WO2019042447A1 - Nouvelle toxine et procédé de préparation d'un intermédiaire de celle-ci - Google Patents

Nouvelle toxine et procédé de préparation d'un intermédiaire de celle-ci Download PDF

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WO2019042447A1
WO2019042447A1 PCT/CN2018/103781 CN2018103781W WO2019042447A1 WO 2019042447 A1 WO2019042447 A1 WO 2019042447A1 CN 2018103781 W CN2018103781 W CN 2018103781W WO 2019042447 A1 WO2019042447 A1 WO 2019042447A1
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compound
formula
group
antibody
protecting group
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PCT/CN2018/103781
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English (en)
Chinese (zh)
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许建烟
章瑛
屈博磊
蒋贵阳
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201880004457.6A priority Critical patent/CN109963835B/zh
Publication of WO2019042447A1 publication Critical patent/WO2019042447A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • 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 method for preparing a new toxin and an intermediate thereof.
  • Patent application WO2016127790A1 (Publication No. 2016.08.18) relates to a class of ligand-cytotoxic drug conjugates, which are regulated by a receptor in the preparation of a medicament for treating cancer, by a receptor-cytotoxic drug conjugate
  • the compound represented by the formula (I) is found to be an important intermediate, and the structure is as follows:
  • the preparation method is as follows:
  • the compound 1i is directly condensed with the compound 7d to give the intermediate 7e, and finally reacted with 6-maleimidocaproyl chloride to obtain the target compound Mc-MMAF analog, which is a total of four steps.
  • Mc-MMAF The preparation method of Mc-MMAF is disclosed in the patent application WO2005081711A2 (publication date 2005.09.09).
  • the synthesis method of the invention adopts two fragments separately synthesized, and finally directly condenses to obtain the compound represented by the general formula (I), and the total yield is greatly improved.
  • the synthetic route of the method has the characteristics of low synthesis cost and is suitable for industrial production, and has remarkable characteristics. Social and economic benefits.
  • the technical problem to be solved by the present invention is to provide a process for preparing a compound of the formula (I) and an intermediate thereof, which comprises a compound of the formula (III) which undergoes a series of upper protecting groups, deprotecting groups, Amidation reaction with 6-maleimidocaproyl chloride to obtain a compound of the formula (I), which overcomes the limitations of the prior art on the substrate, has mild reaction conditions, is easy to operate, has high optical purity and is synthesized.
  • the advantages of low cost and the like are suitable for mass production.
  • the present invention provides a compound of the formula (III):
  • R 1 is selected from a hydrogen atom or a carboxyl protecting group.
  • the carboxy protecting group is selected from the group consisting of methyl, substituted methyl, ethyl, 2-substituted ethyl, allyl, tert-butyl, alkoxyalkyl, alkoxyalkoxyalkyl a class, a 2,6-dialkylphenyl group, a benzyl group, a substituted benzyl group, a silane group or a tin alkyl group;
  • the substituted methyl group is selected from the group consisting of 9-fluorenylmethyl, triisopropylsilylmethyl, cyclopropylmethyl, diphenylmethyl or triphenylmethyl;
  • the 2-substituted ethyl group is selected from the group consisting of 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(p-toluenesulfonyl)ethyl or 2-cyanoethyl base;
  • the alkoxyalkyl group is selected from the group consisting of methoxymethyl, benzyloxymethyl or triisopropylsiloxymethyl;
  • the alkoxyalkoxyalkyl group is selected from the group consisting of methoxyethoxymethyl groups
  • the 2,6-dialkylphenyl group is selected from the group consisting of 2,6-dimethylphenyl, 2,6-diisopropylphenyl or 2,6-di-tert-butyl-4-methoxybenzene base;
  • the substituted benzyl group is selected from the group consisting of p-methylbenzyl, 2,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, p-nitrobenzyl or o-nitrobenzyl;
  • the silane group is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl or phenyldimethylsilyl;
  • the tin alkyl group is selected from the group consisting of trimethylstannyl
  • the compound of the formula (III) is selected from the group consisting of:
  • the invention further relates to a process for the preparation of a compound of the formula (III), which comprises reacting a compound of the formula (II) with 6-maleimidocaproic acid to give a formula (III) The step of showing the compound,
  • R 1 is as defined in formula (III);
  • R 2 is selected from a hydrogen atom or an amino protecting group
  • the amino protecting group is preferably an alkoxycarbonylamino protecting group, an acylamino protecting group, a sulfonylamino protecting group or an alkylamino protecting group;
  • the alkoxycarbonylamino protecting group is selected from the group consisting of benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl or ethoxycarbonyl;
  • the acylamino protecting group is selected from the group consisting of phthaloyl, trifluoroacetyl, pivaloyl, benzoyl, formyl or acetyl;
  • the sulfonyl amino protecting group is selected from p-toluenesulfonyl, o-nitrophenylsulfonyl or p-nitrophenylsulfonyl;
  • the alkyl-based amino protecting group is selected from the group consisting of trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl or benzyl; preferably an alkoxycarbonyl-based amino protecting group, more preferably t-butoxy Carbonyl or fluorenylmethoxycarbonyl.
  • the reaction is a condensation reaction
  • the amide bond-forming condensing agent is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbamate Imine, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzene And triazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-even Nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphat
  • the above condensation reaction is preferably carried out under basic conditions selected from the group consisting of organic or inorganic bases, preferably triethylamine, diethylamine, N,N-diisopropylethylamine (diisopropyl) Ethyl ethylamine), pyridine, sodium hexamethyldisilazide, n-butyllithium, potassium t-butoxide or tetrabutylammonium bromide, the inorganic base being selected from the group consisting of lithium hydroxide, sodium hydroxide, and hydroxide Potassium, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate, more preferably N,N-diisopropylethylamine.
  • organic or inorganic bases preferably triethylamine, diethylamine, N,N-diisopropylethylamine (diisopropyl) Ethyl
  • R 1 carboxy protecting group is DMB (2,4-dimethoxybenzyl)
  • the compound of the formula (II) is as shown in the compound of the formula (IIa).
  • the compound of the formula (III) is represented by the compound of the formula (IIIa); or when the R 1 is a hydrogen atom, the compound of the formula (III) is represented by the compound of the formula (IIIb).
  • the method is
  • the compound of the formula (IIa) is condensed with 6-maleimidocaproic acid to give a compound of the formula (IIIa).
  • the method further comprises the following steps
  • the compound of the formula (II), wherein R 1 is a hydrogen atom, R 2 is an amino protecting group, the compound of the formula (II) is as shown by the compound of the formula (IIc); more preferably, The R 1 carboxy protecting group is DMB (2,4-dimethoxybenzyl), R 2 is an amino protecting group, and the compound of formula (II) is as shown in the compound of formula (IIb).
  • the method further comprises the following steps
  • the method further comprises the compound of the formula (IIc), wherein a compound represented by the formula (IIb) is obtained by adding a carboxy protecting group, and the compound of the formula (IIb) is deprotected by a Fmoc protecting group under basic conditions.
  • the base is selected from an organic base or an inorganic base, and the organic base is preferably triethylamine, diethylamine, N,N'-diisopropylethylamine, pyridine, sodium hexamethyldisilazide, n-butyl a lithium base, potassium t-butoxide or tetrabutylammonium bromide, the inorganic base being selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or Barium carbonate, more preferably diethylamine.
  • the present invention also relates to a process for the preparation of a compound of the formula (I), which comprises reacting a compound of the formula (III) with a compound of the formula (IV) to give a compound of the formula (V): a step of deprotecting a compound of (V) to give a compound of formula (I),
  • A is selected from a 3-8 membered cycloalkyl group, preferably a 3-membered cycloalkyl group;
  • R is selected from halogen, preferably fluorine, chlorine, bromine or iodine, most preferably fluorine;
  • R 1 is as defined in formula (III);
  • R 3 is selected from a carboxy protecting group selected from the group consisting of 2,4-dimethoxybenzyl, benzyl, allyl, pentafluorophenyl, methyl, p-methylbenzyl, methoxy Ethoxymethyl or tert-butyl, preferably 2,4-dimethoxybenzyl;
  • R x is selected from an optionally substituted alkyl or cycloalkyl group selected from alkyl, haloalkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl a heterocyclic group, an aryl group or a heteroaryl group;
  • n is selected from 1, 2, 3, 4 or 5.
  • the method further comprises the step of: condensing a compound of the formula (III) with a compound of the formula (IV) by a compound of the formula (III) to obtain a compound of the formula (V),
  • the condensing agent is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diiso Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazole hexafluorophosphate-
  • the above condensation reaction is preferably carried out under basic conditions selected from the group consisting of organic or inorganic bases, preferably triethylamine, diethylamine, N,N-diisopropylethylamine (diisopropyl) Ethyl ethylamine), pyridine, sodium hexamethyldisilazide, n-butyllithium, potassium t-butoxide or tetrabutylammonium bromide, the inorganic base being selected from the group consisting of lithium hydroxide, sodium hydroxide, and hydroxide Potassium, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate, more preferably N,N-diisopropylethylamine.
  • organic or inorganic bases preferably triethylamine, diethylamine, N,N-diisopropylethylamine (diisopropyl) Ethyl
  • the method is
  • the method comprises the condensation of a compound of the formula (IIIb) with a compound of the formula (IVa) under basic conditions and a condensing agent to obtain a compound of the formula (Va), (Va).
  • the compound is deprotected under the action of an acid to give a compound of the formula (Ia).
  • the condensing agent is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diiso Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazole hexafluorophosphate
  • the base is selected from an organic base or an inorganic base, and the organic base is preferably triethylamine, diethylamine, N,N-diisopropylethylamine (diisopropylethylamine), pyridine or hexamethyl.
  • Sodium silylamino, n-butyllithium, potassium t-butoxide or tetrabutylammonium bromide the inorganic base being selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, sodium hydrogencarbonate Potassium carbonate, potassium hydrogencarbonate or cesium carbonate, more preferably N,N-diisopropylethylamine.
  • Agents that provide acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, ammonium chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, and para-benzene. Methanesulfonic acid, preferably trifluoroacetic acid.
  • the invention also provides a process for the preparation of a compound of formula (IVa):
  • the compound of the formula (M3) is amidated with a compound of the formula (i) by a condensing agent to obtain a compound of the formula (IVb), and the compound of the formula (IVb) is deprotected by a base. a compound of the formula (IVa),
  • the condensing agent is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diiso Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazole hexafluorophosphate-
  • the base is selected from an inorganic base or an organic base, preferably an organic base selected from the group consisting of amine organic bases such as diethylamine, triethylamine or aqueous ammonia.
  • the invention also provides a preparation method of the compound of the formula (M3):
  • the base is selected from an inorganic base or an organic base, preferably an organic base selected from the group consisting of amine organic bases such as diethylamine, triethylamine, 4-dimethylaminopyridine or 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide.
  • amine organic bases such as diethylamine, triethylamine, 4-dimethylaminopyridine or 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide.
  • the invention further provides a process for the preparation of a compound of formula (i):
  • the compound of the formula (a) is reacted with a compound of the formula (b) under the action of an organic base and an organic boron to give a compound of the formula (c), the compound of the formula (c) in an oxidizing agent (such as hydrogen peroxide) and a base.
  • the reaction is carried out under the action of lithium hydroxide monohydrate to obtain a compound of the formula (d).
  • the compound of the formula (d) is reacted with a benzyl bromide in the presence of a base such as sodium hydrogencarbonate to obtain a compound of the formula (e).
  • the compound of the formula (e) is reacted with methyl iodide to obtain a compound of the formula (f), and the compound of the formula (f) is deprotected to give a compound of the formula (g), and the compound of the formula (g) is reacted with hydrochloric acid to obtain a compound of the formula (h) wherein a compound of the formula (h) is reacted with a 9-fluorenylmethyl-N-succinimidylcarboxylate under the action of a base such as N,N-diisopropylethylamine. a compound of formula (i).
  • the present invention also provides a method for producing an antibody drug conjugate or a pharmaceutically acceptable salt thereof, wherein the antibody drug conjugate is passed from the antibody to the linker unit and the formula (I) in the above scheme
  • the compound is preferably conjugated, and the antibody is preferably a TNF- ⁇ antibody, a VEGF antibody, a c-MET antibody, an EGFR antibody, a Her2 antibody or a PD-1 antibody, and the linker unit is preferably an alkylene group, an arylene group or a heteroarylene group. , alkylene sulfanyl or iminothioalkyl.
  • the TNF- ⁇ antibody is selected from the group consisting of etanercept, infliximab, or adalimumab
  • the VEGF antibody is selected from bevacizumab
  • the EGFR antibody is selected from the group consisting of cetuximab, Pani Monoclonal antibody or nimotuzumab
  • the Her2 antibody is selected from trastuzumab (Herceptin) or pertuzumab
  • the PD-1 antibody is selected from the group consisting of navobizumab or palmeduzumab.
  • the antibody drug conjugate is selected from the group consisting of
  • the antibody Ab is preferably a TNF- ⁇ antibody, a VEGF antibody, an EGFR antibody, a Her2 antibody or a PD-1 antibody, and y is in the range of 1-8, preferably 2-5; y is a positive real number and may be an integer or a non-integer.
  • halogenated as used in the present invention means substituted by "halogen atom", and "halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
  • alkyl group in the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms, and includes, for example, "C 1-4 alkyl group", "C 1-3 alkyl group” and the like, and specific examples include But not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, new Pentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2 - dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-B A butyl group
  • haloalkyl refers to a group derived by substituting one or more "halogen atoms” for one or more hydrogen atoms on an "alkyl group” as described above. Defined.
  • hydroxyalkyl refers to a radical derived from one or more "hydroxy” groups substituted by one or more hydrogen atoms on an "alkyl group” as defined above.
  • alkoxy group as used in the present invention means a group which is bonded in an alkyl-O- form, wherein “alkyl group” is as defined above.
  • cycloalkyl group as used in the present invention means a saturated or partially unsaturated monocyclic or polycyclic cyclic group, and the number of ring atoms includes 3 to 20, preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atom. Specific examples include, but are not limited to, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl and the like.
  • heterocyclic group as used in the present invention means a cyclic group having 3 to 8 ring atoms in which at least one ring atom is a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom.
  • a ring atom in the cyclic structure may be oxidized, preferably a "5-6 membered heterocyclic group.”
  • a ring atom e.g., a carbon atom, a nitrogen atom, or a sulfur atom
  • a ring atom in the cyclic structure may be oxidized, preferably a "5-6 membered heterocyclic group.”
  • Specific examples include, but are not limited to, aziridine, 2H-azepine, diaziryl, 3H-diazapropenyl, azetidinyl, 1,4-dioxo Heterocyclohexane, 1,3-dioxanyl, 1,3-dioxolyl, 1,4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl , pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidin
  • aryl group as used in the present invention means an aromatic cyclic group having 6 to 15 ring carbon atoms, and includes “6-8 membered aryl group” and "6-15 membered fused aryl group".
  • a ring atom for example, a carbon atom, a nitrogen atom or a sulfur atom
  • examples thereof include, but are not limited to, phenyl, cyclooctadecenyl, naphthyl, anthryl, phenanthryl and the like.
  • heteroaryl group as used in the present invention means an aromatic cyclic group having 5 to 15 ring atoms (at least one of which is a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom), including "5-8 membered heteroaryl", “5-15 membered heteroaryl”, optionally, a ring atom (for example, a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxidized.
  • a "linker unit” as used herein refers to a chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches an antibody to a drug moiety, for example, an alkylene group, an arylene group, a heteroarylene group, an alkylene sulfanyl group or The iminothioalkyl group, the linker unit together with the maleimide group of formula (I), forms a complete linker.
  • Linkers are known in the art, such as SMCC, SPP, SPDP, and the like.
  • Substituted as used in the present invention means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • the reaction step is shortened, and the reactants in the key step of the preparation of the compound of the formula (I) are different in the present invention.
  • the first step in the key step of the present invention consists of the compound of the formula (IIIb) and the formula (IVa).
  • the compound shown is reacted to give a compound of the formula (Va), and the second step is obtained by decarboxylation of a compound represented by the formula (Va) to give a compound of the formula (Ia), which is compared with the prior art.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10-6 (ppm).
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane ( TMS).
  • DMSO-d6 dimethyl sulfoxide
  • CDCl3 deuterated chloroform
  • CD3OD deuterated methanol
  • TMS tetramethylsilane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • Chiral HPLC analysis assays were performed using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.).
  • the average inhibition rate of the kinase and the IC50 value were determined using a NovoStar plate reader (BMG, Germany).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • Purification compounds using column chromatography eluent systems and thin layer chromatography developer systems include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone
  • A dichloromethane and methanol systems
  • B n-hexane and ethyl acetate systems
  • C dichloromethane and acetone
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.
  • the reaction mixture was evaporated to dryness and evaporated, evaporated, evaporated, evaporated
  • the organic layer was dried (MgSO4), filtered, evaporated,
  • the aqueous phase was washed with dichloromethane (150 mL ⁇ 3), and a 2N hydrochloric acid solution was added dropwise to pH 2-3 under ice bath, extracted with ethyl acetate (100 mL ⁇ 3), washed with water (500 mL) The sodium solution (500 mL) was evaporated.
  • the amount of the intermediate 1n required is completely different, the amount of the intermediate 1n of the present invention can be greatly reduced, the amount of the intermediate 1n is 1.94 g, and the prior art is 2.82 g; the present invention and the present invention
  • the technically important reaction steps are different.
  • the present invention is a 2-step reaction, and the prior art is a 4-step reaction.
  • the prior art requires a multi-step complex route synthesis of the compound of Formula 1, which can be greatly reduced after the synthesis method of the present invention is employed. Production costs, shortened reaction time, improved production efficiency, outstanding technical progress and significant economic effects.

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Abstract

L'invention concerne une nouvelle toxine et un procédé de préparation d'un intermédiaire de celle-ci. L'invention concerne particulièrement un composé représenté par la formule (III) et son procédé de préparation, ainsi qu'un procédé de préparation d'un composé tel que représenté par la formule (I) obtenu à partir du composé tel que représenté par la formule (III) au moyen de l'introduction d'une série de groupes protecteurs, de l'élimination de groupes protecteurs et de réactions de condensation.
PCT/CN2018/103781 2017-09-04 2018-09-03 Nouvelle toxine et procédé de préparation d'un intermédiaire de celle-ci WO2019042447A1 (fr)

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CN113813399A (zh) * 2021-04-19 2021-12-21 联宁（苏州）生物制药有限公司 喜树碱类化合物、其抗体药物偶联物及其应用

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CN109912684A (zh) * 2019-03-08 2019-06-21 联宁（苏州）生物制药有限公司 一种用于抗体药物偶联物的药物-连接子mc-mmaf的制备方法及其中间体
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CN113813399A (zh) * 2021-04-19 2021-12-21 联宁（苏州）生物制药有限公司 喜树碱类化合物、其抗体药物偶联物及其应用

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