R 3 and R 4 together form a cycloheptyl group, Y is a carboxyl group, and X is a compound with a C atom;
  • R 1 and R 2 in the general formula (I) are both methyl, R 3 and R 4 together form a cyclooctyl group, Y is a carboxyl group, and X is a C atom;
  • R 1 and R 2 are both methyl groups, R 3 is an ethyl group, R 4 is a hydrogen atom, Y is a carboxyl group, and X is a compound of a C atom;
  • R 1 and R 2 are both methyl groups, R 3 is an isopropyl group, R 4 is a hydrogen atom, Y is a carboxyl group, and X is a compound of a C atom;
  • R 1 and R 2 in the general formula (I) are both methyl groups, R 3 is a phenyl group, R 4 is a hydrogen atom, Y is a carboxyl group, and X is a C atom;
  • R 1 and R 2 are both methyl groups, R 3 is a cyclopropyl group, R 4 is a hydrogen atom, Y is a carboxyl group, and X is a compound of a C atom;
  • R 1 and R 2 are both methyl groups, R 3 is a cyclobutyl group, R 4 is a hydrogen atom, Y is a carboxyl group, and X is a compound of a C atom;
  • R 1 and R 2 are both methyl groups, R 3 is a cyclopentyl group, R 4 is a hydrogen atom, Y is a carboxyl group, and X is a compound of a C atom;
  • R 1 and R 2 are both methyl groups, R 3 is a cyclohexyl group, R 4 is a hydrogen atom, Y is a carboxyl group, and X is a compound of a C atom;
  • R 1 is a hydrogen atom
  • R 2 is an ethyl group
  • R 3 and R 4 together form a cyclopropyl group
  • Y is a carboxyl group
  • X is a compound of a C atom
  • R 1 is a hydrogen atom
  • R 2 is an ethyl group
  • R 3 and R 4 together form a cyclobutyl group
  • Y is a carboxyl group
  • X is a compound of a C atom
  • R 1 is a hydrogen atom
  • R 2 is an ethyl group
  • R 3 and R 4 together form a cyclopentyl group
  • Y is a carboxyl group
  • X is a compound of a C atom
  • R 1 is a hydrogen atom
  • R 2 is an ethyl group
  • R 3 and R 4 together form a cyclohexyl group
  • Y is a carboxyl group
  • X is a compound of a C atom
  • R 1 and R 2 in the general formula (I) are both ethyl, R 3 and R 4 together form a cyclopropyl group, Y is a carboxyl group, and X is a C atom;
  • R 1 and R 2 in the general formula (I) are both ethyl, R 3 and R 4 together form a cyclobutyl group, Y is a carboxyl group, and X is a C atom;
  • R 1 and R 2 in the general formula (I) are both ethyl, R 3 and R 4 together form a cyclopentyl group, Y is a carboxyl group, and X is a C atom;
  • R 1 and R 2 in the general formula (I) are both ethyl, R 3 and R 4 together form a cyclohexyl group, Y is a carboxyl group, and X is a C atom;
  • R 1 and R 2 in the general formula (I) are both methyl, R 3 and R 4 together form a cyclopropyl group, Y is a carboxyl group, and X is a N atom;
  • R 1 and R 2 are both methyl groups, R 3 and R 4 together form a cyclobutyl group, Y is a carboxyl group, and X is a compound with a N atom;
  • R 1 and R 2 in the general formula (I) are both methyl groups, R 3 and R 4 together form a cyclopentyl group, Y is a carboxyl group, and X is a N atom;
  • R 1 and R 2 in the general formula (I) are both methyl groups, R 3 and R 4 together form a cyclohexyl group, Y is a carboxyl group, and X is a N atom;
  • R 1 and R 2 in the general formula (I) are both ethyl, R 3 and R 4 together form a cyclopropyl group, Y is a carboxyl group, and X is a N atom;
  • R 1 and R 2 are both ethyl, R 3 and R 4 together form a cyclobutyl compound, Y is a carboxyl group, and X is a compound of N atom;
  • R 1 and R 2 in the general formula (I) are both ethyl, R 3 and R 4 together form a cyclopentyl group, Y is a carboxyl group, and X is a N atom;
  • R 1 and R 2 in the general formula (I) are both ethyl, R 3 and R 4 together form a cyclohexyl group, Y is a carboxyl group, and X is a N atom;
  • R 5 in the general formula (I-2) is an allyl group and X is a C atom;
  • R 5 in the general formula (I-2) is propargyl and X is a C atom;
  • R 5 in the general formula (I-2) is an enbutyl group and X is a C atom;
  • R 5 in the general formula (I-2) is alkynyl butyl group and X is a C atom;
  • R 5 in the general formula (I-2) is an allyl group and X is a N atom;
  • R 5 in the general formula (I-2) is propargyl and X is a N atom;
  • R 5 in the general formula (I-2) is an enbutyl group and X is a N atom;
  • R 5 in the general formula (I-2) is an alkynyl butyl group and X is a N atom;
  • the compound of the present invention is not limited to each compound example listed above.
  • the "pharmaceutically acceptable salt” of the present invention refers to a salt that ensures the biological effectiveness of the compound of the present invention itself, and typically does not have adverse biological or other properties.
  • the compounds of the present invention can form acid and/or base salts through the presence of amino and/or carboxyl or similar groups.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • Inorganic bases that can form inorganic salts with the compound of the present invention include, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonia, and the like.
  • Examples of the inorganic acid that can form an inorganic salt with the compound of the present invention include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • the organic base that can form an organic salt with the compound of the present invention includes, for example, primary amine, secondary amine, tertiary amine, ethylenediamine, propylenediamine, butanediamine, benzylamine, phenethylamine and the like.
  • organic acids examples include formic acid, acetic acid, propionic acid, oxalic acid, citric acid, and benzoic acid.
  • Step 1a Dissolve compound 7a (1.0mmol) in DMF (10.0v/g), add triethylamine (2.0mmol), add triphenylchloromethane (1.2mmol) in batches, and stir at room temperature to react After 6 hours, TLC monitoring, after the completion of the reaction, water/ethyl acetate was added for extraction, the organic phases were combined, dried and concentrated, and the target compound 7b was separated by column chromatography.
  • Step 1b Dissolve compound 7b (1.0mmol) in 1,4-dioxane (5v/g)/water (5v/g), stir at room temperature, add sodium hydroxide (5.0mmol), Continue to stir the reaction, monitor by TLC, the raw materials disappear, distill 1,4-dioxane under reduced pressure, adjust the pH to 2-3, stir for 10 minutes, filter, wash the filter cake until the filtrate is neutral, collect and dry filter Cake to obtain compound 7c.
  • Step 2 Disperse compound 2a (1.0mmol) and diphenylphosphoramide (1.1mmol) in anhydrous tetrahydrofuran solution (10.0v/g), and purge 3-4 times with nitrogen at 0°C Stir, then add sodium tert-butoxide (1.5mmol), stir at constant temperature and react for 1-2 hours, monitored by TLC, the reactant conversion is complete, add saturated sodium chloride solution (5.0v/g) to the reaction solution, stir for 30 minutes , Filter out the insoluble matter, wash the filter cake with ethyl acetate, add ethyl acetate (10.0v/g), water (5.0v/g) to the filtrate, separate the layers, wash the organic phase with water once, combine the aqueous phase, and ethyl acetate Backwash the aqueous phase, combine the organic phases, dry, and concentrate to obtain the oil 3a[ 1 H NMR(600MHz,DMSO) ⁇ (ppm)7.46–7.27(m,10
  • Step 3 Compound 7c was dispersed in methanol (10.0v/g), and the methanol solution of compound 3a was added under stirring at room temperature, and the reaction was stirred at constant temperature for 30 minutes. TLC monitored, the conversion of the raw materials was complete, and the solvent was evaporated under reduced pressure.
  • the off-white solid compound 4a [ 1 H NMR (600MHz, DMSO) ⁇ (ppm) 8.84 (s, 1H), 7.51-7.15 (m, 25H), 6.86 (s, 2H), 1.48-1.28 ( m,4H)].
  • Step 4 Dissolve compound 4a (1.0mmol) in DMF (10.0v/g), stir at room temperature, add HATU (1.2mmol), NaHCO 3 (2.0mmol), compound 8 (1.3mmol), continue The reaction was stirred at a constant temperature for 12 hours, and the reaction was monitored until the raw materials disappeared.
  • Step 5 Dissolve the above white solid 5a (1.0mmol) in anhydrous dichloromethane (10.0v/g), stir at -5 ⁇ -10°C, and add triethylsilane (2.0mmol) to it And trifluoroacetic acid (100.0 mmol), react at constant temperature for 5-6 hours, monitored by TLC until the reaction is complete, distill off the solvent under reduced pressure at room temperature, add ethyl acetate to the residue, stir at room temperature for 1 hour, filter, and filter with ethyl acetate Cake 3 times, collect the filter cake, dry, dissolve the above solid in methanol/water, pre-HPLC (YMC ODS-A, 5um, 10*250mm, 2.5mL/min, 2%-50% acetonitrile/0.1% formic acid Water) preparation and separation to obtain the target product (A-1).
  • YMC ODS-A 5um, 10*250mm, 2.5mL/min, 2%-50% acetonitrile/0.1% formic acid Water
  • Step 1 Combine compound 1c (1.0mmol), diphenylbromomethane (1.1mmol) were dispersed in the toluene solution (10.0v/g), and stirred at room temperature, DBU (1.5mmol) was added, the temperature was raised to 70-80°C, and the reaction was stirred for 12-16 After hours, TLC monitors that the raw materials no longer decrease, cool to room temperature, add water (10.0v/g ⁇ 2) to extract the reaction solution, ethyl acetate (10v/g ⁇ 2) backwash the water layer, combine the organic phases, dry, and concentrate The residue was obtained, and column chromatography was separated to obtain a transparent oily compound 2c (post-curing) [ 1 H NMR (600MHz, DMSO) ⁇ (ppm) 7.45-7.24 (m, 10H), 6.80 (s, 1H), 5.27 (s, 1H), 2.03–1.91(m,2H), 1.79–1.63(m,6H)].
  • Step 2 Disperse compound 2c (1.0mmol) and diphenylphosphoramide (1.1mmol) in anhydrous tetrahydrofuran solution (10.0v/g), exhaust nitrogen 3-4 times, stir at 0°C, and then add Sodium tert-butoxide (1.5mmol), stirred at constant temperature for 1-2 hours, monitored by TLC, the conversion of the reactants was complete, added saturated sodium chloride solution (5.0v/g) to the reaction solution, stirred for 30 minutes, filtered to remove insoluble Wash the filter cake with ethyl acetate, add ethyl acetate (10.0v/g), water (5.0v/g) to the filtrate, separate the layers, wash the organic phase once with water, combine the aqueous phase, and backwash the aqueous phase with ethyl acetate , The organic phases were combined, dried, and concentrated to obtain the oil 3c, which was directly used in the next reaction without further purification.
  • Step 3 Disperse compound 7c in methanol (10.0v/g), add the methanol solution of compound 3c under stirring at room temperature, stir at constant temperature and react for 30 minutes, monitor by TLC, the conversion of raw materials is complete, the solvent is evaporated under reduced pressure, and column chromatography is separated The off-white solid compound 4c[ 1 H NMR (600MHz, DMSO) ⁇ (ppm) 8.86 (s, 1H), 7.50-7.17 (m, 25H), 6.80 (s, 1H), 6.78 (s, 1H), 2.11 –1.94(m,4H),1.69–1.68(d,4H)].
  • Step 4 Dissolve compound 4c (1.0mmol) in DMF (10.0v/g), stir at room temperature, add HATU (1.2mmol), NaHCO 3 (2.0mmol), compound 8 (1.3mmol), and continue to stir at constant temperature for reaction 12 After hours, monitor the reaction until the raw material disappears.
  • Step 5 Dissolve the above white solid 5c (1.0mmol) in anhydrous dichloromethane (10.0v/g), stir at -5 ⁇ -10°C, add triethylsilane (2.0mmol) and trifluoroacetic acid to it (100.0 mmol), react at constant temperature for 5-6 hours, TLC monitors until the reaction is complete, the solvent is evaporated under reduced pressure at room temperature, ethyl acetate is added to the residue, stirred at room temperature for 1 hour, filtered, and the filter cake is washed with ethyl acetate 3 times.
  • Step 2 Disperse compound 2d (1.0mmol) and diphenylphosphohydroxylamide (1.1mmol) in anhydrous tetrahydrofuran solution (10.0v/g), exhaust nitrogen for 3-4 times, stir at 0°C, and then add Sodium tert-butoxide (1.5mmol), stirred at constant temperature for 1-2 hours, monitored by TLC, the conversion of the reactants was complete, added saturated sodium chloride solution (5.0v/g) to the reaction solution, stirred for 30 minutes, filtered to remove insoluble Wash the filter cake with ethyl acetate, add ethyl acetate (10.0v/g), water (5.0v/g) to the filtrate, separate the layers, wash the organic phase once with water, combine the aqueous phase, and backwash the aqueous phase with ethyl acetate , Combine the organic phases, dry and concentrate to obtain an oil 3d[ –59.0(c 0.10,MeOH); 1 H NMR(600MHz,CDCl 3 ) ⁇
  • Step 3 Disperse compound 7c in methanol (10.0v/g), add the methanol solution of compound 3d under stirring at room temperature, stir at constant temperature for 30 minutes, monitor by TLC, the conversion of the raw materials is complete, the solvent is evaporated under reduced pressure, and separated by column chromatography
  • Step 4 Dissolve compound 4d (1.0mmol) in DMF (10.0v/g), stir at room temperature, add HATU (1.2mmol), NaHCO 3 (2.0mmol), compound 8 (1.3mmol), and continue to stir at constant temperature for reaction 12 After hours, monitor the reaction until the raw material disappears. Add ethyl acetate (10.0v/g) to dilute, wash twice with water, and backwash with ethyl acetate once, combine the organic phases, dry, concentrate, and separate by column chromatography to obtain an off-white foamy solid compound 5d, which is directly used in the next reaction .
  • Step 5 Dissolve the above white solid 5d (1.0mmol) in anhydrous dichloromethane (10.0v/g), stir at -5 ⁇ -10°C, add triethylsilane (2.0mmol) and trifluoroacetic acid to it (100.0 mmol), react at constant temperature for 5-6 hours, TLC monitors until the reaction is complete, the solvent is evaporated under reduced pressure at room temperature, ethyl acetate is added to the residue, stirred at room temperature for 1 hour, filtered, and the filter cake is washed with ethyl acetate 3 times.
  • Step 2 Disperse compound 2e (1.0mmol) and diphenylphosphoramide (1.1mmol) in anhydrous tetrahydrofuran solution (10.0v/g), exhaust nitrogen for 3-4 times, stir at 0°C, and then add Sodium tert-butoxide (1.5mmol), stirred at constant temperature for 1-2 hours, monitored by TLC, the conversion of the reactants was complete, added saturated sodium chloride solution (5.0v/g) to the reaction solution, stirred for 30 minutes, filtered to remove insoluble Wash the filter cake with ethyl acetate, add ethyl acetate (10.0v/g), water (5.0v/g) to the filtrate, separate the layers, wash the organic phase once with water, combine the aqueous phase, and backwash the aqueous phase with ethyl acetate , The organic phases were combined, dried, and concentrated to obtain an oil 3e[ 1 H NMR(600MHz,DMSO) ⁇ (ppm)7.43–7.40(m,4
  • Step 4 Dissolve compound 4e (1.0mmol) in DMF (10.0v/g), stir at room temperature, add HATU (1.2mmol), NaHCO 3 (2.0mmol), compound 8 (1.3mmol), and continue to stir at constant temperature for reaction 12 After hours, monitor the reaction until the raw material disappears. Add ethyl acetate (10.0v/g) to dilute, wash twice with water, backwash with ethyl acetate once, combine the organic phases, dry, concentrate, and separate by column chromatography to obtain the off-white foamy solid compound 5e, which is directly used in the next reaction .
  • Step 5 Dissolve the above white solid 5e (1.0mmol) in anhydrous dichloromethane (10.0v/g), stir at -5 ⁇ -10°C, add triethylsilane (2.0mmol) and trifluoroacetic acid to it (100.0 mmol), react at constant temperature for 5-6 hours, TLC monitors until the reaction is complete, the solvent is evaporated under reduced pressure at room temperature, ethyl acetate is added to the residue, stirred at room temperature for 1 hour, filtered, and the filter cake is washed 3 times with ethyl acetate.
  • Step 3 Disperse compound 7c in methanol (10.0v/g), add the methanol solution of compound 3a under stirring at room temperature, stir at constant temperature and react for 30 minutes, monitor by TLC, the conversion of raw materials is complete, the solvent is evaporated under reduced pressure, and column chromatography is separated The off-white solid compound 4e[ 1 H NMR (600MHz, DMSO) ⁇ (ppm) 8.84 (s, 1H), 7.51-7.15 (m, 25H), 6.86 (s, 2H), 1.48-1.28 (m, 4H) ].
  • Step 4 Dissolve compound 4e (1.0mmol) in DMF (10.0v/g), stir at room temperature, add HATU (1.2mmol), NaHCO 3 (2.0mmol), compound 8 (1.3mmol), and continue to stir at constant temperature for reaction 12 After hours, monitor the reaction until the raw material disappears.
  • Step 5 Dissolve the above white solid 5e (1.0mmol) in anhydrous dichloromethane (10.0v/g), stir at -5 ⁇ -10°C, add triethylsilane (2.0mmol) and trifluoroacetic acid to it (100.0 mmol), react at constant temperature for 5-6 hours, TLC monitors until the reaction is complete, the solvent is evaporated under reduced pressure at room temperature, ethyl acetate is added to the residue, stirred at room temperature for 1 hour, filtered, and the filter cake is washed with ethyl acetate 3 times.
  • Step 1 Combine compound 1g (1.0mmol), diphenylbromomethane (1.1mmol) were dispersed in toluene solution (10.0v/g), and stirred at room temperature, DBU (1.5mmol) was added, the temperature was raised to 70-80°C, and the reaction was stirred for 12-16 After hours, TLC monitors that the raw materials no longer decrease, cool to room temperature, add water (10.0v/g ⁇ 2) to extract the reaction solution, ethyl acetate (10v/g ⁇ 2) backwash the water layer, combine the organic phases, dry, and concentrate The residue was obtained, which was separated by column chromatography to obtain 2 g of a transparent oily compound (post-solidification).
  • Step 2 Disperse 2g (1.0mmol) of compound and diphenylphosphohydroxylamide (1.1mmol) in anhydrous tetrahydrofuran solution (10.0v/g), exhaust nitrogen for 3-4 times, stir at 0°C, and then add Sodium tert-butoxide (1.5mmol), stirred at constant temperature for 1-2 hours, monitored by TLC, the conversion of the reactants was complete, added saturated sodium chloride solution (5.0v/g) to the reaction solution, stirred for 30 minutes, filtered to remove insoluble Wash the filter cake with ethyl acetate, add ethyl acetate (10.0v/g), water (5.0v/g) to the filtrate, separate the layers, wash the organic phase once with water, combine the aqueous phase, and backwash the aqueous phase with ethyl acetate , The organic phases were combined, dried, and concentrated to obtain 3 g of oil, which was directly used in the next reaction without further purification.
  • Step 3 Disperse compound 7c in methanol (10.0v/g), add compound 3g methanol solution under stirring at room temperature, stir at constant temperature and react for 30 minutes, TLC monitoring, the conversion of raw materials is complete, and the solvent is evaporated under reduced pressure to obtain an off-white solid Compound 4g crude product. Directly used in the next reaction
  • Step 4 Dissolve compound 4g (1.0mmol) in DMF (10.0v/g), stir at room temperature, add HATU (1.2mmol), NaHCO 3 (2.0mmol), compound 8 (1.3mmol), and continue to stir at constant temperature for reaction 12 After hours, monitor the reaction until the raw material disappears. Add ethyl acetate (10.0v/g) to dilute, wash twice with water, and backwash once with ethyl acetate, combine the organic phases, dry and concentrate to obtain 5 g crude product of off-white foamy solid compound. Used directly in the next reaction.
  • Step 5 Dissolve 5g (1.0mmol) of the above white solid in anhydrous dichloromethane (10.0v/g), stir at -5 ⁇ -10°C, add triethylsilane (2.0mmol) and trifluoroacetic acid to it (100.0 mmol), react at constant temperature for 5-6 hours, TLC monitors until the reaction is complete, the solvent is evaporated under reduced pressure at room temperature, ethyl acetate is added to the residue, stirred at room temperature for 1 hour, filtered, and the filter cake is washed with ethyl acetate 3 times.
  • Step 1 Dissolve compound 7 (1.0mmol) in DMF (10.0v/g), add triethylamine (2.0mmol), add triphenylchloromethane (1.2mmol) in batches, and stir at room temperature to react After 6 hours, monitored by TLC, after the reaction was completed, water/ethyl acetate was added for extraction, the organic phases were combined, dried and concentrated to obtain the crude target compound 8a.
  • Step 2 Dissolve compound 8a (1.0mmol) in DMF (10.0v/g), add K 2 CO 3 (2.0mmol), add allyl bromide (1.2mmol), and stir at room temperature to react for 6 hours , Monitored by TLC, after the reaction was completed, water/ethyl acetate was added for extraction, the organic phases were combined, dried and concentrated to obtain the crude target compound 9a.
  • Step 3 Dissolve compound 9a (1.0mmol) in 1,4-dioxane (5v/g)/water (5v/g), stir at room temperature, add sodium hydroxide (5.0mmol), Continue to stir the reaction, monitor by TLC, the raw materials disappear, distill 1,4-dioxane under reduced pressure, adjust the pH to 2-3, stir for 10 minutes, filter, wash the filter cake until the filtrate is neutral, collect and dry filter Cake to obtain compound 10a.
  • Step 4 Dissolve compound 10a (1.0mmol) in DMF (10.0v/g), stir at room temperature, add HATU (1.2mmol), NaHCO 3 (2.0mmol), compound 8 (1.3mmol), continue to keep constant temperature The reaction was stirred for 12 hours, and the reaction was monitored until the raw materials disappeared. Add ethyl acetate (10.0v/g) to dilute, wash twice with water, backwash with ethyl acetate once, combine the organic phases, dry and concentrate to obtain the off-white foamy solid compound 11a. Used directly in the next reaction.
  • Step 5 Dissolve the above white solid 11a (1.0mmol) in anhydrous dichloromethane (10.0v/g), stir at -5 ⁇ -10°C, and add triethylsilane (2.0mmol) to it And trifluoroacetic acid (100.0 mmol), react at constant temperature for 5-6 hours, monitored by TLC until the reaction is complete, distill off the solvent under reduced pressure at room temperature, add ethyl acetate to the residue, stir at room temperature for 1 hour, filter, and filter with ethyl acetate Cake 3 times, collect the filter cake, dry, dissolve the above solid in methanol/water, pre-HPLC (YMC ODS-A, 5um, 10*250mm, 2.5mL/min, 2%-50% acetonitrile/0.1% formic acid Water) preparation and separation to obtain the target product (B-1).
  • YMC ODS-A 5um, 10*250mm, 2.5mL/min, 2%-50% acetonitrile/0.1% formic acid Water
  • this study used the plate agar double dilution method and the Denlay Multipoint Inoculator A400 for the antibacterial activity determination test, and used the hydrolyzed casein peptone (Mueller-Hinton agar) broth and brain heart infusion Amplify test strains.
  • the strains used in this study were purchased from ATCC and clinically isolated bacterial strains from Chinese hospitals, and aztreonam, polymyxin or levofloxacin were used as positive controls.
  • ESBLs in the table means ⁇ -lactamase
  • NDM-1 means type I New Delhi metal ⁇ -lactamase
  • CRE means carbapenem-resistant enterobacteria
  • (+) means the presence of such resistance
  • (+) means that there is no such resistance; if there is no record under the resistance, it means that the bacteria are not restricted to show resistance through specific enzymes.
  • the ⁇ -lactam compound of the present invention has a low minimal inhibitory concentration against bacteria, especially gram-negative bacteria, and has antibacterial properties. Excellent and extremely low drug resistance, suitable for the preparation of antibacterial agents with excellent performance.
  • the ⁇ -lactam compound of the present invention is suitable for preparing antibacterial agents with excellent antibacterial properties and extremely low drug resistance.

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Abstract

本发明涉及一种下述通式(I)所示化合物，其对于细菌、尤其是革兰阴性菌具有很好的抗菌性，且耐药性低，具有有效治疗多种病症的良好前景(式(I)中，R1、R2各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基，或者两者一起形成成环碳数为3至8的环烷基；R3、R4各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基、任选具有取代基的C6～12的芳基，或者两者一起形成成环碳数为3至8的环烷基；X表示C或者N；Y表示任选具有取代基的碳数为2～6的直链或支链的烯基或炔基，或者羧基。)。

Description

一种β-内酰胺化合物、其用途及其制备方法 技术领域
本发明涉及一种新型的β-内酰胺化合物及其制备方法。该β-内酰胺化合物对于细菌、尤其是革兰阴性菌具有很好的抗菌性，且耐药性极低，适于制备性能优异的抗菌剂。
背景技术
目前为止，已经开发出了多种抗菌剂，例如β-内酰胺类，氨基糖苷类、四环素类、氟喹诺酮类、糖肽类、大环内酯类等。其中，β-内酰胺类、例如下述式所示的氨曲南因其抗菌谱广，抗菌活性强、对β-内酰胺酶等稳定以及毒性低等特点，已经成为治疗严重细菌感染最主要的抗菌药物之一。然而氨曲南对部分菌类、尤其是革兰氏阴性菌的抗菌活性不甚理想，针对于此，相继出现氨曲南衍生物的合成与研究。例如以下专利文献1～3中公开了氨曲南的相关衍生物。但是，目前获得的氨曲南衍生物在耐药性方面仍然存在极大的改善空间。
Figure PCTCN2021091320-appb-000001
现有技术文献
专利文献
专利文献1：CN106164072A
专利文献2：US4816582A
专利文献3：国际公开第WO2017/050218A1号
发明内容
发明要解决的问题
本发明的技术问题在于，提供一种针对革兰氏阴性菌的耐药性低、抗菌活性优异的新型的β-内酰胺化合物、其用途及其制备方法。
用于解决问题的技术手段
本发明如下所示。
[1]一种通式(I)所示化合物或其药学上可接受的盐：
Figure PCTCN2021091320-appb-000002
式(I)中，R 1、R 2各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基，或者两者一起形成成环碳数为3至8的环烷基；R 3、R 4各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基、任选具有取代基的C6～12的芳基，或者两者一起形成成环碳数为3至8的环烷基；X表示C或者N；Y表示任选具有取代基的碳数为2～6的直链或支链的烯基或炔基，或者羧基。
[2]根据[1]所述的化合物或其药学上可接受的盐，所述化合物如下述通式(I-1)所示：
Figure PCTCN2021091320-appb-000003
式(I-1)中，R 1、R 2、R 3、R 4、X的定义同上。
[3]根据[1]或[2]所述的化合物或其药学上可接受的盐，所述化合物如下述通式(A)所示：
Figure PCTCN2021091320-appb-000004
式(A)中，R 1、R 2、R 3、R 4的定义同上。
[4]根据[1]～[3]中任一项所述的化合物或其药学上可接受的盐，其中，R 3和R 4一起形成成环碳数为3至8的环烷基。
[5]根据[1]～[4]中任一项所述的化合物或其药学上可接受的盐，其中，R 1和R 2一起形成成环碳数为3至8的环烷基。
[6]根据[1]～[4]中任一项所述的化合物或其药学上可接受的盐，所述化合物为下述化合物：
Figure PCTCN2021091320-appb-000005
[7]根据[1]所述的化合物或其药学上可接受的盐，所述化合物如下述通式(I-2)所示：
Figure PCTCN2021091320-appb-000006
式(I-2)中，R 5表示任选具有取代基的碳数为3～7的烯基或炔基、X的定义同上。
[8]根据[7]所述的化合物或其药学上可接受的盐，所述化合物如下述通式(B)所示：
Figure PCTCN2021091320-appb-000007
式(B)中，R 5的定义同上。
[9]根据[8]所述的化合物或其药学上可接受的盐，所述化合物为选自下述的化合物：
Figure PCTCN2021091320-appb-000008
[10]一种通式(I)所示化合物的制备方法，其包括：
步骤a：
通过下述式(1)所示化合物和式(2)所示化合物反应生成式(3)所示的化合物；
Figure PCTCN2021091320-appb-000009
上述各式中，PG表示保护基；R 1、R 2各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基，或者两者一起形成成环碳数为3至8的环烷基；R 3、R 4各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基、任选具有取代基的C6～12的芳基，或者两者一起形成成环碳数为3至8的环烷基；X表示C或者N；Y表示任选具有取代基的碳数为2～6的直链或支链的烯基或炔基，或者羧基；
步骤b：
通过上述式(3)和三氟乙酸及三乙基硅烷反应脱去保护基而制备通式(I) 所示化合物，
Figure PCTCN2021091320-appb-000010
式(I)中，R 1、R 2、R 3、R 4、X、Y的定义同上。
[11]一种通式(I)所示化合物在制备革兰氏阴性菌的抗菌剂中的用途，
Figure PCTCN2021091320-appb-000011
式(I)中，R 1、R 2各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基，或者两者一起形成成环碳数为3至8的环烷基；R 3、R 4各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基、任选具有取代基的C6～12的芳基，或者两者一起形成成环碳数为3至8的环烷基；X表示C或者N；Y表示任选具有取代基的碳数为2～6的直链或支链的烯基或炔基，或者羧基。
发明的效果
本发明化合物对于对于革兰氏阴性菌、诸如大肠埃希菌、肺炎克雷伯杆菌、铜绿假单胞菌、鲍曼不动杆菌、阴沟肠杆菌、产气肠杆菌、伤寒沙门菌、粘质沙雷氏菌、弗劳地枸橼酸菌、雷极普鲁菲登杆菌、普通变形杆菌、奇异变形杆菌、嗜麦芽假单胞菌、福氏志贺菌等具有优异的抗菌活性优异，且耐药性低。
具体实施方式
首先，对本发明中的一些表述做以说明。
“任选具有取代基”的含义包括：在一个或多个位置上被其后列出的基团中的任意一个或任意组合所取代；
“卤素”或“卤代”可以是氟、氯、溴或碘；
“C1～X(例如C1～10)烷基”表示具有1～X(例如1～10)个碳原子的直链或支链烷基；可列举出例如甲基、乙基、丙基、异丙基、1,1-二甲基丙基、1,2-二甲基丙基、1-乙基丙基、丁基、叔丁基、戊基及己基等，其可以解释为包括C1、C2、C3、C4、C5、C6、C7、C8、...CX(例如C10)在内的各个形态结构的烷基，并不限定于上述列举的例子；
上述各个形态的烷基是指包括直链或支链的各种可能基团，例如丁基，包括正丁基、异丁基、叔丁基。
“C3～X(例如C3～8)环烷基”表示具有3～X(例如3～8)个成环碳原子的环烷基；可列举出例如环丙基、环丁基、环戊基、环己基及环庚基等，其可以解释为包括C3、C4、C5、C6、...CX(例如C8)在内的各个形态结构的环烷基，并不限定于上述列举的例子；
“C6～X(例如C6～12)芳基”表示具有6～X(例如6～12)个碳原子的芳基；其可以解释为包括C6、C7、C8、...CX(例如C12)在内的各个形态结构的芳基，并不限定于上述列举的例子；
“C2～X(例如C2～6)烯基”表示具有2～X(例如2～6)个碳原子的直链或支链烯基；其可以解释为包括C2、C3、...CX(例如C6)在内的各个形态结构的烯基，并不限定于上述列举的例子；
“C2～X(例如C2～6)炔基”表示具有2～X(例如2～6)个碳原子的直链或支链炔基；其可以解释为包括C2、C3、...CX(例如C6)在内的各个形态结构的炔基，并不限定于上述列举的例子；
“羧基”是指基团-COOH；
本发明中的取代基选自由任选具有1个以上卤素原子的C1-C6烷氧基、任选具有1个以上卤素原子的C1-C6烷基、任选具有1个以上卤素原子的C1-C6烷硫基、硫基、氧基、氰基、羟基、硝基及卤素原子组成的组；
本发明的化合物中存在光学异构体、几何异构体时，其包括所有的异构体类别。
在本发明的一个方面，提供下述通式(I)所示化合物或其药学上可接受的盐：
Figure PCTCN2021091320-appb-000012
式(I)中，R 1、R 2各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基，或者两者一起形成成环碳数为3至8的环烷基；R 3、R 4各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基、任选具有取代基的C6～12的芳基，或者两者一起形成成环碳数为3至8的环烷基；X表示C或者N；Y表示任选具有取代基的碳数为2～6的直链或支链的烯基或炔基，或者羧基。
R 1、R 2各自独立地表示：
氢原子、任选具有取代基的C1～10的直链或支链烷基，或者两者一起形成成环碳数为3至8的环烷基；优选表示任选具有取代基的C1～10的直链或支链烷基；更优选表示任选具有取代基的C1～6的直链或支链烷基；进一步优选表示任选具有取代基的C1～3的直链或支链烷基；特别优选表示甲基；
R 3、R 4各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基、任选具有取代基的C6～12的芳基，或者两者一起形成成环碳数为3至8的环烷基；优选表示氢原子、任选具有取代基的C1～6的直链或支链烷基、或者两者一起形成成环碳数为3至6的环烷基；更优选表示氢原子、任选具有取代基的C1～6的直链或支链烷基、或者两者一起形成成环碳数为3至6的环烷基；特别优选各自为氢原子、异丙基、或者两者一起形成成环碳数为3至6的环烷基。
Y表示任选具有取代基的碳数为2～6的直链或支链的烯基或炔基，或者羧基；优选表示任选具有取代基的碳数为2～4的直链或支链的烯基或炔基，或者羧基；特别优选表示任选具有取代基的乙烯基、或者任选具有取代基的乙炔基、或者羧基。
作为本发明化合物的形态，可列举如下。
〔形态1〕在本发明通式(I)中的Y表示羧基的化合物，即下述通式(I-1)所示的化合物：
Figure PCTCN2021091320-appb-000013
式(I-1)中，R 1、R 2、R 3、R 4、X的定义同上。
〔形态2〕在本发明通式(I)中的Y表示任选具有取代基的碳数为2～6的烯基或炔基的化合物，即下述通式(I-2)所示的化合物：
Figure PCTCN2021091320-appb-000014
式(I-2)中，R 5表示任选具有取代基的碳数为3～7的烯基或炔基、X的定义同上。
〔形态3〕下述通式(I-1-1)所示的化合物：
Figure PCTCN2021091320-appb-000015
式(I-1-1)中，R 1、R 2各自独立地表示氢原子、甲基或乙基，环A表示成环碳数为3至6的环烷基，X表示C或N。
〔形态4〕下述通式(I-1-2)所示的化合物：
Figure PCTCN2021091320-appb-000016
式(I-1-2)中，R 1、R 2各自独立地表示氢原子、甲基或乙基，R 3表示乙基、异丙基、苯基、或成环碳数为3至6的环烷基，X表示C或N。
〔形态5〕下述通式(I-1-3)所示的化合物：
Figure PCTCN2021091320-appb-000017
式(I-1-3)中，环A表示成环碳数为3至6的环烷基，环B表示成环碳数为3至6的环烷基，X表示C或N。
〔形态6〕下述通式(A)所示的化合物：
Figure PCTCN2021091320-appb-000018
式(A)中，R 1、R 2各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基，或者两者一起形成成环碳数为3至8的环烷基；R 3、R 4各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基、任选具有取代基的C6～12的芳基，或者两者一起形成成环碳数为3至8的环烷基。
〔形态7〕下述通式(B)所示的化合物：
Figure PCTCN2021091320-appb-000019
式(B)中，R 5表示任选具有取代基的碳数为3～7的烯基或炔基。
〔形态8〕下述各化合物：
Figure PCTCN2021091320-appb-000020
Figure PCTCN2021091320-appb-000021
Figure PCTCN2021091320-appb-000022
在本发明的另一个方面，提供下述通式(I)所示化合物的制备方法，其包括：
步骤a：
通过下述式(1)所示化合物和式(2)所示化合物反应生成式(3)所示的化合物；
Figure PCTCN2021091320-appb-000023
上述各式中，PG表示保护基；
R 1、R 2各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基，或者两者一起形成成环碳数为3至8的环烷基；R 3、R 4各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基、任选具有取代基的C6～12的芳基，或者两者一起形成成环碳数为3至8的环烷基；X表示C或者N；Y表示任选具有取代基的碳数为2～6的直链或支链的烯基或炔基，或者羧基；
步骤b：
通过上述式(3)和三氟乙酸及三乙基硅烷反应脱去保护基而制备通式(I)所示化合物，
Figure PCTCN2021091320-appb-000024
式(I)中，R 1、R 2、R 3、R 4、X、Y的定义同上。
作为本发明通式(I)所示化合物的制备方法的形态，可列举如下。
〔形态一〕
通式(A)所示化合物的制备方法，其合成路线如下：
Figure PCTCN2021091320-appb-000025
上述各式中，R 1、R 2各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基，或者两者一起形成成环碳数为3至8的环烷基；R 3、R 4各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基、任选具有取代基的C6～12的芳基，或者两者一起形成成环碳数为3至8的环烷基；PG1、PG2表示保护基。
在上述步骤1a(step 1a)中，将化合物7a溶解在溶剂中，并加入三乙胺、分批加入三苯基氯甲烷，在室温下进行反应。反应完全后，获得中间化合物7b。
作为在上述步骤1a的反应中使用的有机溶剂，可列举出例如：二氯甲烷、氯仿、甲苯、四氢呋喃、N,N-二甲基甲酰胺、乙腈、甲醇、乙醇、异丙醇以及它们的混合物。
在上述步骤1b(step 1b)中，将化合物7b溶解在1,4-二氧六环/水(50:50)中，并加入氢氧化钠，继续搅拌反应直至原料消失。减压蒸出1,4-二氧六环，调节pH至2-3，搅拌、过滤，水洗滤饼，至滤液中性，收集并干燥滤饼，得到化合物7c。
在上述步骤1(step 1)中，将化合物1、二苯基溴甲烷分散于有机溶剂中，并于室温下搅拌，加入DBU(1,8-二氮杂二环-十一碳-7-烯)，升温至70-80℃，搅拌反应直至原料不再减少后，降温至室温。萃取反应液，合并有机相，干燥，浓缩得残余物，柱层析分离得化合物2。
作为在上述步骤1的反应中使用的有机溶剂，可列举出例如：二氯甲烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺等。
在上述步骤2(step 2)中，将化合物2、二苯基磷酰羟胺分散于有机溶剂中,氮气抽排3-4次，于0℃搅拌，然后加入叔丁醇钠，恒温搅拌反应直至反应物转化完全，向反应液中加入饱和氯化钠溶液,搅拌并滤除不溶物，得到化合物3。
作为在上述步骤2的反应中使用的有机溶剂，可列举出例如：二氯甲烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺等。
在上述步骤3(step 3)中，将化合物7c分散于有机溶剂中,室温搅拌下，加入化合物3的甲醇溶液，恒温搅拌反应直至原料转化完全，柱层析得到化合物4。
作为在上述步骤3的反应中使用的有机溶剂，可列举出例如：甲醇、乙醇、 异丙醇、N,N-二甲基甲酰胺等。
在上述步骤4(step 4)中，将化合物4分散于有机溶剂中,分别加入HATU(2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯)、NaHCO 3、化合物8，室温搅拌反应直至原料转化完全，柱层析得到化合物5。
作为在上述步骤4的反应中使用的有机溶剂，可列举出例如：二氯甲烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺等。
在上述步骤5(step 5)中，将化合物5溶解于有机溶剂中,于-5～-10℃搅拌，向其中加入三乙基硅烷及三氟乙酸，恒温反应至反应完全，室温减压蒸除溶剂，分离得到目标产物、即通式(A)所示化合物。
作为在上述步骤5的反应中使用的有机溶剂，可列举出例如：无水二氯甲烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺等。
〔形态二〕
通式(B)所示化合物的制备方法，其合成路线如下：
Figure PCTCN2021091320-appb-000026
上述各式中，R 5表示任选具有取代基的碳数为3～7的烯基或炔基，PG2表示 保护基。
在上述步骤1(step 1)中，将化合物7溶于有机溶剂中,加入三乙胺,分批加入三苯基氯甲烷,室温搅拌反应直至反应完全后，萃取、干燥浓缩，得到化合物8。
作为在上述步骤1的反应中使用的有机溶剂，可列举出例如：二氯甲烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺等。
在上述步骤2(step 2)中，将化合物8溶于有机溶剂中,加入K 2CO 3,加入烯丙基溴,室温搅拌反应直至反应完全后，萃取、干燥浓缩，得到化合物9。
作为在上述步骤2的反应中使用的有机溶剂，可列举出例如：二氯甲烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺等。
在上述步骤3(step 3)中，将化合物9溶于1,4-二氧六环/水(50:50)，于室温搅拌，加入氢氧化钠,继续搅拌反应直至原料消失，减压蒸出1,4-二氧六环,将pH调至2-3，搅拌、过滤，水洗至滤液中性，得到化合物10。
在上述步骤4(step 4)中，将化合物10分散于有机溶剂中,分别加入HATU(2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲；六氟磷酸酯)、NaHCO 3、化合物8，室温搅拌反应直至原料转化完全，柱层析得到化合物11。
作为在上述步骤4的反应中使用的有机溶剂，可列举出例如：二氯甲烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺等。
在上述步骤5(step 5)中，将化合物11溶解于有机溶剂中,于-5～-10℃搅拌，向其中加入三乙基硅烷及三氟乙酸，恒温反应至反应完全，室温减压蒸除溶剂，分离得到目标产物、即通式(B)所示化合物。
作为在上述步骤5的反应中使用的有机溶剂，可列举出例如：无水二氯甲烷、甲苯、四氢呋喃、N,N-二甲基甲酰胺等。
在本发明的又一个方面，提供上述通式(I)所示化合物或其盐在制备革兰氏阴性菌的抗菌剂中的用途。
接下来，本发明化合物的具体例如下所示。
通式(I)中的R 1～R 4均为氢原子、Y为羧基、X为C原子的化合物；
通式(I)中的R 1～R 4均为甲基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4均为乙基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3为氢原子、R 4为丙基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3为氢原子、R 4为丁基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4均为丙基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4均为丁基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4均为戊基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4均为己基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4一起形成环丙基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4一起形成环丁基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4一起形成环戊基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4一起形成环己基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4一起形成环庚基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4一起形成环辛基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3为乙基、R 4为氢原子、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3为异丙基、R 4为氢原子、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3为苯基、R 4为氢原子、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3为环丙基、R 4为氢原子、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3为环丁基、R 4为氢原子、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3为环戊基、R 4为氢原子、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3为环己基、R 4为氢原子、Y为羧基、X为C原子的化合物；
通式(I)中的R 1为氢原子、R 2为乙基、R 3、R 4一起形成环丙基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1为氢原子、R 2为乙基、R 3、R 4一起形成环丁基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1为氢原子、R 2为乙基、R 3、R 4一起形成环戊基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1为氢原子、R 2为乙基、R 3、R 4一起形成环己基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为乙基、R 3、R 4一起形成环丙基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为乙基、R 3、R 4一起形成环丁基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为乙基、R 3、R 4一起形成环戊基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为乙基、R 3、R 4一起形成环己基、Y为羧基、X为C原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4一起形成环丙基、Y为羧基、X为N原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4一起形成环丁基、Y为羧基、X为N原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4一起形成环戊基、Y为羧基、X为N原子的化合物；
通式(I)中的R 1、R 2均为甲基、R 3、R 4一起形成环己基、Y为羧基、X为N原子的化合物；
通式(I)中的R 1、R 2均为乙基、R 3、R 4一起形成环丙基、Y为羧基、X为N原子的化合物；
通式(I)中的R 1、R 2均为乙基、R 3、R 4一起形成环丁基、Y为羧基、X为N原子的化合物；
通式(I)中的R 1、R 2均为乙基、R 3、R 4一起形成环戊基、Y为羧基、X为N原子的化合物；
通式(I)中的R 1、R 2均为乙基、R 3、R 4一起形成环己基、Y为羧基、X为N原子的化合物；
通式(I-2)中的R 5为烯丙基、X为C原子的化合物；
通式(I-2)中的R 5为炔丙基、X为C原子的化合物；
通式(I-2)中的R 5为烯丁基、X为C原子的化合物；
通式(I-2)中的R 5为炔丁基、X为C原子的化合物；
通式(I-2)中的R 5为烯丙基、X为N原子的化合物；
通式(I-2)中的R 5为炔丙基、X为N原子的化合物；
通式(I-2)中的R 5为烯丁基、X为N原子的化合物；
通式(I-2)中的R 5为炔丁基、X为N原子的化合物；
等等。
本发明的化合物并不限定于上述列出的各个化合物例。
本发明的“药学上可接受的盐”是指确保本发明化合物自身具备的生物学有效性、且典型地在生物学或其他方面不具有不良性能的盐。在多种情形之下，通过氨基和/或羧基或与其类似的基团的存在，本发明的化合物能够形成酸和/或碱盐。
药学上可接受的盐包括无机盐和有机盐。
可以与本发明化合物形成无机盐的无机碱，可以列举例如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、氨等。
可以与本发明化合物形成无机盐的无机酸，可以列举例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以与本发明化合物形成有机盐的有机碱，可以列举例如伯胺、仲胺、叔胺、 乙二胺、丙二胺、丁二胺、苯甲胺、苯乙胺等。
可以与本发明化合物形成有有机盐的有机酸，可以列举例如甲酸、乙酸、丙酸、草酸、柠檬酸、苯甲酸等。
实施例
以下，利用制造例及试验例等对本发明进行更详细的说明，但本发明不仅仅限定于这些例子。
化合物(A-1)～(A-7)的具体合成路线如下所示：
Figure PCTCN2021091320-appb-000027
Figure PCTCN2021091320-appb-000028
<制造例>
制造例1：化合物(A-1)的合成
Figure PCTCN2021091320-appb-000029
步骤1a(Step 1a):将化合物7a(1.0mmol)溶于DMF(10.0v/g)中,加入三乙胺(2.0mmol),分批加入三苯基氯甲烷(1.2mmol),室温搅拌反应6小时，TLC监测，反应完全后，加入水/乙酸乙酯萃取，合并有机相，干燥浓缩，柱层析分离得目标化合物7b.
步骤1b(Step 1b):将化合物7b(1.0mmol)溶于1,4-二氧六环(5v/g)/水(5v/g)，于室温搅拌，加入氢氧化钠(5.0mmol),继续搅拌反应，TLC监测，原料消失，减压蒸出1,4-二氧六环,将pH调至2-3，搅拌10分钟，过滤，水洗滤饼，至滤液中性，收集并干燥滤饼，得化合物7c。
步骤1(Step 1):将化合物1a
Figure PCTCN2021091320-appb-000030
(1.0mmol)、二苯基溴甲烷(1.1mmol)分散于甲苯溶液(10.0v/g)中，并于室温下搅拌，加入DBU(1.5mmol)，升温至70-80℃，搅拌反应12-16小时，TLC监控原料不再减少后，降温至室温，加入水(10.0v/g×2)萃取反应液，乙酸乙酯(10v/g×2)反洗水层，合并有机相， 干燥，浓缩得残余物，柱层析分离得透明油状化合物2a(后固化)[ 1H NMR(400MHz,CDCl 3)δ(ppm)7.42–7.31(m,10H),6.96(s,1H),1.44(dd,J＝8.1,4.9Hz,2H),1.25(dd,J＝8.1,4.9Hz,2H)]。
步骤2(Step 2):将化合物2a(1.0mmol)、二苯基磷酰羟胺(1.1mmol)分散于无水四氢呋喃溶液(10.0v/g)中,氮气抽排3-4次，于0℃搅拌，然后加入叔丁醇钠(1.5mmol)，恒温搅拌反应1-2小时，TLC监控，反应物转化完全，向反应液中加入饱和氯化钠溶液(5.0v/g),搅拌30分钟后，滤除不溶物，乙酸乙酯洗涤滤饼，向滤液中加入乙酸乙酯(10.0v/g)，水(5.0v/g)，分液，水洗有机相一次，合并水相，乙酸乙酯反洗水相，合并有机相，干燥，浓缩得油状物3a[ 1H NMR(600MHz,DMSO)δ(ppm)7.46–7.27(m,10H),6.84(s,1H),6.36(s,2H),1.30–1.22(m,4H)]。
步骤3(Step 3):化合物7c分散于甲醇(10.0v/g)中,室温搅拌下，加入化合物3a的甲醇溶液，恒温搅拌反应30分钟，TLC监测，原料转化完全，减压蒸出溶剂，柱层析分离的类白色固体化合物4a[ 1H NMR(600MHz,DMSO)δ(ppm)8.84(s,1H),7.51–7.15(m,25H),6.86(s,2H),1.48–1.28(m,4H)]。
步骤4(Step 4):将化合物4a(1.0mmol)溶于DMF(10.0v/g),室温搅拌，分别加入HATU(1.2mmol),NaHCO 3(2.0mmol),化合物8(1.3mmol),继续恒温搅拌反应12小时，监控反应至原料消失。加入乙酸乙酯(10.0v/g)稀释，水洗2次，乙酸乙酯反洗一次，合并有机相，干燥，浓缩，柱层析分离得类白色泡状固体化合物5a[ 1H NMR(600MHz,DMSO)δ(ppm)9.29(d,J＝7.9Hz,1H),8.91(s,1H),7.45–7.43(m,3H),7.36–7.33(m,6H),7.32–7.22(m,15H),6.86(s,1H),6.76(d,J＝0.5Hz,1H),4.56(d,J＝7.9Hz,1H),1.50–1.40(m,5H),1.30(m,2H),1.20(s,2H)]。
步骤5(Step 5):将上述白色固体5a(1.0mmol)溶于无水二氯甲烷(10.0v/g)，于-5～-10℃搅拌，向其中加入三乙基硅烷(2.0mmol)及三氟乙酸(100.0mmol)，恒温反应5-6小时，TLC监测至反应完全，室温减压蒸除溶剂，向残余物中加入乙酸乙酯，室温搅拌1小时，过滤，乙酸乙酯洗滤饼3次，收集滤饼，干燥，将上述固体，溶于甲醇/水中，pre-HPLC(YMC ODS-A,5um,10*250mm,2.5mL/min,2％-50％乙腈/0.1％甲酸水)制备分离得目标产物(A-1)。
1H NMR(600MHz,DMSO)δ(ppm)9.40(d,J＝7.9Hz,1H),6.89(s,1H),4.62(d,J＝8.0Hz,1H),1.44(s,3H),1.36(m,4H),1.25(s,3H). 13C NMR(151MHz,DMSO)δ(ppm)173.7,169.8,161.9,111.6,68.3,63.3,61.3,60.2,23.8,21.0,16.2. 13C NMR(151MHz,DMSO)δ173.7,169.8,161.9,111.6,68.3,63.3,61.3,60.2,23.8,21.0,16.2.HRMS:cacled for C 14H 17N 5O 9S 2[M-H]462.0396,found 462.0394
制造例2：化合物(A-2)的合成
Figure PCTCN2021091320-appb-000031
化合物(A-2)的合成方法，参见(A-1)。
2b: 1H NMR(600MHz,DMSO)δ(ppm)7.44(d,J＝7.4Hz,4H),7.37(t,J＝7.6Hz,4H),7.29(t,J＝7.3Hz,2H),6.83(s,1H),5.87(s,1H),2.47–2.40(m,2H),2.16–2.07(m,2H),1.89–1.74(m,2H).；
3b: 1H NMR(600MHz,DMSO)δ(ppm)7.35(ddd,J＝46.9,31.4,7.3Hz,10H),6.85(s,1H),6.11(s,2H),2.35(ddd,J＝13.4,7.2,3.7Hz,2H),2.22–2.09(m,2H),1.92–1.74(m,2H).；
4b: 1H NMR(600MHz,DMSO)δ(ppm)8.58(s,1H),7.50–7.15(m,25H),6.78(s,1H),6.12(s,1H),2.42(s,2H),2.25–2.22(m,2H),1.96–1.69(m,2H).(含有50％杂质，参考Z21e)；
(A-2):1H NMR(600MHz,DMSO)δ(ppm)9.56(d,J＝7.3Hz,1H),6.89(s,1H),4.66(d,J＝7.8Hz,1H),2.45(s,2H),2.35–2.19(m,2H),1.99–1.79(m,2H),1.46(s,3H),1.32(s,3H). 13C NMR(151MHz,DMSO)δ(ppm)173.6,170.3,161.8,129.5,128.8,126.7,111.5,83.7,68.4,61.4,30.6,30.5,23.7,21.0,13.9.HRMS:cacled for C 15H 19N 5O 9S 2[M+Na]500.0516,found 500.0500.
制造例3：化合物(A-3)的合成
Figure PCTCN2021091320-appb-000032
步骤1:将化合物1c
Figure PCTCN2021091320-appb-000033
(1.0mmol)、二苯基溴甲烷(1.1mmol)分散于甲苯溶液(10.0v/g)中，并于室温下搅拌，加入DBU(1.5mmol)，升温至70-80℃，搅拌反应12-16小时，TLC监控原料不再减少后，降温至室温，加入水(10.0v/g×2)萃取反应液，乙酸乙酯(10v/g×2)反洗水层，合并有机相，干燥，浓缩得残余物，柱层析分离得透明油状化合物2c(后固化)[ 1H NMR(600MHz,DMSO)δ(ppm)7.45–7.24(m,10H),6.80(s,1H),5.27(s,1H),2.03–1.91(m,2H),1.79–1.63(m,6H)]。
步骤2:将化合物2c(1.0mmol)、二苯基磷酰羟胺(1.1mmol)分散于无水四氢呋喃溶液(10.0v/g)中,氮气抽排3-4次，于0℃搅拌，然后加入叔丁醇钠(1.5mmol)，恒温搅拌反应1-2小时，TLC监控，反应物转化完全，向反应液中加入饱和氯化钠溶液(5.0v/g),搅拌30分钟后，滤除不溶物，乙酸乙酯洗涤滤饼，向滤液中加入乙酸乙酯(10.0v/g)，水(5.0v/g)，分液，水洗有机相一次，合并水相，乙酸乙酯反洗水相，合并有机相，干燥，浓缩得油状物3c,未进一步纯化，直接用于下一步反应。
步骤3:化合物7c分散于甲醇(10.0v/g)中,室温搅拌下，加入化合物3c的甲醇溶液，恒温搅拌反应30分钟，TLC监测，原料转化完全，减压蒸出溶剂，柱层析分离的类白色固体化合物4c[ 1H NMR(600MHz,DMSO)δ(ppm)8.86(s,1H),7.50–7.17(m,25H),6.80(s,1H),6.78(s,1H),2.11–1.94(m,4H),1.69–1.68(d,4H)]。
步骤4:将化合物4c(1.0mmol)溶于DMF(10.0v/g),室温搅拌，分别加入HATU(1.2mmol),NaHCO 3(2.0mmol),化合物8(1.3mmol),继续恒温搅拌反应12小时，监控反应至原料消失。加入乙酸乙酯(10.0v/g)稀释，水洗2次，乙酸乙酯反洗一次，合并有机相，干燥，浓缩，柱层析分离得类白色泡状固体化合物5c[ 1H NMR(600MHz,DMSO)δ(ppm)9.35(d,J＝7.6Hz,1H),8.88(s,1H),7.48–7.17(m,25H),6.80(s,1H),6.68(s,1H),4.57(d,J＝7.7Hz,1H),2.16–1.90(m,4H),1.81–1.57(m,4H),1.45(s,3H),1.27(s,3H)]。
步骤5:将上述白色固体5c(1.0mmol)溶于无水二氯甲烷(10.0v/g)，于-5～-10℃搅拌，向其中加入三乙基硅烷(2.0mmol)及三氟乙酸(100.0mmol)，恒温反应5-6小时，TLC监测至反应完全，室温减压蒸除溶剂，向残余物中加入乙酸乙酯，室温搅拌1小时，过滤，乙酸乙酯洗滤饼3次，收集滤饼，干燥，将上述固体，溶于甲醇/水中，pre-HPLC(YMC ODS-A,5um,10*250mm,2.5mL/min,2％-50％乙腈/0.1％甲酸水)制备分离得目标产物(A-3)。
1H NMR(600MHz,DMSO)δ(ppm)9.51(d,J＝7.6Hz,1H),6.86(s,1H),4.63(d,J＝7.7Hz,1H),2.09–1.97(m,4H),1.73–1.64(m,4H),1.46(s,3H),1.29(s,3H). 13C NMR(151MHz,DMSO)δ(ppm)174.83,163.48,161.82,149.85,140.60,110.92,92.84,68.28,61.44,35.83,24.64,24.51,23.75,20.91.HRMS:cacled forC 16H 21N 5O 9S 2[M-H]490.0708,found 490.0700.
制造例4：化合物(A-4)的合成
Figure PCTCN2021091320-appb-000034
步骤1:将化合物1d
Figure PCTCN2021091320-appb-000035
(1.0mmol)、二苯基溴甲烷(1.1mmol)分散于甲苯溶液(10.0v/g)中，并于室温下搅拌，加入DBU(1.5mmol)，升温至70-80℃，搅拌反应12-16小时，TLC监控原料不再减少后，降温至室温，加入水(10.0v/g× 2)萃取反应液，乙酸乙酯(10v/g×2)反洗水层，合并有机相，干燥，浓缩得残余物，柱层析分离得透明油状化合物2d(后固化)[
Figure PCTCN2021091320-appb-000036
–27.0(c 0.10,MeOH)； 1H NMR(600MHz,DMSO)δ(ppm)7.44–7.26(m,10H),6.84(s,1H),5.37(d,J＝6.0Hz,1H),3.95(dd,J＝5.8,5.2Hz,1H),2.07–1.95(m,1H),0.86(d,J＝6.9Hz,3H),0.78(d,J＝6.8Hz,3H)]。
步骤2:将化合物2d(1.0mmol)、二苯基磷酰羟胺(1.1mmol)分散于无水四氢呋喃溶液(10.0v/g)中,氮气抽排3-4次，于0℃搅拌，然后加入叔丁醇钠(1.5mmol)，恒温搅拌反应1-2小时，TLC监控，反应物转化完全，向反应液中加入饱和氯化钠溶液(5.0v/g),搅拌30分钟后，滤除不溶物，乙酸乙酯洗涤滤饼，向滤液中加入乙酸乙酯(10.0v/g)，水(5.0v/g)，分液，水洗有机相一次，合并水相，乙酸乙酯反洗水相，合并有机相，干燥，浓缩得油状物3d[
Figure PCTCN2021091320-appb-000037
–59.0(c 0.10,MeOH)； 1H NMR(600MHz,CDCl 3)δ7.37–7.26(m,10H),7.00(s,1H),4.11(d,J＝5.3Hz,1H),2.11–2.06(m,1H),0.92(d,J＝6.9Hz,3H),0.87(d,J＝6.9Hz,3H)]。
步骤3:化合物7c分散于甲醇(10.0v/g)中,室温搅拌下，加入化合物3d的甲醇溶液，恒温搅拌反应30分钟，TLC监测，原料转化完全，减压蒸出溶剂，柱层析分离的类白色固体化合物4d[ 1H NMR(600MHz,DMSO)δ(ppm)8.84(s,1H),7.51–7.15(m,25H),6.86(s,1H),6.81(s,1H),4.49(d,J＝5.9Hz,1H),2.18–2.04(m,1H),0.86(dd,J＝19.0,6.7Hz,6H).杂质 1H NMR(600MHz,DMSO)δ(ppm)8.82(s,1H),7.48–7.11(m,25H),6.81(s,1H),6.27(s,1H)]。
步骤4:将化合物4d(1.0mmol)溶于DMF(10.0v/g),室温搅拌，分别加入HATU(1.2mmol),NaHCO 3(2.0mmol),化合物8(1.3mmol),继续恒温搅拌反应12小时，监控反应至原料消失。加入乙酸乙酯(10.0v/g)稀释，水洗2次，乙酸乙酯反洗一次，合并有机相，干燥，浓缩，柱层析分离得类白色泡状固体化合物5d，直接用于下一步反应。
步骤5:将上述白色固体5d(1.0mmol)溶于无水二氯甲烷(10.0v/g)，于-5～-10℃搅拌，向其中加入三乙基硅烷(2.0mmol)及三氟乙酸(100.0mmol)，恒温反应5-6小时，TLC监测至反应完全，室温减压蒸除溶剂，向残余物中加入乙酸乙酯，室温搅拌1小时，过滤，乙酸乙酯洗滤饼3次，收集滤饼，干燥，将上述固体，溶于甲醇/水中，pre-HPLC(YMC ODS-A,5um,10*250mm,2.5mL/min,2％-50％乙腈/0.1％甲酸水)制备分离得目标产物(A-4)。
1H NMR(600MHz,DMSO)δ(ppm)9.58(d,J＝7.5Hz,1H),6.89(s,1H),4.65(d,J＝7.6Hz,1H),4.37(d,J＝5.2Hz,1H),2.13–2.07(m,1H),1.45(s,3H),1.30(s,3H),1.00–0.86(m,6H)。 13C NMR(151MHz,DMSO)δ172.2,170.2,164.4,163.5,161.8,11.7,111.4,87.6,68.1,61.4,30.1,23.8,21.1,18.8,18.2.HRMS:cacled for C 15H 21N 5O 9S 2[M+Na]502.0673,found 502.0677
制造例5：化合物(A-5)的合成
Figure PCTCN2021091320-appb-000038
步骤1:将化合物1e
Figure PCTCN2021091320-appb-000039
(1.0mmol)、二苯基溴甲烷(1.1mmol)分散于甲苯溶液(10.0v/g)中，并于室温下搅拌，加入DBU(1.5mmol)，升温至70-80℃，搅拌反应12-16小时，TLC监控原料不再减少后，降温至室温，加入水(10.0v/g×2)萃取反应液，乙酸乙酯(10v/g×2)反洗水层，合并有机相，干燥，浓缩得残余物，柱层析分离得透明油状化合物2e(后固化)[ 1H NMR(600MHz,DMSO)δ(ppm)7.43–7.26(m,10H),6.84(s,1H),5.37(d,J＝6.0Hz,1H),3.95(dd,J＝5.9,5.0Hz,1H),2.07–1.98(m,1H),0.86(d,J＝6.9Hz,3H),0.78(d,J＝6.8Hz,3H)]。
步骤2:将化合物2e(1.0mmol)、二苯基磷酰羟胺(1.1mmol)分散于无水四氢呋喃溶液(10.0v/g)中,氮气抽排3-4次，于0℃搅拌，然后加入叔丁醇钠(1.5mmol)，恒温搅拌反应1-2小时，TLC监控，反应物转化完全，向反应液中加入饱和氯化钠溶液(5.0v/g),搅拌30分钟后，滤除不溶物，乙酸乙酯洗涤滤饼，向滤液中加入乙酸乙酯(10.0v/g)，水(5.0v/g)，分液，水洗有机相一次，合并水相，乙酸乙酯反洗水相，合并有机相，干燥，浓缩得油状物3e[ 1H NMR(600MHz,DMSO)δ(ppm)7.43–7.40(m,4H),7.37–7.34(m,4H),7.31–7.27(m,2H),6.89(s,1H),6.20(s,2H),3.94(d,J＝5.8Hz,1H),1.95(m,1H),0.82(m,6H)]。
步骤3:化合物7c分散于甲醇(10.0v/g)中,室温搅拌下，加入化合物3e的甲醇溶液，恒温搅拌反应30分钟，TLC监测，原料转化完全，减压蒸出溶剂，柱层析分离的类白色固体化合物4e[ 1H NMR(600MHz,DMSO)δ(ppm)8.57(s,1H),7.39–7.19(m,25H),6.84(s,1H),6.12(s,1H),4.27(d,J＝5.8Hz,1H),2.09–1.92(m,1H),0.91–0.79(m,6H)]。
步骤4:将化合物4e(1.0mmol)溶于DMF(10.0v/g),室温搅拌，分别加入HATU(1.2mmol),NaHCO 3(2.0mmol),化合物8(1.3mmol),继续恒温搅拌反应12小时，监控反应至原料消失。加入乙酸乙酯(10.0v/g)稀释，水洗2次，乙酸乙酯反洗一次，合并有机相，干燥，浓缩，柱层析分离得类白色泡状固体化合物5e，直接用于下一步反应。
步骤5:将上述白色固体5e(1.0mmol)溶于无水二氯甲烷(10.0v/g)，于-5～-10℃搅拌，向其中加入三乙基硅烷(2.0mmol)及三氟乙酸(100.0mmol)，恒温反应5-6小时，TLC监测至反应完全，室温减压蒸除溶剂，向残余物中加入乙酸乙酯，室温搅拌1小时，过滤，乙酸乙酯洗滤饼3次，收集滤饼，干燥，将上述固体，溶于甲醇/水中，pre-HPLC(YMC ODS-A,5um,10*250mm,2.5mL/min,2％-50％乙腈/0.1％甲酸水)制备分离得目标产物(A-5)。
1H NMR(600MHz,DMSO)δ9.53(d,J＝7.4Hz,1H),6.87(s,1H),4.62(d,J＝7.5Hz,1H),4.31(d,J＝5.7Hz,1H),2.08(dd,J＝13.1,6.6Hz,1H),1.45(s,3H),1.30(s,3H),0.96(dd,J＝15.5,6.7Hz,6H). 13C NMR(151MHz,DMSO)δ172.4,169.9,166.0,163.6,161.8,111.2,110.1,87.6,68.2,61.4,30.2,23.9,20.9,19.0,18.3.HRMS:cacled for C 15H 21N 5O 9S 2[M+Na]502.0673,found 502.0661
制造例6：化合物(A-6)的合成
Figure PCTCN2021091320-appb-000040
步骤3:化合物7c分散于甲醇(10.0v/g)中,室温搅拌下，加入化合物3a的甲醇溶液，恒温搅拌反应30分钟，TLC监测，原料转化完全，减压蒸出溶剂，柱层析分离的类白色固体化合物4e[ 1H NMR(600MHz,DMSO)δ(ppm)8.84(s,1H),7.51–7.15(m,25H),6.86(s,2H),1.48–1.28(m,4H)]。
步骤4:将化合物4e(1.0mmol)溶于DMF(10.0v/g),室温搅拌，分别加入HATU(1.2mmol),NaHCO 3(2.0mmol),化合物8(1.3mmol),继续恒温搅拌反应12小时，监控反应至原料消失。加入乙酸乙酯(10.0v/g)稀释，水洗2次，乙酸乙酯反洗一次，合并有机相，干燥，浓缩，柱层析分离得类白色泡状固体化合物5e[ 1H NMR(600MHz,DMSO)δ(ppm)9.29(d,J＝7.9Hz,1H),8.91(s,1H),7.45–7.43(m,3H),7.36–7.33(m,6H),7.32–7.22(m,15H),6.86(s,1H),6.76(d,J＝0.5Hz,1H),4.56(d,J＝7.9Hz,1H),1.50–1.40(m,5H),1.30(m,2H),1.20(s,2H)]。
步骤5:将上述白色固体5e(1.0mmol)溶于无水二氯甲烷(10.0v/g)，于-5～-10℃搅拌，向其中加入三乙基硅烷(2.0mmol)及三氟乙酸(100.0mmol)，恒温反应5-6小时，TLC监测至反应完全，室温减压蒸除溶剂，向残余物中加入乙酸乙酯，室温搅拌1小时，过滤，乙酸乙酯洗滤饼3次，收集滤饼，干燥，将上述固体，溶于甲醇/水中，pre-HPLC(YMC ODS-A,5um,10*250mm,2.5mL/min,2％-50％乙腈/0.1％甲酸水)制备分离得目标产物(A-6)。
1H NMR(600MHz,DMSO)δ(ppm)9.40(d,J＝7.9Hz,1H),6.89(s,1H),4.62(d,J＝8.0Hz,1H),1.44(s,3H),1.36(m,4H),1.25(s,3H). 13C NMR(151MHz,DMSO)δ(ppm)173.7,169.8,161.9,111.6,68.3,63.3,61.3,60.2,23.8,21.0,16.2. 13C NMR(151MHz,DMSO)δ173.7,169.8,161.9,111.6,68.3,63.3,61.3,60.2,23.8,21.0,16.2.HRMS:calcd for C 13H 16N 6O 9S 2[M-H]463.0347。
制造例7：化合物(A-7)的合成
Figure PCTCN2021091320-appb-000041
步骤1:将化合物1g
Figure PCTCN2021091320-appb-000042
(1.0mmol)、二苯基溴甲烷(1.1mmol)分散于甲苯溶液(10.0v/g)中，并于室温下搅拌，加入DBU(1.5mmol)，升温至70–80℃，搅拌反应12-16小时，TLC监控原料不再减少后，降温至室温，加入水(10.0v/g×2)萃取反应液，乙酸乙酯(10v/g×2)反洗水层，合并有机相，干燥，浓缩得残余物，柱层析分离得透明油状化合物2g(后固化)。
步骤2:将化合物2g(1.0mmol)、二苯基磷酰羟胺(1.1mmol)分散于无水四氢呋喃溶液(10.0v/g)中,氮气抽排3-4次，于0℃搅拌，然后加入叔丁醇钠(1.5mmol)，恒温搅拌反应1-2小时，TLC监控，反应物转化完全，向反应液中加入饱和氯化钠溶液(5.0v/g),搅拌30分钟后，滤除不溶物，乙酸乙酯洗涤滤饼，向滤液中加入乙酸乙酯(10.0v/g)，水(5.0v/g)，分液，水洗有机相一次，合并水相，乙酸乙酯反洗水相，合并有机相，干燥，浓缩得油状物3g,未进一步纯化，直接用于下一步反应。
步骤3:化合物7c分散于甲醇(10.0v/g)中,室温搅拌下，加入化合物3g的甲醇溶液，恒温搅拌反应30分钟，TLC监测，原料转化完全，减压蒸出溶剂，得类白色固体化合物4g粗品。直接用于下一步反应
步骤4:将化合物4g(1.0mmol)溶于DMF(10.0v/g),室温搅拌，分别加入HATU(1.2mmol),NaHCO 3(2.0mmol),化合物8(1.3mmol),继续恒温搅拌反应12小时，监控反应至原料消失。加入乙酸乙酯(10.0v/g)稀释，水洗2次，乙酸乙酯反洗一次，合并有机相，干燥，浓缩，得类白色泡状固体化合物5g粗品。直接用于下一步反应。
步骤5:将上述白色固体5g(1.0mmol)溶于无水二氯甲烷(10.0v/g)，于-5～-10℃搅拌，向其中加入三乙基硅烷(2.0mmol)及三氟乙酸(100.0mmol)，恒温反应5–6小时，TLC监测至反应完全，室温减压蒸除溶剂，向残余物中加入乙酸乙酯，室温搅拌1小时，过滤，乙酸乙酯洗滤饼3次，收集滤饼，干燥，将上述固体，溶于甲醇/水中，pre-HPLC(YMC ODS-A,5um,10*250mm,2.5mL/min,2％-50％乙腈/0.1％甲酸水)制备分离得目标产物(A-7)。
1H NMR(600MHz,DMSO)δ9.37(s,1H),6.72(s,1H),4.60(d,1H),4.22(s,1H),2.02(s,1H),1.43(s,3H),1.29(s,3H),0.93(s,6H).HRMS:calcd for C 17H 23N 5O 9S 2[M-H]504.0864,found 504.0850。
化合物(B-1)和(B-2)的具体合成路线如下所示：
Figure PCTCN2021091320-appb-000043
制造例8：化合物(B-1)的合成
Figure PCTCN2021091320-appb-000044
步骤1(Step 1):将化合物7(1.0mmol)溶于DMF(10.0v/g)中,加入三乙胺(2.0mmol),分批加入三苯基氯甲烷(1.2mmol),室温搅拌反应6小时，TLC监测，反应完全后，加入水/乙酸乙酯萃取，合并有机相，干燥浓缩，得目标化合物粗品8a。
步骤2(Step 2):将化合物8a(1.0mmol)溶于DMF(10.0v/g)中,加入K 2CO 3(2.0mmol),加入烯丙基溴(1.2mmol),室温搅拌反应6小时，TLC监测，反应完全后，加入水/乙酸乙酯萃取，合并有机相，干燥浓缩，得目标化合物粗品9a。
步骤3(Step 3):将化合物9a(1.0mmol)溶于1,4-二氧六环(5v/g)/水(5v/g)，于室温搅拌，加入氢氧化钠(5.0mmol),继续搅拌反应，TLC监测，原料消失，减压蒸出1,4-二氧六环,将pH调至2-3，搅拌10分钟，过滤，水洗滤饼，至滤液中性，收集并干燥滤饼，得化合物10a。
步骤4(Step4):将化合物10a(1.0mmol)溶于DMF(10.0v/g),室温搅拌，分别加入HATU(1.2mmol),NaHCO 3(2.0mmol),化合物8(1.3mmol),继续恒温搅拌反应12小时，监控反应至原料消失。加入乙酸乙酯(10.0v/g)稀释，水洗2次，乙酸乙酯反洗一次，合并有机相，干燥，浓缩，得类白色泡状固体化合物11a。直接用于下一步反应。
步骤5(Step 5):将上述白色固体11a(1.0mmol)溶于无水二氯甲烷(10.0v/g)，于-5～-10℃搅拌，向其中加入三乙基硅烷(2.0mmol)及三氟乙酸(100.0mmol)，恒温反应5-6小时，TLC监测至反应完全，室温减压蒸除溶剂，向残余物中加入乙酸乙酯，室温搅拌1小时，过滤，乙酸乙酯洗滤饼3次，收集滤饼，干燥，将上述固体，溶于甲醇/水中，pre-HPLC(YMC ODS-A,5um,10*250mm,2.5mL/min,2％-50％乙腈/0.1％甲酸水)制备分离得目标产物(B-1)。
1H NMR(600MHz,DMSO)δ(ppm)9.60(d,J＝7.8Hz,1H),6.85(s,1H),6.00–5.60(m,1H),5.36–5.31(m,1H),5.24-5.21(m,1H),4.64(dd,J＝5.4,1.3Hz,2H),4.62(d,J＝7.8Hz,1H),1.44(s,3H),1.26(s,4H).HRMS:calcd for C 13H 17O 7N 5S 2[M-H] +418.0486,found 418.0484.
制造例9：化合物(B-2)的合成
Figure PCTCN2021091320-appb-000045
化合物(B-2)的合成方法参见化合物(B-1)。
1H NMR(600MHz,DMSO)δ(ppm)9.64(d,J＝7.8Hz,1H),6.89(s,1H),4.76(s,2H),4.61(d,J＝7.8Hz,1H),3.57(t,J＝2.4Hz,1H),1.44(s,3H),1.28(s,3H).HRMS:calcd for C 13H 14O 7N 5S 2[M-H] +416.0329,found 416.0315.
<活性试验测定>
抗菌活性评价方法(MIC测定)
本研究按照CLSI/NCCLS标准，采用平皿琼脂二倍稀释法以及Denlay多点接种器(Multipoint Inoculator A400)进行抑菌活性测定试验，用水解酪蛋白胨(Mueller-Hinton agar)肉汤以及脑心浸液扩增试验菌株。本研究使用的菌株购自ATCC以及中国医院临床分离的细菌菌株，以氨曲南、多粘菌素或者左氧氟沙星为阳性对照药。用水解酪蛋白肉汤将药物稀释成128.0、64.0、32.0、16.0、8.0、4.0、2.0、1.0、0.5、0.25、0.125、0.06和0.03μg/mL等各种所需浓度，分别置于平皿内，充分混匀。试验菌株接种后，于35℃恒温培养18小时，观察菌株生长情况，无菌生长的平皿中所含药物浓度就是测定的最低抑菌浓度(Minimal Inhibitory Concentration,MIC)。本发明中的化合物A-1～A-7、B-1～B-2以及作为对照的氨曲南(AZN)、粘菌素B以及左氧氟沙星的抗菌活性如下述表1～表4所示。
表1
Figure PCTCN2021091320-appb-000046
表2
Figure PCTCN2021091320-appb-000047
表3
Figure PCTCN2021091320-appb-000048
表4
Figure PCTCN2021091320-appb-000049
备注：表中的ESBLs表示β-内酰胺酶；NDM-1表示I型新德里金属β-内酰胺酶；CRE表示碳青霉烯类耐药肠杆菌；其中的(+)表示存在此种耐药、(-)表示不存在此种耐药；若耐药项下没有任何记载，表示不限定该菌通过特定的酶表现耐药。
根据表1～4可知，与作为对照的氨曲南、粘菌素B以及左氧氟沙星相比，本发明的β-内酰胺化合物对于细菌、尤其是革兰阴性菌的最小抑菌浓度低、抗菌性优异，且耐药性极低，适于制备性能优异的抗菌剂。
产业上的可利用性
本发明的β-内酰胺化合物适用于制备抗菌性优异且耐药性极低的抗菌剂。

Claims (10)

  1. 下述通式(I)所示化合物或其药学上可接受的盐：
    Figure PCTCN2021091320-appb-100001
    式(I)中，R 1、R 2各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基，或者两者一起形成成环碳数为3至8的环烷基；R 3、R 4各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基、任选具有取代基的C6～12的芳基，或者两者一起形成成环碳数为3至8的环烷基；X表示C或者N；Y表示任选具有取代基的碳数为2～6的直链或支链的烯基或炔基，或者羧基。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，所述化合物如下述通式(I-1)所示：
    Figure PCTCN2021091320-appb-100002
    式(I-1)中，R 1、R 2、R 3、R 4、X的定义同上。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，所述化合物如下述通式(A)所示：
    Figure PCTCN2021091320-appb-100003
    式(A)中，R 1、R 2、R 3、R 4的定义同上。
  4. 根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐，其中，R 3和R 4一起形成成环碳数为3至8的环烷基。
  5. 根据权利要求1～4中任一项所述的化合物或其药学上可接受的盐，所述化合物为下述化合物：
    Figure PCTCN2021091320-appb-100004
  6. 根据权利要求1所述的化合物或其药学上可接受的盐，所述化合物如下述通式(I-2)所示：
    Figure PCTCN2021091320-appb-100005
    式(I-2)中，R 5表示任选具有取代基的碳数为3～7的烯基或炔基、X的定义同上。
  7. 根据权利要求6所述的化合物或其药学上可接受的盐，所述化合物如下述通式(B)所示：
    Figure PCTCN2021091320-appb-100006
    式(B)中，R 5的定义同上。
  8. 根据权利要求7所述的化合物或其药学上可接受的盐，所述化合物为选自下述的化合物：
    Figure PCTCN2021091320-appb-100007
  9. 一种通式(I)所示化合物的制备方法，其包括：
    步骤a：
    通过下述式(1)所示化合物和式(2)所示化合物反应生成式(3)所示的化合物；
    Figure PCTCN2021091320-appb-100008
    上述各式中，PG表示保护基；R 1、R 2各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基，或者两者一起形成成环碳数为3至8的环烷基；R 3、R 4各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基、任选具有取代基的C6～12的芳基，或者两者一起形成成环碳数为3至8的环烷基；X表示C或者N；Y表示任选具有取代基的碳数为2～6的直链或支链的烯基或炔基，或者羧基；
    步骤b：
    通过上述式(3)和三氟乙酸及三乙基硅烷反应脱去保护基而制备通式(I)所示化合物，
    Figure PCTCN2021091320-appb-100009
    式(I)中，R 1、R 2、R 3、R 4、X、Y的定义同上。
  10. 一种通式(I)所示化合物在制备革兰氏阴性菌的抗菌剂中的用途，
    Figure PCTCN2021091320-appb-100010
    式(I)中，R 1、R 2各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基，或者两者一起形成成环碳数为3至8的环烷基；R 3、R 4各自独立地表示氢原子、任选具有取代基的C1～10的直链或支链烷基、任选具有取代基的C6～12的芳基，或者两者一起形成成环碳数为3至8的环烷基；X表示C或者N；Y表示任选具有取代基的碳数为2～6的直链或支链的烯基或炔基，或者羧基。
PCT/CN2021/091320 2020-06-02 2021-04-30 一种β-内酰胺化合物、其用途及其制备方法 WO2021244199A1 (zh)

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