WO2019223653A1 - 一种抗体药物偶联物中间体的制备工艺 - Google Patents

一种抗体药物偶联物中间体的制备工艺 Download PDF

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WO2019223653A1
WO2019223653A1 PCT/CN2019/087641 CN2019087641W WO2019223653A1 WO 2019223653 A1 WO2019223653 A1 WO 2019223653A1 CN 2019087641 W CN2019087641 W CN 2019087641W WO 2019223653 A1 WO2019223653 A1 WO 2019223653A1
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reaction
pab
cit
val
maa
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PCT/CN2019/087641
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English (en)
French (fr)
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黄长江
叶慧
姚雪静
接浩华
翟世重
房健民
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荣昌生物制药（烟台）有限公司
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Priority to SG11202006515VA priority Critical patent/SG11202006515VA/en
Priority to KR1020207020184A priority patent/KR102454638B1/ko
Priority to JP2020515844A priority patent/JP6949206B2/ja
Priority to CN201980002405.XA priority patent/CN110740753A/zh
Priority to AU2019268215A priority patent/AU2019268215B2/en
Priority to US16/618,110 priority patent/US20200138968A1/en
Priority to EP19807031.0A priority patent/EP3797795A4/en
Priority to RU2019142484A priority patent/RU2724436C1/ru
Priority to BR112020005596-4A priority patent/BR112020005596A2/pt
Priority to CA3062265A priority patent/CA3062265C/en
Publication of WO2019223653A1 publication Critical patent/WO2019223653A1/zh

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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
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    • 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
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
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    • 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
    • A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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    • A61K47/6869—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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    • 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
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Definitions

  • the invention relates to the field of pharmaceutical preparation, in particular to a process for preparing an antibody-drug conjugate intermediate.
  • Antibody drug conjugates are a class of antitumor drugs, which include three component parts: an antibody part (Antibody), a linker part (Linker), and a drug part (Drug).
  • the number of drugs determines the homogeneity of antibody-drug conjugates. Too high numbers of connected drugs will lead to unstable pharmacokinetics, increased drug metabolism rate, reduced half-life, and increased systemic toxicity .
  • the DAR value is mainly determined by the linker.
  • Classical ADCs have two coupling methods, one is amino coupling and the other is thiol coupling. This is currently the most commonly used coupling method.
  • Amino coupling is the coupling of a drug to the lysine (Lys) residue of an antibody through a linker. Since there are 80 lysines on an antibody, about 30 of these 80 lysines are available for connection.
  • the ADC formed by lysine coupling has a DAR value of 0-30, and the product uniformity is extremely poor.
  • the thiol coupling is to open the interchain disulfide bond in the antibody to form a free cysteine (Cys) residue, and then couple it with a linker-drug complex that can be paired with a cysteine residue. Because there are only 4 pairs of interchain disulfide bonds on an antibody, 8 free cysteine residues will be formed after all interchain disulfide bonds are opened. Therefore, ADC formed by coupling of cysteine residues, Its DAR value is 0-8. Although thiol coupling can better control the number of linkages on each antibody, the cleavage of inter-chain disulfide bonds will greatly reduce the stability of the antibody.
  • bridge coupling is a new coupling method developed on the basis of thiol coupling.
  • the linker is coupled to two free thiol groups on the antibody at the same time.
  • the DAR value of the antibody-drug conjugate thus formed is 0-4.
  • the Chinese patent application with publication number CN107921030A discloses a variety of bridges with the antibody.
  • a covalently linked linker in a coupling manner which discloses an antibody drug conjugate intermediate (Py-MAA-Val-Cit-PAB-MMAE) as shown on page 42 of the specification (where Py is 1 , 3,5-triacryloylhexahydro-1,3,5-triazine, whose CAS is 959-52-4, can be purchased from Brilliant Technology Co., Ltd., Nanjing Kangmanlin Chemical Industry Co., Ltd.).
  • the process is to first couple Val-Cit-PAB and the drug moiety (MMAD) to form a Val-Cit-PAB-MMAD conjugate, and then react with Py-MAA to generate an antibody drug conjugate intermediate Py-MAA -Val-Cit-PAB-MMAD.
  • the price of the drug part such as MMAD / MMAE or MMAF
  • the input loss of the drug part produced by the above process is high, so the production cost is high, which is not suitable for industrial large-scale production .
  • the invention provides a process for preparing an antibody-drug conjugate intermediate, and specifically provides a process for preparing an antibody-drug conjugate intermediate including a linker portion and a drug portion.
  • the body is Py-MAA-Val-Cit-PAB-D
  • Py-MAA-Val-Cit-PAB in the intermediate is a linker moiety
  • the D in the intermediate represents a linked drug moiety, which It is characterized by including the following reaction routes:
  • preparation process includes the following reaction process:
  • Reaction A Dissolve Py-MAA-Val-Cit-PAB-OH in a solvent, add di (p-nitrobenzene) carbonate, stir until dissolved or slightly turbid, and then add an organic base;
  • Reaction B After the reaction A is completed, a triazolium catalyst, a drug part D, and an organic base are added. After the reaction is completed, purification is performed to obtain Py-MAA-Val-Cit-PAB-D. Purification is preferably performed using pre-HPLC.
  • the drug part D is an auristatin cytotoxic agent, an anthramycin cytotoxic agent, an anthracycline cytotoxic agent, or puromycin Cytotoxic agent.
  • the auristatin cytotoxic agent is MMAE, MMAF, MMAD or a derivative thereof;
  • the anthramycin cytotoxic agent is an astronomycin;
  • Anthracycline cytotoxic agents are daunorubicin, doxorubicin, epirubicin, idarubicin, pentarubicin, and mitoxantrone;
  • the puromycin cytotoxicity The agent is a purine toxin.
  • the structure of the Py-MAA-Val-Cit-PAB-D is as shown in formula (1-11):
  • the solvent is a polar solvent and / or a non-polar solvent
  • the polar solvent is one or more of DMF, DMA, and NMP
  • the non-polar solvent is dichloromethane, One or more kinds of carbon tetrachloride.
  • the organic base is one or more of N, N diisopropylethylamine, triethylamine, and pyridine, preferably one or two of N, N diisopropylethylamine and pyridine .
  • the triazole catalyst is 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, 1-hydroxy-1H-1,2,3-triazole- One or more ethyl 4-carboxylates, preferably 1-hydroxybenzotriazole.
  • reaction temperature of the reaction A is 5-35 ° C, and the reaction time is 2-10 hours.
  • the temperature of the reaction system is controlled to be 5-15 ° C, and the temperature is preferably 10 ° C before the bis (p-nitrobenzene) carbonate is added.
  • the reaction temperature of the reaction A is controlled between 20-35 ° C, preferably 30 ° C.
  • reaction temperature of the reaction B is 5-30 ° C, and the reaction time is 15-48 hours.
  • the temperature of the reaction system is controlled to be 5-15 ° C, preferably 10 ° C, before the triazole catalyst is added.
  • the reaction temperature of the system is controlled to be 15-30 ° C, preferably 20 ° C.
  • the molar ratio of Py-MAA-Val-Cit-PAB-OH to bis (p-nitrobenzene) carbonate and organic base in the reaction A is 1: 1-5: 1-3.
  • the molar ratio of the triazole compound, MMAE, organic base, and Py-MAA-Val-Cit-PAB-OH in the reaction B is 1-3: 1-3: 1.5-30: 1.
  • the present invention also provides an antibody-drug conjugate intermediate prepared by using any of the above preparation processes.
  • the antibody-drug conjugate intermediate is Py-MAA-Val-Cit-PAB-MMAF, and its structure is as follows: (2) shown:
  • the present invention also provides an antibody-drug conjugate intermediate prepared by using any of the above preparation processes.
  • the antibody-drug conjugate intermediate is Py-MAA-Val-Cit-PAB-MMAD, and its structure is as follows: (3) shown:
  • the present invention also provides an antibody-drug conjugate intermediate prepared by using any of the above-mentioned preparation processes.
  • the structure of the antibody-drug conjugate intermediate is shown in formula (4):
  • the present invention also provides an antibody-drug conjugate intermediate prepared by using any of the above-mentioned preparation processes.
  • the structure of the antibody-drug conjugate intermediate is shown in formula (5):
  • the present invention also provides an antibody-drug conjugate intermediate prepared by using any of the above preparation processes.
  • the structure of the antibody-drug conjugate intermediate is shown by formula (6):
  • the present invention also provides an antibody-drug conjugate intermediate prepared by using any of the above-mentioned preparation processes.
  • the structure of the antibody-drug conjugate intermediate is shown by formula (7):
  • the present invention also provides an antibody-drug conjugate intermediate prepared by using any of the above-mentioned preparation processes.
  • the structure of the antibody-drug conjugate intermediate is shown by formula (8):
  • the present invention also provides an antibody-drug conjugate intermediate prepared by using any of the above preparation processes.
  • the structure of the antibody-drug conjugate intermediate is shown by formula (9):
  • the present invention also provides an antibody-drug conjugate intermediate prepared by using any of the above-mentioned preparation processes.
  • the structure of the antibody-drug conjugate intermediate is shown in formula (10):
  • the present invention also provides an antibody-drug conjugate intermediate prepared by using any of the above-mentioned preparation processes.
  • the structure of the antibody-drug conjugate intermediate is shown by formula (11):
  • the process includes the following steps:
  • Reaction A Dissolve Py-MAA-Val-Cit-PAB in DMF, add bis (p-nitrobenzene) carbonate, stir until dissolved or slightly turbid, and add N, N-diisopropylethylamine dropwise to separate Purified to obtain Py-MAA-Val-Cit-PAB-PNP;
  • Reaction B Dissolve Py-MAA-Val-Cit-PAB-PNP in DMF, add 1-hydroxybenzotriazole, MMAE, N, N-diisopropylethylamine and pyridine, and perform pre after the reaction is completed. Purification by HPLC gave the compound Py-MAA-Val-Cit-PAB-MMAE shown by the structural formula (1).
  • the off-white powder was obtained by suction filtration, that is, the purified Py-MAA-Val-Cit-PAB-PNP.
  • solvent 1 is a medium-polar solvent, preferably ethyl acetate, dichloromethane, methanol, methyl tert-butyl ether, etc., and most preferably ethyl acetate;
  • Solvent 2 is a small polar solvent, preferably petroleum ether, n-hexane, n-pentane, cyclohexane, etc., and most preferably petroleum ether;
  • Solvents 3 and 4 are Py-MAA-Val-Cit-PAB-PNP soluble solvents, preferably acetic acid, trifluoroacetic acid, formic acid, methanol, ethanol, etc., most preferably acetic acid and methanol;
  • the solvent 5 is a solvent insoluble in Py-MAA-Val-Cit-PAB-PNP, and is preferably acetonitrile, ethyl acetate, dichloromethane, water, etc., and most preferably water.
  • the volume weight ratio of the solvent 1, solvent 2, solvent 3 and solvent 4 and Py-MAA-Val-Cit-PAB is 40-100: 80-200: 5-15: 1-3: 15-30: 1 .
  • the above separation and purification may be performed as follows:
  • the off-white powder was obtained by suction filtration, that is, the purified Py-MAA-Val-Cit-PAB-PNP.
  • the antibody-drug conjugate intermediate provided by the present invention Because the drug part is a reaction involved in the last step in the preparation process of the body, the consumption loss of the drug part (such as MMAD / MMAE or MMAF, etc.) is significantly reduced, the production cost is effectively reduced, and the production efficiency is improved. .
  • the process provided by the present invention is simple and environmentally friendly, and is suitable for large-scale industrialization.
  • antibody drug conjugate used in the present invention refers to a compound in which an antibody / antibody functional fragment, a linker, and a drug moiety are linked together through a chemical reaction, and the structure thereof generally consists of three parts: an antibody or an antibody-like ligand, A drug portion, and a linker that couples the antibody or antibody-like ligand to the drug.
  • the preparation of antibody-drug conjugates is usually divided into two steps: the first step is to form a "linker-drug” conjugate through a chemical reaction between the linker and the drug part, and the second step is to convert the "linker-drug"
  • the linker moiety in the conjugation is covalently coupled to the antibody / antibody functional fragment via a thiol or amino group.
  • the term "antibody drug conjugate intermediate” used in the present invention refers to the "linker-drug” conjugate described above. Further, the “antibody drug conjugate intermediate” according to the present invention generally refers to those A "linker-drug” conjugate is formed by linking the linker and the drug through amine transesterification and the "-CO-NH-” bond is coupled together.
  • linker and “linker portion” used in the present invention refer to the portion of the antibody-drug coupling that connects the antibody to the drug, which may be cleavable or non-cleavable.
  • a cleavable linker i.e., a cleavable linker or a biodegradable linker
  • the linker of the present invention is selected from cleavable linkers, such as disulfide-based linkers (which are selectively cleaved in tumor cells with higher thiol concentration), peptide linkers (which are Cells are cleaved by enzymes), ⁇ linkers.
  • the linker of the invention is selected from a non-cleavable linker (ie, a non-cleavable linker), such as a thioether linker.
  • the linker of the invention is a combination of a cleavable linker and a non-breakable linker.
  • drug and “drug moiety” as used herein generally refer to any compound that has the desired biological activity and has reactive functional groups in order to prepare the conjugates of the present invention. Desirable biological activities include diagnosis, cure, remission, treatment, prevention of diseases in humans or other animals. As new drugs are continuously discovered and developed, these new drugs should also be included in the drugs described in the present invention. Specifically, the drugs include, but are not limited to, cytotoxic drugs, cell differentiation factors, stem cell nutrition factors, steroid drugs, drugs for treating autoimmune diseases, anti-inflammatory drugs or drugs for infectious diseases. More specifically, the medicament includes, but is not limited to, a tubulin inhibitor or a DNA or RNA damaging agent.
  • Example 2 Comparative Example: Preparation of Py-MAA-Val-Cit-PAB-MMAE (Process disclosed on page 32 of the specification of Chinese Patent Publication No. CN107921030A)
  • Fmoc-Val-Cit-PAB-PNP (388.4 mg, 0.507 mmol) was dissolved in DMF (40 ml) under nitrogen protection at 0 ° C, and HOBt (68.4 mg, 0.507 mmol) and compound MMAE (400.0 mg, 0.558 mmol) were added. After 15 minutes, pyridine (8 ml) and DIPEA (106.2 ⁇ L, 0.608 mmol) were added and reacted at 0 ° C. for 30 minutes. Then it was warmed to room temperature and stirred for 3 hours. To the reaction mixture was added DIPEA (106.2 ⁇ L, 0.608 mmol), and the reaction was continued at room temperature for 24 h. After the reaction was completed, the mixture was concentrated in vacuo. The crude product was purified by column chromatography to obtain Fmoc-Val-Cit-PAB-MMAE (325 mg, yield 47.7%) as a white solid compound.
  • Py-MAA-Val-Cit-PAB-MMAD disclosed on page 32 of the specification of Chinese Patent Publication No. CN107921030A.
  • Py-MAA-Val-Cit-PAB-MMAE is prepared.
  • the dosage of MMAE is 400mg, and Py -MAA-Val-Cit-PAB-MMAE is 147.4 mg.
  • the white solid was purified by using a preparative high-performance liquid phase, and the preparation was subjected to rotary evaporation under reduced pressure to obtain Py-MAA-Val-Cit-PAB-OH (6.67 g, 32.4%, white solid powder).
  • the amount of MMAE added is 8.93 g, and Py-MAA-Val-Cit-PAB-MMAE is obtained at 9.79 g.
  • Example 2 Compare the input amount of MMAE and the quality of the final product in the process provided in Example 2 and Example 3 (the comparison results are shown in Table 1). From Table 1, we can see that Py prepared by the preparation process of Example 2 -MAA-Val-Cit-PAB-MMAE was finally obtained in an amount of 147.4mg, and MMAE was put in an amount of 400mg; Py-MAA-Val-Cit-PAB-MMAE was finally obtained in an amount of 9.79 using the preparation process of Example g, while the amount of MMAE is 8.93g.
  • the MMAE input-output rate represents how many unit masses of MMAE need to be invested for each unit of Py-MAA-Val-Cit-PAB-MMAE obtained from the preparation.
  • Table 1 the method of Example 2 is used to prepare 1 unit.
  • the mass of Py-MAA-Val-Cit-PAB-MMAE requires 2.71 unit mass of MMAE, while using the method of Example 3, only 0.91 unit mass of MMAE is required, and the input amount is reduced by 66.4%, which significantly reduces production. cost.

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Abstract

本发明涉及一种抗体药物偶联物中间体的制备工艺，与现有技术相比，本发明提供的抗体药物偶联物中间体的制备工艺由于药物部分是在最后一步参与的反应，显著地降低了药物部分,例如MMAD/MMAE或MMAF等投料的损耗，有效地降低了生产成本，提高了生产效益。另外，本发明提供的工艺简单、对环境友好，适于工业化大规模推广。

Description

一种抗体药物偶联物中间体的制备工艺 技术领域
本发明涉及药物制备领域，具体涉及一种抗体药物偶联物中间体的制备工艺。
背景技术
抗体药物偶联物(Antibody drug comjugate，简称ADC)是一类抗肿瘤药物，其包括三个组成部分：抗体部分(Antibody)、连接子部分(Linker)和药物部分(Drug)，抗体上连接的药物的个数(Drug-antibody Ratio，DAR)决定了抗体药物偶联物的均一性，连接的药物个数过高会导致药理动力性不稳定、药物代谢速度增加、半衰期减少和全身毒性的增加。
DAR值的高低主要由连接子决定，经典的ADC有两种偶联方式，一种是氨基偶联，一种是巯基偶联，这也是目前最常用的偶联方式。氨基偶联是将药物通过连接子偶联在抗体的赖氨酸(Lys)残基上，由于一个抗体上有80个赖氨酸，这80个赖氨酸中有大约30个可供连接，通过赖氨酸偶联而形成的ADC，其DAR值为0-30，产物均一性极差。巯基偶联是先将抗体中的链间二硫键打开形成游离的半胱氨酸(Cys)残基，再和能与半胱氨酸残基配对的连接子-药物复合物进行偶联，由于一个抗体上只有4对链间二硫键，链间二硫键被全部打开后会形成8个游离的半胱氨酸残基，因此通过半胱氨酸残基偶联而形成的ADC，其DAR值为0-8，尽管巯基偶联能够较好地控制每个抗体上连接的数量，但是链间二硫键的断去会极大的降低抗体的稳定性。
目前，除经典的氨基偶联和巯基偶联外，还有一种新的偶联方式：桥接偶联，桥接偶联方式是在巯基偶联的基础上开发的一种新的偶联方式，其是将连接子同时于抗体上两个游离的巯基偶联，如此形成的抗体药物偶联物的DAR值为0-4，公开号为CN107921030A的中国专利申请中公开了多种能够与抗体以桥接偶联方式共价连接的连接子，其在说明书第42页公开了一种如下所示的抗体药物偶联物中间体(Py-MAA-Val-Cit-PAB-MMAE)(其中，Py为1,3,5-三丙烯酰基六氢-1,3,5-三嗪，其CAS为959-52-4，可购自百灵威科技有限公司、南京康满林化工实业有限公司)。
Figure PCTCN2019087641-appb-000001
此外，在该专利申请第32页中还公开了一种药物部分是MMAD(Demethyldolastatin)的抗体药物偶联物中间体(Py-MAA-Val-Cit-PAB-MMAD)的制备工艺：
Figure PCTCN2019087641-appb-000002
该工艺是先将Val-Cit-PAB与药物部分(MMAD)偶联在一起形成Val-Cit-PAB-MMAD偶联物后，再与Py-MAA反应生成抗体药物偶联物中间体Py-MAA-Val-Cit-PAB-MMAD。由于抗体药物偶联物中连接的药物部分(例如MMAD/MMAE或MMAF等)的价格通常都比较昂贵，通过上述工艺生产药物部分投料损耗较高，因此导致生产成本高，不适于工业化大规模生产。
发明内容
本发明提供了一种抗体药物偶联物中间体的制备工艺，具体提供了一种包含连接子部分和药物部分的抗体药物偶联物中间体的制备工艺，所述的抗体药物偶联物中间体为Py-MAA-Val-Cit-PAB-D，所述中间体中的Py-MAA-Val-Cit-PAB为连接子部分，所述中间体中的所述D代表连接的 药物部分，其特征在于，包括以下反应路线：
Figure PCTCN2019087641-appb-000003
进一步的，所述的制备工艺包括如下反应过程：
反应A：将Py-MAA-Val-Cit-PAB-OH溶于溶剂中，加入二(对硝基苯)碳酸酯，搅拌至溶解或略微浑浊后加入有机碱；
反应B：反应A结束后，加入三氮唑类催化剂、药物部分D、有机碱，反应结束后进行纯化，得Py-MAA-Val-Cit-PAB-D。纯化优选使用pre-HPLC纯化。
更进一步的，所述的药物部分D为奥瑞他汀(auristatin)类细胞毒性剂、安曲霉素(Anthramycin)类细胞毒性剂、蒽环(anthracycline)类细胞毒性剂或嘌呤霉素(puromycin)细胞毒性剂。
优选的，所述的奥瑞他汀(auristatin)类细胞毒性剂为MMAE、MMAF、MMAD或其衍生物；所述的安曲霉素(Anthramycin)类细胞毒性剂为安曲霉素；所述的蒽环(anthracycline)类细胞毒性剂为柔红霉素、阿霉素、表阿霉素、伊达比星、戊柔比星、米托蒽醌；所述的嘌呤霉素(puromycin)细胞毒性剂为嘌呤毒素。
优选的，所述的Py-MAA-Val-Cit-PAB-D的结构如式(1-11)所示：
Figure PCTCN2019087641-appb-000004
Figure PCTCN2019087641-appb-000005
Figure PCTCN2019087641-appb-000006
进一步的，所述的溶剂为极性溶剂和/或非极性溶剂，所述的极性溶剂为DMF、DMA、NMP的一种或几种；所述的非极性溶剂为二氯甲烷、四氯化碳的一种或几种。
进一步的，所述的有机碱为N，N二异丙基乙胺、三乙胺、吡啶的一种或几种，优选为N，N二异丙基乙胺、吡啶的一种或两种。
进一步的，所述的三氮唑类催化剂为1-羟基苯并三氮唑、1-羟基-7-偶氮苯并三氮唑、1-羟基-1H-1,2,3-三唑-4-羧酸乙酯的一种或几种，优选为1-羟基苯并三氮唑。
进一步的，所述反应A的反应温度为5-35℃，反应时间为2-10小时。
优选的，所述反应A中在加入二(对硝基苯)碳酸酯前控制反应体系温度为5-15℃，进一步优选温度为10℃。
优选的，所述的反应A在加入有机碱后，控制体系反应温度为20-35℃之间，优选为30℃。
进一步的，所述反应B的反应温度为5-30℃，反应时间为15-48小时。
优选的，所述的反应B中，在加入三氮唑类催化剂前控制反应体系的温度为5-15℃，优选为10℃。
优选的，所述的反应B中，在加入有机碱后，控制体系反应温度为15-30℃，优选为20℃。进一步的，所述反应A中Py-MAA-Val-Cit-PAB-OH和二(对硝基苯)碳酸酯以及有机碱的摩尔比为1：1-5：1-3。
进一步的，所述反应B中三氮唑类催化剂、MMAE、有机碱和Py-MAA-Val-Cit-PAB-OH的摩尔比为1-3：1-3：1.5-30：1。
进一步的，本发明还提供了利用上述任一制备工艺制备抗体药物偶联物中间体，所述的抗体药物偶联物中间体为Py-MAA-Val-Cit-PAB-MMAF，其结构如式(2)所示：
Figure PCTCN2019087641-appb-000007
进一步的，本发明还提供了利用上述任一制备工艺制备抗体药物偶联物中间体，所述的抗体药物偶联物中间体为Py-MAA-Val-Cit-PAB-MMAD，其结构如式(3)所示：
Figure PCTCN2019087641-appb-000008
进一步的，本发明还提供了利用上述任一制备工艺制备抗体药物偶联物中间体，所述的抗体药物偶联物中间体的结构如式(4)所示：
Figure PCTCN2019087641-appb-000009
进一步的，本发明还提供了利用上述任一制备工艺制备抗体药物偶联物中间体，所述的抗体药物偶联物中间体的结构如式(5)所示：
Figure PCTCN2019087641-appb-000010
进一步的，本发明还提供了利用上述任一制备工艺制备抗体药物偶联物中间体，所述的抗体药物偶联物中间体的结构如式(6)所示：
Figure PCTCN2019087641-appb-000011
进一步的，本发明还提供了利用上述任一制备工艺制备抗体药物偶联物中间体，所述的抗体药物偶联物中间体的结构如式(7)所示：
Figure PCTCN2019087641-appb-000012
进一步的，本发明还提供了利用上述任一制备工艺制备抗体药物偶联物中间体，所述的抗体药物偶联物中间体的结构如式(8)所示：
Figure PCTCN2019087641-appb-000013
进一步的，本发明还提供了利用上述任一制备工艺制备抗体药物偶联物中间体，所述的抗体药物偶联物中间体的结构如式(9)所示：
Figure PCTCN2019087641-appb-000014
进一步的，本发明还提供了利用上述任一制备工艺制备抗体药物偶联物中间体，所述的抗体药物偶联物中间体的结构如式(10)所示：
Figure PCTCN2019087641-appb-000015
进一步的，本发明还提供了利用上述任一制备工艺制备抗体药物偶联物中间体，所述的抗体药物偶联物中间体的结构如式(11)所示：
Figure PCTCN2019087641-appb-000016
在一些特定的实施例中，所述的工艺包括如下步骤：
反应A：将Py-MAA-Val-Cit-PAB溶于DMF中，加入二(对硝基苯)碳酸酯，搅拌至溶解或略微浑浊后滴加N,N-二异丙基乙胺，分离纯化，得Py-MAA-Val-Cit-PAB-PNP；
反应B：将Py-MAA-Val-Cit-PAB-PNP溶于DMF中，加入1-羟基苯并三氮唑、MMAE、N,N-二异丙基乙胺和吡啶，反应结束后进行pre-HPLC纯化，得到如结构式(1)所示的化合物Py-MAA-Val-Cit-PAB-MMAE。
其中所述的Py-MAA-Val-Cit-PAB-PNP的结构如下所示：
Figure PCTCN2019087641-appb-000017
更进一步的，上述反应过程中的分离纯化可以是以下操作：
(1)将反应A的反应液离心，获取上清液；
(2)向上清液中加入溶剂1，搅拌均匀；
(3)在0-10℃条件下滴加溶剂2，搅拌均匀；
(4)抽滤，取滤饼；
(5)将滤饼复溶于溶剂3和溶剂4的混合溶液中；
(6)在0-10℃条件下滴加到溶剂5中，搅拌；
(7)抽滤得类白色粉末，即为纯化后的Py-MAA-Val-Cit-PAB-PNP。
其中，溶剂1为中等极性溶剂，优选为乙酸乙酯，二氯甲烷，甲醇， 甲基叔丁基醚等，最优选为乙酸乙酯；
溶剂2为小极性溶剂，优选为石油醚，正己烷，正戊烷，环己烷等，最优选为石油醚；
溶剂3和4为Py-MAA-Val-Cit-PAB-PNP易溶的溶剂，优选为乙酸，三氟乙酸，甲酸，甲醇，乙醇等，最优选为乙酸和甲醇；
溶剂5为Py-MAA-Val-Cit-PAB-PNP不易溶的溶剂，优选为乙腈，乙酸乙酯，二氯甲烷，水等，最优选为水。
所述的溶剂1、溶剂2、溶剂3和溶剂4和Py-MAA-Val-Cit-PAB的体积重量比为40-100:80-200:5-15:1-3:15-30:1。
在某些特定的实施例中，上述分离纯化可以是以下操作：
(1)将中间产物A离心，获取上清液；
(2)向上清液中加入乙酸乙酯，搅拌均匀；
(3)在0-10℃条件下滴加石油醚，搅拌均匀；
(4)抽滤，取滤饼；
(5)将滤饼复溶于乙酸和甲醇的混合溶液中；
(6)在0-10℃条件下滴加纯化水，搅拌；
(7)抽滤得类白色粉末，即为纯化后的Py-MAA-Val-Cit-PAB-PNP。
与公开号为CN107921030A的中国专利的说明书43页公开的抗体药物偶联物中间体(Py-MAA-Val-Cit-PAB-MMAD)的制备工艺相比，本发明提供的抗体药物偶联物中间体的制备工艺由于药物部分是在最后一步参与的反应，显著地降低了药物部分(例如MMAD/MMAE或MMAF等)投料的损耗，有效地降低了生产成本，提高了生产效益。。另外，本发明提供的工艺简单、对环境友好，适于工业化大规模推广。
具体实施方式
缩写
Figure PCTCN2019087641-appb-000018
Figure PCTCN2019087641-appb-000019
Figure PCTCN2019087641-appb-000020
Figure PCTCN2019087641-appb-000021
定义
除非另有定义，本文使用的所有科技术语具有本领域普通技术人员所理解的相同含义。
尽管本发明的广义范围所示的数字范围和参数近似值，但是具体实施例中所示的数值尽可能准确的进行记载。然而，任何数值本来就必然含有一定的误差，其是由它们各自的测量中存在的标准偏差所致。另外，本文公开的所有范围应理解为涵盖其中包含的任何和所有子范围。例如记载的“1至10”的范围应认为包含最小值1和最大值10之间(包含端点)的任何和所有子范围；也就是说，所有以最小值1或更大起始的子范围，例如1至6.1，以及以最大值10或更小终止的子范围，例如5.5至10。另外，任 何称为“并入本文”的参考文献应理解为以其整体并入。
另外应注意，如本说明书中所使用的，单数形式包括其所指对象的复数形式，除非清楚且明确的限于一个所指对象。术语“或”可与术语“和/或”互换使用，除非上下文另有清楚指明。
本发明所使用的术语“抗体药物偶联物”表示抗体/抗体功能性片段、连接子、药物部分经过化学反应连接在一起的化合物，其结构通常由三部分组成：抗体或抗体类配体、药物部分、以及将抗体或抗体类配体及药物偶联起来的连接子(linker)。目前抗体药物偶联物的制备通常分为两步：第一步是将连接子与药物部分通过化学反应形成“连接子-药物”偶联物，第二步是将“连接子-药物”偶联物中的连接子部分与抗体/抗体功能性片段通过巯基或者氨基共价偶合在一起。本发明所使用的术语“抗体药物偶联物中间体”是指上述所述的“连接子-药物”偶联物，进一步的，本发明涉及的“抗体药物偶联物中间体”泛指那些连接子和药物之间通过胺酯交换形成“-CO-NH-”键偶合在一起的“连接子-药物”偶联物。
本发明所使用的术语“连接子”以及“连接子部分”是指抗体药物偶联中将抗体与药物相连接的部分，其可以是可切割的或者不可切割的。可切割的连接子(即可断裂的连接子或生物可降解连接子)可以在靶标细胞内或其上断裂，从而释放药物。在一些实施方案中，本发明的连接子选自可切割的连接子，例如基于二硫化物的连接子(其在巯基浓度更高的肿瘤细胞中选择性断裂)、肽连接子(其被肿瘤细胞中的酶所切割)、腙连接子。在另一些实施方案中，本发明的接头选自不可切割的连接子(即，不可断裂的连接子)，例如硫醚连接子。在又一些实施方案中，本发明的连接子为可断裂连接子与不可断裂连接子的组合。
本发明所使用的术语“药物”以及“药物部分”泛指任何具有期望的生物活性，并具有反应性官能团以便制备本发明所述偶联物的化合物。期望的生物活性包括诊断、治愈、缓解、治疗、预防人或其它动物的疾病。随着新型药物不断被发现和发展，这些新药也应纳入本发明所述的药物中。具体的，所述的药物包括但不限于细胞毒性药物、细胞分化因子、干细胞营养因子、类固醇类药物、治疗自身免疫疾病的药物、抗炎症药物或传染性疾病的药物。更具体的，所述的药物包括但不限于微管蛋白抑制剂或者DNA、RNA损伤剂。
实施例
以下是本发明的方法和组合物的实施例。应当理解，鉴于上文提供的定义及一般描述，可以实施各种其他实施方案。
实施例1 Py-MAA的制备
Figure PCTCN2019087641-appb-000022
将化合物Py(1.87g,7.51mmol)(CAS:959-52-4)和Et 3N(104μL,0.75mmol)溶于无水CH 2Cl 2(40mL)，逐滴加入巯基乙酸(103.9μL,1.50mmol)的CH 2Cl 2(40mL)溶液；滴加完毕后，将体系升至室温下搅拌过夜。反应结束后，真空去除溶剂，粗产品通过柱层析纯化得到白色固体Py-MAA(1.87g,40.1％)。
实施例2对照例：Py-MAA-Val-Cit-PAB-MMAE的制备(公开号为CN107921030A的中国专利的说明书第32页公开的工艺)
工艺流程及方法如下所示：
Figure PCTCN2019087641-appb-000023
(1)Fmoc-Val-Cit-PAB-MMAE的制备
在0℃氮气保护下取Fmoc-Val-Cit-PAB-PNP(388.4mg,0.507mmol)溶于DMF(40ml)，加入HOBt(68.4mg,0.507mmol)和化合物MMAE(400.0mg,0.558mmol)。15分钟后，加入吡啶(8ml)和DIPEA(106.2μL,0.608mmol)，并在0℃下反应30min。然后升至室温下搅拌3小时。向反应混合物反应混合物补加DIPEA(106.2μL,0.608mmol)，室温下继续反应24h。反应结束后，将混合物真空浓缩。粗产品通过柱层析纯化，得到白色固体化合物Fmoc-Val-Cit-PAB-MMAE(325mg,收率47.7％)。
(2)Val-Cit-PAB-MMAE的制备
将化合物Fmoc-Val-Cit-PAB-MMAE(325mg,0.289mmol)溶于DMF(6ml)，加入二乙胺(3mL)，继续搅拌反应2.5h。反应结束后，减压去除溶剂，得到粗产品Val-Cit-PAB-MMAE(220mg，收率67.8％)，无需纯化，可直接进行下一步反应。
(3)Py-MAA-Val-Cit-PAB-MMAE的合成
取化合物Py-MAA(80.2mg,0.235mmol)，HOBt(31.8mg,0.235mmol)和DIC(29.6mg,0.235mmol)溶于DMF(10ml)，冰浴降温至0℃。将化合物Val-Cit-PAB-MMAE(220.0mg,0.196mmol)和DIPEA(25.3mg,0.196mmol)加入到反应溶液液中，升至室温下反应24h。反应结束后，粗产品通过柱层析纯化(甲醇：二氯甲烷＝60：1-30：1)，得到白色固体化合物Py-MAA-Val-Cit-PAB-MMAE(147.4mg,收率52％)。LCMS m/z(ES+)，1445.78(M+H)+。
公开号为CN107921030A的中国专利的说明书第32页公开的Py-MAA-Val-Cit-PAB-MMAD的制备工艺制备Py-MAA-Val-Cit-PAB-MMAE，MMAE的投放量为400mg，得到Py-MAA-Val-Cit-PAB-MMAE为147.4mg。
实施例3 Py-MAA-Val-Cit-PAB-MMAE的改进制备法
(1)Py-MAA-Val-Cit-PAB的制备
Figure PCTCN2019087641-appb-000024
将化合物Py-MAA(10.00g，29.33mmol)置于四氢呋喃(200mL)中，加入N'N-羰基二咪唑(7.13g，44.00mmol)，Val-Cit-PAB-OH(13.34g，35.20mmol)，室温搅拌24小时。加入石油醚(200mL)，搅拌0.5小时，过滤，得到白色固体。白色固体用制备型高效液相进行纯化，制备液减压旋蒸后得到Py-MAA-Val-Cit-PAB-OH(6.67g，32.4％，白色固体粉末)。
(2)Py-MAA-Val-Cit-PAB-PNP的制备
Figure PCTCN2019087641-appb-000025
在氮气保护下往三口烧瓶中加入Py-MAA-Val-Cit-PAB-OH(10.00g， 1.0eq)、DMF(V DMF/W Py-MAA-Val-Cit-PAB＝15～25mL/g)，氮气保护下搅拌至固体溶解或略微浑浊。三口烧瓶降温至10℃，一次性加入NPC(1.5～2.5eq,6.50～10.83g)固体，搅拌至溶解或略微浑浊。氮气保护下，滴加DIPEA(1.0～1.5eq，1.84～2.76g)。升温至30℃，UPLC监控反应，直至Py-MAA-Val-Cit-PAB纯度少于5.0％，停止反应。
将反应液离心，上清液倒入大小合适的烧杯中，加入EA(V EA/W Py-MAA-Val-Cit-PAB＝60±2)，用电动搅拌机搅拌；0～6℃下滴加PE(V PE/W Py-MAA-Val-Cit-PAB＝120±2)，滴加完毕再搅拌20～30min。抽滤取滤饼。得将滤饼用乙酸(V AcOH/W Py-MAA-Val-Cit-PAB＝7)和甲醇(V MeOH/W Py-MAA-Val-Cit-PAB)溶解得溶液。
将纯化水(V 水/W Py-MAA-Val-Cit-PAB＝21)倒入大小合适的烧杯中，机械搅拌，降温至约3℃。将上述溶液滴加到纯化水中，滴加完毕再搅拌15分钟，抽滤得滤饼，冻干后得Py-MAA-Val-Cit-PAB-PNP(白色至类白色粉末，10.69g，收率为86.54％)。
(3)Py-MAA-Val-Cit-PAB-MMAE的制备
Figure PCTCN2019087641-appb-000026
向反应容器中加入Py-MAA-Val-Cit-PAB-PNP(9.00g，1.0eq)，DMF(V DMF/W Py-MAA-Val-Cit-PAB-PNP＝15.0～25.0mL/g)，氮气保护下搅拌至澄清或略微浑浊。保持内温10℃，加入HOBt(2.10g，1.5eq)，搅拌20分钟。加入MMAE(8.93g，1.2eq)，继续搅拌20分钟。滴加DIPEA(1.34g，1.0eq)和吡啶(V 吡啶/V DIPEA＝5)的混合溶液，升温并保持内温在20℃。反应36小时后，每隔1小时进行1次UPLC监控，当反应液中MMAE 的纯度<2.00％时，终止反应。
取一大小合适的烧杯，加入饱和氯化钠水溶液(记为brine,V brine/V 反 应液＝10)，降温至内温为5℃。将反应液滴加至饱和氯化钠溶液中。离心得粗品，将粗品用制备型高效液相进行纯化。冻干得Py-MAA-Val-Cit-PAB-MMAE(白色粉末，9.79g，收率为65.27％)。
本实施例中MMAE的投放量为8.93g，得到Py-MAA-Val-Cit-PAB-MMAE为9.79g。
对比实施例2、实施例3提供的工艺中MMAE的投入量和最终产品的质量(对比结果如表1所示)，从表1中我们可以看出，利用实施例2的制备工艺制备的Py-MAA-Val-Cit-PAB-MMAE最终得到量为147.4mg，而MMAE的投放量为400mg；利用实施例3的制备工艺制备的Py-MAA-Val-Cit-PAB-MMAE最终得到量为9.79g，而MMAE的投放量为8.93g。
表1 MMAE投放量及最终产物得到量对比
Figure PCTCN2019087641-appb-000027
MMAE投入产出率代表每制备获得1单位质量的Py-MAA-Val-Cit-PAB-MMAE需投入多少单位质量的MMAE，从表1中可以看出，采用实施例2的方法，制备1单位质量的Py-MAA-Val-Cit-PAB-MMAE需投入2.71单位质量的MMAE，而采用实施例3的方法，则只需要投入0.91单位质量的MMAE，投料用量降低66.4％，显著的降低了生产成本。
以上描述地仅是优选实施方案，其只作为示例而不限制实施本发明所必需特征的组合。所提供的标题并不意指限制本发明的多种实施方案。术语例如“包含”、“含”和“包括”不意在限制。此外，除非另有说明，没有数词修饰时包括复数形式，以及“或”、“或者”意指“和/或”。除非本文另有定义，本文使用的所有技术和科学术语的意思与本领域技术人员通常理解 的相同。
本申请中提及的所有公开物和专利通过引用方式并入本文。不脱离本发明的范围和精神，本发明的所描述的方法和组合物的多种修饰和变体对于本领域技术人员是显而易见的。虽然通过具体的优选实施方式描述了本发明，但是应该理解所要求保护的本发明不应该被不适当地局限于这些具体实施方式。事实上，那些对于相关领域技术人员而言显而易见的用于实施本发明的所描述的模式的多种变体意在包括在随附的权利要求的范围内。

Claims (15)

  1. 一种包含连接子部分和药物部分的抗体药物偶联物中间体的制备工艺，所述的抗体药物偶联物中间体为Py-MAA-Val-Cit-PAB-D，所述中间体中的Py-MAA-Val-Cit-PAB为连接子部分，所述中间体中所述D代表连接的药物部分，所述连接的药物部分含有游离的氨基基团，其特征在于，包括以下反应路线：
    Figure PCTCN2019087641-appb-100001
  2. 权利要求1所述的制备工艺，其特征在于：
    反应A：将Py-MAA-Val-Cit-PAB-OH溶于溶剂中，加入二(对硝基苯)碳酸酯，搅拌至溶解或略微浑浊后加入有机碱；
    反应B：反应A结束后，加入三氮唑类催化剂、药物部分D、有机碱，反应结束后进行纯化，获得Py-MAA-Val-Cit-PAB-D。
  3. 权利要求1或2所述的制备工艺，其特征在于：所述的药物部分D为奥瑞他汀(auristatin)类细胞毒性剂、安曲霉素(Anthramycin)类细胞毒性剂、蒽环(anthracycline)类细胞毒性剂或嘌呤霉素(puromycin)细胞毒性剂。
  4. 权利要求3所述的制备工艺，其特征在于：所述的奥瑞他汀(auristatin)类细胞毒性剂为MMAE、MMAF、MMAD或其衍生物；所述的安曲霉素(Anthramycin)类细胞毒性剂为安曲霉素或其衍生物；所述的蒽环(anthracycline)类细胞毒性剂为柔红霉素、阿霉素、表阿霉素、伊达比星、戊柔比星、米托蒽醌或其衍生物；所述的嘌呤霉素(puromycin)细胞毒性剂为嘌呤毒素或其衍生物。
  5. 权利要求4所述的制备工艺，其特征在于：所述的 Py-MAA-Val-Cit-PAB-D的结构如式(1-11)所示：
    Figure PCTCN2019087641-appb-100002
    Figure PCTCN2019087641-appb-100003
    Figure PCTCN2019087641-appb-100004
  6. 根据前述任一权利要求所述的制备工艺，其特征在于所述的溶剂为极性溶剂和/或非极性溶剂，所述的极性溶剂为DMF、DMA、NMP的一种或几种；所述的非极性溶剂为二氯甲烷、四氯化碳的一种或几种。
  7. 根据前述任一权利要求所述的制备工艺，其特征在于所述的有机碱为N，N二异丙基乙胺、三乙胺、吡啶的一种或几种，优选为N，N二异丙基乙胺、吡啶的一种或两种。
  8. 根据前述任一权利要求所述的制备工艺，其特征在于所述的三氮唑类催化剂为1-羟基苯并三氮唑、1-羟基-7-偶氮苯并三氮唑、1-羟基-1H-1,2,3-三唑-4-羧酸乙酯的一种或几种，优选为1-羟基苯并三氮唑。
  9. [根据细则26改正03.06.2019]　
    根据前述任一权利要求所述的制备工艺，其特征在于，所述反应A中在加入二(对硝基苯)碳酸酯前控制反应体系的温度为5-15℃，进一步优选为10℃；进一步优选的，所述的反应A在加入有机碱后，控制体系反应温度为20-35℃，优选为30℃。。
  10. [根据细则26改正03.06.2019]　
    根据前述任一权利要求所述的制备工艺，其特征在于，所述反应B在加入三氮唑类催化剂前控制反应体系的温度为5-15℃，优选为10℃；进一步优选的，所述的反应B中，在加入有机碱后，控制体系反应温度为15-30℃，优选为20℃。
  11. [根据细则26改正03.06.2019]　
    根据前述任一权利要求所述的制备工艺，其特征在于，所述反应A中Py-MAA-Val-Cit-PAB-OH和二(对硝基苯)碳酸酯以及有机碱的摩尔比为1：1-5：1-3。
  12. [根据细则26改正03.06.2019]　
    根据前述任一权利要求所述的制备工艺，其特征在于，所述反应B中三氮唑类催化剂、MMAE、有机碱和Py-MAA-Val-Cit-PAB-OH的摩尔比为1-3：1-3：1.5-30：1。
  13. [根据细则26改正03.06.2019]　
    根据前述任一权利要求所述的制备工艺，其特征在于，所述反应B结束后进行pre-HPLC纯化，获得Py-MAA-Val-Cit-PAB-D。
  14. [根据细则26改正03.06.2019]
    根据前述任一权利要求所述的制备工艺，其特征在于，反应A通常过以下方法纯化获得Py-MAA-Val-Cit-PAB-PNP：
    (1)将反应A的反应液离心，获取上清液；
    (2)向上清液中加入溶剂1，搅拌均匀；
    (3)在0-10℃条件下滴加溶剂2，搅拌均匀；
    (4)抽滤，取滤饼；
    (5)将滤饼复溶于溶剂3和溶剂4的混合溶液中；
    (6)在0-10℃条件下滴加到溶剂5中，搅拌；
    (7)抽滤得类白色粉末，即为纯化后的Py-MAA-Val-Cit-PAB-PNP；
    其中，溶剂1为中等极性溶剂，优选为乙酸乙酯，二氯甲烷，甲醇，甲基叔丁基醚等，最优选为乙酸乙酯；溶剂2为小极性溶剂，优选为石油醚，正己烷，正戊烷，环己烷等，最优选为石油醚；溶剂3和4为Py-MAA-Val-Cit-PAB-PNP易溶的溶剂，优选为乙酸，三氟乙酸，甲酸，甲醇，乙醇等，最优选为乙酸和甲醇；溶剂5优选为乙腈，乙酸乙酯，二氯甲烷，水等，最优选为水。
  15. [根据细则26改正03.06.2019]　
    根据前述任一权利要求所述的制备工艺，其特征在于，所述反应均在氮气保护下进行。
PCT/CN2019/087641 2018-05-21 2019-05-20 一种抗体药物偶联物中间体的制备工艺 WO2019223653A1 (zh)

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AU2019268215A AU2019268215B2 (en) 2018-05-21 2019-05-20 Process for preparing intermediate of antibody drug conjugate
US16/618,110 US20200138968A1 (en) 2018-05-21 2019-05-20 Process for preparing intermediate of antibody drug conjugate
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RU2019142484A RU2724436C1 (ru) 2018-05-21 2019-05-20 Способ получения промежуточного соединения конъюгата антитело-лекарственное средство
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