WO2022204947A1 - Procédé de préparation d'un conjugué de médicament de liaison et intermédiaire de celui-ci - Google Patents

Procédé de préparation d'un conjugué de médicament de liaison et intermédiaire de celui-ci Download PDF

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WO2022204947A1
WO2022204947A1 PCT/CN2021/083989 CN2021083989W WO2022204947A1 WO 2022204947 A1 WO2022204947 A1 WO 2022204947A1 CN 2021083989 W CN2021083989 W CN 2021083989W WO 2022204947 A1 WO2022204947 A1 WO 2022204947A1
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compound
formula
preparation
solvent
base
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PCT/CN2021/083989
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English (en)
Chinese (zh)
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鲍彬
邱雪飞
杨彤
张文伯
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上海复旦张江生物医药股份有限公司
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Priority to PCT/CN2021/083989 priority Critical patent/WO2022204947A1/fr
Priority to CN202180093749.3A priority patent/CN116897149A/zh
Publication of WO2022204947A1 publication Critical patent/WO2022204947A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/44—Antibodies bound to carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups

Definitions

  • the invention belongs to the field of drug synthesis, in particular to a preparation method of a linker drug conjugate and an intermediate thereof.
  • ADCs Antibody-drug conjugates
  • the basic building blocks of ADC drugs include antibodies, linkers, and effector molecules. Antibodies are used to transport effector molecules to the tumor site for enrichment, thereby killing tumor cells. Most of the traditional effector molecules are highly active tubulin inhibitors, which usually have large toxic and side effects, which limit the application of ADCs.
  • Immunomedics invented a new type of ADC drug IMMU-132 (ZL200980156218) with camptothecin compounds as effector molecules, which showed good anti-tumor effect.
  • Daiichi Sankyo invented another camptothecin compound as an effector.
  • the ADC drug DS-8201a (ZL201380053256) of the effector molecule also showed good anti-tumor effect.
  • WO2020259258A1 discloses an ADC compound with a camptothecin derivative Dxd as an effector molecule, which also shows good antitumor effect.
  • the target ADC compound can be obtained by coupling the camptothecin derivative shown in formula I with an antibody, wherein the linker drug conjugate shown in formula I can be prepared by the following synthetic route 1 or synthetic route 2 .
  • the synthesis method of route 1 comprises: reacting compound 1-1 with 4-aminobenzyl alcohol, reacting the obtained compound with bis(p-nitrobenzene) carbonate and then reacting with substituted alkylamine to obtain compound 1-2, compound 1- 2 react with paraformaldehyde and trimethylchlorosilane to obtain compound 1-3, compound 1-3 reacts with tert-butyl glycolate and then removes the tert-butyl group under the action of trifluoroacetic acid to obtain compound 1-4, compound 1- 4 was reacted with Exatecan mesylate to obtain compounds 1-5, which were deprotected by Fmoc on the amino group under the action of DBU and then coupled with 6-(maleimido)hexanoic acid succinimidyl ester to obtain target compound I.
  • the synthesis method of route 2 includes: reacting compound 2-1 with paraformaldehyde and trimethylchlorosilane, and then reacting the obtained compound with tert-butyl glycolate to obtain compound 2-2, and compound 2-2 is reacted with trifluoroacetic acid under the action of trifluoroacetic acid. After removing the tert-butyl group, react with Exatecan mesylate to obtain compound 2-3, which reduces azide under the action of triethylphosphine
  • the amino group is formed to obtain compound 2-4, and the target compound I is obtained by coupling reaction of compound 2-4 with MC-V.
  • the technical problem to be solved by this invention is that the preparation method of the linker drug conjugate shown in formula I in the prior art is difficult to obtain the final product with qualified purity and provides a linker drug conjugate shown in formula I
  • the new preparation method and its intermediates The preparation method of the invention has one or more of the following advantages: simple operation, good yield, easy product quality control and suitability for industrial production.
  • the present invention provides a compound of formula III:
  • R 1 is C 1 -C 6 alkyl, one or more R 1-3 S(O) 2 -substituted C 1 -C 6 alkyl, or one or more N(R 1-1 )( R 1-2 )-substituted C 1 -C 6 alkyl;
  • R 2 and R 3 are each independently C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one or more halogens, or halogen;
  • R 1-1 , R 1-2 and R 1-3 are each independently a C 1 -C 4 alkyl group.
  • R 1 is an R 1-3 S(O) 2 -substituted C 1 -C 6 alkyl
  • R 2 is C 1 -C 6 alkyl
  • R 3 is halogen
  • R 1-3 is a C 1 -C 4 alkyl group.
  • the C 1 -C 6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl group or tert-butyl group, preferably methyl or ethyl.
  • the halogen in the definitions of R 1 , R 2 and R 3 , can be fluorine, chlorine, bromine or iodine, preferably fluorine.
  • the C 1 -C 4 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
  • R 1 is a R 1-3 S(O) 2 -substituted C 1 -C 6 alkyl or a -NR 1-1 R 1-2 substituted C 1 -C 6 alkyl, It is preferably methylsulfonylethyl or N,N-dimethylethyl, more preferably methylsulfonylethyl.
  • R 2 is C 1 -C 6 alkyl, preferably methyl.
  • R3 is halo, preferably fluoro or chloro, more preferably fluoro.
  • R 1 is an R 1-3 S(O) 2 -substituted C 1 -C 6 alkyl, such as methylsulfonylethyl;
  • R 2 is C 1 -C 6 alkyl, such as methyl
  • R 3 is halogen, such as fluorine
  • R 1-3 is C 1 -C 4 alkyl, such as ethyl.
  • R 1 is as defined in any of the preceding schemes, R 2 is methyl, and R 3 is fluoro.
  • R 1 is methylsulfonylethyl
  • R 2 is methyl
  • R 3 is fluoro
  • the compound of formula III is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-phenyl
  • the present invention also provides a method for preparing a compound of formula III, which comprises the steps of: performing a substitution reaction with a compound of formula IV and a compound of formula IV' in a solvent and in the presence of a base to obtain the compound of formula III;
  • R 1 , R 2 and R 3 are as described above.
  • R 2 is methyl
  • R 3 is fluorine
  • the molar ratio of the compound of formula IV to the compound of formula IV' may be 1:1-5:1, preferably 2:1-4:1, More preferably, it is 3.0:1-3.5:1.
  • the base in the preparation method of the compound of formula III, can be a conventional base for such reactions in the art, such as an organic base, an inorganic base or a mixture thereof, preferably an organic base; wherein, the The organic base is preferably tert-butyl potassium, triethylamine, DMAP, pyridine, panmidine or a mixture of any two or more thereof, more preferably panmidine; the inorganic base is preferably an alkali metal hydroxide, an alkali metal carbonate , alkali metal phosphate or a mixture of any two or more thereof, more preferably potassium phosphate, potassium carbonate, potassium hydroxide, cesium carbonate or a mixture of any two or more thereof.
  • the base in the method for preparing the compound of formula III, is panpididine.
  • the molar ratio of the base to the compound of formula IV' can be 3:1-6:1, preferably 4.5:1-5.5:1, more preferably 4.8:1.
  • the solvent in the preparation method of the compound of formula III, can be a conventional solvent for this type of reaction in the art, preferably an aprotic organic solvent, such as ether solvent, chlorinated alkane solvent, Nitrile-based solvent or a mixture of any two or more thereof, preferably an ether-based solvent;
  • the ether-based solvent can be tetrahydrofuran, diethyl ether, 1,4-dioxane, anisole, methyl tert-butyl ether or wherein A mixture of any two or more, preferably 1,4-dioxane;
  • the chlorinated alkane solvent is preferably dichloromethane, dichloroethane, chloroform or a mixture of any two or more thereof; the nitriles
  • the solvent is preferably acetonitrile.
  • the solvent is 1,4-dioxane.
  • the temperature of the substitution reaction may be a conventional temperature for such reactions in the art, for example, 20-80°C, preferably 40-60°C, more preferably is 60°C.
  • the operation of the substitution reaction can be a conventional operation of this type of reaction in the art, for example, including the following steps: stirring the compound of the formula IV, the compound of the formula IV' , a mixture of solvent and base for substitution reaction.
  • the progress of the substitution reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC, or NMR, etc.), generally no longer
  • the compound of formula IV or the compound of formula IV' is detected as the end point of the reaction.
  • the reaction time of the substitution reaction may be 2 to 12 hours, more preferably 2 to 3 hours, and still more preferably 2 hours.
  • the following post-processing steps may be further included: removing the solvent in the reaction solution, washing the organic phase, and removing the organic phase obtained by washing.
  • the organic phase in the washing can be ethyl acetate or dichloromethane, preferably dichloromethane.
  • the aqueous phase in the washing can be an aqueous acid solution, water and/or saturated brine; the aqueous acid solution can be 0.1N hydrochloric acid, 0.05N sulfuric acid or a mixture thereof, preferably 0.1N hydrochloric acid.
  • the washing may include sequentially washing the organic phase with an aqueous acid solution, water and saturated brine, preferably with 0.1N dilute acid, water and saturated brine in this order.
  • the purification can adopt conventional purification methods in the field, such as beating, crystallization, preparative chromatography or silica gel column chromatography, etc., preferably the method of column silica gel column chromatography, the eluent used It is preferably a mixture of dichloromethane and methanol, and the elution gradient is preferably 100:1-10:1, more preferably 60:1-10:1.
  • the substitution reaction is preferably carried out under anhydrous conditions.
  • the preparation method of the compound of the formula III may further include a preparation method of the compound of the formula IV, which may include the steps of: reacting the compound of the formula V with paraformaldehyde and trimethylchlorosilane in a solvent to obtain the formula IV compound;
  • R1 is as described above.
  • the molar ratio of the paraformaldehyde to the compound of formula V in formaldehyde conversion is 3:1-12:1, preferably 3:1-4:1 , more preferably 3.1:1.
  • the molar ratio of the trimethylchlorosilane to the compound of formula V is 3:1-12:1, preferably 3:1-4:1, More preferably, it is 3.9:1.
  • the solvent in the preparation method of the compound of formula IV, can be a conventional solvent for this type of reaction in the art, preferably an aprotic organic solvent, such as ether solvent, chlorinated alkane solvent or
  • the mixture is preferably an ether solvent;
  • the ether solvent can be tetrahydrofuran, diethyl ether, 1,4-dioxane, anisole, methyl tert-butyl ether or a mixture of any two or more thereof, preferably Tetrahydrofuran;
  • the chlorinated alkane solvent is preferably dichloromethane, dichloroethane, chloroform or a mixture of any two or more thereof.
  • the solvent in the preparation method of the compound of formula IV, is tetrahydrofuran.
  • the reaction temperature in the preparation method of the compound of formula IV, can be a conventional temperature for such reactions in the art, for example, 10-40° C., preferably 25-40° C., and more preferably 25-30° C. °C.
  • the reaction is preferably carried out under anhydrous conditions.
  • the operation of the reaction can be a conventional operation of this type of reaction in the art, for example, including the following steps: batch (eg dropwise) trimethylsilyl chloride dropwise method) is added to the mixture of the compound of formula IV, paraformaldehyde and solvent, and the reaction is carried out with stirring.
  • the progress of the reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.) to the compound of formula V as the reaction endpoint.
  • the reaction time of the reaction may be 1-24 hours, preferably 12-20 hours, more preferably 16-20 hours, still more preferably 16 hours.
  • the following post-processing steps may be further included: solid-liquid separation of the reaction liquid, removal of the solvent from the obtained liquid phase, and the obtained residue used directly in the next reaction.
  • the preparation method of the compound of the formula IV may further include a preparation method of the compound of the formula V, which may comprise the steps of: reacting the compound of the formula VI with a sulfonyl azide compound in a solvent in the presence of a base and a catalyst to obtain the formula V compound;
  • R 1 is as described above.
  • the sulfonyl azide compound in the preparation method of the compound of formula V, can be 1H-imidazole-1-sulfonyl azide hydrochloride, 2-azido-1,3- Dimethylimidazole hexafluorophosphate, trifluorosulfonyl azide, p-toluenesulfonyl azide or methanesulfonyl azide, preferably 1H-imidazole-1-sulfonyl azide hydrochloride.
  • the molar ratio of the sulfonyl azide compound to the compound of formula VI is 1.0:1-1.5:1, preferably 1.0:1-1.2:1, More preferably, it is 1.02:1.
  • the base in the preparation method of the compound of formula V, can be a conventional base for such reactions in the art, such as an organic base, an inorganic base or a mixture thereof, preferably an inorganic base; wherein, the The inorganic base is preferably an alkali metal hydroxide, an alkali metal carbonate, an alkali metal phosphate or a mixture of any two or more thereof, more preferably potassium phosphate, potassium carbonate, potassium hydroxide, cesium carbonate or any two of them The above mixture is more preferably potassium carbonate; the organic base is preferably tert-butyl potassium, triethylamine, DMAP, pyridine, panbidine, 2,6-lutidine or a mixture of any two or more thereof. In some embodiments, in the method for preparing the compound of formula V, the base is an alkali metal carbonate, such as potassium carbonate.
  • the molar ratio of the base to the compound of formula VI is 1.5:1-3.0:1, preferably 2.0:1-2.5:1, more preferably 2.0 : 1.
  • the catalyst in the preparation method of the compound of formula V, can be a conventional catalyst for this type of reaction in the art, such as a ketone salt, preferably copper sulfate, more preferably copper sulfate pentahydrate.
  • the molar ratio of the ketone salt to the compound of formula VI can be 0.1:1-0.5:1, preferably 0.1:1-0.3:1, more preferably 0.1:1 to 0.2:1, most preferably 0.1:1.
  • the solvent in the preparation method of the compound of formula V, can be a conventional solvent for this type of reaction in the art, preferably a mixed solvent of an organic solvent and water, and the organic solvent can be an alcohol A solvent, a chlorinated alkane solvent, an ether solvent or a mixture of any two or more thereof, preferably a mixture of an alcohol solvent and a chlorinated alkane solvent;
  • the alcohol solvent can be methanol, ethanol, isopropanol or The mixture is preferably methanol;
  • the chlorinated alkane solvent can be dichloromethane, chloroform, dichloroethane or a mixture of any two or more thereof, preferably dichloromethane;
  • the ether solvent is preferably Tetrahydrofuran, diethyl ether, 1,4-dioxane, anisole, methyl tert-butyl ether or a mixture of any two or more thereof.
  • the solvent in the preparation method of the compound of formula IV, the solvent is a mixed solvent
  • the reaction temperature in the preparation method of the compound of formula V, can be a conventional temperature for such reactions in the art, for example, 10-40° C., preferably 25-40° C., more preferably 25-30° C. °C.
  • the operation of the reaction can be a conventional operation of this type of reaction in the art, for example, including the following steps: adding a sulfonyl azide compound to the compound of formula VI, a base In the mixed system of , catalyst and solvent (preferably, the sulfonyl azide compound is added after the mixed system is clarified), and the reaction is carried out by stirring.
  • the progress of the reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.), and generally the formula is no longer detected.
  • Compound VI served as the reaction endpoint.
  • the reaction time of the reaction may be 1-24 hours, preferably 12-20 hours, more preferably 16-20 hours, still more preferably 16 hours.
  • the following post-processing steps may be further included: removing the organic solvent in the reaction solution, extracting (for example, extracting with dichloromethane), extracting The resulting organic phase is recrystallized with ethanol and activated carbon to obtain the compound of formula V.
  • the preparation method of the compound of the formula V may further include a preparation method of the compound of the formula VI, which may include the following steps: the compound of the formula VII is subjected to a de-Fmoc reaction in the presence of a base and an organic solvent to obtain the compound of the formula VI;
  • R 1 is as described above.
  • the base in the preparation method of the compound of formula VI, can be a conventional base for such reactions in the art, such as an organic base, an inorganic base or a mixture thereof, preferably an organic base; wherein, the base
  • the organic base is preferably diethylamine, tert-butyl potassium, triethylamine, DMAP, pyridine, pampidine, 2,6-lutidine or a mixture of any two or more thereof, more preferably ethylenediamine;
  • the inorganic base is preferably alkali metal hydroxide, alkali metal carbonate, alkali metal phosphate or a mixture of any two or more thereof, more preferably potassium phosphate, potassium carbonate, potassium hydroxide, cesium carbonate or any two or more of them the mix of.
  • the base in the method for preparing the compound of formula VI, the base is diethylamine.
  • the volume ratio of the base to the organic solvent may be 0.1:1-0.5:1, preferably 0.2:1-0.3:1, and more preferably 0.2:1.
  • the organic solvent may be DMF, DMSO, tetrahydrofuran, 1,4-dioxane or a mixture of any two or more thereof, preferably DMF.
  • the temperature of the de-Fmoc reaction can be a conventional temperature for such reactions in the art, for example, 10-40°C, preferably 25-40°C, and more preferably 25-30°C.
  • the operation of the de-Fmoc reaction can be a conventional operation of this type of reaction in the art, such as including the following steps: stirring the compound of formula VII, a base and an organic solvent The mixed system was subjected to the de-Fmoc reaction.
  • the progress of the de-Fmoc reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.) to the compound of formula VII as the reaction end point.
  • the reaction time of the reaction may be 1-24 hours, preferably 4-12 hours, more preferably 4-6 hours, and still more preferably 4 hours.
  • the following post-processing step may be further included: the reaction solution is subjected to solid-liquid separation, and the solvent in the obtained liquid phase is removed to obtain a crude product.
  • the post-processing step may further include the following step: beating the crude product to obtain a solid product of the compound of formula VI.
  • the solvent used for beating can be an ether solvent, such as tetrahydrofuran, diethyl ether, 1,4-dioxane, anisole, methyl tert-butyl ether or a mixture of any two or more thereof, preferably methyl tertiary Butyl ether.
  • the post-processing step may further include the following step: recrystallization and purification of the solid product of the compound of formula VI obtained by pulping.
  • the solvent used for recrystallization can be an alcohol solvent, such as methanol, ethanol, isopropanol or a mixture of any two or more thereof, preferably ethanol.
  • the preparation method of the compound of the formula VI may further include a preparation method of the compound of the formula VII, which may comprise the steps of: compounding the compound of the formula VIII with N-Fmoc-L-valine N-butadienylamine imide ester in the compound of the formula VII.
  • the coupling reaction is carried out in a solvent to obtain the compound of formula VII;
  • R 1 is as described above.
  • the molar ratio of the N-Fmoc-L-valine N-butadienimide to the compound of formula VIII may be 0.8:1- 5:1, preferably 0.8:1 to 1.2:1, more preferably 1:1.
  • the solvent in the preparation method of the compound of formula VII, can be DMF, DMSO, acetonitrile, dichloromethane, dichloroethane or a mixture of any two or more thereof, preferably dichloromethane Methane.
  • the temperature of the coupling reaction can be a conventional temperature for such reactions in the art, for example, 10-40°C, preferably 35-40°C, more preferably 40°C.
  • the coupling reaction is preferably carried out under the protection of gas.
  • the gas in the gas shielding does not participate in the reaction, such as argon, helium or nitrogen, or nitrogen.
  • the operation of the coupling reaction can be a conventional operation of this type of reaction in the art, for example, including the following steps: stirring the compound of formula VIII, N-Fmoc-L -The mixed system of valine N-butadienylamine imide ester and solvent is used for coupling reaction.
  • the progress of the coupling reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.) to the compound of formula VIII as the reaction endpoint.
  • the reaction time of the coupling reaction may be 1-24 hours, preferably 12-20 hours, more preferably 16-20 hours, still more preferably 16 hours.
  • a post-processing step may be further included, and the post-processing step may include: adding an alcohol solvent (such as methanol) into the reaction system , ethanol, isopropanol or any two or more of them, preferably methanol), stir (the stirring temperature can be 20-40 ° C, preferably 35-40 ° C, more preferably 40 ° C; the stirring time can be 1-24 hours, preferably 4-12 hours, more preferably 4-6 hours, still more preferably 4 hours), and the solid in the system is separated to obtain the compound of formula VII.
  • an alcohol solvent such as methanol
  • stir the stirring temperature can be 20-40 ° C, preferably 35-40 ° C, more preferably 40 ° C
  • the stirring time can be 1-24 hours, preferably 4-12 hours, more preferably 4-6 hours, still more preferably 4 hours
  • the preparation method of the compound of formula VII may further include a preparation method of the compound of formula VIII, which may include the following steps: performing a de-Fmoc reaction on the compound of formula IX in the presence of a base and a solvent to obtain the compound of formula VIII;
  • R 1 is as described above.
  • the base in the preparation method of the compound of formula VIII, can be a conventional base for such reactions in the art, such as an organic base, an inorganic base or a mixture thereof, preferably an organic base; wherein, the base
  • the organic base is preferably diethylamine, tert-butyl potassium, triethylamine, DMAP, pyridine, pampidine, 2,6-lutidine or a mixture of any two or more thereof, more preferably ethylenediamine;
  • the inorganic base is preferably alkali metal hydroxide, alkali metal carbonate, alkali metal phosphate or a mixture of any two or more thereof, more preferably potassium phosphate, potassium carbonate, potassium hydroxide, cesium carbonate or any two or more of them the mix of.
  • the base in the method for preparing the compound of formula VIII, the base is diethylamine.
  • the solvent in the preparation method of the compound of formula VIII, may be DMF, DMSO, tetrahydrofuran, 1,4-dioxane or a mixture of any two or more thereof, preferably DMF.
  • the volume ratio of the base to the solvent may be 0.2:1-0.5:1, preferably 0.3:1-0.4:1, more preferably 0.3 : 1.
  • the reaction temperature of the de-Fmoc reaction can be a conventional temperature for such reactions in the art, for example, 10-40°C, preferably 25-40°C, more preferably 25-30°C.
  • the operation of the de-Fmoc reaction can be a conventional operation of this type of reaction in the art, such as including the following steps: stirring the mixture of the compound of formula IX, the base and the solvent The system undergoes a de-Fmoc reaction.
  • the progress of the de-Fmoc reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.) to the compound of formula VII as the reaction end point.
  • the reaction time of the reaction may be 1-24 hours, preferably 2-12 hours, more preferably 2-6 hours, still more preferably 2 hours.
  • a post-processing step may be further included, and the post-processing step may include: removing the solvent in the reaction solution, and the obtained residue is treated with The solid obtained by beating is the compound of formula VIII.
  • the solvent used for beating can be an ether solvent, such as tetrahydrofuran, diethyl ether, 1,4-dioxane, anisole, methyl tert-butyl ether or a mixture of any two or more thereof, preferably methyl tertiary Butyl ether.
  • the preparation method of the compound of the formula VIII may further include a preparation method of the compound of the formula IX, which may include the following steps: the compound of the formula X and the amino compound R1NH2 are subjected to a coupling reaction in the presence of a base and a solvent to obtain the compound of the formula IX;
  • R 1 is as described above.
  • the molar ratio of the amino compound R 1 NH 2 to the compound of formula X may be 1.0:1-3.0:1, preferably 1.1:1-1.5: 1, more preferably 1.1:1.
  • the base in the preparation method of the compound of formula IX, can be a conventional base for such reactions in the art, such as an organic base, an inorganic base or a mixture thereof, preferably an organic base; wherein, the The organic base is preferably diethylamine, tert-butyl potassium, triethylamine, DMAP, pyridine, pampidine, 2,6-lutidine or a mixture of any two or more thereof, more preferably DMAP; the inorganic base It is preferably alkali metal hydroxide, alkali metal carbonate, alkali metal phosphate or a mixture of any two or more thereof, more preferably potassium phosphate, potassium carbonate, potassium hydroxide, cesium carbonate or a mixture of any two or more thereof . In some embodiments, in the method for preparing the compound of formula IX, the base can be DMAP.
  • the molar ratio of the base to the compound of formula X may be 2.0:1-4.0:1, preferably 2.5:1-3.0:1, more preferably 2.5:1.
  • the solvent in the preparation method of the compound of formula IX, can be DMF, DMSO, dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane or any two of them
  • the above mixture is preferably dichloromethane.
  • the coupling reaction temperature can be a conventional temperature for such reactions in the art, for example, 10-40°C, preferably 25-40°C, more preferably 25°C -30°C.
  • the operation of the coupling reaction can be a conventional operation of this type of reaction in the art, for example, including the following steps: stirring the compound of formula X, the amino compound R 1 NH 2.
  • the mixed system of base and solvent is used for coupling reaction.
  • the progress of the coupling reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.) to the compound of formula VII as the reaction end point.
  • the reaction time of the reaction may be 1-24 hours, preferably 12-20 hours, more preferably 12-16 hours, still more preferably 12 hours.
  • a post-processing step may be further included, and the post-processing step may include: solid-liquid separation of the reaction solution, solid-liquid separation
  • the isolated solid (which can be washed with an organic solvent such as diethyl ether, ethyl acetate or a mixture thereof, preferably ethyl acetate, after solid-liquid separation) is a part of the product of the compound of formula IX.
  • the post-processing step may further include: extracting and washing the liquid phase obtained by the solid-liquid separation, and beating the solid obtained after removing the solvent from the organic phase to obtain another part of the product of the compound of formula IX.
  • the extraction and washing can be carried out using an aqueous acid solution, an aqueous alkali solution, water and a saturated saline solution, preferably an aqueous acid solution, an aqueous alkali solution, water and a saturated saline solution in sequence; further preferably, an aqueous acid solution is used for washing in sequence 1 time, 2 times with alkali aqueous solution, 1 time with water and 1 time with saturated brine;
  • the acid aqueous solution can be hydrochloric acid aqueous solution, sulfuric acid aqueous solution or phosphoric acid aqueous solution, preferably 1N hydrochloric acid, 0.5N sulfuric acid or 0.33N phosphoric acid, more preferably 1N hydrochloric acid;
  • the aqueous solution of the alkali can be sodium hydroxide aqueous solution, potassium hydroxide aqueous solution or its mixture, preferably 1N sodium hydroxide, 1N potassium hydroxide or its mixture, more preferably 1N
  • the preparation method of the compound of the formula IX may further include a preparation method of the compound of the formula X, which may include the following steps: the compound of the formula XI and the compound of the formula XII are subjected to the following reaction in the presence of a base and a solvent to obtain the compound of the formula X. ;
  • the molar ratio of the compound of formula XII to the compound of formula XI may be 3.0:1-1.2:1, preferably 2.0:1-1.5:1, and further Preferably it is 1.5:1.
  • the base in the preparation method of the compound of formula X, can be a conventional base for such reactions in the art, such as an organic base, an inorganic base or a mixture thereof, preferably an organic base; wherein, the The organic base is preferably diethylamine, tert-butyl potassium, triethylamine, DMAP, pyridine, pampidine, 2,6-lutidine or a mixture of any two or more thereof, more preferably pyridine; the inorganic base It is preferably alkali metal hydroxide, alkali metal carbonate, alkali metal phosphate or a mixture thereof, more preferably potassium phosphate, potassium carbonate, potassium hydroxide, cesium carbonate or a mixture of any two or more thereof. In some embodiments, in the method for preparing the compound of formula X, the base is pyridine.
  • the molar ratio of the base to the compound of formula XI may be 1.0:1-4.0:1, preferably 2.0:1-3.0:1, more preferably 2.0:1.
  • the solvent in the preparation method of the compound of formula X, can be DMF, DMSO, dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane or any two of them
  • the above mixture is preferably dichloromethane.
  • the reaction temperature can be a conventional temperature for such reactions in the art, for example, 10-40° C., preferably 25-40° C., more preferably 25-30° C. °C.
  • the operation of the reaction can be a conventional operation of this type of reaction in the art, for example, the following steps are included: the compound of formula XII is divided into batches (which can be divided into 6-3 batches) , preferably divided into 5-4 batches) add the mixed system of the compound of formula XI, alkali and solvent (the temperature of the mixed system can be controlled to be 0-20°C during the addition process, preferably 10-0°C, more preferably 0-5°C) , stirring to carry out the reaction.
  • the progress of the reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.), and generally the formula is no longer detected.
  • Compound XI served as the reaction endpoint.
  • the reaction time of the reaction may be 1-24 hours, preferably 2-12 hours, more preferably 4-8 hours, still more preferably 4 hours.
  • a post-processing step may be further included, and the post-processing step may include: performing solid-liquid separation on the reaction liquid, and obtaining the result by solid-liquid separation The solid is part of the product of the compound of formula X.
  • the post-processing step may further include: extracting and washing the liquid phase obtained by the solid-liquid separation, and beating the solid obtained after removing the solvent from the organic phase to obtain another part of the product of the compound of formula X.
  • the extraction and washing can be carried out using an aqueous acid solution, an aqueous alkali solution, water and a saturated saline solution, preferably an aqueous acid solution, an aqueous alkali solution, water and a saturated saline solution in sequence; further preferably, an aqueous acid solution is used for washing in sequence 1 time, 2 times with alkali aqueous solution, 1 time with water and 1 time with saturated brine;
  • the acid aqueous solution can be hydrochloric acid aqueous solution, sulfuric acid aqueous solution or phosphoric acid aqueous solution, preferably 1N hydrochloric acid, 0.5N sulfuric acid or 0.33N phosphoric acid, more preferably 1N hydrochloric acid;
  • the aqueous solution of the alkali can be sodium hydroxide aqueous solution, potassium hydroxide aqueous solution or its mixture, preferably 1N sodium hydroxide, 1N potassium hydroxide or its mixture, more preferably 1N
  • the solvent for beating can be tetrahydrofuran, diethyl ether, 1,4-dioxane, anisole, methyl tert-butyl ether or a mixture of any two or more thereof, preferably methyl tert-butyl ether.
  • the present invention also provides a compound of formula II:
  • R 1 , R 2 and R 3 are as defined above for compounds of formula III;
  • the present invention also provides a method for preparing a compound of formula II, which comprises the following steps: subjecting the compound of formula III and a reducing agent to a reduction reaction in an organic solvent and in the presence of an acid buffer to obtain the compound of formula II;
  • R 1 , R 2 and R 3 are as defined above for compounds of formula III.
  • the reducing agent in the preparation method of the compound of formula II, may be a conventional reducing agent for such reactions in the art, preferably triphenylphosphine, tri-tert-butylphosphine or trimethylphosphine , more preferably trimethylphosphine.
  • the molar ratio of the reducing agent to the compound of formula III may be 1:1-5:1, preferably 2:1-4:1, more preferably It is 2.9:1-3.5:1, more preferably 2.9:1-3.0:1.
  • the organic solvent in the preparation method of the compound of formula II, can be a conventional organic solvent for this type of reaction in the art, preferably an ether solvent, such as tetrahydrofuran, diethyl ether, 1,4-dioxane Hexacyclic ring, anisole, methyl tert-butyl ether, or a mixture of any two or more thereof, more preferably tetrahydrofuran.
  • an ether solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane Hexacyclic ring, anisole, methyl tert-butyl ether, or a mixture of any two or more thereof, more preferably tetrahydrofuran.
  • the volume-to-mass ratio of the organic solvent to the compound of formula II can be 5-50 mL/g, preferably 10-20 mL/g, more preferably 13- 14mL/g.
  • the acid buffer in the preparation method of the compound of formula II, can be a conventional acid buffer for such reactions in the art, such as acetate buffer, formic acid buffer, preferably acetate buffer;
  • the pH of the acetate buffer used may be 4.0-6.0, preferably 4.5-5.5, more preferably 5.0.
  • the volume ratio of the organic solvent and the acid buffer may be 1:1-5:1, preferably 1:1-2:1, more preferably 1.25:1-1.35:1, most preferably 1.28:1-1.30:1.
  • the temperature of the reduction reaction can be a temperature conventional for such reactions in the field, for example, 0-20°C, preferably 0-10°C, more preferably 0-5°C.
  • the operation of the reduction reaction can be a conventional operation of this type of reaction in the art, for example, including the following steps: stirring an organic solvent, an acid buffer, the compound of formula III and a reducing agent to carry out the reduction reaction.
  • the progress of the reduction reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.), generally no longer The compound of formula III was detected as the reaction endpoint.
  • the reaction time of the reduction reaction is 1-24 hours, preferably 2-5 hours, more preferably 2 hours.
  • the following post-processing steps may be further included: extracting the reaction solution, and extracting the organic phase obtained by the extraction to remove the solvent.
  • Purification yields the compound of formula II.
  • the purification can adopt conventional purification methods in the field, such as pulping, crystallization, preparative chromatography or silica gel column chromatography, etc., preferably the method of column silica gel column chromatography, and the eluents used are preferably dichloromethane and methanol mixing, the elution gradient is preferably 50:1-10:1, more preferably 20:1-10:1.
  • the method for preparing the compound of formula II may further include the method for preparing the compound of formula III as described herein.
  • the present invention provides a method for preparing a compound of formula I, which comprises the following steps: subjecting a compound of formula II and 6-(maleimido)hexanoic acid succinimidyl ester to a coupling reaction in a solvent to obtain the The compound of formula I;
  • R 1 , R 2 and R 3 are as defined above for compounds of formula III.
  • the molar ratio of the 6-(maleimido)hexanoic acid succinimidyl ester to the compound of formula II can be 1.0:1- 5.0:1, preferably 1.0:1-2.0:1, more preferably 1.9:1-2.0:1, still more preferably 1.96:1.
  • the solvent in the preparation method of the compound of formula I, can be a conventional solvent for such reactions in the art, such as amide solvents, chlorinated alkane solvents, ether solvents, nitrile solvents Or a mixture of any two or more of them, preferably an amide solvent, a chlorinated alkane solvent or a mixture thereof, more preferably an amide solvent or a chlorinated alkane solvent, more preferably a chlorinated alkane solvent;
  • the amide solvent is preferably DMF, DMAC or a mixture thereof, more preferably DMF;
  • the chlorinated alkane solvent is preferably dichloromethane, chloroform, dichloroethane or a mixture of any two or more thereof, more preferably two methyl chloride;
  • the ether solvent is preferably tetrahydrofuran, diethyl ether, 1,4-dioxane, anisole, methyl tert-butyl ether or a mixture of any two or more thereof, more
  • the volume-to-mass ratio of the solvent to the compound of formula II can be 20-200 mL/g, preferably 30-80 mL/g, more preferably 35-40 mL /g.
  • the reaction temperature can be a temperature conventional for such reactions in the art, for example, 0-50°C, preferably 25-40°C, more preferably 40°C.
  • the operation of the coupling reaction can be a conventional operation of this type of reaction in the art, for example, including the following steps: stirring the compound of formula II, 6-( maleimide) a mixture of a hexanoyl compound and a solvent to carry out the coupling reaction.
  • the progress of the reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.), and generally the formula is no longer detected.
  • Compound II served as the reaction endpoint.
  • the reaction time of the coupling reaction may be 1-24 hours, preferably 12-20 hours, more preferably 16 hours.
  • the method for preparing the compound of formula I may further include the following post-processing step after the coupling reaction is completed: removing the solvent in the reaction solution, and purifying the obtained residue to obtain the compound of formula I.
  • the purification can adopt conventional purification methods in the field, such as pulping, crystallization, preparative chromatography or silica gel column chromatography, etc., preferably the method of column silica gel column chromatography, and the eluents used are preferably dichloromethane and methanol Mixing, the elution gradient is preferably 50:1-10:1, more preferably 50:1-15:1.
  • the described preparation method of the compound of formula I may further comprise the preparation method of the compound of formula II as described herein.
  • the present invention also provides a compound of formula IV:
  • R1 is as previously defined for compounds of formula III.
  • the present invention also provides a preparation method of the compound of formula IV, which comprises the steps of: reacting the compound of formula V with paraformaldehyde and trimethylchlorosilane in a solvent to obtain the compound of formula IV;
  • R1 is as previously defined for compounds of formula III.
  • the reaction conditions can be as described above.
  • the method for preparing the compound of formula IV may further include the method for preparing the compound of formula V described herein.
  • the compound of formula IV is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the present invention also provides a compound of formula V:
  • R1 is as previously defined for compounds of formula III.
  • the compound of formula V is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe-N-N-phenyl
  • the present invention also provides a preparation method of a compound of formula V, comprising the steps of: reacting the compound of formula VI with a sulfonyl azide compound in a solvent in the presence of a base and a catalyst to obtain the compound of formula V;
  • R1 is as previously defined for compounds of formula III.
  • the reaction conditions can be as described above.
  • the method for preparing the compound of formula V may further include the method for preparing the compound of formula VI described herein.
  • the present invention also provides a compound of formula VI:
  • R1 is as previously defined for compounds of formula III.
  • the compound of formula VI is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the present invention also provides a preparation method of a compound of formula VI, which comprises the steps of: performing a de-Fmoc reaction on the compound of formula VII in the presence of a base and an organic solvent to obtain the compound of formula VI;
  • R1 is as previously defined for compounds of formula III.
  • reaction conditions can be as described above.
  • the method for preparing the compound of formula VI may further include the method for preparing the compound of formula VII described herein.
  • the present invention also provides a method for preparing a compound of formula VII, which comprises the steps of: coupling the compound of formula VIII with N-Fmoc-L-valine N-butadienimide in a solvent to obtain the compound of formula VII;
  • R1 is as previously defined for compounds of formula III.
  • the reaction conditions can be as described above.
  • the method for preparing the compound of formula VII may further include the method for preparing the compound of formula VIII described herein.
  • the present invention also provides a compound of formula VIII:
  • R1 is as previously defined for compounds of formula III.
  • the compound of formula VIII is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the present invention also provides a method for preparing a compound of formula VIII, which comprises the following steps: performing a de-Fmoc reaction on the compound of formula IX in the presence of a base and a solvent to obtain a compound of formula VIII;
  • R1 is as previously defined for compounds of formula III.
  • the reaction conditions can be as described above.
  • the method for preparing the compound of formula VIII may further include the method for preparing the compound of formula IX described herein.
  • the present invention also provides a compound of formula IX:
  • R1 is as previously defined for compounds of formula III.
  • the compound of formula IX is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the present invention also provides a method for preparing a compound of formula IX, which comprises the following steps: subjecting the compound of formula X and amino compound R 1 NH 2 to a coupling reaction in the presence of a base and a solvent to obtain the compound of formula IX;
  • R1 is as previously defined for compounds of formula III.
  • the reaction conditions can be as described above.
  • the method for preparing the compound of formula IX may further include the method for preparing the compound of formula X described herein.
  • the present invention also provides a compound of formula X:
  • the present invention also provides a method for preparing a compound of formula X, comprising the steps of: performing the following reaction with a compound of formula XI and a compound of formula XII in the presence of a base and a solvent to obtain the compound of formula X;
  • reaction conditions can be as described above.
  • C1-C6 alkyl denotes a saturated straight-chain or branched alkyl group comprising 1-6, especially 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, tert-butyl, etc., especially methyl or ethyl.
  • halogen denotes fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is to provide a new preparation method of the linker drug conjugate represented by formula I and its intermediate.
  • the preparation method has one or more of the following advantages: simple operation, good yield, easy product quality control, and suitability for industrial production.
  • the mass spectrometer adopts Waters Acquity Xevo G2-XS QTof UPLC/MS ultra-performance liquid chromatography high-resolution mass spectrometry system
  • the 1 H-NMR adopts Bruker AVANCE III 400MHz nuclear magnetic resonance apparatus or Bruker AVANCE III HD 300 MHz nuclear magnetic resonance apparatus , HPLC using Agilent 1260 high performance liquid chromatography.
  • the reaction solution was suction filtered, the filter cake was collected and dried to obtain the first batch of solids; the filtrate was washed with 1N hydrochloric acid, 1N sodium hydroxide (twice), water and saturated brine successively, dried, concentrated, and then washed with formic acid After slurried for 1 hour, filtered, the filter cake was collected and dried to give a 2nd crop of solids. The two batches of solid were combined to give compound 10 as a pale yellow solid (12 g, 78% yield).
  • compound 9 (9.6 g, 17.0 mmol) was dissolved in 50 mL of DMF, 15 mL of diethylamine was added, the resulting mixture was further stirred at room temperature for 2 hours, and the reaction of the starting materials was monitored by TLC. The reaction solution was directly concentrated to remove the solvent, and the obtained residue was slurried with methyl tert-butyl ether (50 mL) to obtain compound 8 (5.2 g, yield 89%) as a white solid.
  • N-Fmoc-L-valine N-butadienimide 5 g, 11.5 mmol
  • amino compound 8 4 g, 11.6 mmol
  • compound 6 (5.0 g, 11.3 mmol) was dispersed in 50 mL of methanol, 10 mL of dichloromethane and 25 mL of water, potassium carbonate (3.1 g, 22.4 mmol, 2.0 equiv.) and copper sulfate pentahydrate (0.30 g, 1.2 mmol) were added. , 0.1 equiv). After the resulting mixture became clear with stirring, 1H-imidazole-1-sulfonyl azide hydrochloride (CAS: 952234-36-5, 2.4 g, 11.5 mmol, 1.02 equiv) was added, and the resulting reaction mixture was stirred at room temperature overnight.
  • 1H-imidazole-1-sulfonyl azide hydrochloride (CAS: 952234-36-5, 2.4 g, 11.5 mmol, 1.02 equiv) was added, and the resulting reaction mixture was stirred at room temperature overnight.
  • the crude product of compound 4 obtained in step 6 was dissolved in 2 L of ultra-dry 1,4-dioxane, and then Dxd (50 g, 0.10 mol, commercially available) and pampidine (87 mL, 0.48 mol) were added to it, and the resulting mixture was Heat to 60°C and stir for 2 hours.
  • the obtained reaction solution was evaporated under reduced pressure to remove the solvent, the obtained crude product was dissolved in 1.5 L of dichloromethane, and then the crude product solution was washed with 0.1 mol/L dilute hydrochloric acid, water and saturated brine successively, and the obtained organic phase was dried with anhydrous sodium sulfate overnight. .
  • Phase A is 0.1% formic acid aqueous solution
  • Phase B is 0.1% formic acid acetonitrile solution
  • the detection wavelength is 370 nm
  • the instrument is Agilent 1260
  • the chromatographic column is ZORBAX Eclipse Plus C18, 3.5 ⁇ m, 4.6 ⁇ 150 mm.
  • the gradient settings are shown in Table 2 below.

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Abstract

L'invention concerne un procédé de préparation d'un conjugué de médicament de liaison et un intermédiaire de celui-ci. L'invention concerne spécifiquement un procédé de préparation d'un composé de formule (I), dans laquelle R1 représente un groupe alkyle en C1-C6, un ou plusieurs groupes alkyle en C1-C6 à substitution R1-3S(O)2, ou un ou plusieurs groupes alkyle en C1-C6 à substitution N(R1-1)(R1-2) ; R2 et R3 représentent chacun indépendamment un groupe alkyle en C1-C6, un ou plusieurs groupes alkyle en C1-C6 à substitution halogène, ou un halogène ; et R1-1, R1-2 et R1-3 représentent chacun indépendamment un groupe alkyle en C1-C4. Le procédé de préparation présente un ou plusieurs des avantages suivants : l'opération est simple, le rendement est bon, la qualité du produit est facile à contrôler, et le procédé est approprié pour une production industrielle.
PCT/CN2021/083989 2021-03-30 2021-03-30 Procédé de préparation d'un conjugué de médicament de liaison et intermédiaire de celui-ci WO2022204947A1 (fr)

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CN202180093749.3A CN116897149A (zh) 2021-03-30 2021-03-30 一种连接基药物偶联物的制备方法及其中间体

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104379168A (zh) * 2012-05-15 2015-02-25 索伦托医疗有限公司 药物偶联物,偶联方法,及其用途
CN109200291A (zh) * 2018-10-24 2019-01-15 中国医学科学院医药生物技术研究所 一种靶向于egfr的抗体偶联药物及其制备方法和其用途
WO2020259258A1 (fr) * 2019-06-28 2020-12-30 上海复旦张江生物医药股份有限公司 Conjugué anticorps-médicament, intermédiaire correspondant, procédé de préparation associé, et application correspondante

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104379168A (zh) * 2012-05-15 2015-02-25 索伦托医疗有限公司 药物偶联物,偶联方法,及其用途
CN109200291A (zh) * 2018-10-24 2019-01-15 中国医学科学院医药生物技术研究所 一种靶向于egfr的抗体偶联药物及其制备方法和其用途
WO2020259258A1 (fr) * 2019-06-28 2020-12-30 上海复旦张江生物医药股份有限公司 Conjugué anticorps-médicament, intermédiaire correspondant, procédé de préparation associé, et application correspondante

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