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WO2017148416A1 - Procédé de préparation d'esters de maytansine et de leur intermédiaire - Google Patents

Procédé de préparation d'esters de maytansine et de leur intermédiaire Download PDF

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Publication number
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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English (en)
Chinese (zh)
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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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Publication of WO2017148416A1 publication Critical patent/WO2017148416A1/fr

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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

L'invention concerne un procédé de préparation d'esters de maytansine de formule I et d'un intermédiaire de ces derniers. Le procédé comprend une étape de mise en œuvre d'une réaction d'interestérification du composé Ia et de RCOOR' en présence d'un solvant organique et d'une base pour obtenir le composé. Le procédé de préparation présente des conditions de réaction douces, des étapes de synthèse et de post-traitement faciles, et une conversion et un rendement de réaction élevés. Le phénomène de racémisation n'est pas observé pendant la réaction, la pureté du produit est élevée, le coût de production est faible, et le procédé de préparation est approprié pour une production industrielle. Réaction (1)
PCT/CN2017/075448 2016-03-03 2017-03-02 Procédé de préparation d'esters de maytansine et de leur intermédiaire WO2017148416A1 (fr)

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WO2006078809A2 (fr) * 2005-01-21 2006-07-27 Immunogen, Inc. Procede de preparation d'esters de maytansinoide
CN101289475A (zh) * 2008-05-30 2008-10-22 常州市牛塘化工厂有限公司 选择性合成蔗糖-6-酯的方法
CN102286076A (zh) * 2011-06-23 2011-12-21 成都圣诺科技发展有限公司 比伐卢定的制备方法
CN103254213A (zh) * 2012-12-21 2013-08-21 百奥泰生物科技(广州)有限公司 类美登素酯的制备方法及用于所述方法的组合物

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WO2006078809A2 (fr) * 2005-01-21 2006-07-27 Immunogen, Inc. Procede de preparation d'esters de maytansinoide
CN101289475A (zh) * 2008-05-30 2008-10-22 常州市牛塘化工厂有限公司 选择性合成蔗糖-6-酯的方法
CN102286076A (zh) * 2011-06-23 2011-12-21 成都圣诺科技发展有限公司 比伐卢定的制备方法
CN103254213A (zh) * 2012-12-21 2013-08-21 百奥泰生物科技(广州)有限公司 类美登素酯的制备方法及用于所述方法的组合物

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