WO2017148416A1 - 一种美登素酯的制备方法及其中间体 - Google Patents

一种美登素酯的制备方法及其中间体 Download PDF

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WO2017148416A1
WO2017148416A1 PCT/CN2017/075448 CN2017075448W WO2017148416A1 WO 2017148416 A1 WO2017148416 A1 WO 2017148416A1 CN 2017075448 W CN2017075448 W CN 2017075448W WO 2017148416 A1 WO2017148416 A1 WO 2017148416A1
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group
compound
substituted
independently
alkyl
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PCT/CN2017/075448
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French (fr)
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向少云
杨鸿裕
朱华萍
马兴泉
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凯惠科技发展(上海)有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • 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
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 preparation method of maytansin ester and an intermediate thereof, in particular to a preparation method of maytansin ester C-3 ester and an intermediate thereof.
  • Another method for preparing maytansinol C-3 ester is to react with a base such as Li(HMDS), Na(HMDS), K(HMDS), Zn(HMDS) 2 to form a maytansine anion, and then
  • a base such as Li(HMDS), Na(HMDS), K(HMDS), Zn(HMDS) 2
  • the activated carboxylic acid compound such as an acid anhydride is reacted with an acid fluoride.
  • carboxylic acid to active anhydride and acyl fluoride intermediate tends to be unstable, the reaction needs to be carried out at a low temperature, and the experimental operation is complicated and the repeatability is poor.
  • the technical problem to be solved by the present invention is to overcome the prior art preparation method of maytansin ester, the reaction conditions are harsh, the synthesis step is cumbersome, the reaction conversion rate is low, the racemization is serious during the reaction, the yield is low, and the post-treatment is difficult.
  • the obtained product has poor purity, high production cost, is not suitable for amplification experiments, and is not suitable for industrial production and the like, and provides a method for preparing maytansin ester and an intermediate thereof.
  • the preparation method of the invention has mild reaction conditions, simple synthesis steps, high reaction conversion rate, no racemization observed during the reaction, high yield, simple post-treatment, high purity of the obtained product, low production cost, and amplification reaction.
  • the manufactured maytansyl C3-ester can be used to prepare DM1, DM4, etc. (see J. Med. Chem, 2006, 49, 4392-4408).
  • the present invention provides a process for the preparation of a compound of formula I, which comprises the steps of: presenting in an organic solvent in the presence of a base The compound Ia is subjected to a transesterification reaction with RCOOR' to obtain a compound of the formula I;
  • X is hydrogen or halogen (such as fluorine, chlorine, bromine or iodine, and further chlorine);
  • R 5 is C 1 -C 6 alkyl or benzyl base;
  • R 1 is hydrogen or C 1 -C 6 alkyl (eg methyl);
  • R 2 is hydrogen or C 1 -C 6 alkyl
  • R 3 is methyl, -CH 2 OH or -CH 2 OR 17 ;
  • R 4 is a hydroxyl group, -OR 17 or a fluorenyl group
  • the R 17 is independently a hydroxy protecting group (the hydroxy protecting group may be a conventional hydroxy protecting group in the transesterification reaction, including but not limited to a silicon group, an acyl group).
  • the hydroxy protecting group may be a conventional hydroxy protecting group in the transesterification reaction, including but not limited to a silicon group, an acyl group).
  • oxaalkyl and oxacycloalkyl such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, benzoyl, );
  • R is a substituted or unsubstituted alkyl group (the "alkyl group” such as a C 1 -C 14 alkyl group, and further, for example, a C 1 -C 6 alkyl group; the "C 1 -C 6 alkyl group” such as a Or ethyl), substituted or unsubstituted aryl (the "aryl” group such as C 5 -C 10 aryl; said “C 5 -C 10 aryl” such as phenyl), substituted or not Substituted cycloalkyl (the "cycloalkyl” such as C 3 -C 8 cycloalkyl), substituted or unsubstituted cycloalkenyl (the "cycloalkenyl” such as C 5 -C 10 cycloalkenene a substituted or unsubstituted heteroaryl group (the "heteroaryl group” is, for example, a nitrogen or oxygen atom, a C
  • L is independently a chemical bond, a substituted or unsubstituted -(CH 2 ) m - (for example, a methylene group, Or "alternative or unsubstituted C 3 -C 8 cycloalkylene", m is 0-20; wherein the "substituted” in the "substituted or unsubstituted -(CH 2 ) m -" is independent
  • the ground is substituted with 1-4 groups selected from the group consisting of -SO 3 H, -P(O)(OH) 2 and R 23 , and said R 23 is independently selected from -SH, -SSC 1- 4- alkyl, -CONR 11 R 11 and "C 1-6 alkyl substituted by one or more -NR 11 R 11 groups"; said "alternative or unsubstituted C 3 -C 8 cycloalkylene""Substitute” in the group "is independently substituted for one or more -CH 2 - groups
  • R 7 is independently hydrogen, C 1 -C 6 alkyl (eg methyl, isopropyl, sec-butyl or isobutyl) or an amino acid side chain (the amino acid side chain means a group forming an amino acid, such as 4-OH-Phenyl-CH 2 -, CH 3 -CH(OH)-, HS-CH 2 -, Phenyl-CH 2 - or CH 3 -S-(CH 2 ) 2 -;
  • the configuration of the "*" carbon atom may be R type and / or S type);
  • R 8 is independently hydrogen or C 1-6 alkyl (eg methyl);
  • hetero atom is nitrogen or oxygen atoms, 1 to 4 hetero atom number of C 5 ⁇ C 10 heteroaryl group), heteroaryl a ring group (for example, a hetero atom is a nitrogen or oxygen atom, a C 3 to C 10 heterocyclic group having 1-4 hetero atoms),
  • R 11 is independently hydrogen, alkyl (for example, C 1 -C 6 alkyl), aryl-cycloalkyl- (for example, C 5 -C 10 aryl-C 3 -C 8 cycloalkyl-), cycloolefin a group (for example, a C 5 -C 10 cycloalkenyl group), a heteroaryl group (for example, a hetero atom is a nitrogen or oxygen atom, a C 5 to C 10 heteroaryl group having a hetero atom number of 1 to 4) or a heterocyclic group ( For example, a hetero atom is a nitrogen or oxygen atom, a C 3 -C 10 heterocyclic group having 1-4 hetero atoms; or two R 11 atoms together with a nitrogen atom to form a substituted or unsubstituted hetero atom
  • the ring (the "heterocycle” such as a hetero atom is one or more of nitrogen, sulfur and oxygen atoms, and a C 3
  • R 12 is independently C 1 -C 6 alkyl or benzyl
  • R 13 is independently alkyl (for example, C 1 -C 6 alkyl; said "C 1 -C 6 alkyl” such as methyl), aryl (e.g., C 5 -C 10 aryl), ring
  • An alkyl group for example, a C 3 -C 8 cycloalkyl group
  • a cycloalkenyl group for example, a C 5 -C 10 cycloalkenyl group
  • a heteroaryl group for example, a hetero atom is a nitrogen or an oxygen atom, and the number of hetero atoms is 1-4
  • a C 5 -C 10 heteroaryl group or a heterocyclic group for example, a hetero atom is a nitrogen or oxygen atom, a heterocyclic group of from 1 to 4 C 3 to C 10 );
  • Pr is independently an amino protecting group; the amino protecting group may be a conventional amino protecting group for such transesterification, such as t-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl ( CBz), benzoyl (Bz) or acetyl (Ac);
  • a conventional amino protecting group for such transesterification such as t-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl ( CBz), benzoyl (Bz) or acetyl (Ac);
  • R' is a C 1 -C 6 alkyl group, a C 5 -C 10 aryl group, a hetero atom is a nitrogen or oxygen atom, and a C 4 -C 10 heteroaryl group having 1 to 4 hetero atoms (for example And a substituted or unsubstituted "heteroatom is a nitrogen or oxygen atom, a C 4 -C 10 heterocyclic group having 1-4 hetero atoms" (the “alternative” means one of the heterocyclic groups or Multiple -CH 2 - groups are Substituted; the "alternative hetero atom is a nitrogen or oxygen atom, and a C 4 - C 10 heterocyclic group having 1-4 hetero atoms", for example a halogen-substituted C 5 -C 10 aryl group (the "halogen-substituted C 5 -C 10 aryl group", wherein the halogen is preferably fluorine, chlorine, bromine or iodine; the number of
  • the compound Ia includes various stereoisomers thereof, and preferably, the stereostructure thereof is preferably
  • the X is, for example, a halogen.
  • the Y is, for example, hydrogen or a C 1 -C 6 alkyl group (e.g., methyl group), and further, for example, a C 1 -C 6 alkyl group.
  • R 1 is, for example, a C 1 -C 6 alkyl group (also, for example, a methyl group).
  • the R 2 is, for example, hydrogen.
  • the R 3 is, for example, a methyl group.
  • the R 4 is, for example, a hydroxyl group.
  • R is, for example, a substituted or unsubstituted alkyl group (also, for example, a methyl group or an ethyl group), a substituted or unsubstituted aryl group (also a phenyl group), a substituted or unsubstituted heterocyclic group (again For example, tetrahydropyrrol-2-yl), Further, for example, a substituted or unsubstituted alkyl group (also known as methyl or ethyl), a substituted or unsubstituted aryl group (also known as a phenyl group), a substituted or unsubstituted heterocyclic group (also, for example, tetrahydropyrrole-2- base),
  • the L is, for example, a chemical bond, or a substituted or unsubstituted -(CH 2 ) m -, for example, -(CH 2 ) m -; wherein m is, for example, 1-10, and is, for example, 1 5 (eg methylene, ).
  • R 7 is independently, for example, hydrogen, C 1 -C 6 alkyl (such as methyl, isopropyl, sec-butyl or isobutyl) or an amino acid side chain (for example, Phenyl-CH 2 - or CH 3 -S-(CH 2 ) 2 -), for example, C 1 -C 6 alkyl (for example methyl).
  • R 8 is independently, for example, hydrogen or C 1-6 alkyl (e.g., methyl), and further, for example, C 1 -C 6 alkyl.
  • said R 10 is independently, for example, hydrogen, Pr, -SSR 13 (for example ), Another example - SSR 13 (for example ).
  • R 13 is independently, for example, an alkyl group (e.g., a C 1 - C 6 alkyl group; the "C 1 - C 6 alkyl group” such as a methyl group).
  • an alkyl group e.g., a C 1 - C 6 alkyl group; the "C 1 - C 6 alkyl group” such as a methyl group.
  • the Pr is independently, for example, tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc) or acetyl (Ac).
  • the R' for example, a hetero atom is a nitrogen or oxygen atom, and a C 4 to C 10 heteroaryl group having 1 to 4 hetero atoms (for example, a substituted or unsubstituted "heteroatom is a nitrogen or oxygen atom, a C 4 -C 10 heterocyclic group having 1-4 heteroatoms" (eg Or a halogen-substituted C 5 -C 10 aryl group (for example, a halogen-substituted phenyl group; said halogen-substituted phenyl group, for example) ).
  • the RCOOR' may be any organic radical
  • the organic solvent may be a conventional organic solvent of the type conventionally reacted in the art, such as an ether solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, a nitrile solvent. And one or more of the amide solvents.
  • the ether solvent is, for example, a C 2 -C 6 ether solvent, and the C 2 -C 6 ether solvent such as tetrahydrofuran.
  • the halogenated hydrocarbon solvent such as a C 1 - C 4 halogenated hydrocarbon solvent, the C 1 - C 4 halogenated hydrocarbon solvent such as a C 1 - C 4 chlorinated hydrocarbon solvent, A C 1 -C 4 chlorinated hydrocarbon solvent such as dichloromethane.
  • the aromatic hydrocarbon solvent is, for example, a C 6 to C 8 aromatic hydrocarbon solvent.
  • the amide solvent is, for example, N,N-dimethylformamide.
  • the nitrile solvent is, for example, a C 2 -C 6 nitrile solvent.
  • the volume-to-mass ratio of the organic solvent to the compound Ia is, for example, 1 mL/g to 200 mL/g, and further, for example, 50 mL/g to 170 mL/g (for example, 70 mL). /g, 80 mL/g, or 100 mL/g).
  • the base is, for example, an organic base;
  • the organic base is, for example, bis(trimethylsilyl)aminozinc (Zn(HMDS) 2 ), bis(trimethyl) One of silicon-based lithium hydride (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), and lithium diisopropylamide (LDA) Or a plurality of, for example, bis(trimethylsilyl)aminozinc (Zn(HMDS) 2 ).
  • LiHMDS silicon-based lithium hydride
  • NaHMDS sodium bis(trimethylsilyl)amide
  • KHMDS potassium bis(trimethylsilyl)amide
  • LDA lithium diisopropylamide
  • the molar ratio of the base to the compound Ia is, for example, 1 to 10, and further, for example, 1 to 5 (for example, 2.5 to 4, for example, 3).
  • the molar ratio of the RCOOR' to the compound Ia is, for example, 1 to 10, further, for example, 1 to 4, and further, for example, 2 to 3 (for example, 2.5).
  • the temperature of the transesterification reaction is, for example, -78 ° C to 100 ° C, further, for example, -20 ° C to 50 ° C, and further, for example, 20 ° C to 30 ° C (for example, 25 ° C). ).
  • the progress of the transesterification reaction can be monitored by conventional monitoring methods in the art (for example, TLC, HPLC or NMR), generally when the compound Ia content is no longer reduced.
  • the transesterification reaction is carried out, for example, for 2 hours to 24 hours, and further, for example, 8 hours to 16 hours (for example, 12 hours).
  • the preparation of the compound of formula I can be carried out in the presence of a protective gas which can be a conventional protective gas for such reactions in the art, such as argon, nitrogen, helium and neon. One or more.
  • the method for preparing the compound of the formula I may be carried out by adding a mixture of the base and the organic solvent to a mixture of the compound Ia and the organic solvent. And stirring (time may be 5 minutes to 10 minutes), and further adding a mixture of the RCOOR' and the organic solvent to carry out the transesterification reaction to obtain the compound I.
  • the manner of addition is, for example, dropwise, and the rate of addition is based on the temperature of the reaction system not exceeding 40 °C.
  • the preparation method of the compound represented by Formula I can be carried out by the following post-treatment steps: after the reaction is completed, the reaction is quenched, extracted, the organic phase is dried, and the solvent is removed to obtain Compound I.
  • the quenching reaction uses, for example, dilute hydrochloric acid, and the molar volume concentration of the diluted hydrochloric acid is, for example, 1 mol/L to 2 mol/L, and the molar volume concentration refers to the ratio of the molar amount of hydrogen chloride to the volume of dilute hydrochloric acid.
  • the extraction, drying and removal of the solvent may be carried out by a conventional method of such operation in the art, by extraction using a solvent such as an ester solvent, such as ethyl acetate.
  • the number of extractions is, for example, 2 to 3 times.
  • the reagents used for the drying may be conventional reagents of this type in the art, such as anhydrous sodium sulfate.
  • the solvent to be removed is, for example, a method of concentration under reduced pressure.
  • the method for preparing the compound of the formula I may further comprise the steps of: subjecting RCOOH to R'OH to carry out a condensation reaction to obtain the RCOOR';
  • R and R' are as described above.
  • the preparation method of the RCOOR' may be a conventional method and condition of the condensation reaction in the art, and the following reaction conditions are particularly preferred in the present invention: RCOOH in an organic solvent in the presence of a base and/or a condensing agent The condensation reaction with R'OH gives the RCOOR'.
  • the R is (ie RCOOR' is RCOOH is );
  • the organic solvent is preferably one or more selected from the group consisting of an ether solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, a nitrile solvent, and an amide solvent, and more preferably an ether.
  • an ether solvent is preferably a C 2 -C 6 ether solvent
  • the C 2 -C 6 ether solvent is preferably diethyl ether, 1,4-dioxane, tert-butyl methyl ether or ethylene glycol.
  • One or more of methyl ether and tetrahydrofuran are further preferably tetrahydrofuran.
  • the halogenated hydrocarbon solvent is preferably a C 1 - C 4 halogenated hydrocarbon solvent, and the C 1 - C 4 halogenated hydrocarbon solvent is preferably a C 1 - C 4 chlorinated hydrocarbon solvent,
  • the C 1 - C 4 chlorinated hydrocarbon solvent is preferably dichloromethane.
  • the aromatic hydrocarbon solvent is preferably a C 6 - C 8 aromatic hydrocarbon solvent, and the C 6 - C 8 aromatic hydrocarbon solvent is preferably toluene, xylene or benzene.
  • the amide solvent is preferably N,N-dimethylformamide.
  • the nitrile solvent is preferably a C 2 to C 6 nitrile solvent, and the C 2 to C 6 nitrile solvent is preferably acetonitrile.
  • the volume-to-mass ratio of the organic solvent to the RCOOH is preferably 1 mL/g to 200 mL/g, and more preferably 30 mL/g to 50 mL/g.
  • the condensing agent is preferably 1-ethyl-3(3-dimethylpropylamine) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), One of N,N'-diisopropylcarbodiimide (DIC) and N,N'-carbonyldiimidazole (CDI) or A variety.
  • EDCI 1-ethyl-3(3-dimethylpropylamine) carbodiimide
  • DCC dicyclohexylcarbodiimide
  • DIC N,N'-diisopropylcarbodiimide
  • CDI N,N'-carbonyldiimidazole
  • the molar ratio of the condensing agent to the RCOOH is preferably from 1 to 5, more preferably from 1 to 2 (e.g., 1.3).
  • the base is preferably an organic base or an inorganic base; and the organic base is preferably triethylamine, diisopropylethylamine, pyridine or 4-dimethylaminopyridine (DMAP). And one or more of 2,6-lutidine.
  • the inorganic base is preferably potassium carbonate and/or sodium carbonate.
  • the molar ratio of the base to the RCOOH is preferably from 1 to 5, more preferably from 1 to 2.
  • the molar ratio of the R'OH to the RCOOH is preferably from 1 to 5, more preferably from 1 to 2 (e.g., 1.3).
  • the temperature of the condensation reaction is preferably -78 ° C to 100 ° C, more preferably -20 ° C to 50 ° C, still more preferably 20 ° C to 30 ° C (for example, 25 ° C).
  • the progress of the condensation reaction can be monitored by a conventional monitoring method (for example, TLC, HPLC or NMR) in the art, generally when the compound RCOOH disappears as the reaction end point.
  • the time of the condensation reaction is preferably 2 hours to 24 hours, more preferably 2 hours to 12 hours.
  • the preparation method of the RCOOR' preferably includes the following post-treatment step: after completion of the reaction, the solvent is removed and column chromatography is carried out to obtain a purified RCOOR'.
  • the solvent to be removed may be carried out by a conventional method of such operation in the art, preferably by a method of decompressing the concentration.
  • the column chromatography separation can employ conventional methods and conditions of operation in the art.
  • the solvent used for the column chromatography separation is preferably a mixed solvent of an alkane solvent and an ester solvent, and the alkane solvent is preferably petroleum ether, and the ester solvent is preferably ethyl acetate.
  • the volume ratio of the alkane solvent described in the "mixed solvent of an alkane solvent to an ester solvent" to the ester solvent is preferably 1-2.
  • the present invention also provides a process for the preparation of RCOOR', which comprises the steps of: subjecting RCOOH to R'OH to carry out a condensation reaction to obtain RCOOR';
  • R and R' are as described above.
  • the invention also provides a process for the preparation of a compound of formula II, which comprises the steps of:
  • the steric structure of the compound I, X, Y, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , Pr and the "configuration of the ⁇ carbon atom" are as defined above.
  • reaction for removing the amino protecting group can employ conventional methods and conditions for such reactions in the art.
  • the preparation method of the compound of the formula II is particularly preferably the following reaction conditions: deamination of the compound I in an organic solvent in the presence of a base
  • the reaction of the protecting group can be carried out to obtain the compound II.
  • the organic solvent is preferably a nitrile solvent, and the nitrile solvent is preferably acetonitrile.
  • the volume-to-mass ratio of the organic solvent to the compound I is preferably from 1 mL/g to 100 mL/g (for example, 38 mL/g).
  • the base is preferably an organic base, and the organic base is preferably diethylamine.
  • the molar ratio of the organic base to the compound I is preferably from 1 to 100.
  • the temperature of the Pr-removing reaction is preferably -5 ° C to 0 ° C.
  • the progress of the reaction for removing the amino protecting group can be monitored by conventional monitoring methods in the art (for example, TLC, HPLC or NMR), generally the end point of the reaction when the compound I disappears, and the amino group is removed.
  • the reaction time is preferably 5 minutes to 1 hour, more preferably 10 minutes to 30 minutes.
  • the present invention also provides a method for preparing a compound as shown in Formula III, which is Method 1 or Method 2;
  • Method 1 includes the following steps:
  • Method 2 includes the following steps:
  • R 9 is a C 1 -C 6 alkyl group, a C 5 -C 10 aryl group, a hetero atom is a nitrogen or an oxygen atom, and a C 4 -C 10 heteroaryl group having 1 to 4 hetero atoms (for example)
  • a substituted or unsubstituted "heteroatom is a nitrogen or oxygen atom, a C 4 -C 10 heterocyclic group having 1-4 hetero atoms” (the “alternative” means one of the heterocyclic groups or Multiple -CH 2 - groups are Substituted; the "alternative hetero atom is a nitrogen or oxygen atom, and a C 4 - C 10 heterocyclic group having 1-4 hetero atoms", for example a halogen-substituted C 5 -C 10 aryl group (the "halogen-substituted C 5 -C 10 aryl group", wherein the halogen is preferably fluorine, chlorine, bromine or iodine;
  • the R 11 is preferably a C 1 - C 4 alkyl group (the C 1 - C 4 alkyl group is preferably an isopropyl group or an isobutyl group).
  • the R 10 is preferably -SSR 13 (for example ), said L is preferably -(CH 2 ) m - (for example ).
  • Process 1 can be a conventional method and condition for such a condensation reaction in the art.
  • the following reaction methods and conditions are particularly preferred: in the organic solvent, in the presence of a condensing agent, the compound II and the compound R 10 -L-COOH Performing a condensation reaction to obtain a compound III;
  • the organic solvent is preferably one or more selected from the group consisting of an ether solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, a nitrile solvent, and an amide solvent.
  • the ether solvent is preferably a C 2 - C 6 ether solvent, and the C 2 - C 6 ether solvent is preferably tetrahydrofuran.
  • the halogenated hydrocarbon solvent is preferably a C 1 - C 4 halogenated hydrocarbon solvent, and the C 1 - C 4 halogenated hydrocarbon solvent is preferably a C 1 - C 4 chlorinated hydrocarbon solvent;
  • the C 1 - C 4 chlorinated hydrocarbon solvent is preferably dichloromethane.
  • the aromatic hydrocarbon solvent is preferably a C 6 to C 8 aromatic hydrocarbon solvent.
  • the amide solvent is preferably N,N-dimethylformamide.
  • the nitrile solvent is preferably a C 2 to C 6 nitrile solvent.
  • the volume-to-mass ratio of the organic solvent to the compound II is preferably from 1 mL/g to 100 mL/g (for example, 60 mL/g).
  • the condensing agent is preferably 1-ethyl-3(3-dimethylpropylamine) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), N, N'-di One or more of propyl carbodiimide (DIC) and N, N'-carbonyl diimidazole (CDI).
  • EDCI 1-ethyl-3(3-dimethylpropylamine) carbodiimide
  • DCC dicyclohexylcarbodiimide
  • DIC propyl carbodiimide
  • CDI N, N'-carbonyl diimidazole
  • the molar ratio of the condensing agent to the compound II is preferably from 1 to 5, more preferably from 2 to 3.
  • the temperature of the condensation reaction is preferably -78 ° C to 100 ° C, more preferably -20 ° C to 50 ° C, still more preferably 20 ° C to 30 ° C (for example, 25 ° C).
  • the progress of the condensation reaction can be monitored by a conventional monitoring method (for example, TLC, HPLC or NMR) in the art, generally when the compound II disappears as the reaction end point, and the time of the condensation reaction is preferably 2 The hour to 24 hours, further preferably 2 hours to 16 hours, for example, 8 hours to 12 hours.
  • a conventional monitoring method for example, TLC, HPLC or NMR
  • the time of the condensation reaction is preferably 2 The hour to 24 hours, further preferably 2 hours to 16 hours, for example, 8 hours to 12 hours.
  • the preparation method described in the method 1 is preferably carried out in the presence of a shielding gas, which may be a conventional shielding gas for such a reaction in the art, preferably one of argon, nitrogen, helium and neon. Or a variety.
  • a shielding gas which may be a conventional shielding gas for such a reaction in the art, preferably one of argon, nitrogen, helium and neon. Or a variety.
  • the preparation method according to the method 1 preferably employs the steps of: adding a condensing agent to a mixture of the compound II, the compound R 10 -L-COOH and an organic solvent, and performing a condensation reaction to obtain a compound III.
  • the preparation method described in the method 1 preferably employs the following post-treatment step: after completion of the reaction, the solvent is removed and column chromatography is carried out to obtain the purified compound III.
  • the solvent to be removed may be carried out by a conventional method of such operation in the art, preferably by a method of decompressing the concentration.
  • the column chromatography separation can employ conventional methods and conditions of operation in the art.
  • the solvent used for the column chromatography separation is preferably a mixed solvent of a halogenated hydrocarbon solvent and an alcohol solvent, the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent, and the chlorinated hydrocarbon solvent is preferably dichloromethane. .
  • the alcohol solvent is preferably methanol.
  • the volume ratio of the halogenated hydrocarbon solvent described in the "mixed solvent of a halogenated hydrocarbon solvent to an alcohol solvent" to the above alcohol solvent is preferably 10 to 20.
  • Process 2 may be a conventional method and condition for such a condensation reaction in the art.
  • the following reaction methods and conditions are particularly preferred: in an organic solvent, in the presence of a base, Compound II, and "Compound R 10 -L- COOR 9 , R 10 -L-COCl or "Condensation reaction is carried out to obtain compound III;
  • the organic solvent is preferably one or more selected from the group consisting of an ether solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, a nitrile solvent, and an amide solvent.
  • the ether solvent is preferably a C 2 - C 6 ether solvent, and the C 2 - C 6 ether solvent is preferably tetrahydrofuran.
  • the halogenated hydrocarbon solvent is preferably a C 1 - C 4 halogenated hydrocarbon solvent, and the C 1 - C 4 halogenated hydrocarbon solvent is preferably a C 1 - C 4 chlorinated hydrocarbon solvent;
  • the C 1 - C 4 chlorinated hydrocarbon solvent is preferably dichloromethane.
  • the aromatic hydrocarbon solvent is preferably a C 6 to C 8 aromatic hydrocarbon solvent.
  • the amide solvent is preferably N,N-dimethylformamide.
  • the nitrile solvent is preferably a C 2 to C 6 nitrile solvent.
  • the volume-to-mass ratio of the organic solvent to the compound II is preferably from 1 mL/g to 100 mL/g.
  • the compound R 10 -L-COOR 9 , R 10 -L-COCl or The molar ratio to the above-mentioned compound II is preferably from 1 to 5, more preferably from 2 to 3.
  • the temperature of the condensation reaction is preferably 0 to 35 ° C, and more preferably 20 to 30 ° C.
  • the progress of the condensation reaction can be monitored by a conventional monitoring method (for example, TLC, HPLC or NMR) in the art, generally when the compound II disappears as the reaction end point, and the time of the condensation reaction is preferably 5 The hour to 24 hours, further preferably 2 hours to 16 hours, for example, 8 hours to 12 hours.
  • a conventional monitoring method for example, TLC, HPLC or NMR
  • the preparation method described in the method 2 is preferably carried out in the presence of a shielding gas, which may be a conventional protective gas for such a reaction in the art, preferably one of argon, nitrogen, helium and neon. Or a variety.
  • a shielding gas which may be a conventional protective gas for such a reaction in the art, preferably one of argon, nitrogen, helium and neon. Or a variety.
  • the preparation method described in Process 2 preferably employs the following steps: the compound R 10 -L-COOR 9 , R 10 -L-COCl or It is added to a mixture of the compound II and an organic solvent, and a condensation reaction is carried out to obtain a compound III.
  • the preparation method described in the method 2 preferably employs the following post-treatment step: after completion of the reaction, the solvent is removed and column chromatography is carried out to obtain the purified compound III.
  • the solvent to be removed may be carried out by a conventional method of such operation in the art, preferably by a method of decompressing the concentration.
  • the column chromatography separation can employ conventional methods and conditions of operation in the art.
  • the solvent used for the column chromatography separation is preferably a mixed solvent of a halogenated hydrocarbon solvent and an alcohol solvent, the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent, and the chlorinated hydrocarbon solvent is preferably dichloromethane. .
  • the alcohol solvent is preferably methanol.
  • the volume ratio of the halogenated hydrocarbon solvent described in the "mixed solvent of a halogenated hydrocarbon solvent to an alcohol solvent" to the above alcohol solvent is preferably 10 to 20.
  • the invention also provides a process for the preparation of a compound of formula IV, comprising the steps of:
  • the steric structure of the compound III, X, Y, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 13 and the "configuration of the ⁇ carbon atom" are as defined above.
  • the method and conditions of the reduction reaction may be conventional methods and conditions for such reduction reaction in the art, and the following reaction methods and conditions are particularly preferred in the present invention: organic solvent
  • the compound III can be subjected to a reduction reaction in the presence of water, a reducing agent and a buffer salt to obtain a compound IV;
  • the organic solvent is preferably one or more selected from the group consisting of an ester solvent, an alcohol solvent ether solvent, a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, a nitrile solvent, and an amide solvent.
  • the ether solvent is preferably a C 2 - C 6 ether solvent, and the C 2 - C 6 ether solvent is preferably tetrahydrofuran.
  • the halogenated hydrocarbon solvent is preferably a C 1 - C 4 halogenated hydrocarbon solvent, and the C 1 - C 4 halogenated hydrocarbon solvent is preferably a C 1 - C 4 chlorinated hydrocarbon solvent;
  • the C 1 - C 4 chlorinated hydrocarbon solvent is preferably dichloromethane.
  • the aromatic hydrocarbon solvent is preferably a C 6 to C 8 aromatic hydrocarbon solvent.
  • the amide solvent is preferably N,N-dimethylformamide.
  • the nitrile solvent is preferably a C 2 to C 6 nitrile solvent.
  • the alcohol solvent is preferably methanol.
  • the ester solvent is preferably ethyl acetate.
  • the volume-to-mass ratio of the organic solvent to the compound III is preferably from 1 mL/g to 100 mL/g.
  • the organic solvent is preferably composed of an alcohol solvent and an ester solvent, and the volume ratio of the alcohol solvent to the ester solvent is 1-2.
  • the reducing agent is preferably dithiothreitol (DTT).
  • the molar ratio of the reducing agent to the compound III is preferably 8.
  • the temperature of the reduction reaction is preferably -78 ° C to 100 ° C, more preferably -20 ° C to 50 ° C, still more preferably 20 ° C to 30 ° C (for example, 25 ° C).
  • the progress of the reduction reaction can be monitored by conventional monitoring methods in the art (for example, TLC, HPLC or NMR), generally when the disappearance of the compound III is the end point of the reaction, the condensation reaction
  • TLC time is for example 48 hours.
  • the reduction reaction is preferably carried out in the presence of a protective gas which may be a conventional protective gas for such a reaction in the art, preferably one or more of argon, nitrogen, helium and neon. kind.
  • a protective gas which may be a conventional protective gas for such a reaction in the art, preferably one or more of argon, nitrogen, helium and neon. kind.
  • the reduction reaction preferably employs the following post-treatment step: after completion of the reaction, the reaction is quenched, extracted, concentrated, and subjected to column chromatography to obtain the purified compound IV.
  • the present invention also provides a compound RCOOR' wherein R' and R are as defined above.
  • said RCOOR' is as shown in formula Ic:
  • the RCOOR' is N-(RCOOR')
  • Fmoc represents a 9-fluorenylmethoxycarbonyl group, and the structural formula is
  • substituted with an oxo group means that one or more -CH 2 - groups in the group are Replaced.
  • oxaalkyl means, unless otherwise specified, a group which is formed by substituting one or more -CH 2 - in the alkyl group by -O-.
  • alkyl is a branched or straight-chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms unless otherwise specified; and "C 1 -C 4 alkyl” is defined as including A group having 1, 2, 3 or 4 carbon atoms in a linear or branched structure.
  • C 1 -C 4 alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl and the like.
  • alkoxy means, unless otherwise specified, a group formed by linking an alkyl group to an oxygen atom, that is, "RO-", and R is an alkyl group.
  • halogen means fluorine, chlorine, bromine, iodine or hydrazine unless otherwise specified.
  • cycloalkyl means, unless otherwise specified, an all-carbon monocyclic or polycyclic group in which each ring is saturated.
  • 3 to 20 carbon atoms are formed by 1 to 3 ring cycloalkyl groups, more preferably 3 to 10 carbons, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl Base, cyclodecane and cyclododecyl.
  • aryl means, unless otherwise specified, any stable monocyclic or bicyclic carbon ring which may be up to 7 atoms in each ring, at least one of which is an aromatic ring.
  • aryl unit examples include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. It will be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the linkage is carried out through an aromatic ring.
  • cycloalkenyl means, unless otherwise specified, an all-carbon monocyclic or polycyclic group in which each ring may contain one or more double bonds, but none of the rings have a complete conjugate. ⁇ electronic system. It is preferably 1 to 3 ring cycloalkenyl groups formed by 3 to 20 carbons, more preferably 3 to 10 carbons, for example, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptane Alkenyl, cyclooctenyl, cyclodecene and cyclododecenyl.
  • heteroaryl means, unless otherwise specified, a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and contains 1 to 4 selected from Heteroatoms of O, N, and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, acridine, oxazole, porphyrin, porphyrin, quinoxaline, imidazole, pyrazole, pyrrole, indole, indoline, benzotriazole, Benzimidazole, furan, thiophene, isothiazole, benzothiophene, dihydrobenzothiophene, benzofuran, isobenzofuran, benzoxazole, benzofurazan, benzopyrazole, quinoline, isonitrogen Heteroquinone, isoquinoline, oxazole, oxadiazole, isoxazole, hydrazine, pyrazine, pyridopyridine, tetrazolopyridine, pyridazine, pyridine, naphthyl pyrimidine, pyrimidine, pyrrole, tetrazole,
  • Heteroaryl is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl ring.
  • the heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a hetero atom, it is understood that the linkage is carried out through an aromatic ring or through a hetero atom in the ring, respectively.
  • the “heteroaryl” may be attached to other groups via a carbon atom or a hetero atom therein.
  • heterocyclic ring or “heterocyclic group”, unless otherwise specified, means that when used alone or as part of another group, it means 1 to 4 hetero atoms (such as nitrogen, a 4 to 12 membered monocyclic or polycyclic group of one or more of oxygen and sulfur, Wherein each ring may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • any heterocycloalkyl ring can be fused to a cycloalkyl, aryl, heteroaryl or heterocycloalkyl ring.
  • Heterocycloalkyl groups within the scope of this definition include, but are not limited to, oxazoline, oxocyclobutyl, pyranyl, tetrahydropyranyl, azetidinyl, 1,4-dioxyl, Hexahydropyrazine, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydroimidazolyl, indanyl, dihydroisoxazole , dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrogen Tetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydr
  • HMDS represents a hexamethyldisilazide group unless otherwise specified.
  • the reagents and starting materials used in the present invention are commercially available.
  • the positive progress of the invention is that the preparation method of the invention has mild reaction conditions, simple synthesis steps, high reaction conversion rate, no racemization observed during the reaction, high yield, simple post-treatment, high purity of the obtained product, Low production cost, suitable for industrial production.
  • UV absorption wavelength 214 nm, column temperature 40 ° C, flow rate 1.2 ml / min, injection volume 10 ⁇ L, MS (ESI, Pos mode, 110 to 1500 amu), retention time t (S) 7.01 min.
  • reaction product 4 (870 mg, 1.34 mmol) and compound 5 (780 mg, 4.02 mmol) in the previous step were dissolved in 50 mL of dichloromethane, and 1-ethyl-3(3-dimethylpropylamine) carbodiimide (EDCI) was added. (768 mg, 4.02 mmol), the reaction mixture was stirred at room temperature 25 ° C under nitrogen atmosphere overnight.
  • EDCI 1-ethyl-3(3-dimethylpropylamine) carbodiimide
  • UV absorption wavelength 214 nm, column temperature 40 ° C, flow rate 1.2 ml / min, injection volume 10 ⁇ L, MS (ESI, Pos mode, 110 to 1500 amu), retention time t (S) 9.93 min.
  • the reaction product of the previous step 5 (1.04 g, 1.26 mmol) was dissolved in 50 mL of ethyl acetate.
  • Potassium buffer solution 94 mL.
  • the reaction solution was stirred under a nitrogen atmosphere (25 ° C) for 2 days.
  • UV absorption wavelength 214 nm, column temperature 40 ° C, flow rate 1.2 ml / min, injection volume 10 ⁇ L, MS (ESI, Pos mode, 110 to 1500 amu), retention time t (S) 9.46 min.
  • Acetic acid 500 mg, 8.33 mmol was dissolved in 50 mL of dichloromethane, and 1-hydroxybenzotriazole (HOBt) (1.08 g, 7.97 mmol) and 1-ethyl-3(3-dimethylpropylamine) carbon two were added.
  • Imine (EDCI) (2.08 g, 10.83 mmol). The reaction solution was stirred at room temperature (25 ° C) overnight.
  • N-methyl-L alanine (3.10 g, 30 mmol) was weighed and suspended in 600 mL of dichloromethane, and N,N-diisopropylethylamine (10 mL, 60 mmol) was added, and the solid was uniformly dispersed by ultrasonic treatment. The mixture was slowly added with N,N'-carbonyldiimidazole (3.7 mL, 30 mmol), and the mixture was stirred over EtOAc over EtOAc. The product was 1.6 g as a white solid in a yield of 42%.

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Abstract

一种式(I)所示美登素酯的制备方法及其中间体，所述方法包括在有机溶剂和碱存在下，将化合物(Ia)与RCOOR'进行酯交换反应得到所述化合物的步骤。该制备方法反应条件温和，合成及后处理步骤简单，反应转化率及产率高，反应过程中未观察到消旋现象，产品纯度高，生产成本低，适合于工业化生产。

Description

一种美登素酯的制备方法及其中间体
本申请要求申请日为2016年3月3日的中国专利申请CN201610119508.2的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种美登素酯的制备方法及其中间体，具体涉及美登素酯C-3酯的制备方法及其中间体。
背景技术
目前美登醇与羧酸在DCC/ZnCl2下直接缩合的方法具有产率低和重复性差等缺点。而且当使用手性氨基酸如N-甲基-L-丙氨酸衍生物和美登醇缩合时，侧链氨基酸手性中心完全消旋，得到1:1的R-和S-氨基酸羧酸酯，导致一般只能得到不到30％产率的预期产物，而且分离非对映异构体的混合物非常困难。(参考文献US4137230；4260608；US5208020；US5416064；US6333410；Chem.Pharm.Bull.,32,3441-3451；J.Med.Chem.49,4392-4408)。
此外，中国专利CN201310081867.X报道了美登醇和羧酸在DIC/Sc(OTf)3/DMAP条件下的缩合，消旋体的收率为90.5％，经手性制备，异构体收率分别46％和43.1％，但侧链氨基酸手性中心同样完全消旋，得到的是两个非对映异构体的混合物。
制备美登醇C-3酯的另外一种方法是美登醇先与Li(HMDS),Na(HMDS),K(HMDS),Zn(HMDS)2等碱反应生成美登醇负离子，然后与活化的羧酸化合物如酸酐和酰氟反应。但是，羧酸转化为活性酸酐和酰氟中间体往往不稳定，反应需要在低温下进行，而且实验操作也比较复杂，重复性较差。而且当使用手性氨基酸如N-甲基-L-丙氨酸衍生物和美登醇缩合时，侧链氨基酸手性中心有约5％发生消旋，异构体混合物的分离纯化同样比较困难(US20060167245)。
因此，开发一种简单高效的美登醇C3-酯的制备方法具有十分重要的意义。
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美登素酯的制备方法反应条件苛刻、合成步骤繁琐、反应转化率低、反应过程中消旋化严重、产率低、后处理困难、得到的产品纯度差、生产成本高、不适合放大实验、不适合于工业化生产等缺陷而提供了一种美登素酯的制备方法及其中间体。本发明的制备方法反应条件温和、合成步骤简单、反应转化率高、反应过程中未观察到消旋现象、产率高、后处理简单、得到的产品纯度高、生产成本低，可以放大量反应、适合于工业化生产，制得的美登醇C3-酯可用于制备DM1,DM4等(见J.Med.Chem,2006,49,4392-4408)。
本发明提供了一种如式I所示的化合物的制备方法，其包括以下步骤：在有机溶剂中，在碱存在 的条件下，将化合物Ia与RCOOR’进行酯交换反应，得到如式I所示的化合物即可；
Figure PCTCN2017075448-appb-000001
其中，X为氢或卤素(例如氟、氯、溴或碘，又例如氯)；
Y为氢、C1-C6烷基(例如甲基)、C3-C6环烷基、苄基或-C(＝O)R5；R5为C1-C6烷基或苄基；
R1为氢或C1-C6烷基(例如甲基)；
R2为氢或C1-C6烷基；
R3为甲基、-CH2OH或-CH2OR17；
R4为羟基、-OR17或巯基；
所述的R3和R4中，所述的R17独立地为羟基保护基(所述的羟基保护基可为该类酯交换反应中常规的羟基保护基，包括但不限于硅基、酰基或氧杂烷基和氧杂环烷基，例如三甲基硅基、三乙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、乙酰基、苯甲酰基、
Figure PCTCN2017075448-appb-000002
)；
R为取代或未取代的烷基(所述的“烷基”例如C1-C14烷基，再例如C1-C6烷基；所述的“C1-C6烷基”例如甲基或乙基)、取代或未取代的芳基(所述的“芳基”例如C5-C10芳基；所述的“C5-C10芳基”例如苯基)、取代或未取代的环烷基(所述的“环烷基”例如C3-C8环烷基)、取代或未取代的环烯基(所述的“环烯基”例如C5-C10环烯基)、取代或未取代的杂芳基(所述的“杂芳基”例如杂原子为氮或氧原子、杂原子数为1-4个的C5～C10的杂芳基)、取代或未取代的杂环基(所述的“杂环基”例如杂原子为氮或氧原子、杂原子数为1-4个的C3～C10的杂环基；所述的“杂原子为氮或氧原子、杂原子数为1-4个的C3～C10的杂环基”例如四氢吡咯-2-基)、
Figure PCTCN2017075448-appb-000003
Figure PCTCN2017075448-appb-000004
其中，所述的“取代或未取代的烷基、取代或未取代的芳基、取代或未取代的环烷基、取代或未取代的环烯基、取代或未取代的杂芳基和取代或未取代的杂环基”中的“取代”独立地为被1至3个R10取代，“α碳原子的构型”可独立地为R型和/或S型(例如为S型)；
所述的R中，L独立地为化学键、取代或未取代的-(CH2)m-(例如亚甲基、
Figure PCTCN2017075448-appb-000005
Figure PCTCN2017075448-appb-000006
)或“替代或未替代的C3-C8环亚烷基”，m为0-20；其中，所述的“取代或未取代的-(CH2)m-”中的“取代”独立地为被1-4个选自以下的基团所取代：-SO3H、-P(O)(OH)2和R23，所述的R23独立地选自-SH、-S-S-C1-4烷基、-CONR11R11和“被一个或多个-NR11R11基团取代的C1-6烷基”；所述的“替代或未替代的C3-C8环亚烷基”中的“替代”独立地为C3-C8环亚烷基中一个或多个-CH2-基团被选自以下的基团所替代：C3-C8环亚烷基、-O-、-S-、-NR8-、-C(＝O)-、-C(＝O)NR8-、-NR8C(＝O)-、-SO2NR8-和-NR8SO2-；
R7独立地为氢、C1-C6烷基(例如甲基、异丙基、仲丁基或异丁基)或氨基酸侧链(所述的氨基酸侧链是指与
Figure PCTCN2017075448-appb-000007
形成氨基酸的基团，例如4-OH-Phenyl-CH2-、CH3-CH(OH)-、HS-CH2-、Phenyl-CH2-或CH3-S-(CH2)2-；所述的“*”碳原子的构型可为R型和/或S型)；
R8独立地为氢或C1-6烷基(例如甲基)；
R10独立地为氢、Pr、-NR11Pr、-NR11C(＝O)CH2Br、-COOR12、-CONR11R11、-NR11COR13、-S-S-R13(例如
Figure PCTCN2017075448-appb-000008
)、-Si(R13)3、烷基(例如C1-C6烷基)、芳基(例如C5-C10芳基)、环烷基(例如C3-C8环烷基)、环烯基(例如C5-C10环烯基)、杂芳基(例如杂原子为氮或氧原子、杂原子数为1-4个的C5～C10的杂芳基)、杂环基(例如杂原子为氮或氧原子、杂原子数为1-4个的C3～C10的杂环基)、
Figure PCTCN2017075448-appb-000009
R11独立地为氢、烷基(例如C1-C6烷基)、芳基-环烷基-(例如C5-C10芳基-C3-C8环烷基-)、环烯基(例如C5-C10环烯基)、杂芳基(例如杂原子为氮或氧原子、杂原子数为1-4个的C5～C10的杂芳基)或杂环基(例如杂原子为氮或氧原子、杂原子数为1-4个的C3～C10的杂环基)；或者，两个R11同与之相连的氮原子共同形成取代或未取代的杂环(所述的“杂环”例如杂原子为氮、硫和氧原子中的一个或多个、杂原子数为1-4个的C3～C10的杂环基，再例如
Figure PCTCN2017075448-appb-000010
)，其中，所述的“取代或未取代的杂环”中的取代是指被氧代基团和烷基(例如C1-C6烷基)中的一个或多个取代；
R12独立地为C1-C6烷基或苄基；
R13独立地为烷基(例如C1～C6的烷基；所述的“C1～C6的烷基”例如甲基)、芳基(例如C5-C10 芳基)、环烷基(例如C3-C8环烷基)、环烯基(例如C5-C10环烯基)、杂芳基(例如杂原子为氮或氧原子、杂原子数为1-4个的C5～C10的杂芳基)或杂环基(例如杂原子为氮或氧原子、杂原子数为1-4个的C3～C10的杂环基)；
Pr独立地为氨基保护基；所述的氨基保护基可为该类酯交换反应常规的氨基保护基，例如叔丁氧羰基(Boc)、9-芴甲氧羰基(Fmoc)、苄氧羰基(CBz)、苯甲酰基(Bz)或乙酰基(Ac)；
R’为C1～C6的烷基、C5～C10的芳基、杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂芳基(例如
Figure PCTCN2017075448-appb-000011
)、替代或未替代的“杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂环基”(所述的“替代”是指杂环基中一个或多个-CH2-基团被
Figure PCTCN2017075448-appb-000012
所替代；所述的“替代的杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂环基”例如
Figure PCTCN2017075448-appb-000013
)、卤素取代的C5～C10的芳基(所述的“卤素取代的C5～C10的芳基”中，所述的卤素优选氟、氯、溴或碘；卤素原子的个数优选1-6个，进一步优选5个；所述的“卤素取代的C5～C10的芳基”中，所述的C5～C10的芳基优选苯基；所述的“卤素取代的C5～C10的芳基”例如卤素取代的苯基；所述的卤素取代的苯基优选
Figure PCTCN2017075448-appb-000014
)或C3～C8的环烷基。
本发明中，所述的化合物Ia包含其各种立体异构体，较佳地，其立体结构优选为
Figure PCTCN2017075448-appb-000015
本发明中，所述的X例如卤素。
本发明中，所述的Y例如氢或C1-C6烷基(例如甲基)，又例如C1-C6烷基。
本发明中，所述的R1例如C1-C6烷基(又例如甲基)。
本发明中，所述的R2例如氢。
本发明中，所述的R3例如甲基。
本发明中，所述的R4例如羟基。
本发明中，所述的R例如取代或未取代的烷基(又例如甲基或乙基)、取代或未取代的芳基(又例如苯基)、取代或未取代的杂环基(又例如四氢吡咯-2-基)、
Figure PCTCN2017075448-appb-000016
Figure PCTCN2017075448-appb-000017
再例如取代或未取代的烷基(又例如甲基或乙基)、取代或未取代的芳基(又例如苯基)、取代或未取代的杂环基(又例如四氢吡咯-2-基)、
Figure PCTCN2017075448-appb-000018
本发明中，所述的L例如化学键、或、取代或未取代的-(CH2)m-，又例如-(CH2)m-；其中，m例如为1-10，又例如为1-5(例如亚甲基、
Figure PCTCN2017075448-appb-000019
)。
本发明中，所述的R7独立地例如氢、C1-C6烷基(例如甲基、异丙基、仲丁基或异丁基)或氨基酸侧链(例如Phenyl-CH2-或CH3-S-(CH2)2-)，又例如C1-C6烷基(例如甲基)。
本发明中，所述的R8独立地例如氢或C1-6烷基(例如甲基)，又例如C1-C6烷基。
本发明中，所述的R10独立地例如氢、Pr、-S-S-R13(例如
Figure PCTCN2017075448-appb-000020
)、
Figure PCTCN2017075448-appb-000021
Figure PCTCN2017075448-appb-000022
又例如-S-S-R13(例如
Figure PCTCN2017075448-appb-000023
)。
本发明中，所述的R13独立地例如烷基(例如C1～C6的烷基；所述的“C1～C6的烷基”例如甲基)。
本发明中，所述的Pr独立地例如叔丁氧羰基(Boc)、9-芴甲氧羰基(Fmoc)或乙酰基(Ac)。
本发明中，所述的R’例如杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂芳基(例如
Figure PCTCN2017075448-appb-000024
)、替代或未替代的“杂原子为氮或氧原子、杂原子数为1-4 个的C4～C10的杂环基”(例如
Figure PCTCN2017075448-appb-000025
)或卤素取代的C5～C10的芳基(例如卤素取代的苯基；所述的卤素取代的苯基例如
Figure PCTCN2017075448-appb-000026
)。
本发明中，所述的RCOOR’可为
Figure PCTCN2017075448-appb-000027
Figure PCTCN2017075448-appb-000028
Figure PCTCN2017075448-appb-000029
在如式I所示的化合物的制备方法中，所述的有机溶剂可为本领域常规的该类反应常规的有机溶剂，例如醚类溶剂、卤代烃类溶剂、芳烃类溶剂、腈类溶剂和酰胺类溶剂中的一种或多种。所述的醚类溶剂例如C2～C6的醚类溶剂，所述的C2～C6的醚类溶剂例如四氢呋喃。所述的卤代烃类溶剂例如C1～C4的卤代烃类溶剂，所述的C1～C4的卤代烃类溶剂例如C1～C4的氯代烃类溶剂，所述的C1～C4的氯代烃类溶剂例如二氯甲烷。所述的芳烃类溶剂例如C6～C8的芳烃类溶剂。所述的酰胺类溶剂例如N,N-二甲基甲酰胺。所述的腈类溶剂例如C2～C6的腈类溶剂。
在如式I所示的化合物的制备方法中，所述的有机溶剂与所述的化合物Ia的体积质量比例如1mL/g～200mL/g，进一步例如50mL/g～170mL/g(又例如70mL/g、80mL/g、或100mL/g)。
在如式I所示的化合物的制备方法中，所述的碱例如有机碱；所述的有机碱例如二(三甲基硅基)氨基锌(Zn(HMDS)2)、二(三甲基硅基)氨基锂(LiHMDS)、二(三甲基硅基)氨基钠(NaHMDS)、二(三甲基硅基)氨基钾(KHMDS)和二异丙基氨基锂(LDA)中的一种或多种，又例如二(三甲基硅基)氨基锌(Zn(HMDS)2)。
在如式I所示的化合物的制备方法中，所述的碱与所述的化合物Ia的摩尔比值例如1～10，进一步例如1～5(例如2.5～4，又例如3)。
在如式I所示的化合物的制备方法中，所述的RCOOR’与所述的化合物Ia的摩尔比值例如1～10，进一步例如1～4，再进一步例如2～3(例如2.5)。
在如式I所示的化合物的制备方法中，所述的酯交换反应的温度例如-78℃～100℃，进一步例如-20℃～50℃，再进一步例如20℃～30℃(例如25℃)。
在如式I所示的化合物的制备方法中，所述的酯交换反应的进程可以采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行监测，一般以化合物Ia含量不再减少时为反应终点，所述的酯交换反应的时间例如2小时～24小时，进一步例如8小时～16小时(例如12小时)。
如式I所示的化合物的制备方法可在保护气体存在的条件下进行，所述的保护气体可以为本领域中该类反应的常规保护气体，例如氩气、氮气、氦气和氖气中的一种或多种。
所述的如式I所示的化合物的制备方法可采用以下步骤：将所述的碱与所述的有机溶剂形成的混合物，加入到所述的化合物Ia与所述的有机溶剂形成的混合物中，搅拌(时间可为5分钟～10分钟)，再加入所述的RCOOR’与所述的有机溶剂形成的混合物，进行所述的酯交换反应，得到所述的化合物I即可。所述的加入的方式例如滴加，滴加的速度以反应体系的温度不超过40℃为准。
所述的如式I所示的化合物的制备方法可采用以下后处理步骤：反应结束后，淬灭反应、萃取、有机相干燥、除去溶剂得到化合物I。所述的淬灭反应例如采用稀盐酸，所述的稀盐酸的摩尔体积浓度例如1mol/L～2mol/L，所述的摩尔体积浓度是指氯化氢的摩尔量与稀盐酸体积的比例。所述的萃取、干燥和除去溶剂可以采用本领域中该类操作的常规方法，萃取采用的溶剂例如酯类溶剂，所述的酯类溶剂例如乙酸乙酯。所述的萃取的次数例如2～3次。所述的干燥采用的试剂可以为本领域中该类操作的常规试剂，例如无水硫酸钠。所述的除去溶剂例如采用减压浓缩的方法。
本发明中，所述的如式I所示的化合物的制备方法还可进一步包括以下步骤：将RCOOH与R’OH进行缩合反应，得到所述的RCOOR’即可；
RCOOH+HOR′→RCOOR′；
其中，R和R’同上所述。
所述的RCOOR’的制备方法可以为本领域中该类缩合反应的常规方法和条件，本发明中特别优选以下反应条件：在有机溶剂中，碱和/或缩合剂存在的条件下，将RCOOH与R’OH进行缩合反应，得到所述的RCOOR’即可。
在所述的RCOOR’的制备方法中，较佳地，所述的R为
Figure PCTCN2017075448-appb-000030
(即RCOOR’为
Figure PCTCN2017075448-appb-000031
RCOOH为
Figure PCTCN2017075448-appb-000032
)；
在所述的RCOOR’的制备方法中，所述的有机溶剂优选醚类溶剂、卤代烃类溶剂、芳烃类溶剂、腈类溶剂和酰胺类溶剂中的一种或多种，进一步优选醚类溶剂、卤代烃类溶剂和酰胺类溶剂中的一种或多种。所述的醚类溶剂优选C2～C6的醚类溶剂，所述的C2～C6的醚类溶剂优选***、1,4-二氧六环、叔丁基甲基醚、乙二醇二甲醚和四氢呋喃中的一种或多种，进一步优选四氢呋喃。所述的卤代烃类溶剂优选C1～C4的卤代烃类溶剂，所述的C1～C4的卤代烃类溶剂优选C1～C4的氯代烃类溶剂，所述的C1～C4的氯代烃类溶剂优选二氯甲烷。所述的芳烃类溶剂优选C6～C8的芳烃类溶剂，所述的C6～C8的芳烃类溶剂优选甲苯、二甲苯或苯。所述的酰胺类溶剂优选N,N-二甲基甲酰胺。所述的腈类溶剂优选C2～C6的腈类溶剂，所述的C2～C6的腈类溶剂优选乙腈。
在所述的RCOOR’的制备方法中，所述的有机溶剂与所述的RCOOH的体积质量比优选1mL/g～200mL/g，进一步优选30mL/g～50mL/g。
在所述的RCOOR’的制备方法中，所述的缩合剂优选1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)、二环己基碳二亚胺(DCC)、N,N'-二异丙基碳二亚胺(DIC)和N,N'-羰基二咪唑(CDI)中的一种或 多种。
在所述的RCOOR’的制备方法中，所述的缩合剂与所述的RCOOH的摩尔比值优选1～5，进一步优选1～2(例如1.3)。
在所述的RCOOR’的制备方法中，所述的碱优选有机碱或无机碱；所述的有机碱优选三乙胺、二异丙基乙胺、吡啶、4-二甲氨基吡啶(DMAP)和2，6-二甲基吡啶中的一种或多种。所述的无机碱优选碳酸钾和/或碳酸钠。
在所述的RCOOR’的制备方法中，所述的碱与所述的RCOOH的摩尔比值优选1～5，进一步优选1～2。
在所述的RCOOR’的制备方法中，所述的R’OH与所述的RCOOH的摩尔比值优选1～5，进一步优选1～2(例如1.3)。
在所述的RCOOR’的制备方法中，所述的缩合反应的温度优选-78℃～100℃，进一步优选-20℃～50℃，再进一步优选20℃～30℃(例如25℃)。
在所述的RCOOR’的制备方法中，所述的缩合反应的进程可以采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行监测，一般以化合物RCOOH消失时为反应终点，所述的缩合反应的时间优选2小时～24小时，进一步优选2小时～12小时。
所述的RCOOR’的制备方法优选包括以下后处理步骤：反应结束后，除去溶剂、柱色谱分离，得到纯化后的RCOOR’。所述的除去溶剂可以采用本领域中该类操作的常规方法，优选采用减压浓度的方法。所述的柱色谱分离可以采用本领域中该类操作的常规方法和条件。所述的柱色谱分离采用的溶剂优选烷烃类溶剂与酯类溶剂的混合溶剂，所述的烷烃类溶剂优选石油醚，所述的酯类溶剂优选乙酸乙酯。所述的“烷烃类溶剂与酯类溶剂的混合溶剂”中所述的烷烃类溶剂与所述的酯类溶剂的体积比值优选1～2。
本发明还提供了一种RCOOR’的制备方法，其包括下述步骤：将RCOOH与R’OH进行缩合反应，得到RCOOR’即可；
RCOOH+HOR′→RCOOR′；
其中，R和R’同上所述。
所述的RCOOR’的制备方法中，所述的缩合反应的条件同上所述。
本发明还提供了一种如式II所示的化合物的制备方法，其包括下述步骤：
(1)按照上述化合物I的制备方法制备化合物I；
(2)将所述的化合物I进行脱除氨基保护基(即Pr)的反应，得到化合物II即可；
Figure PCTCN2017075448-appb-000033
其中，化合物I的立体结构、X、Y、R1、R2、R3、R4、R7、R8、Pr和“α碳原子的构型”的定义均同上所述。
在如式II所示的化合物的制备方法中，所述的脱除氨基保护基的反应可以采用本领域中该类反应的常规方法和条件。
例如，当所述的氨基保护基为Fmoc时，所述的如式II所示的化合物的制备方法特别优选以下反应条件：在有机溶剂中，碱存在的条件下，将化合物I进行脱除氨基保护基的反应，得到化合物II即可。所述的有机溶剂优选腈类溶剂，所述的腈类溶剂优选乙腈。所述的有机溶剂与所述的化合物I的体积质量比优选1mL/g～100mL/g(例如38mL/g)。所述的碱优选有机碱，所述的有机碱优选二乙胺。所述的有机碱与所述的化合物I的摩尔比值优选1～100。所述的脱除Pr的反应的温度优选-5℃～0℃。所述的脱除氨基保护基的反应的进程可以采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行监测，一般以化合物I消失时为反应终点，所述的脱除氨基保护基的反应的时间优选5分钟～1小时，进一步优选10分钟小时～30分钟。
本发明还提供了一种如式III所示的化合物的制备方法，其为方法1或方法2；
方法1包括以下步骤：
(S1)按照上述的如式II所示的化合物的制备方法制备化合物II；
(S2)将所述的化合物II与化合物R10-L-COOH进行缩合反应，得到化合物III即可；
方法2包括以下步骤：
(S1’)按照上述的如式II所示的化合物的制备方法制备化合物II；
(S2’)将所述的化合物II、与“化合物R10-L-COOR9、R10-L-COCl或
Figure PCTCN2017075448-appb-000034
”进行缩合反应，得到化合物III即可；
Figure PCTCN2017075448-appb-000035
其中，化合物II的立体结构、X、Y、L、R1、R2、R3、R4、R7、R8、R10、R11和“α碳原子的构型”的定义均同上所述；
R9为C1～C6的烷基、C5～C10的芳基、杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂芳基(例如
Figure PCTCN2017075448-appb-000036
)、替代或未替代的“杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂环基”(所述的“替代”是指杂环基中一个或多个-CH2-基团被
Figure PCTCN2017075448-appb-000037
所替代；所述的“替代的杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂环基”例如
Figure PCTCN2017075448-appb-000038
)、卤素取代的C5～C10的芳基(所述的“卤素取代的C5～C10的芳基”中，所述的卤素优选氟、氯、溴或碘；所述的卤素原子的个数优选1-6个，进一步优选5个；所述的“卤素取代的C5～C10的芳基”中，所述的C5～C10的芳基优选苯基；所述的“卤素取代的C5～C10的芳基”例如卤素取代的苯基，所述的卤素取代的苯基优选
Figure PCTCN2017075448-appb-000039
)或C3～C8的环烷基。
在如式III所示的化合物的制备方法中，所述的R11优选C1～C4的烷基(所述的C1～C4的烷基优选异丙基或异丁基)。
在如式III所示的化合物的制备方法中，所述的R10优选-S-S-R13(例如
Figure PCTCN2017075448-appb-000040
)，所述的L优 选-(CH2)m-(例如
Figure PCTCN2017075448-appb-000041
)。
方法1可以为本领域中该类缩合反应的常规方法和条件，本发明中特别优选以下反应方法和条件：有机溶剂中，缩合剂存在的条件下，将化合物II与化合物R10-L-COOH进行缩合反应，得到化合物III即可；
方法1中，所述的有机溶剂优选醚类溶剂、卤代烃类溶剂、芳烃类溶剂、腈类溶剂和酰胺类溶剂中的一种或多种。所述的醚类溶剂优选C2～C6的醚类溶剂，所述的C2～C6的醚类溶剂优选四氢呋喃。所述的卤代烃类溶剂优选C1～C4的卤代烃类溶剂，所述的C1～C4的卤代烃类溶剂优选C1～C4的氯代烃类溶剂；所述的C1～C4的氯代烃类溶剂优选二氯甲烷。所述的芳烃类溶剂优选C6～C8的芳烃类溶剂。所述的酰胺类溶剂优选N,N-二甲基甲酰胺。所述的腈类溶剂优选C2～C6的腈类溶剂。
方法1中，所述的有机溶剂与所述的化合物II的体积质量比优选1mL/g～100mL/g(例如60mL/g)。
方法1中，所述的缩合剂优选1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)、二环己基碳二亚胺(DCC)、N,N'-二异丙基碳二亚胺(DIC)和N,N'-羰基二咪唑(CDI)中的一种或多种。
方法1中，所述的缩合剂与所述的化合物II的摩尔比值优选1～5，进一步优选2～3。
方法1中，所述的缩合反应的温度优选-78℃～100℃，进一步优选-20℃～50℃，再进一步优选20℃～30℃(例如25℃)。
方法1中，所述的缩合反应的进程可以采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行监测，一般以化合物II消失时为反应终点，所述的缩合反应的时间优选2小时～24小时，进一步优选2小时～16小时，例如8小时～12小时。
方法1所述的制备方法优选在保护气体存在的条件下进行，所述的保护气体可以为本领域中该类反应的常规保护气体，优选氩气、氮气、氦气和氖气中的一种或多种。
方法1所述的制备方法优选采用以下步骤：将缩合剂加入到化合物II、化合物R10-L-COOH与有机溶剂形成的混合物中，进行缩合反应，得到化合物III即可。
方法1所述的制备方法优选采用以下后处理步骤：反应结束后，除去溶剂、柱色谱分离，得到纯化后的化合物III。所述的除去溶剂可以采用本领域中该类操作的常规方法，优选采用减压浓度的方法。所述的柱色谱分离可以采用本领域中该类操作的常规方法和条件。所述的柱色谱分离采用的溶剂优选卤代烃类溶剂与醇类溶剂的混合溶剂，所述的卤代烃类溶剂优选氯代烃类溶剂，所述的氯代烃类溶剂优选二氯甲烷。所述的醇类溶剂优选甲醇。所述的“卤代烃类溶剂与醇类溶剂的混合溶剂”中所述的卤代烃类溶剂与所述的醇类溶剂的体积比值优选10～20。
方法2可以为本领域中该类缩合反应的常规方法和条件，本发明中特别优选以下反应方法和条件：有机溶剂中，碱存在的条件下，将化合物II、与“化合物R10-L-COOR9、R10-L-COCl或
Figure PCTCN2017075448-appb-000042
”进行缩合反应，得到化合物III即可；
方法2中，所述的有机溶剂优选醚类溶剂、卤代烃类溶剂、芳烃类溶剂、腈类溶剂和酰胺类溶剂中的一种或多种。所述的醚类溶剂优选C2～C6的醚类溶剂，所述的C2～C6的醚类溶剂优选四氢呋喃。所述的卤代烃类溶剂优选C1～C4的卤代烃类溶剂，所述的C1～C4的卤代烃类溶剂优选C1～C4的氯代烃类溶剂；所述的C1～C4的氯代烃类溶剂优选二氯甲烷。所述的芳烃类溶剂优选C6～C8的芳烃类溶剂。所述的酰胺类溶剂优选N,N-二甲基甲酰胺。所述的腈类溶剂优选C2～C6的腈类溶剂。
方法2中，所述的有机溶剂与所述的化合物II的体积质量比优选1mL/g～100mL/g。
方法2中，所述的化合物R10-L-COOR9、R10-L-COCl或
Figure PCTCN2017075448-appb-000043
与所述的化合物II的摩尔比值优选1～5，进一步优选2～3。
方法2中，所述的缩合反应的温度优选0～35℃，进一步优选20℃～30℃。
方法2中，所述的缩合反应的进程可以采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行监测，一般以化合物II消失时为反应终点，所述的缩合反应的时间优选5小时～24小时，进一步优选2小时～16小时，例如8小时～12小时。
方法2所述的制备方法优选在保护气体存在的条件下进行，所述的保护气体可以为本领域中该类反应的常规保护气体，优选氩气、氮气、氦气和氖气中的一种或多种。
方法2所述的制备方法优选采用以下步骤：将化合物R10-L-COOR9、R10-L-COCl或
Figure PCTCN2017075448-appb-000044
加入到化合物II与有机溶剂形成的混合物中，进行缩合反应，得到化合物III即可。
方法2所述的制备方法优选采用以下后处理步骤：反应结束后，除去溶剂、柱色谱分离，得到纯化后的化合物III。所述的除去溶剂可以采用本领域中该类操作的常规方法，优选采用减压浓度的方法。所述的柱色谱分离可以采用本领域中该类操作的常规方法和条件。所述的柱色谱分离采用的溶剂优选卤代烃类溶剂与醇类溶剂的混合溶剂，所述的卤代烃类溶剂优选氯代烃类溶剂，所述的氯代烃类溶剂优选二氯甲烷。所述的醇类溶剂优选甲醇。所述的“卤代烃类溶剂与醇类溶剂的混合溶剂”中所述的卤代烃类溶剂与所述的醇类溶剂的体积比值优选10～20。
本发明还提供了一种如式IV所示的化合物的制备方法，其包括以下步骤：
(S1”)按照上述的如式III所示的化合物的制备方法制备化合物III；
(S2”)将所述的化合物III进行还原反应，得到化合物IV即可；
Figure PCTCN2017075448-appb-000045
其中，化合物III的立体结构、X、Y、R1、R2、R3、R4、R7、R8、R13和“α碳原子的构型”的定义均同上所述。
在如式IV所示的化合物的制备方法中，所述的还原反应的方法和条件可以为本领域中该类还原反应的常规方法和条件，本发明中特别优选以下反应方法和条件：有机溶剂和水中，还原剂和缓冲盐存在的条件下，将化合物III进行还原反应，得到化合物IV即可；
所述的还原反应中，所述的有机溶剂优选酯类溶剂、醇类溶剂醚类溶剂、卤代烃类溶剂、芳烃类溶剂、腈类溶剂和酰胺类溶剂中的一种或多种。所述的醚类溶剂优选C2～C6的醚类溶剂，所述的C2～C6的醚类溶剂优选四氢呋喃。所述的卤代烃类溶剂优选C1～C4的卤代烃类溶剂，所述的C1～C4的卤代烃类溶剂优选C1～C4的氯代烃类溶剂；所述的C1～C4的氯代烃类溶剂优选二氯甲烷。所述的芳烃类溶剂优选C6～C8的芳烃类溶剂。所述的酰胺类溶剂优选N,N-二甲基甲酰胺。所述的腈类溶剂优选C2～C6的腈类溶剂。所述的醇类溶剂优选甲醇。所述的酯类溶剂优选乙酸乙酯。
所述的还原反应中，所述的有机溶剂与所述的化合物III的体积质量比优选1mL/g～100mL/g。
所述的还原反应中，所述的有机溶剂优选由醇类溶剂和酯类溶剂组成，所述的醇类溶剂与酯类溶剂的体积比为1～2.
所述的还原反应中，所述的还原剂优选二硫代苏糖醇(DTT)。
所述的还原反应中，所述的还原剂与所述的化合物III的摩尔比值优选8。
所述的还原反应中，所述的还原反应的温度优选-78℃～100℃，进一步优选-20℃～50℃，再进一步优选20℃～30℃(例如25℃)。
所述的还原反应中，所述的还原反应的进程可以采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行监测，一般以化合物III消失时为反应终点，所述的缩合反应的时间例如48小时。
所述的还原反应优选在保护气体存在的条件下进行，所述的保护气体可以为本领域中该类反应的常规保护气体，优选氩气、氮气、氦气和氖气中的一种或多种。
所述的还原反应优选采用以下后处理步骤：反应结束后，淬灭反应、萃取、浓缩、柱色谱分离，得到纯化后的化合物IV。
本发明还提供了一种化合物RCOOR’，其中，R’和R的定义均同上所述。
较佳地，所述的RCOOR’如式Ic所示：
Figure PCTCN2017075448-appb-000046
其中，R’、R7、R8、Pr和“α碳原子的构型”的定义均同上所述。
较佳地，所述的RCOOR’为
Figure PCTCN2017075448-appb-000047
Figure PCTCN2017075448-appb-000048
Figure PCTCN2017075448-appb-000049
本发明中，如无特别说明，May是指美登醇，结构式为
Figure PCTCN2017075448-appb-000050
本发明中，如无特别说明，Fmoc表示9-芴甲氧羰基，结构式为
Figure PCTCN2017075448-appb-000051
本发明中，如无特别说明，Bt表示
Figure PCTCN2017075448-appb-000052
本发明中，如无特别说明，所述的术语“酰基”表示烷基或氢、与羰基连接后的生成基团，即“R(C＝O)-”，R为烷基或氢。
本发明中，如无特别说明，所述的“被氧代基团取代”是指基团中一个或多个-CH2-基团被
Figure PCTCN2017075448-appb-000053
所替代。
本发明中，如无特别说明，所述的术语“氧杂烷基”表示烷基中的一个或多个-CH2-被-O-取代后的生成基团。
本发明中，如无特别说明，所述的术语“烷基”为包括具有指定碳原子数目的支链或直链的饱和脂肪族烃基；如“C1-C4烷基”的定义为包括在直链或者支链结构中具有1、2、3或4个碳原子的基团。例如，“C1-C4烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基等。
本发明中，如无特别说明，所述的术语“烷氧基”表示烷基与氧原子连接后的生成基团，即“RO-”，R为烷基。
本发明中，如无特别说明，所述的确定了碳数范围的“Cx1-y1”的烷基(x1和y1为整数)，如“C1-C4烷基”，均表示未包含取代基的C1-C4烷基。
本发明中，如无特别说明，所述的术语“卤素”表示氟、氯、溴、碘或砹。
本发明中，如无特别说明，所述的术语“氰基”表示
Figure PCTCN2017075448-appb-000054
本发明中，如无特别说明，所述的术语“苄基”表示
Figure PCTCN2017075448-appb-000055
本发明中，如无特别说明，所述的术语“环烷基”表示指全碳单环或多环基团，其中每个环为饱和。优选3～20个碳所形成的1～3个环的环烷基，更优选3～10个碳，例如：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸烷和环十二烷基。
本发明中，如无特别说明，所述的术语“巯基”表示
Figure PCTCN2017075448-appb-000056
本发明中，如无特别说明，所述的术语“羟基”表示
Figure PCTCN2017075448-appb-000057
本发明中，如无特别说明，所述的术语“芳基”表示任何稳定的在各环中可高达7个原子的单环或者双环碳环，其中至少一个环是芳香环。上述芳基单元的实例包括苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基或者苊基(acenaphthyl)。可以理解，在芳基取代基是二环取代基，且其中一个环是非芳香环的情况中，连接是通过芳环进行的。
本发明中，如无特别说明，所述的术语“环烯基”表示全碳单环或多环基团，其中每个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子体系。优选3～20个碳所形成的1～3个环的环烯基，更优选3～10个碳，例如：环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基、环癸烯和环十二烯基。
本发明中，如无特别说明，所述的术语“杂芳基”表示各环中可高达7个原子的稳定单环或者二环，其中至少一个环是芳香环并且含有1～4个选自O、N、和S的杂原子。在此定义范围内的杂芳基包括但不限于：吖啶、咔唑、噌啉、咔啉、喹喔啉、咪唑、吡唑、吡咯、吲哚、二氢吲哚、苯并***、苯并咪唑、呋喃、噻吩、异噻唑、苯并噻吩、二氢苯并噻吩、苯并呋喃、异苯并呋喃、苯并噁唑、苯并呋咱、苯并吡唑、喹啉、异氮杂茚、异喹啉、噁唑、噁二唑、异噁唑、吲哚、吡嗪、吡啶并吡啶、四唑并吡啶、哒嗪、吡啶、萘嘧啶、嘧啶、吡咯、四唑、噻二唑、噻唑、噻吩、***、喹唑啉、四氢喹啉、二氢苯并咪唑、二氢苯并呋喃、二氢苯并噁唑、二氢喹啉。“杂芳基”还应当理解为包括任何含氮杂芳环的N-氧化物衍生物。在其中杂芳基取代基是二环取代基并且一个环是非芳香环或者不包含杂原子的情况下，可以理解，连接分别通过芳环或者通过环中的杂原子进行。所述的“杂芳基”可以经其中的碳原子或者杂原子与其他基团进行连接。
本发明中，如无特别说明，所述的术语“杂环”或“杂环基”表示在此单独或作为另一个基团的一部分使用时，指包含1～4个杂原子(如氮、氧和硫中的一种或多种)的4～12元单环或多环基团， 其中每个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子体系。此外，任何杂环烷基环可以稠合于环烷基、芳基、杂芳基或杂环烷基环上。在此定义范围内的杂环烷基包括但不限于：噁唑啉、氧环丁基、吡喃基、四氢吡喃基、氮杂环丁烷基、1,4-二噁烷基、六氢氮杂草基、哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、二氢呋喃基、二氢咪唑基、二氢吲哚基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢***基、二氢氮杂环丁烷基、四氢呋喃基和四氢噻吩基及其N-氧化物。杂环基可以经其中的碳原子或者杂原子与其他基团进行连接。
本发明中，如无特别说明，HMDS表示六甲基二硅基。
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。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的制备方法反应条件温和、合成步骤简单、反应转化率高、反应过程中未观察到消旋现象、产率高、后处理简单、得到的产品纯度高、生产成本低，适合于工业化生产。
具体实施方式
实施例1 DM4的制备
Figure PCTCN2017075448-appb-000058
实验步骤
化合物2的合成：
Figure PCTCN2017075448-appb-000059
化合物1(5g,15.38mmol)溶于150mL二氯甲烷中，加入1-羟基苯并***(HOBt)(2.18g,16.15mmol)和1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)(3.82g,20mmol)。反应液室温(25℃)搅拌过夜。减压移除溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯＝1：1)纯化得5.5g产物2，为白色固体，收率81％，纯度96％(LCMS,214nm)。LCMS(ESI)m/z 465.1(M+Na)+,1H NMR(400MHz,CDCl3)δppm7.77-7.74(m,2H),7.61-7.55(m,2H),7.42-7.37(m,2H),7.32-7.27(m,6H),4.94(q,J＝9.6Hz,1H),4.60-4.52(m,2H),4.31-4.27(m,1H),3.09(s,3H),1.68(d,J＝7.2Hz,3H).
化合物3的合成：
Figure PCTCN2017075448-appb-000060
氩气保护下，将美登醇(2g,3.55mmol)溶于100mL干燥四氢呋喃中，室温下逐滴缓慢加入Zn(HMDS)2(5.7mL,14.2mmol)。反应液室温25℃搅拌5分钟，将化合物2(4g,9.05mmol)溶于40mL四氢呋喃中逐滴缓慢加入，反应液室温(25℃)搅拌过夜。缓慢加入1M稀盐酸100mL淬灭反应，乙酸乙酯萃取3次(100mL×3)，合并有机相，无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝10:1)得1.3g产品3，为浅棕黄色固体，产率42％，回收美登醇760mg。LC-MS(ESI)m/z872.3(M+H)+。HPLC：Chiral OD-H Column(4.6×150mm)detected at 254nm；CO2/MeOH＝55:45；保留时间:t(S)＝2.85min,ee:>99.9％,purity:99％by LCMS(254nm)。
需说明的是，2.85min出峰的产物继续反应得到的化合物6以及DM4，分别与商品化的DM4-SMe、DM4(其结构为
Figure PCTCN2017075448-appb-000061
)的核磁及手性HPLC图谱保留时间一致，因此确认2.85min出峰的产物为S构型。
1H NMR(400MHz,CDCl3)δppm 7.72(t,J＝5.6Hz,2H),7.49(d,J＝6.4Hz,1H),7.42(d,J＝6.4Hz,1H),7.37(t,J＝6.0Hz,1H),7.33(t,J＝6.4Hz,1H),7.22(t,J＝6.0Hz,1H),7.16(t,J＝6.0Hz,1H),6.79(s, 1H),6.70(d,J＝8.8Hz,1H),6.65(s,1H),6.43&6.41(dd,J1＝12.3Hz,J2＝9.2Hz,1H),6.27(s,1H),5.66&5.64(dd,J1＝12.0Hz,J2＝7.2Hz,1H),5.02(q,J＝6.4Hz,1H),4.77-4.74(m,2H),4.25(t,J＝9.6Hz,1H),4.18-4.14(m,2H),3.98(s,3H),3.59(d,J＝10.0Hz,1H),3.50(d,J＝7.6Hz,1H),3.36(s,3H),3.08(d,J＝10.0Hz,1H),3.01(d,J＝7.6Hz,1H),2.89(s,3H),2.65(s,3H),2.54(t,J＝10.4Hz,1H),2.15&2.12(dd,J1＝11.2Hz,J2＝2.8Hz,1H),1.54(d,J＝11.2Hz,2H),1.47-1.41(m,2H),1.29(t,J＝5.6Hz,6H),1.22(t,J＝10.4Hz,1H),0.78(s,3H).
CN201310081867.X分离出了化合物3的两个非对映异构体，且两个非对映异构体的氨基酸侧链手性位置H的化学位移有非常明显的差别，化合物3(S构型)中氨基酸侧链手性位置H的化学位移是5.03(1H,q,J＝6.8Hz)，本实施例所得到的产物的化学位移为5.02，与该专利报道一致，据此也可得出本实施例的产物构型为S构型。
化合物4的合成：
Figure PCTCN2017075448-appb-000062
上一步2.85min出峰的反应产物3(1.3g,1.5mmol)溶于50mL乙腈中，冰水浴冷却至0℃，加入15mL二乙胺，反应液0℃搅拌10分钟。室温减压浓缩，加入100mL饱和碳酸氢钠溶液淬灭反应，乙酸乙酯萃取3次(70mL×3)，合并有机相，无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝10:1)得870mg产品4，为浅棕黄色固体，产率90％，纯度94％(LCMS)。LCMS(ESI)m/z649.7(M+H)+。
HPLC：手性柱Eclipse XDB-C18(5μm,4.6*150mm)，流动相A：0.01％三氟乙酸水溶液，流动相B：0.01％三氟乙酸乙腈溶液，梯度洗脱0→2min，A:B＝95:5；2→9min，A:B＝95:5→5:95；9→15min，A:B＝5:95。紫外吸收波长214nm，柱温40℃，流速1.2ml/min，进样量10μL，MS(ESI,Pos mode,110to 1500amu)，保留时间t(S)＝7.01min。
将化合物4溶于20mL乙腈中，加入0.5M稀盐酸10mL，减压移除乙腈，剩余物冷冻干燥可以得到化合物4的盐酸盐，为浅黄色固体。
化合物6的合成：
Figure PCTCN2017075448-appb-000063
上一步反应产物4(870mg,1.34mmol)和化合物5(780mg,4.02mmol)溶于50mL二氯甲烷中，加入1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)、(768mg,4.02mmol)，反应液氮气保护下室温25℃搅拌过夜。减压移除溶剂，剩余物硅胶柱层析纯化(二氯甲烷/甲醇＝20:1)得1.04g产品6，为白色固体，产率94％。LCMS(ESI)m/z 827.3(M+H)+,1H NMR(400MHz,CDCl3)δppm 6.82(s,1H),6.74(d,J＝8.8Hz,1H),6.63(s,1H),6.44&6.42(dd,J1＝15.6Hz,J2＝11.2Hz,1H),6.39(s,1H),5.68&5.66(dd,J1＝12.4Hz,J2＝7.2Hz,1H),5.40(q,J＝7.2Hz,1H),4.78(d,J＝7.6Hz,1H),4.29(t,J＝11.2Hz,1H),3.99(s,3H),3.65(d,J＝9.6Hz,1H),3.51(d,J＝7.2Hz,1H),3.36(s,3H),3.23(s,3H),3.12(d,J＝10.4Hz,1H),3.04(d,J＝9.6Hz,1H),2.86(s,3H),2.61(t,J＝9.6Hz,1H),2.52-2.45(m,1H),2.37-2.30(m,1H),2.33(s,3H),2.21&2.17(dd,J1＝11.2Hz,J2＝2.4Hz,1H),2.01-1.95(m,1H),1.86-1.78(m,1H),1.64(s,3H),1.29(d,J＝5.2Hz,6H),1.25(d,J＝3.2Hz,6H),0.80(s,3H).
J.Med.Chem.2006,49,4392-4408报道了化合物6的两个非对映异构体，且两个非对映异构体的氨基酸侧链手性位置H的化学位移有非常明显的差别，本实施例所得到的产物的化学位移，与该文献记载的S构型的化学位移报道一致，据此也可得出本实施例的产物构型为S构型。
HPLC：手性柱Eclipse XDB-C18(5μm,4.6*150mm)，流动相A：0.01％三氟乙酸水溶液，流动相B：0.01％三氟乙酸乙腈溶液，梯度洗脱0→2min，A:B＝95:5；2→9min，A:B＝95:5→5:95；9→15min，A:B＝5:95。紫外吸收波长214nm，柱温40℃，流速1.2ml/min，进样量10μL，MS(ESI,Pos mode,110to 1500amu)，保留时间t(S)＝9.93min。
化合物DM4的合成：
Figure PCTCN2017075448-appb-000064
上一步反应产物5(1.04g,1.26mmol)溶于50mL乙酸乙酯中，将二硫代苏糖醇(DTT)(1.55g,10.06mmol)溶于50mL甲醇中加入，加入PH＝7.5的磷酸钾缓冲溶液94mL。反应液在氮气保护下 (25℃)搅拌2天。加入PH＝6.0的磷酸钾缓冲溶液80mL淬灭反应。乙酸乙酯萃取3次(80mL×3)，合并有机相，饱和食盐水洗涤3次(50mL×3)，无水硫酸钠干燥，浓缩。粗产品使用制备HPLC(CH3CN in H2O-0.05％三氟乙酸(TFA)from 5％to 95％)纯化得到610mg产物DM4，为白色固体，产率62％。LCMS(ESI)m/z 780.7(M+H)+.1H NMR(400MHz,CDCl3)δppm 6.83(s,1H),6.74(d,J＝11.2Hz,1H),6.65(s,1H),6.55(s,1H),6.44&6.42(dd,J1＝15.6Hz,J2＝11.2Hz,1H),5.69&5.65(dd,J1＝15.2Hz,J2＝11.2Hz,1H),5.41(q,J＝7.2Hz,1H),4.80&4.77(dd,J1＝12.0Hz,J2＝3.2Hz,1H),4.29(t,J＝11.2Hz,1H),3.99(s,3H),3.63(d,J＝12.8Hz,1H),3.51(d,J＝8.8Hz,1H),3.36(s,3H),3.24(s,3H),3.12(d,J＝12.4Hz,1H),3.04(d,J＝9.6Hz,1H),2.89(s,3H),2.64-2.56(m,2H),2.51-2.43(m,1H),2.21&2.17(dd,J1＝14.4Hz,J2＝3.2Hz,1H),2.00-1.92(m,1H),1.86-1.78(m,1H),1.64(s,3H),1.59(d,J＝14.0Hz,1H),1.49-1.40(m,1H),1.34(s,3H),1.33(s,3H),1.31-1.28(m,6H),0.80(s,3H).
J.Med.Chem.2006,49,4392-4408报道了化合物DM4的两个非对映异构体，且两个非对映异构体的氨基酸侧链手性位置H的化学位移有非常明显的差别，本实施例所得到的产物的化学位移，与该文献记载的S构型的化学位移报道一致，据此也可得出本实施例的产物构型为S构型。
HPLC：手性柱Eclipse XDB-C18(5μm,4.6*150mm)，流动相A：0.01％三氟乙酸水溶液，流动相B：0.01％三氟乙酸乙腈溶液，梯度洗脱0→2min，A:B＝95:5；2→9min，A:B＝95:5→5:95；9→15min，A:B＝5:95。紫外吸收波长214nm，柱温40℃，流速1.2ml/min，进样量10μL，MS(ESI,Pos mode,110to 1500amu)，保留时间t(S)＝9.46min。
实施例2 化合物3的制备
Figure PCTCN2017075448-appb-000065
实验步骤
化合物2的合成：
Figure PCTCN2017075448-appb-000066
乙酸(500mg,8.33mmol)溶于50mL二氯甲烷中，加入1-羟基苯并***(HOBt)(1.08g,7.97mmol)和1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)(2.08g,10.83mmol)。反应液室温(25℃)搅拌过夜。减压移除溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯＝1：1)纯化得1g产物2，为白色固体，收率68％。LCMS(ESI)m/z＝178.1(M+H)+，1H NMR(400MHz,CDCl3)δ8.41(d,J＝8.4Hz,1H),8.08–7.93(m, 1H),7.79(t,J＝7.6Hz,1H),7.57(dd,J1＝15.6,J2＝7.6Hz,1H),2.78(s,3H).
化合物3的合成：
Figure PCTCN2017075448-appb-000067
氩气保护下，将美登醇(50mg,0.089mmol)溶于4mL干燥四氢呋喃中，室温下逐滴缓慢加入Zn(HMDS)2(0.15mL,0.355mmol)。反应液室温搅拌5分钟，将化合物2(40mg,0.23mmol)溶于30mL四氢呋喃中逐滴缓慢加入，反应液室温(25℃)搅拌过夜。缓慢加入1M稀盐酸5mL淬灭反应，乙酸乙酯萃取3次(20mL×3)，合并有机相，无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝10:1)得26mg产品3，为浅黄色固体，产率48％，回收美登醇20mg。LC-MS(ESI)m/z＝607.3(M+H)+。purity:97.8％by LCMS(254nm)。1H NMR(400MHz,MeOD)δppm 7.17(s,1H),6.92(s,1H),6.65(dd,J1＝12.4Hz,J2＝8.8Hz,1H),6.30(d,J＝9.2Hz,1H),5.61(dd,J1＝12.8Hz,J2＝7.6Hz,1H),4.79(dd,J1＝9.6,J2＝2.0Hz,1H),4.22(t,J＝8.8Hz,1H),4.00(s,3H),3.60(t,J＝7.2Hz,2H),3.39(s,3H),3.34(s,3H),3.18(s,3H),2.77(d,J＝8.0Hz,1H),2.60(t,J＝9.6Hz,1H),2.24(s,3H),2.18-2.10(m,1H),1.75(s,3H),1.53-1.63(m,3H),1.25(d,J＝4.8Hz,3H),0.90(s,3H).
实施例3 化合物3的制备
Figure PCTCN2017075448-appb-000068
实验步骤
化合物2的合成：
Figure PCTCN2017075448-appb-000069
化合物1(490mg,4mmol)溶于40mL二氯甲烷中，加入1-羟基苯并***(HOBt)(567mg,4.2mmol) 和1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)(993mg,5.2mmol)。反应液室温(25℃)搅拌过夜。减压移除溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯＝2：1)纯化得950mg产物2，为白色固体，收率93％，纯度98％(LCMS,214nm)。LCMS(ESI)m/z＝240.1(M+H)+,1H NMR(400MHz,CDCl3)δppm 8.29(d,J＝8.0Hz,2H),8.11(d,J＝8.0Hz,1H),7.79(t,J＝8.0Hz,1H),7.64-7.55(m,3H),7.50-7.43(m,2H).
化合物3的合成：
Figure PCTCN2017075448-appb-000070
氩气保护下，将美登醇(40mg,0.071mmol)溶于2mL干燥四氢呋喃中，室温下逐滴缓慢加入Zn(HMDS)2(0.1mL,0.284mmol)。反应液室温25℃搅拌5分钟，将化合物2(47mg,0.18mmol)溶于2mL四氢呋喃中逐滴缓慢加入，反应液室温(25℃)搅拌过夜。缓慢加入1M稀盐酸5mL淬灭反应，乙酸乙酯萃取3次(15mL×3)，合并有机相，无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝20:1)得21mg产品3，为白色固体，产率45％，回收美登醇16mg。LC-MS(ESI)m/z＝669.7(M+H)+。1H NMR(400MHz,CDCl3)δppm 8.06(d,J＝7.2Hz,2H),7.67(t,J＝7.2Hz,1H),7.54(t,J＝8.0Hz,2H),7.08(s,1H),6.86(s,1H),6.68(s,1H),6.31&6.27(dd,J1＝15.2Hz,J2＝10.8Hz,1H),5.82(d,J＝11.2Hz,1H),5.02&4.99(dd,J1＝12.0Hz,J2＝3.6Hz,1H),4.77&4.73(dd,J1＝15.6Hz,J2＝9.2Hz,1H),4.32(d,J＝11.2Hz,1H),4.01(s,3H),3.46(d,J＝12.8Hz,1H),3.35(d,J＝8.8Hz,1H),3.25(s,3H),3.21(s,3H),3.16(d,J＝9.6Hz,1H),2.76(t,J＝12.8Hz,1H),2.37&2.34(dd,J1＝15.6Hz,J2＝2.8Hz,1H),1.66(s,3H),1.62(d,J＝13.6Hz,1H),1.54-1.43(m,1H),1.31(d,J＝6.4Hz,3H),1.17(t,J＝12.8Hz,1H),0.84(s,3H).
实施例4 化合物3的制备
Figure PCTCN2017075448-appb-000071
实验步骤
化合物2的合成：
Figure PCTCN2017075448-appb-000072
化合物1(100mg,0.32mmol)溶于10mL二氯甲烷中，加入1-羟基苯并***(HOBt)(48mg,0.35mmol)和1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)(80mg,0.42mmol)。反应液室温(25℃)搅拌过夜。减压移除溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯＝1：1)纯化得110mg产物2，为白色固体，收率80％。LCMS(ESI)m/z＝451.0(M+Na)+。
化合物3的合成：
Figure PCTCN2017075448-appb-000073
氩气保护下，将美登醇(30mg,0.053mmol)溶于5mL干燥四氢呋喃中，室温下逐滴缓慢加入Zn(HMDS)2(108uL,0.26mmol)。反应液室温25℃搅拌5分钟，将化合物2(57mg,0.13mmol)溶于2mL四氢呋喃中逐滴缓慢加入，反应液室温(25℃)搅拌过夜。缓慢加入1M稀盐酸10mL淬灭反应，乙酸乙酯萃取3次(20mL×3)，合并有机相，无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝10:1)得20mg产品3，为浅棕黄色固体，产率43％，回收美登醇12mg。LC-MS(ESI)m/z＝858.2(M+H)+。
1H NMR(400MHz,CDCl3)δppm 7.76(d,J＝7.6Hz,2H),7.59(dd,J1＝2.0Hz,J2＝7.2Hz,2H),7.40(t,J＝7.6Hz,2H),7.31(t,J＝7.2Hz,2H),6.81(d,J＝15.6Hz,2H),6.48-6.41(m,1H),6.29-6.24(m,2H),5.77-5.71(m,1H),4.98(dd,J1＝2.8Hz,J2＝12Hz,1H),4.46-4.35(m,2H),4.30-4.22(m,2H),4.20-4.16(m,1H),4.03-3.94(m,5H),3.52-3.49(m,2H),3.34(s,3H),3.20-3.14(m,4H),3.02(s,3H),2.82-2.77(m,1H),2.53(t,J＝12.4Hz,1H),2.20(dd,J1＝2.4Hz,J2＝14Hz,1H),1.67-1.61(m,2H),1.51-1.45(m,1H),1.33-1.25(m,6H),0.86(s,3H).
实施例5 化合物3的制备
Figure PCTCN2017075448-appb-000074
实验步骤
化合物2的合成：
Figure PCTCN2017075448-appb-000075
化合物1(100mg,0.34mmol)溶于10mL二氯甲烷中，加入1-羟基苯并***(HOBt)(50mg,0.37mmol)和1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)(84mg,0.44mmol)。反应液室温(25℃)搅拌过夜。减压移除溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯＝1：1)纯化得81mg产物2，为白色固体，收率58％。LCMS(ESI)m/z＝436.9(M+Na)+。
化合物3的合成：
Figure PCTCN2017075448-appb-000076
氩气保护下，将美登醇(30mg,0.053mmol)溶于5mL干燥四氢呋喃中，室温下逐滴缓慢加入Zn(HMDS)2(107uL,0.26mmol)。反应液室温25℃搅拌5分钟，将化合物2(55mg,0.13mmol)溶于2mL四氢呋喃中逐滴缓慢加入，反应液室温(25℃)搅拌过夜。缓慢加入1M稀盐酸10mL淬灭反应，乙酸乙酯萃取3次(20mL×3)，合并有机相，无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝10:1)得8mg产品3，为浅棕黄色固体，产率18％，回收美登醇18mg。LC-MS(ESI)m/z＝844.0(M+H)+。
1H NMR(400MHz,CDCl3)δppm 7.78(d,J＝7.2Hz,2H),7.60(t,J＝6.8Hz,2H),7.42(t,J＝7.6Hz,2H),7.33(t,J＝7.2Hz,2H),6.83(d,J＝1.2Hz,1H),6.71(d,J＝1.2Hz,1H),6.47-6.40(m,1H),6.25-6.22(m,2H),5.63-5.53(m,2H),4.94(dd,J1＝2.4Hz,J2＝11.6Hz,1H),4.49-4.45(m,1H),4.41-4.36(m,1H),4.26-4.21(m,2H),4.17-4.03(m,2H),3.99(s,3H),3.54-3.48(m,2H),3.33(s,3H),3.25-3.17(m,5H),2.87(d,J＝9.6Hz,1H),2.53(t,J＝12.4Hz,1H),2.21(dd,J1＝2.8Hz,J2＝14Hz,1H),1.66(s,3H),1.53-1.44(m,1H),1.29-1.23(m,5H),0.81(s,3H).
实施例6
Figure PCTCN2017075448-appb-000077
实验步骤
化合物2的合成：
Figure PCTCN2017075448-appb-000078
化合物1(100mg,0.3mmol)溶于10mL二氯甲烷中，加入1-羟基苯并***(HOBt)(50mg,0.36mmol)和1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)(70mg,0.36mmol)。反应液室温(25℃)搅拌过夜。减压移除溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯＝1：1)纯化得70mg产物2，为无色透明油状物，收率51.4％，(LCMS,214nm)。LCMS(ESI)m/z＝477.2(M+Na)+。
化合物3的合成：
Figure PCTCN2017075448-appb-000079
氩气保护下，将美登醇(42mg,0.075mmol)溶于3mL干燥四氢呋喃中，室温下加入Zn(HMDS)2(0.1mL,0.23mmol)。反应液室温搅拌5分钟，将化合物2(70mg,0.15mmol)溶于2mL四氢呋喃中逐滴缓慢加入，反应液室温(25℃)搅拌过夜。缓慢加入1M稀盐酸5mL淬灭反应，乙酸乙酯萃取3次(20mL×3)，合并有机相，无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝30:1)得32mg产品3，为白色固体，产率48％，回收美登醇16mg。LCMS(ESI)m/z＝884.0(M+H)+,HPLC：Chiral OD-H Column(4.6×150mm)detected at 254nm；CO2/MeOH＝55:45；保留时间:t(S)＝2.27min,ee:>99.9％,purity:99％by LCMS(254nm)。
1H NMR(400MHz,CDCl3)δppm 7.75(d,J＝7.6Hz,2H),7.56(dd,J1＝19.2,J2＝7.6Hz,2H), 7.39(t,J＝7.6Hz,2H),7.28-7.32(m,3H),6.79(s,1H),6.48(dd,J1＝15.2Hz,J2＝11.2Hz,1H),6.31(d,J＝11.2Hz,1H),6.24(s,1H),5.52(dd,J1＝15.2Hz,J2＝9.2Hz,1H),4.95(d,J＝9.6Hz,1H),4.43-4.50(m,1H),4.26-4.37(m,3H),4.23(t,J＝7.2Hz,1H),3.96(s,3H),3.67-3.71(m,1H),3.48-3.60(m,3H),3.37(s,3H),3.23(s,1H),3.09-3.19(m,4H),2.64(d,J＝9.6Hz,1H),2.51-2.59(m,1H),2.16-2.24(m,2H),2.07-2.12(m,1H),1.96(s,1H),1.79(d,J＝13.6Hz,1H),1.70(s,3H),1.43-1.54(m,1H),1.26-1.31(m,5H),0.88(s,3H).
实施例7
实验步骤
化合物2的合成：
Figure PCTCN2017075448-appb-000081
化合物1(200mg,0.52mmol)溶于10mL二氯甲烷中，加入1-羟基苯并***(HOBt)(84mg,0.62mmol)和1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)(120mg,0.62mmol)。反应液室温(25℃)搅拌过夜。减压移除溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯＝1：1)纯化得120mg产物2，为白色泡沫状固体，收率46％。LCMS(ESI)m/z＝525.2(M+Na)+。
化合物3的合成：
Figure PCTCN2017075448-appb-000082
氩气保护下，将美登醇(56mg,0.1mmol)溶于3mL干燥四氢呋喃中，室温下加入Zn(HMDS)2(0.1 mL,0.23mmol)。反应液室温25℃搅拌5分钟，将化合物2(100mg,0.2mmol)溶于2mL四氢呋喃中逐滴缓慢加入，反应液室温(25℃)搅拌过夜。缓慢加入1M稀盐酸5mL淬灭反应，乙酸乙酯萃取3次(10mL×3)，合并有机相，无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝30:1)得41mg产品3，为白色固体，产率44％，回收美登醇23mg。LCMS(ESI)m/z 932.2(M+H)+；HPLC：Chiral OD-H Column(4.6×150mm)detected at 254nm；CO2/MeOH＝55:45；保留时间:t(S)＝2.22min,ee:>99.9％,purity:99％by LCMS(254nm)。
1H NMR(400MHz,CDCl3)δppm 7.73(dd,J1＝7.6Hz,J2＝2.8Hz,2H),7.50(d,J＝7.6Hz,1H),7.34-7.44(m,3H),7.25-7.28(m,2H),7.21(t,J＝7.6Hz,1H),6.81(d,J＝1.6Hz,1H),6.77(d,J＝11.2Hz,1H),6.66(d,J＝1.6Hz,1H),6.42(dd,J＝15.3,11.2Hz,1H),6.22(s,1H),5.81(dd,J1＝15.2Hz,J2＝9.2Hz,1H),5.03(dd,J1＝11.2Hz,J2＝3.6Hz,1H),4.91(dd,J1＝10.8Hz,J2＝5.6Hz,1H),4.75(dd,J1＝12.0Hz,J2＝3.2Hz,1H),4.23(t,J＝10.8Hz,1H),4.16(t,J＝6.0Hz,1H),4.07(dd,J1＝10.8Hz,J2＝6.4Hz,1H),3.99(s,3H),3.67(d,J＝12.4Hz,1H),3.51(d,J＝9.2Hz,1H),3.42(s,1H),3.35(s,3H),3.09(d,J＝12.4Hz,1H),3.00(d,J＝9.6Hz,1H),2.86(s,3H),2.50-2.61(m,4H),2.29-2.43(m,2H),1.93-2.16(m,6H),1.65(s,1H),1.56(d,J＝13.2Hz,1H),1.41-1.49(m,1H),1.19-1.29(m,5H),0.78(s,3H)。
实施例8
Figure PCTCN2017075448-appb-000083
实验步骤
化合物2的合成：
Figure PCTCN2017075448-appb-000084
化合物1(200mg,0.57mmol)溶于20mL二氯甲烷中，加入1-羟基苯并***(HOBt)(80mg,0.59mmol)和1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)(141mg,0.74mmol)。反应液室温(25℃)搅拌过夜。减压移除溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯＝1：1)纯化得210mg产物2，为白色固体，收率77％，纯度100％(LCMS,254nm)。LCMS(ESI)m/z 485.1(M+H)+.
化合物3的合成：
Figure PCTCN2017075448-appb-000085
氩气保护下，将美登醇(50mg,0.089mmol)溶于5mL干燥四氢呋喃中，室温下逐滴缓慢加入Zn(HMDS)2(0.15mL,0.355mmol)。反应液室温搅拌5分钟，将化合物2(109mg,0.226mmol)溶于2mL四氢呋喃中逐滴缓慢加入，反应液室温搅拌过夜。缓慢加入1M稀盐酸5mL淬灭反应，乙酸乙酯萃取3次(20mL×3)，合并有机相，无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝10:1)得14mg产品3，为白色固体，产率18％，回收美登醇25mg。LC-MS(ESI)m/z＝900.1(M+H)+。Purity:100％by LCMS(254nm),HPLC：Chiral OD-H Column(4.6×150mm)detected at 254nm；CO2/MeOH＝55:45；保留时间:t(S)＝2.09min,ee:>99.9％,purity:99％by LCMS(254nm)。
1H NMR(400MHz,CDCl3)δppm 7.72(dd,J1＝8.0Hz,J2＝3.6Hz,2H),7.47(d,J＝7.6Hz,1H),7.40(d,J＝8.0Hz,1H),7.36(d,J＝7.6Hz,1H),7.23(t,J＝6.8Hz,1H),7.18(t,J＝7.6Hz,1H),6.81(s,1H),6.65(d,J＝11.6Hz,1H),6.61(s,1H),6.47-6.40(m,2H),5.69(dd,J1＝14.8Hz,J2＝9.2Hz,1H),4.93(dd,J1＝12.0Hz,J2＝2.8Hz,1H),4.87(q,J＝5.2Hz,1H),4.57(d,J＝9.2Hz,1H),4.25(t,J＝9.2Hz,1H),4.17-4.06(m,2H),3.98(s,3H),3.66(d,J＝12.0Hz,1H),3.50(d,J＝9.2Hz,1H),3.36(s,3H),3.10(d,J＝12.4Hz,1H),2.88(d,J＝7.6Hz,1H),2.87(s,3H),2.57(s,3H),2.60-2.56(m,1H),2.28-2.18(m,1H),2.11(dd,J1＝14.4Hz,J2＝2.4Hz,1H),1.66(s,3H),1.63(br,1H),1.49-1.41(m,2H),1.29(t,J＝6.4Hz,3H),0.99(d,J＝6.8Hz,3H),0.80(d,J＝6.8Hz,6H).
实施例9
Figure PCTCN2017075448-appb-000086
实验步骤
化合物2的合成：
Figure PCTCN2017075448-appb-000087
化合物1(310mg,1mmol)溶于20mL二氯甲烷中，加入1-羟基苯并***(HOBt)(135mg,1.2mmol)和1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)(192mg,1.2mmol)。反应液室温(25℃)搅拌过夜。减压移除溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯＝1：1)纯化得240mg产物2，为白色泡沫状固体，收率56.1％。LCMS(ESI)m/z 451.1(M+Na)+。
化合物3的合成：
Figure PCTCN2017075448-appb-000088
氩气保护下，将美登醇(56mg,0.1mmol)溶于3mL干燥四氢呋喃中，室温下加入Zn(HMDS)2(0.1mL,0.23mmol)。反应液室温25℃搅拌5分钟，将化合物2(86mg,0.2mmol)溶于2mL四氢呋喃中逐滴缓慢加入，反应液室温(25℃)搅拌过夜。缓慢加入1M稀盐酸5mL淬灭反应，乙酸乙酯萃取3次(15mL×3)，合并有机相，无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝30:1)得17mg产品3，为白色固体，产率20％，回收美登醇28mg；LCMS(ESI)m/z 858.0(M+H)+；HPLC：Chiral OD-H Column(4.6×150mm)detected at 254nm；CO2/MeOH＝55:45；保留时间:t(S)＝1.57min,ee:>99.9％,purity:99％by LCMS(254nm)。
1H NMR(400MHz,CDCl3)δppm 7.72(dd,J1＝7.6Hz,J2＝4.4Hz,2H),7.52(d,J＝7.6Hz,1H),7.45(d,J＝7.6Hz,1H),7.32-7.40(m,2H),7.24-7.28(m,1H),7.19(t,J＝7.6Hz,1H),6.81(d,J＝1.6Hz,1H),6.76(s,1H),6.55(d,J＝12.0Hz,1H),6.44(dd,J＝15.2,11.2Hz,1H),6.27(s,1H),5.61(dd,J1＝15.2Hz,J2＝9.2Hz,1H),5.52(d,J＝9.6Hz,1H),4.85(dd,J1＝12.0Hz,J2＝2.8Hz,1H),4.66(dd,J1＝10.0Hz,J2＝6.0Hz,1H),4.51-4.58(m,1H),4.11-4.27(m,3H),3.98(s,3H),3.57(d,J＝12.8Hz,1H),3.51(d,J＝9.2Hz,1H),3.36(s,3H),3.22(s,1H),3.11(d,J＝12.8Hz,1H),2.90(s,3H),2.87(s,1H),2.55(dd,J1＝14.0Hz,J2＝12.0Hz,1H),2.18(dd,J＝14.0,2.8Hz,1H),1.59-1.66(m,4H),1.42-1.54(m,1H),1.39(d,J＝6.8Hz,3H),1.21-1.29(m,4H),0.82(s,3H).
实施例10
Figure PCTCN2017075448-appb-000089
实验步骤
化合物2的合成：
Figure PCTCN2017075448-appb-000090
化合物1(401mg,1mmol)溶于20mL二氯甲烷中，加入1-羟基苯并***(HOBt)(135mg,1.2mmol)和1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)(192mg,1.2mmol)。反应液室温(25℃)搅拌过夜。减压移除溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯＝3：1)纯化得340mg产物2，为白色泡沫状固体，收率65.6％。LCMS(ESI)m/z 541.2(M+Na)+。
化合物3的合成：
Figure PCTCN2017075448-appb-000091
氩气保护下，将美登醇(56mg,0.1mmol)溶于3mL干燥四氢呋喃中，室温下加入Zn(HMDS)2(0.1mL,0.23mmol)。反应液室温25℃搅拌5分钟，将化合物2(104mg,0.2mmol)溶于2mL四氢呋喃中逐滴缓慢加入，反应液室温(25℃)搅拌过夜。缓慢加入1M稀盐酸5mL淬灭反应，乙酸乙酯萃取3次(10mL×3)，合并有机相，无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝30:1)得41mg产品3，为白色固体，产率43.3％，回收美登醇20mg；LCMS(ESI)m/z 948.0(M+H)+；HPLC：Chiral OD-H Column(4.6×150mm)detected at 254nm；CO2/MeOH＝55:45；保留时间:t(S)＝2.22min,ee:>99.9％,purity:99％by LCMS(254nm)。
1H NMR(400MHz,CDCl3)δppm 7.71(t,J＝7.6Hz,2H),7.34-7.40(m,1H),7.29-7.34(m,3H), 7.28(s,1H),7.24(d,J＝4.0Hz,2H),7.12-7.22(m,4H),6.79(d,J＝1.6Hz,1H),6.73-6.77(m,1H),6.69(d,J＝1.6Hz,1H),6.46(dd,J1＝15.2Hz,J2＝11.2Hz,1H),6.27(s,1H),5.77(dd,J＝15.2,9.2Hz,1H),5.24(s,1H),4.82(d,J＝9.6Hz,1H),4.51(dd,J1＝10.4Hz,J2＝5.6Hz,1H),4.30(t,J＝10.4Hz,1H),3.93-3.99(m,4H),3.75-3.84(m,1H),3.64(d,J＝12.4Hz,1H),3.54(d,J＝9.2Hz,1H),3.39(s,3H),3.21(dd,J1＝14.4Hz,J2＝4.0Hz,1H),3.03-3.11(m,3H),2.84(s,3H),2.66(s,3H),2.57(dd,J1＝14.0Hz,J2＝12.4Hz,1H),2.14(dd,J＝14.0,2.8Hz,1H),1.58-1.68(m,4H),1.43-1.53(m,1H),1.23-1.31(m,5H),0.82(s,3H).
实施例11
Figure PCTCN2017075448-appb-000092
实验步骤
化合物2的合成：
Figure PCTCN2017075448-appb-000093
化合物1(300mg,0.82mmol)溶于20mL二氯甲烷中，加入1-羟基苯并***(HOBt)(116mg,0.86mmol)和1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)(204mg,1.06mmol)。反应液室温(25℃)搅拌过夜。减压移除溶剂，剩余物硅胶柱层析(石油醚/乙酸乙酯＝1：1)纯化得320mg产物2，为白色固体，收率81％。LCMS(ESI)m/z 485.1(M+H)+
化合物3的合成：
Figure PCTCN2017075448-appb-000094
氩气保护下，将美登醇(50mg,0.089mmol)溶于4mL干燥四氢呋喃中，室温下逐滴缓慢加入Zn(HMDS)2(0.15mL,0.355mmol)。反应液室温25℃搅拌5分钟，将化合物2(110mg,0.226mmol)溶于2mL四氢呋喃中逐滴缓慢加入，反应液室温(25℃)搅拌过夜。缓慢加入1M稀盐酸5mL淬灭反应，乙酸乙酯萃取3次(15mL×3)，合并有机相，无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝10:1)得30mg产品3，为白色固体，产率37％，回收美登醇20mg。LC-MS(ESI)m/z914.4(M+H)+。HPLC：Chiral OD-H Column(4.6×150mm)detected at 254nm；CO2/MeOH＝55:45；保留时间:t(S)＝1.94min,ee:>99.9％,purity:99％by LCMS(254nm)。
purity:100％by LCMS(254nm),1H NMR(500MHz,CDCl3)δppm 7.73(d,J＝7.5Hz,2H),7.47(dd,J1＝16.5Hz,J2＝7.5Hz,2H),7.39-7.35(m,2H),7.24-7.20(m,1H),6.98(s,1H),6.82-6.74(m,3H),6.54(s,1H),6.43(dd,J1＝15.5Hz,J2＝11.5Hz,1H),5.68(dd,J1＝15.5Hz,J2＝8.5Hz,1H),5.00(dd,J1＝11.5Hz,J2＝3.0Hz,1H),4.90(dd,J1＝10.5Hz,J2＝6.0Hz,1H),4.72(dd,J1＝12.5Hz,J2＝3.0Hz,1H),4.26(t,J＝10.5Hz,1H),4.15(t,J＝6.0Hz,1H),4.01(dd,J1＝10.5Hz,J2＝6.5Hz,1H),3.97(s,3H),3.72(d,J＝12.5Hz,1H),3.50(d,J＝9.0Hz,1H),3.36(s,3H),3.09(d,J＝9.6Hz,1H),3.02(d,J＝6.0Hz,1H),2.88(s,3H),2.56(s,3H),2.59-2.54(m,1H),2.27(s,2H),2.12(dd,J1＝14.0Hz,J2＝3.0Hz,1H),1.78(t,J＝12.0Hz,1H),1.65(s,3H),1.58(d,J＝13.5Hz,1H),1.52-1.46(m,1H),1.27(d,J＝6.4Hz,3H),1.21(d,J＝13.2Hz,1H),1.00(d,J＝6.4Hz,3H),0.94(d,J＝6.4Hz,3H),0.77(s,3H).
对比例1 参照CN201310081867.X
Figure PCTCN2017075448-appb-000095
称取美登醇(50mg,0.088mmol)，Fmoc-N-甲基-L-丙氨酸(200mg,0.615mmol)，三氟甲烷磺酸钪(42mg,0.086mmol)，N,N-二甲基吡啶(32mg,0.262mmol)置于干燥的Schlenck瓶中，置换氩气3次，冷却至-8℃，加入8mL二氯甲烷，于-8℃下搅拌0.5小时。将N,N-二异丙基碳二亚胺(222mg,1.76mmol)逐滴缓慢加入，继续于-8℃下搅拌0.5小时，缓慢升至室温，搅拌2小时。过滤回收催化剂，稀盐酸淬灭反应(2mL)，二氯甲烷萃取3次(30mL×3)，饱和碳酸氢钠洗涤(30mL)，饱和食盐水洗涤(30mL)，有机相无水硫酸钠干燥，浓缩。粗产品硅胶柱层析纯化(二氯甲烷/甲醇＝30:1)得产品68mg，产率89％，经手性HPLC分析，产物为两个非对映异构体的混合物，Fmoc-N-Me-L-Ala-May：Fmoc-N-Me-D-Ala-May＝39：61。HPLC：Chiral OD-H Column(4.6×150mm)detected at 254nm；CO2/MeOH＝55:45；保留时间:t(S)＝2.97min,t(R)＝4.03min。
对比例2 参照US20060167245
第一步：
Figure PCTCN2017075448-appb-000096
称取N-甲基-L丙氨酸(3.10g,30mmol)悬浮于600mL二氯甲烷中，加入N,N-二异丙基乙胺(10mL,60mmol)，超声波处理使固体分散均匀，分批缓慢加入N,N’-羰基二咪唑(3.7mL,30mmol)，约1h加完，反应液室温搅拌过夜，硅胶过滤，并用大量的二氯甲烷洗涤，滤液浓缩，***/石油醚重结晶得产物1.6g，为白色固体，收率42％。1H NMR(400MHz,d6DMSO)δppm 3.95(q,J＝7.2Hz,1H),2.83(s,3H),1.36(d,J＝7.6Hz,3H).
第二步：
Figure PCTCN2017075448-appb-000097
称取美登醇(500mg，0.89mmol)和上一步反应产物2(690mg,5.34mmol)于干燥的茄型瓶中，置 换氮气3次，加入20mL干燥的N,N-二甲基甲酰胺，室温搅拌。逐滴缓慢加入Zn(HMDS)2(2.13mL,5,25mmol)，室温搅拌过夜。LCMS检测只有15％的产物(S)-4，3％的非对映异构体(R)-4，另有70％的美登醇没有发生反应。LCMS(ESI)m/z 649.7(M+H)+，产物在3min的LCMS保留时间＝1.39min；Maytasinol：保留时间＝1.66min。
HPLC：手性柱Eclipse XDB-C18(5μm,4.6*150mm)，流动相A：0.01％三氟乙酸水溶液，流动相B：0.01％三氟乙酸乙腈溶液，梯度洗脱0→2min，A:B＝95:5；2→9min，A:B＝95:5→5:95；9→15min，A:B＝5:95。紫外吸收波长214nm，柱温40℃，流速1.2ml/min，进样量10μL，MS(ESI,Pos mode,110to 1500amu)，保留时间t(S)＝7.01min,t(R,minor)＝7.10min。
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 (13)

  1. 一种如式I所示的化合物的制备方法，其特征在于，其包括以下步骤：在有机溶剂中，在碱存在的条件下，将化合物Ia与RCOOR’进行酯交换反应，得到如式I所示的化合物即可；
    Figure PCTCN2017075448-appb-100001
    其中，X为氢或卤素；
    Y为氢、C1-C6烷基、C3-C6环烷基、苄基或-C(＝O)R5；R5为C1-C6烷基或苄基；
    R1为氢或C1-C6烷基；
    R2为氢或C1-C6烷基；
    R3为甲基、-CH2OH或-CH2OR17；
    R4为羟基、-OR17或巯基；
    所述的R3和R4中，所述的R17独立地为羟基保护基；
    R为取代或未取代的烷基、取代或未取代的芳基、取代或未取代的环烷基、取代或未取代的环烯基、取代或未取代的杂芳基、取代或未取代的杂环基、
    Figure PCTCN2017075448-appb-100002
    Figure PCTCN2017075448-appb-100003
    其中，所述的“取代或未取代的烷基、取代或未取代的芳基、取代或未取代的环烷基、取代或未取代的环烯基、取代或未取代的杂芳基和取代或未取代的杂环基”中的“取代”独立地为被1至3个R10取代，所述的
    Figure PCTCN2017075448-appb-100004
    中α碳原子的构型独立地为R型和/或S型；
    所述的R中，L独立地为化学键、取代或未取代的-(CH2)m-或“替代或未替代的C3-C8环亚烷基”，m为0-20；其中，所述的“取代或未取代的-(CH2)m-”中的“取代”独立地为被1-4个选自以下的基团所取代：-SO3H、-P(O)(OH)2和R23，所述的R23独立地选自-SH、-S-S-C1-4烷基、-CONR11R11和“被一个或多个-NR11R11基团取代的C1-6烷基”；所述的“替代或未替代的C3-C8环亚烷基”中的“替代”独立地为C3-C8环亚烷基中一个或多个-CH2-基团被选自以下的基团所替代：C3-C8环亚烷基、-O-、-S-、 -NR8-、-C(＝O)-、-C(＝O)NR8-、-NR8C(＝O)-、-SO2NR8-和-NR8SO2-；
    R7独立地为氢、C1-C6烷基或氨基酸侧链；
    R8独立地为氢或C1-6烷基；
    R10独立地为氢、Pr、-NR11Pr、-NR11C(＝O)CH2Br、-COOR12、-CONR11R11、-NR11COR13、-S-S-R13、-Si(R13)3、烷基、芳基、环烷基、环烯基、杂芳基、杂环基、
    Figure PCTCN2017075448-appb-100005
    R11独立地为氢、烷基、芳基环烷基、环烯基、杂芳基或杂环基；或者，两个R11与氮原子共同形成“取代或未取代的杂环”，其中，所述的“取代或未取代的杂环”中的取代是指被氧代基团和烷基中的一个或多个取代；
    R12独立地为C1-C6烷基或苄基；
    R13独立地为烷基、芳基、环烷基、杂芳基或杂环基；
    Pr独立地为氨基保护基；
    R’为C1～C6的烷基、C5～C10的芳基、杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂芳基、替代或未替代的“杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂环基”、卤素取代的C5～C10的芳基或C3～C8的环烷基；其中，所述的“替代”是指杂环基中一个或多个-CH2-基团被
    Figure PCTCN2017075448-appb-100006
    所替代。
  2. 如权利要求1所述的如式I所示的化合物的制备方法，其特征在于：
    所述的化合物Ia为
    Figure PCTCN2017075448-appb-100007
    和/或，
    当所述的X为卤素时，所述的卤素为氟、氯、溴或碘；
    和/或，
    当所述的Y为C1-C6烷基时，所述的C1-C6烷基为甲基；
    和/或，
    当所述的R1为C1-C6烷基时，所述的C1-C6烷基为甲基；
    和/或，
    当所述的R17为羟基保护基时，所述的羟基保护基为三甲基硅基、三乙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、乙酰基、苯甲酰基、
    Figure PCTCN2017075448-appb-100008
    和/或，
    当所述的R为取代或未取代的烷基时，所述的烷基为C1-C14烷基；
    和/或，
    当所述的R为取代或未取代的芳基时，所述的芳基为C5-C10芳基；
    和/或，
    当所述的R为取代或未取代的环烷基时，所述的环烷基为C3-C8环烷基；
    和/或，
    当所述的R为取代或未取代的环烯基时，所述的环烯基为C5-C10环烯基；
    和/或，
    当所述的R为取代或未取代的杂芳基时，所述的杂芳基为杂原子为氮或氧原子、杂原子数为1-4个的C5～C10的杂芳基；
    和/或，
    当所述的R为取代或未取代的杂环基时，所述的杂环基为杂原子为氮或氧原子、杂原子数为1-4个的C3～C10的杂环基；
    和/或，
    当所述的R为
    Figure PCTCN2017075448-appb-100009
    时，所述的“α碳原子的构型”独立地为S型；
    和/或，
    当所述的L独立地为取代或未取代的-(CH2)m-时，所述的-(CH2)m-为亚甲基、
    Figure PCTCN2017075448-appb-100010
    Figure PCTCN2017075448-appb-100011
    和/或，
    当所述的L独立地为取代或未取代的-(CH2)m-时，所述的m为1-10；
    和/或，
    当所述的R7独立地为C1-C6烷基时，所述的C1-C6烷基为甲基、异丙基、仲丁基或异丁基；
    和/或，
    当所述的R7独立地为氨基酸侧链时，所述的氨基酸侧链为与
    Figure PCTCN2017075448-appb-100012
    形成氨基酸的基团，其中，所述的“*”碳原子的构型为R型和/或S型；
    和/或，
    当所述的R8独立地为C1-C6烷基时，所述的C1-C6烷基为甲基；
    和/或，
    当所述的R10独立地为烷基时，所述的烷基为C1-C6烷基；
    和/或，
    当所述的R10独立地为芳基时，所述的芳基为C5-C10芳基；
    和/或，
    当所述的R10独立地为环烷基时，所述的环烷基为C3-C8环烷基；
    和/或，
    当所述的R10独立地为环烯基时，所述的环烯基为C5-C10环烯基；
    和/或，
    当所述的R10独立地为杂芳基时，所述的杂芳基为杂原子为氮或氧原子、杂原子数为1-4个的C5～C10的杂芳基；
    和/或，
    当所述的R10独立地为杂环基时，所述的杂环基为杂原子为氮或氧原子、杂原子数为1-4个的C3～C10的杂环基；
    和/或，
    当所述的R11独立地为烷基时，所述的烷基为C1-C6烷基；
    和/或，
    当所述的R11独立地为芳基环烷基时，所述的芳基环烷基为C5-C10芳基-C3-C8环烷基-；
    和/或，
    当所述的R11独立地为环烯基时，所述的环烯基为C5-C10环烯基；
    和/或，
    当所述的R11独立地为杂芳基时，所述的杂芳基为杂原子为氮或氧原子、杂原子数为1-4个的C5～C10的杂芳基；
    和/或，
    当所述的R11独立地为杂环基时，所述的杂环基为杂原子为氮或氧原子、杂原子数为1-4个的C3～C10的杂环基；
    和/或，
    当所述的两个R11同与之相连的氮原子共同形成取代或未取代的杂环时，所述的“杂环”为杂原子为氮、硫和氧原子中的一个或多个、杂原子数为1-4个的C3～C10的杂环基；
    和/或，
    当所述的两个R11同与之相连的氮原子共同形成取代或未取代的杂环、所述的“取代或未取代的杂环”中的取代是指被烷基取代时，所述的烷基为C1-C6烷基；
    和/或，
    当所述的R13独立地为烷基时，所述的烷基为C1-C6烷基；
    和/或，
    当所述的R13独立地为芳基时，所述的芳基为C5-C10芳基；
    和/或，
    当所述的R13独立地为环烷基时，所述的环烷基为C3-C8环烷基；
    和/或，
    当所述的R13独立地为环烯基时，所述的环烯基为C5-C10环烯基；
    和/或，
    当所述的R13独立地为杂芳基时，所述的杂芳基为杂原子为氮或氧原子、杂原子数为1-4个的C5～C10的杂芳基；
    和/或，
    当所述的R13独立地为杂环基时，所述的杂环基为杂原子为氮或氧原子、杂原子数为1-4个的C3～C10的杂环基；
    和/或，
    当所述的Pr独立地为氨基保护基时，所述的氨基保护基为叔丁氧羰基、9-芴甲氧羰基、苄氧羰基、苯甲酰基或乙酰基；
    和/或，
    当所述的R’独立地为杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂芳基时，所述的杂原子为氮或氧原子、杂原子数为1-4个的C5～C10的杂芳基为杂原子为氮原子、杂原子数为3～4个的C5～C6的杂芳基；
    和/或，
    当所述的R’独立地为替代或未替代的“杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂环基”，所述的“替代的杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂环基”为
    Figure PCTCN2017075448-appb-100013
    和/或，
    当所述的R’独立地为卤素取代的C5～C10的芳基时，所述的卤素为氟、氯、溴或碘，卤素原子的个数为1-6个；
    和/或，
    当所述的R’独立地为卤素取代的C5～C10的芳基时，所述的C5～C10的芳基为苯基。
  3. 如权利要求2所述的如式I所示的化合物的制备方法，其特征在于：
    当所述的R为取代或未取代的烷基、所述的烷基为C1-C14烷基时，所述的C1-C14烷基为C1-C6烷基；
    和/或，
    当所述的R为取代或未取代的芳基、所述的芳基为C5-C10芳基时，所述的C5-C10芳基为苯基；
    和/或，
    当所述的R为杂环基、所述的杂环基为杂原子为氮或氧原子、杂原子数为1-4个的C3～C10的杂环基时，所述的杂原子为氮或氧原子、杂原子数为1-4个的C3～C10的杂环基为四氢吡咯-2-基；
    和/或，
    当所述的L独立地为取代或未取代的-(CH2)m-时，所述的m为1-5；
    和/或，
    当所述的R7独立地为氨基酸侧链时，所述的氨基酸侧链为4-OH-Phenyl-CH2-、CH3-CH(OH)-、HS-CH2-、Phenyl-CH2-或CH3-S-(CH2)2-；
    和/或，
    当所述的两个R11同与之相连的氮原子共同形成取代或未取代的杂环、所述的“杂环”为杂原子为氮、硫和氧原子中的一个或多个、杂原子数为1-4个的C3～C10的杂环基时，所述的杂原子为氮、硫和氧原子中的一个或多个、杂原子数为1-4个的C3～C10的杂环基为
    Figure PCTCN2017075448-appb-100014
    Figure PCTCN2017075448-appb-100015
    和/或，
    当所述的R13独立地为C1-C6烷基时，所述的烷基为甲基；
    和/或，
    当所述的R’独立地为杂原子为氮原子、杂原子数为3～4个的C5～C6的杂芳基时，所述的“杂原子为氮原子、杂原子数为3～4个的C5～C6的杂芳基”为
    Figure PCTCN2017075448-appb-100016
    和/或，
    当所述的R10为-S-S-R13时，所述的-S-S-R13为
    Figure PCTCN2017075448-appb-100017
    和/或，
    当所述的R’为卤素取代的C5～C10的芳基时，所述的“卤素取代的C5～C10的芳基”为卤素取代的苯基。
  4. 如权利要求3所述的如式I所示的化合物的制备方法，其特征在于：
    当所述的R为取代或未取代的烷基、所述的烷基为C1-C14烷基、所述的C1-C14烷基为C1-C6烷基时，所述的C1-C6烷基为甲基或乙基；
    和/或，
    当所述的L独立地为取代或未取代的-(CH2)m-、m为1-5时，所述的-(CH2)m-为亚甲基、
    Figure PCTCN2017075448-appb-100018
    Figure PCTCN2017075448-appb-100019
    和/或，
    当所述的R’为卤素取代的苯基时，所述的卤素取代的苯基为
    Figure PCTCN2017075448-appb-100020
  5. 如权利要求1所述的如式I所示的化合物的制备方法，其特征在于：
    所述的X为卤素；
    和/或，
    所述的Y为氢或C1-C6烷基；
    和/或，
    所述的R1为C1-C6烷基；
    和/或，
    所述的R2为氢；
    和/或，
    所述的R3为甲基；
    和/或，
    所述的R4为羟基；
    和/或，
    所述的R为取代或未取代的烷基、取代或未取代的芳基、取代或未取代的杂环基、
    Figure PCTCN2017075448-appb-100021
    Figure PCTCN2017075448-appb-100022
    和/或，
    所述的L为化学键、或、取代或未取代的-(CH2)m-；
    和/或，
    所述的R7独立地为氢、C1-C6烷基或氨基酸侧链；
    和/或，
    所述的R8独立地为氢或C1-6烷基；
    和/或，
    所述的R10独立地为氢、Pr、-S-S-R13、
    Figure PCTCN2017075448-appb-100023
    和/或，
    所述的R13独立地为烷基；
    和/或，
    所述的Pr独立地为叔丁氧羰基、9-芴甲氧羰基或乙酰基；
    和/或，
    所述的R’为“杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂芳基”、替代或未替代的“杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂环基”、或、卤素取代的C5～C10的芳基。
  6. 如权利要求1所述的如式I所示的化合物的制备方法，其特征在于，所述的RCOOR’为
    Figure PCTCN2017075448-appb-100024
    Figure PCTCN2017075448-appb-100025
  7. 如权利要求1所述的如式I所示的化合物的制备方法，其特征在于，在如式I所示的化合物的制备方法中，所述的有机溶剂为醚类溶剂、卤代烃类溶剂、芳烃类溶剂、腈类溶剂和酰胺类溶剂中的一种或多种；
    和/或，
    在如式I所示的化合物的制备方法中，所述的有机溶剂与所述的化合物Ia的体积质量比为1mL/g～200mL/g；
    和/或，
    在如式I所示的化合物的制备方法中，所述的碱为有机碱；
    和/或，
    在如式I所示的化合物的制备方法中，所述的碱与所述的化合物Ia的摩尔比值为1～10；
    和/或，
    在如式I所示的化合物的制备方法中，所述的RCOOR’与所述的化合物Ia的摩尔比值为1～10；
    和/或，
    在如式I所示的化合物的制备方法中，所述的酯交换反应的温度为-78℃～100℃；
    和/或，
    如式I所示的化合物的制备方法在保护气体存在的条件下进行；
    和/或，
    所述的如式I所示的化合物的制备方法采用以下步骤：将所述的碱与所述的有机溶剂形成的混合物加入到，所述的化合物Ia与所述的有机溶剂形成的混合物中，反应5分钟～10分钟，再加入所述的RCOOR’与所述的有机溶剂形成的混合物，进行所述的酯交换反应，得到所述的化合物I即可；
    和/或，
    所述的如式I所示的化合物的制备方法采用以下后处理步骤：反应结束后，淬灭反应、萃取、有机相干燥、除去所述的溶剂得到所述的化合物I。
  8. 如权利要求1所述的如式I所示的化合物的制备方法，其特征在于，所述的如式I所示的化合物的制备方法进一步包括以下步骤：将RCOOH与R’OH进行缩合反应，得到所述的RCOOR’即可；
    RCOOH+HOR′→RCOOR′。
  9. 一种RCOOR’的制备方法，其特征在于，其包括以下步骤：将RCOOH与R’OH进行缩合反应，得到RCOOR’即可；
    RCOOH+HOR′→RCOOR′；
    其中，R’和R的定义均如权利要求1～6中至少一项所述。
  10. 一种如式II所示的化合物的制备方法，其特征在于，其包括以下步骤：
    (1)按照权利要求1～8中至少一项所述的化合物I的制备方法制备化合物I；
    (2)将所述的化合物I进行脱除氨基保护基的反应，得到化合物II即可；
    Figure PCTCN2017075448-appb-100026
  11. 一种如式III所示的化合物的制备方法，其特征在于，其为方法1或方法2：
    方法1包括步骤(S1)和(S2)：
    (S1)按照权利要求10所述的如式II所示的化合物的制备方法制备化合物II；
    (S2)将所述的化合物II与化合物R10-L-COOH进行缩合反应，得到化合物III即可；
    方法2包括步骤(S1’)和(S2’)：
    (S1’)按照权利要求10所述的如式II所示的化合物的制备方法制备化合物II；
    (S2’)将所述的化合物II、与“化合物R10-L-COOR9、R10-L-COCl或
    Figure PCTCN2017075448-appb-100027
    ”进行缩合反应，得到化合物III即可；
    Figure PCTCN2017075448-appb-100028
    其中，R11的定义如权利要求1～3中至少一项所述；
    R9为C1～C6的烷基、C5～C10的芳基、“杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂芳基”、替代或未替代的“杂原子为氮或氧原子、杂原子数为1-4个的C4～C10的杂环基”、卤素取代的C5～C10的芳基或C3～C8的环烷基。
  12. 一种如式IV所示的化合物的制备方法，其特征在于，其包括以下步骤：
    (S1”)按照权利要求11所述的如式III所示的化合物的制备方法制备化合物III；
    (S2”)将所述的化合物III进行还原反应，得到化合物IV即可；
    Figure PCTCN2017075448-appb-100029
  13. 一种化合物RCOOR’，其中，R’和R的定义均如权利要求1～6中至少一项所述。
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