技术领域technical field
本发明涉及一种制备抗体偶联药物Adcetris连接子的工业化生产方法。本发明属于有机合成领域。The invention relates to an industrial production method for preparing an antibody-coupled drug Adcetris linker. The invention belongs to the field of organic synthesis.
背景技术Background technique
化疗作为一种重要的癌症治疗手段，其所使用的细胞毒性试剂由于对肿瘤细胞缺少特异性，会导致严重的副作用。而抗体偶联药物(Antibody-DrugConjugate，ADC)，作为靶向抗癌药物的一种，能将单克隆抗体和高效细胞毒素完美地结合到一起，即充分利用了单克隆抗体的靶向性以及选择性强的优点；又很好的利用了细胞毒素对肿瘤细胞的高杀伤性的优点；同时由于细胞毒素与抗体偶联后，其所形成的药物对机体的毒性很小，也很好的解决了单一细胞毒素对机体毒性大的缺陷。Chemotherapy, as an important cancer treatment, uses cytotoxic agents that may cause serious side effects due to their lack of specificity for tumor cells. Antibody-Drug Conjugate (ADC), as a targeted anti-cancer drug, can perfectly combine monoclonal antibodies and high-efficiency cytotoxins, that is, it makes full use of the targeting properties of monoclonal antibodies and The advantages of strong selectivity; and the advantages of high lethality of cytotoxins on tumor cells are well utilized; at the same time, due to the coupling of cytotoxins and antibodies, the formed drugs have little toxicity to the body and are also very good The defect that a single cytotoxin is highly toxic to the body is solved.
一般ADC包括靶头抗体、间隔子、化学连接子(Chemical Linker)和药物如细胞毒性化合物四部分。ADC药物开发的关键在于连接子的构建，当药物在进入靶细胞前，要保证抗体与化学药物在体内环境下的完整性，而接近或进入靶细胞后，化学药物又能准确释放。要实现这一过程取决于抗体与毒性化合物通过连接子连接后的“稳定性”。此外ADC药物中抗体所负载的化学药物数量也取决于连接子。早期ADC药物研发的失败，主要是由于抗体与药物分子通过连接子结合后，所形成的药物在体内的稳定性差，毒性化合物在未到达肿瘤细胞前就已经与所连接的抗体断开，造成了对机体的严重毒性。这些因素影响了ADC药物的安全性和有效性。Generally, ADC includes four parts: target antibody, spacer, chemical linker (Chemical Linker) and drugs such as cytotoxic compounds. The key to ADC drug development lies in the construction of the linker. Before the drug enters the target cell, the integrity of the antibody and the chemical drug must be ensured in the in vivo environment, and the chemical drug can be released accurately after approaching or entering the target cell. Achieving this depends on the "stability" of the antibody to the toxic compound via the linker. In addition, the number of chemical drugs loaded on the antibody in the ADC drug also depends on the linker. The failure of early ADC drug development was mainly due to the poor stability of the formed drug in the body after the antibody and the drug molecule were combined through the linker, and the toxic compound was disconnected from the connected antibody before reaching the tumor cells, resulting in Severe toxicity to the body. These factors affect the safety and efficacy of ADC drugs.
目前市场上美国食品与药品监督管理局(FDA)批准上市的ADC药物有三种，分别为Mylotarg，Adcetris和Kadcyla。Adcetris是由Seattle Genetice公司和武田制药共同开发，用于治疗霍奇金淋巴瘤以及系统性间变性大细胞淋巴瘤。该药是目前唯一在市场上取得成功的ADC药物，上市第一年销售额达1.36亿美元。其包含三个部分，其中最重要的是一个能够将抗体cAC10和微管破坏剂单甲基(MMAE)连接的连接子(VIII)，其结构如下，该连接子通过二硫键与抗体结合，并且通过此方式连接的药物在人体内较稳定。There are currently three ADC drugs approved by the US Food and Drug Administration (FDA) on the market, namely Mylotarg, Adcetris and Kadcyla. Adcetris is jointly developed by Seattle Genetice and Takeda Pharmaceuticals for the treatment of Hodgkin's lymphoma and systemic anaplastic large cell lymphoma. The drug is currently the only successful ADC drug on the market, with sales of $136 million in its first year on the market. It consists of three parts, the most important of which is a linker (VIII) that can connect the antibody cAC10 and the microtubule disruptor monomethyl (MMAE), its structure is as follows, the linker binds to the antibody through a disulfide bond, And the drugs connected in this way are relatively stable in the human body.
其合成路线已经在文献Bioconjugate Chem,2002,13,855-869中公开。化合物I经过缩合，去保护，两步取代反应得到连接子VIII。文献中报道的路线如下所示：Its synthetic route has been disclosed in the document Bioconjugate Chem, 2002, 13, 855-869. Compound I undergoes condensation, deprotection, and two-step substitution reactions to obtain linker VIII. The routes reported in the literature are as follows:
该方法文献操作量较小，只有毫克级别。最后一步反应只有15％的收率，并且后处理麻烦，化合物VIII需过柱纯化。显然，该方法不适合工业放大生产。The amount of operation in the literature of this method is small, only at the milligram level. The yield of the last step reaction is only 15%, and post-processing is cumbersome, and compound VIII needs to be purified by column. Obviously, this method is not suitable for industrial scale-up production.
专利US20050238649报道了以化合物I为起始原料经过四步反应得到化合物VIII。该方法虽然后处理操作简单，但是化合物VIII只有94％的纯度，无法达到制药行业API的质量标准。Patent US20050238649 reported that compound VIII was obtained through four-step reaction using compound I as the starting material. Although the post-processing operation of this method is simple, the purity of compound VIII is only 94%, which cannot reach the quality standard of API in the pharmaceutical industry.
连接子VIII的制备，专利US20050238649以及文献BioconjugateChem,2002,13,855-869都没有提到中间体的物理性质，但在实验过程中发现中间体化合物IV容易吸潮，这无疑增加了反应后处理的难度。基于以上事实，本发明通过对化合物IV羟基上保护的方法，改善吸湿性，简化后处理操作，得到较好的结果。The preparation of linker VIII, the patent US20050238649 and the literature BioconjugateChem, 2002, 13, 855-869 did not mention the physical properties of the intermediate, but during the experiment, it was found that the intermediate compound IV was easy to absorb moisture, which undoubtedly increased the difficulty of post-reaction treatment . Based on the above facts, the present invention improves the hygroscopicity and simplifies the post-treatment operation through the method of protecting the hydroxyl group of the compound IV, and obtains better results.
化合物VIII作为目前唯一在市场上取得成功的ADC药物的连接子，却没有文献或专利对该化合物有大量合成的报道。因此设计并实施一条能适用于工业化生产，操作简便且纯度可以达到制药行业标准的连接子VIII的合成方法具有较高的经济价值和社会效益。Compound VIII is currently the only successful ADC drug linker on the market, but there are no literature or patent reports on the synthesis of this compound. Therefore, designing and implementing a synthetic method of linker VIII that is suitable for industrial production, easy to operate and whose purity can reach the pharmaceutical industry standard has high economic value and social benefit.
发明内容Contents of the invention
本发明的目的是提供一种ADC连接子的工业化生产方法，以解决上述背景技术提到的问题。The purpose of the present invention is to provide an industrial production method of ADC linker to solve the problems mentioned above in the background technology.
为了实现上述目的，本发明采用以下技术方案来实现：In order to achieve the above object, the present invention adopts the following technical solutions to achieve:
一种ADC连接子的工业化生产方法，工艺路线如下所示：An industrial production method of an ADC linker, the process route is as follows:
其中，R1可以是硅烷基保护基、烷氧基烷基保护基、烷基保护基。较佳的R1为三甲基硅基(TMS)，叔丁基二甲基硅基(TBS)，烷氧基甲基保护基(MOM)，2-(三甲基硅基)乙氧基甲基(SEM)，更佳的为叔丁基二甲基硅基。Wherein, R1 can be a silyl protecting group, an alkoxyalkyl protecting group, an alkyl protecting group. Preferred R is trimethylsilyl (TMS), tert- butyldimethylsilyl (TBS), alkoxymethyl protecting group (MOM), 2-(trimethylsilyl)ethoxy Methyl (SEM), more preferably tert-butyldimethylsilyl.
更具体的，本发明的制备方法包含如下过程：More specifically, the preparation method of the present invention includes the following processes:
步骤5：在惰性气体保护下，化合物I在羧酸活化试剂和碱的作用下和化合物IX反应得到化合物X。Step 5: under the protection of an inert gas, compound I reacts with compound IX under the action of a carboxylic acid activating reagent and a base to obtain compound X.
其中R1定义如前。wherein R1 is as defined above.
所述的缩合反应方法和条件可以为本领域此类反应的常规方法和条件。较佳的，上述制备方法包含以下步骤：氮气保护下，将化合物I和化合物IX加入到有机溶剂中，室温下搅拌半小时至原料全部溶解，再加入羧酸活化试剂和碱，滴加过程温度控制在-5～15℃。滴加完毕，缓慢升至室温继续缩合反应直至液相跟踪显示反应体系中原料I消失，停止反应。反应停止后经常压脱溶，洗涤，真空干燥得到化合物X。The condensation reaction method and conditions can be the conventional methods and conditions of this type of reaction in the art. Preferably, the above-mentioned preparation method comprises the following steps: under the protection of nitrogen, add compound I and compound IX to the organic solvent, stir at room temperature for half an hour until the raw materials are completely dissolved, then add carboxylic acid activating reagent and alkali, dropwise add process temperature Control at -5 ~ 15 ℃. After the dropwise addition is completed, slowly rise to room temperature and continue the condensation reaction until the liquid phase tracking shows that the raw material I in the reaction system disappears, and the reaction is stopped. After the reaction was stopped, it was desolvated under normal pressure, washed, and dried in vacuum to obtain compound X.
所述的羧酸活化试剂选自氯甲酸乙酯，氯甲酸异丁酯，羰基二咪唑，4-(4，6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐(DMTMM)，2-氯-4，6-二甲氧基-1，3，5-三嗪(CDMT)，优选为氯甲酸乙酯。所述的羧酸活化试剂和化合物I的摩尔投料比为1～4：1。Described carboxylic acid activation reagent is selected from ethyl chloroformate, isobutyl chloroformate, carbonyl diimidazole, 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine salt chloroformate (DMTMM), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), preferably ethyl chloroformate. The molar feed ratio of the carboxylic acid activating reagent and compound I is 1-4:1.
所述的碱为醋酸钾，吡啶，三乙胺，N,N-二异丙基乙胺等有机碱，或磷酸钾，碳酸钾，氢氧化钠，氟化铯，碳酸铯等无机碱，优选为三乙胺。所述的碱和化合物I的摩尔投料比为1～6：1。The base is organic bases such as potassium acetate, pyridine, triethylamine, N,N-diisopropylethylamine, or inorganic bases such as potassium phosphate, potassium carbonate, sodium hydroxide, cesium fluoride, cesium carbonate, etc., preferably For triethylamine. The molar feed ratio of the base and compound I is 1-6:1.
所述的有机溶剂为四氢呋喃，二甲基亚砜，N,N-二甲基甲酰胺，乙酸乙酯，二氯甲烷中的一种，或上述溶剂的任意组合，优选为乙酸乙酯。所述的有机溶剂和化合物I的体积质量比为5～20mL/g。The organic solvent is one of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, ethyl acetate, dichloromethane, or any combination of the above solvents, preferably ethyl acetate. The volume-to-mass ratio of the organic solvent to compound I is 5-20 mL/g.
所述的化合物IX市售可得。所述的化合物IX和化合物I的摩尔投料比为1～4：1。Said compound IX is commercially available. The molar ratio of compound IX to compound I is 1-4:1.
所述的化合物I参考文献US20050238649制得。The compound I is prepared by referring to US20050238649.
步骤6：化合物X在碱性条件下，极性非质子溶剂通过去保护方法得到化合物XI。Step 6: Compound X is deprotected in a polar aprotic solvent under basic conditions to obtain compound XI.
其中R1定义如前。wherein R1 is as defined above.
所述的去保护方法和条件可以为本领域此类反应的常规方法和条件。较佳的，上述制备方法包含以下步骤：室温下将化合物X加入到极性非质子溶剂中，搅拌半小时至原料全部溶解，再加入碱，进行脱保护，直至液相跟踪显示反应体系中原料X消失，停止反应。反应停止后，脱溶，重结晶，洗涤，真空干燥得到化合物XI。所述的碱为醋酸钾，吡啶，二乙胺，二异丙基乙基胺等有机碱，优选为二乙胺。所述的碱和化合物X的摩尔投料比为2～5：1。The deprotection methods and conditions can be conventional methods and conditions for this type of reaction in the art. Preferably, the above-mentioned preparation method comprises the following steps: add compound X into a polar aprotic solvent at room temperature, stir for half an hour until the raw materials are completely dissolved, then add alkali, and perform deprotection until the liquid phase tracking shows that the raw materials in the reaction system The X disappears and the reaction stops. After the reaction was stopped, solvent removal, recrystallization, washing, and vacuum drying were performed to obtain compound XI. The base is organic bases such as potassium acetate, pyridine, diethylamine, diisopropylethylamine, etc., preferably diethylamine. The molar feeding ratio of the base and the compound X is 2-5:1.
所述的极性非质子溶剂为乙腈，丙酮，N,N-二甲基甲酰胺或者二甲基亚砜(DMSO)，优选为N,N-二甲基甲酰胺。所述的极性非质子溶剂和化合物X的体积质量比为5～20mL/g。The polar aprotic solvent is acetonitrile, acetone, N,N-dimethylformamide or dimethylsulfoxide (DMSO), preferably N,N-dimethylformamide. The volume-to-mass ratio of the polar aprotic solvent to compound X is 5-20 mL/g.
步骤7：化合物XI和化合物V通过取代反应，再脱去R1保护得到中间体VI。Step 7: compound XI and compound V undergo a substitution reaction, and then remove the protection of R1 to obtain intermediate VI.
其中R1定义如前。wherein R1 is as defined above.
所述的取代以及脱保护方法和条件可以为本领域此类反应的常规方法和条件，较佳的，上述制备方法包含以下步骤：室温下将化合物XI和化合物V加到极性非质子溶剂中，温室下搅拌半小时至原料全部溶解，然后升温至45～50℃下反应4～6小时，得到取代物反应液，并将取代物反应液冷却至-5～0℃加入脱保护试剂，滴加完毕，升至室温反应直至液相跟踪显示反应体系中原料消失，停止反应。反应停止后，将反应液冷却至-5～0℃调PH值7～8，过滤，收集滤饼，打浆，真空干燥得到化合物VI。所述的极性非质子溶剂为乙腈，丙酮，N,N-二甲基甲酰胺或者二甲基亚砜(DMSO)，优选为N,N-二甲基甲酰胺。其与化合物XI的体积质量比为5～20mL/g。The substitution and deprotection methods and conditions can be conventional methods and conditions of this type of reaction in the art. Preferably, the above-mentioned preparation method includes the following steps: adding compound XI and compound V to a polar aprotic solvent at room temperature , stirred under the greenhouse for half an hour until all the raw materials were dissolved, then raised the temperature to 45-50°C and reacted for 4-6 hours to obtain a reaction solution of the substitute, and cooled the reaction solution of the substitute to -5-0°C, added the deprotection reagent, and dropped After the addition was completed, it was raised to room temperature and reacted until the liquid phase tracking showed that the raw materials in the reaction system disappeared, and the reaction was stopped. After the reaction stopped, the reaction solution was cooled to -5-0°C to adjust the pH value to 7-8, filtered, the filter cake was collected, beaten, and vacuum-dried to obtain compound VI. The polar aprotic solvent is acetonitrile, acetone, N,N-dimethylformamide or dimethylsulfoxide (DMSO), preferably N,N-dimethylformamide. The volume-to-mass ratio of it to compound XI is 5-20 mL/g.
所述的脱保护试剂可以为四丁基氟化铵(TBAF)，四甲基氟化铵，氟化铯，氢氟酸吡啶，氢氟酸三乙胺等氟化试剂，也可以是对甲苯磺酸，三氟乙酸等有机酸，还可以是盐酸，硫酸，硝酸等无机酸。优选为四甲基氟化铵，所述的氟化试剂和化合物XI的摩尔投料比为1～3：1。The deprotection reagent can be tetrabutylammonium fluoride (TBAF), tetramethylammonium fluoride, cesium fluoride, pyridine hydrofluoric acid, triethylamine hydrofluoric acid and other fluorinating reagents, and can also be p-toluene Organic acids such as sulfonic acid and trifluoroacetic acid, and inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid may also be used. Tetramethylammonium fluoride is preferred, and the molar feed ratio of the fluorinating reagent to compound XI is 1-3:1.
所述的化合物V和化合物XI的摩尔投料比为1～5：1。The molar feed ratio of compound V and compound XI is 1-5:1.
所述的反应时间以检测反应完成为止。The reaction time mentioned is until the completion of the detection reaction.
步骤8：在惰性气体保护下，化合物VI和化合物VII在极性非质子溶剂中，碱性条件下，进行取代反应，得到化合物VIII。Step 8: Under the protection of an inert gas, compound VI and compound VII were subjected to a substitution reaction in a polar aprotic solvent under basic conditions to obtain compound VIII.
所述的取代方法和条件可以为本领域此类反应的常规方法和条件。较佳的，上述制备方法包含以下步骤：氮气保护下，将化合物VI和化合物VII加入到极性非质子溶剂中，室温下搅拌半小时至原料全部溶解，再加入碱进行取代反应，反应时间为3～5小时。反应完成后，经常压脱溶，有机溶剂打浆以及重结晶，冷冻干燥得到化合物VIII。Said substitution methods and conditions can be conventional methods and conditions of this type of reaction in the art. Preferably, the above preparation method comprises the following steps: under the protection of nitrogen, add compound VI and compound VII to a polar aprotic solvent, stir at room temperature for half an hour until the raw materials are completely dissolved, and then add a base for substitution reaction, the reaction time is 3 to 5 hours. After the completion of the reaction, precipitation under normal pressure, beating with an organic solvent and recrystallization, freeze-drying to obtain compound VIII.
所述的极性非质子溶剂为乙腈，丙酮，N,N-二甲基甲酰胺或者二甲基亚砜(DMSO)，优选为N,N-二甲基甲酰胺。所述的有机溶剂和化合物VI的体积质量比为5～20mL/g。The polar aprotic solvent is acetonitrile, acetone, N,N-dimethylformamide or dimethylsulfoxide (DMSO), preferably N,N-dimethylformamide. The volume-to-mass ratio of the organic solvent to compound VI is 5-20 mL/g.
所述的碱为醋酸钾，吡啶，二乙胺，三乙胺，二异丙基乙基胺等有机碱，优选为二异丙基乙基胺。所述的碱和化合物VI的摩尔投料比为1～2：1。The base is potassium acetate, pyridine, diethylamine, triethylamine, organic bases such as diisopropylethylamine, preferably diisopropylethylamine. The molar feeding ratio of the base to the compound VI is 1-2:1.
所述的化合物VII和化合物VI的摩尔投料比为1～2：1。The molar feeding ratio of the compound VII to the compound VI is 1-2:1.
所述打浆使用的溶剂为，四氢呋喃，丙酮，二氯甲烷，乙酸乙酯，甲醇，甲苯，石油醚等有机溶剂或上述溶剂的任意组合。优选二氯甲烷和石油醚按照1：1的体积比混合。所述打浆使用的有机溶剂和化合物VI的体积质量比为4～5mL/g。The solvent used in the beating is organic solvents such as tetrahydrofuran, acetone, dichloromethane, ethyl acetate, methanol, toluene, petroleum ether or any combination of the above solvents. Preferably, dichloromethane and petroleum ether are mixed in a volume ratio of 1:1. The volume-to-mass ratio of the organic solvent used in the beating to the compound VI is 4-5 mL/g.
所述重结晶使用的溶剂为二甲基亚砜，四氢呋喃，丙酮，二氯甲烷，乙酸，三氟乙酸，乙酸乙酯，甲醇，甲苯，石油醚等有机溶剂或上述溶剂的任意组合。优选乙酸甲醇按照1：1的体积比混合。所述重结晶使用的有机溶剂和化合物VI的体积质量比为5～20mL/g。The solvent used for the recrystallization is an organic solvent such as dimethyl sulfoxide, tetrahydrofuran, acetone, dichloromethane, acetic acid, trifluoroacetic acid, ethyl acetate, methanol, toluene, petroleum ether, or any combination of the above solvents. Preferably, acetic acid and methanol are mixed at a volume ratio of 1:1. The volume-to-mass ratio of the organic solvent used in the recrystallization to the compound VI is 5-20 mL/g.
本发明的优点主要在于：The advantages of the present invention mainly lie in:
1)连接子VIII的制备，专利US20050238649以及文献BioconjugateChem,2002,13,855-869都没有提到中间体的物理性质，但在实验过程中发现中间体化合物IV容易吸潮，这无疑增加了后处理的难度。基于以上事实，本发明通过对化合物IV羟基上保护的方法，改善吸湿性，简化了后处理操作。1) The preparation of linker VIII, the patent US20050238649 and the literature BioconjugateChem, 2002,13,855-869 do not mention the physical properties of the intermediate, but in the course of the experiment, it is found that the intermediate compound IV is easy to absorb moisture, which undoubtedly increases the cost of post-treatment. difficulty. Based on the above facts, the present invention improves the hygroscopicity and simplifies the post-treatment operation by protecting the hydroxyl group of the compound IV.
2)本发明后处理操作简单易行，通过打浆，重结晶等方法多批次得到纯度>99％，de>98％，单杂<0.1％的终产品ADC连接子VIII，符合药用级原料药的要求。2) The post-processing operation of the present invention is simple and easy, and the final product ADC linker VIII with a purity > 99%, de > 98%, and mono-hybrid < 0.1% can be obtained in multiple batches by beating, recrystallization, etc., which meets the requirements of pharmaceutical grade raw materials drug requirements.
3)该合成方法反应条件温和，操作方法简单方便，不仅适合实验室少量制备，也适合工业化大规模生产。3) The synthesis method has mild reaction conditions and simple and convenient operation method, which is not only suitable for small-scale preparation in the laboratory, but also suitable for large-scale industrial production.
4)本发明对于开发新的抗体偶联药物连接子有很好的参照意义。4) The present invention has good reference significance for the development of new antibody-drug conjugate linkers.
具体实施例：Specific examples:
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件进行。Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods that do not indicate specific conditions in the following examples are usually carried out according to conventional conditions.
实施例中所用的原料或试剂除特别说明之外，均市售可得。Unless otherwise specified, the raw materials or reagents used in the examples are commercially available.
实施例中所述的室温均指20～35℃。除非特别指出，所述的试剂不经纯化直接使用。所有溶剂均购自商业化供应商，例如奥德里奇(Aldrich)，并且不经处理就可使用。反应通过TLC分析和/或通过LC-MS分析，通过起始材料的消耗来判断反应的终止。分析用的薄层层析(TLC)是在预涂覆硅胶60 F254 0.25毫米板的玻璃板(EMD化学品公司(EMD Chemicals))上进行的，用UV光(254nm)和/或硅胶上的碘显象，和/或与TLC染色物如醇制磷钼酸、水合茚三酮溶液、高锰酸钾溶液或硫酸高铈溶液一起加热。The room temperature mentioned in the examples all refers to 20-35°C. Unless otherwise stated, the reagents were used without purification. All solvents were purchased from commercial suppliers such as Aldrich and used without treatment. Reactions were analyzed by TLC and/or analyzed by LC-MS, termination of the reaction was judged by consumption of starting material. Analytical thin layer chromatography (TLC) was performed on glass plates (EMD Chemicals) pre-coated with Silica Gel 60 F254 0.25 mm plates with UV light (254 nm) and/or Develop with iodine, and/or heat with TLC stains such as alcoholic phosphomolybdic acid, ninhydrin solution, potassium permanganate solution, or ceric sulfate solution.
1H-NMR谱是在万瑞安-默丘利-VX400(Varian Mercury-VX400)仪上，在400MHz操作下记录的。1 H-NMR spectra were recorded on a Varian Mercury-VX400 (Varian Mercury-VX400) instrument operating at 400 MHz.
本发明中使用的缩写具有本领域常规含义，如：DCM表示二氯甲烷，DMF表示N,N-二甲基甲酰胺，PE表示石油醚，EA表示乙酸乙酯，HOAc表示乙酸，MeOH表示甲醇。Abbreviations used in the present invention have conventional meanings in the field, such as: DCM means dichloromethane, DMF means N,N-dimethylformamide, PE means petroleum ether, EA means ethyl acetate, HOAc means acetic acid, MeOH means methanol .
实施例1：(9H-芴-9-基)甲基((S)-1-(((S)-1-((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)苯基)氨基)-1-氧代-5-脲基-戊-2-基)氨基)-3-甲基-1-氧代丁-2-基)氨基甲酸的制备Example 1: (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(((tert-butyldimethylsilyl)oxy) Preparation of methyl)phenyl)amino)-1-oxo-5-ureido-pent-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamic acid
氮气保护下，将化合物I(1.08kg，2.18mol，1.0eq)和化合物IX-1(517.6g，2.18mol，1.0eq)加到乙酸乙酯(20.0L)中，室温下搅拌半小时至原料全部溶解，再将氯甲酸乙酯(236.6g，2.18mol，1.0eq)和三乙胺(220.6g，2.18mol，1.0eq)的乙酸乙酯(1.6L)溶液加入到反应体系中，滴加过程温度控制在-5～-15℃。滴加完毕，缓慢升至室温继续反应直至液相跟踪显示反应体系中原料I消失，停止反应。反应停止后，经常压脱溶，剩余固体用石油醚(1L×3)洗涤，真空干燥得到白色固体X-1(1258.7g，收率：80％，纯度：99.2％，de：99.4％)。Under the protection of nitrogen, compound I (1.08kg, 2.18mol, 1.0eq) and compound IX-1 (517.6g, 2.18mol, 1.0eq) were added to ethyl acetate (20.0L), stirred at room temperature for half an hour to the raw material All dissolved, then ethyl chloroformate (236.6g, 2.18mol, 1.0eq) and ethyl acetate (1.6L) solution of triethylamine (220.6g, 2.18mol, 1.0eq) were added to the reaction system, dropwise The process temperature is controlled at -5～-15°C. After the dropwise addition, slowly rise to room temperature and continue the reaction until the liquid phase tracking shows that the raw material I in the reaction system disappears, and the reaction is stopped. After the reaction was terminated, the solution was removed under normal pressure, the remaining solid was washed with petroleum ether (1L×3), and dried in vacuo to obtain a white solid X-1 (1258.7g, yield: 80%, purity: 99.2%, de: 99.4%).
1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.07(d,J＝7.2,1H),7.83(d,J＝7.6,2H),7.71-7.67(m,2H),7.53-7.51(m,2H),7.43-7.40(m,1H),7.37-7.33(m,2H),7.28-7.25(m,2H),7.18-7.16(m,2H),6.01(t,J＝5.2,1H),5.44-5.40(m,2H),4.64(s,2H),4.44-4.43(m,1H),4.31-4.23(m,3H),3.96-3.92(m,1H),3.05-2.94(m,2H),2.01-1.98(m,1H),1.75-1.55(m,2H),1.46-1.37(m,2H),0.88-0.85(m,15H),0.06(s,6H).LC/MS:[M+H]+＝716.1 H NMR (400MHz,DMSO-d6 )δ9.98(s,1H),8.07(d,J=7.2,1H),7.83(d,J=7.6,2H),7.71-7.67(m,2H) ,7.53-7.51(m,2H),7.43-7.40(m,1H),7.37-7.33(m,2H),7.28-7.25(m,2H),7.18-7.16(m,2H),6.01(t, J＝5.2,1H),5.44-5.40(m,2H),4.64(s,2H),4.44-4.43(m,1H),4.31-4.23(m,3H),3.96-3.92(m,1H), 3.05-2.94(m,2H),2.01-1.98(m,1H),1.75-1.55(m,2H),1.46-1.37(m,2H),0.88-0.85(m,15H),0.06(s,6H ).LC/MS: [M+H]+ =716.
实施例2：(S)-2-((S)-2-氨基-3-甲基丁烷酰胺基)-N-(4-(((叔丁基二甲基甲硅烷基)氧基)甲基)苯基)-5-脲基戊酰胺的制备Example 2: (S)-2-((S)-2-amino-3-methylbutanamido)-N-(4-(((tert-butyldimethylsilyl)oxy) Preparation of Methyl)phenyl)-5-ureidopentanamide
室温下将化合物X-1(3.44kg，4.8mol，1.0eq)加到N,N-二甲基甲酰胺(17.2L)中，搅拌半小时至原料全部溶解，再加入二乙胺(700.8g，9.6mol，2.0eq)，直至液相跟踪显示反应体系中原料X-1消失，停止反应。反应停止后，常压脱溶(旋掉溶液总体积的3/4)，再将剩余物加到乙酸乙酯(5L)中，搅拌至澄清后向体系中滴加石油醚至白色浑浊液出现，再反滴加乙酸乙酯至刚溶清，室温敞口静置16～48小时，有固体析出，过滤，收集滤饼用石油醚(3L×2)洗涤，真空干燥，得到白色固体XI-1(2045.0g，收率：85％，纯度：98.5％，de：98.7％)。Add compound X-1 (3.44kg, 4.8mol, 1.0eq) to N,N-dimethylformamide (17.2L) at room temperature, stir for half an hour until all the raw materials are dissolved, then add diethylamine (700.8g , 9.6mol, 2.0eq), until the liquid phase tracking shows that the raw material X-1 in the reaction system disappears, stop the reaction. After the reaction is stopped, desolventize under normal pressure (spin off 3/4 of the total volume of the solution), then add the residue to ethyl acetate (5L), stir until clear, then add petroleum ether dropwise to the system until a white turbid solution appears , then add ethyl acetate back dropwise until just dissolved, leave it open at room temperature for 16-48 hours, solids precipitate out, filter, collect the filter cake and wash with petroleum ether (3L × 2), dry in vacuo to obtain a white solid XI- 1 (2045.0 g, yield: 85%, purity: 98.5%, de: 98.7%).
1H-NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.14-8.12(m,1H),7.58-7.55(m,2H),7.24-7.22(m,2H),5.99(s,1H),5.43(s,2H),4.64(s,2H),4.49-4.47(m,1H),3.02-2.92(m,3H),1.73-1.70(m,1H),1.57-1.59(m,4H),1.41-1.37(m,2H),0.89-0.88(m,12H),0.78(d,J＝6.8,3H)，0.06(s,6H).LC/MS:[M+H]+＝494.1 H-NMR (400MHz,DMSO-d6 )δ10.08(s,1H),8.14-8.12(m,1H),7.58-7.55(m,2H),7.24-7.22(m,2H),5.99( s,1H),5.43(s,2H),4.64(s,2H),4.49-4.47(m,1H),3.02-2.92(m,3H),1.73-1.70(m,1H),1.57-1.59( m,4H),1.41-1.37(m,2H),0.89-0.88(m,12H),0.78(d,J=6.8,3H),0.06(s,6H).LC/MS:[M+H]+ ＝494.
实施例3：6-(2，5-二氧代-2，5-二氢-1H-吡咯-1-基)-N-((S)-1-(((S)-1-((4-(羟甲基)苯基)氨基)-1-氧代-5-脲基戊-2-基)氨基)-3-甲基-1-氧代丁-2-基)己酰胺的制备Example 3: 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-(( Preparation of 4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopent-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide
室温下将化合物XI-1(269g，0.55mol，1.0eq)和化合物V(168.1g，0.55mol，1.0eq)加到N,N-二甲基甲酰胺(1L)，室温下搅拌半小时至原料全部溶解，然后升温至45～50℃下反应4～6小时，得到取代物反应液，将反应液冷却至-5～0℃加入四甲基氟化铵(50.7g，0.55mol，1.0eq)的N,N-二甲基甲酰胺(350mL)溶液中，滴加完毕，升至室温反应直至液相跟踪显示反应体系中原料消失，停止反应。反应停止后，往反应液中加入水至再无固体析出，过滤，收集滤饼。滤饼用水(400mL)和乙酸乙酯(800mL)打浆半小时，过滤，收集滤饼，真空干燥得到类白色固体VI(292.7g，收率：92％，纯度：99.0％，de：98.2％)。Compound XI-1 (269g, 0.55mol, 1.0eq) and compound V (168.1g, 0.55mol, 1.0eq) were added to N,N-dimethylformamide (1L) at room temperature, and stirred at room temperature for half an hour to All the raw materials were dissolved, and then the temperature was raised to 45-50°C and reacted for 4-6 hours to obtain a reaction liquid of the substitute, and the reaction liquid was cooled to -5-0°C and tetramethylammonium fluoride (50.7g, 0.55mol, 1.0eq ) in N,N-dimethylformamide (350 mL) solution, the dropwise addition was completed, and the temperature was raised to room temperature to react until the liquid phase tracking showed that the raw materials in the reaction system disappeared, and the reaction was stopped. After the reaction stopped, water was added to the reaction solution until no solid precipitated, filtered and the filter cake was collected. The filter cake was beaten with water (400mL) and ethyl acetate (800mL) for half an hour, filtered, the filter cake was collected, and vacuum-dried to obtain off-white solid VI (292.7g, yield: 92%, purity: 99.0%, de: 98.2%) .
1H-NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.03(d,J＝7.2,1H),7.78(d,J＝8.8,1H),7.49(d,J＝8.8,2H),7.17(d,J＝8.0,1H),6.95(s,2H),5.96(s,1H),5.38(s,2H),5.05(t,J＝5.6,1H),4.37-4.33(m,3H),4.13(m,1H),3.40-3.21(m,2H),2.95-2.89(m,2H),2.11-2.07(m,2H),1.92-1.90(m,1H),1.63-1.42(m,9H),1.14-1.12(m,2H),0.80-0.75(m,6H).LC/MS:[M+H]+＝573.1 H-NMR (400MHz, DMSO-d6 ) δ9.87(s, 1H), 8.03(d, J=7.2, 1H), 7.78(d, J=8.8, 1H), 7.49(d, J=8.8 ,2H),7.17(d,J=8.0,1H),6.95(s,2H),5.96(s,1H),5.38(s,2H),5.05(t,J=5.6,1H),4.37-4.33 (m,3H),4.13(m,1H),3.40-3.21(m,2H),2.95-2.89(m,2H),2.11-2.07(m,2H),1.92-1.90(m,1H),1.63 -1.42(m,9H),1.14-1.12(m,2H),0.80-0.75(m,6H).LC/MS:[M+H]+ ＝573.
实施例4：4-((S)-2-((S)-2-(6-(2，5-二氧代-2，5-二氢-1H-吡咯-1-基)己酰胺基)-3-甲基丁酰氨)-5-脲基戊基)苄基(4-硝基苯基)碳酸酯的制备Example 4: 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido Preparation of )-3-methylbutyrylamide)-5-ureidopentyl)benzyl(4-nitrophenyl)carbonate
氮气保护下，将化合物VI(198.0g，345.9mmol，1.0eq)和化合物VII(105.2g，345.9mmol，1.0eq)加入到N,N-二甲基甲酰胺(990mL)中，室温下搅拌半小时至原料全部溶解，再加入二异丙基乙基胺(44.7g，345.9mmol，1.0eq)进行取代反应，反应时间为3～5小时。反应完成后，常压脱溶(旋掉溶液总体积的3/4)，剩余物用DCM：PE＝1：1(v/v)(792mL)打浆，打浆完毕，过滤，收集滤饼，再用HOAc：MeOH＝1：1(v/v)(990mL)溶解滤饼，往滤液中加入水直至不再有固体析出，过滤，收集滤饼用水(500mL×3)洗涤，真空干燥得到白色固体VIII(226.2g，收率：88％，纯度：99.2％，de：99.3％，单杂<0.1％)。Under nitrogen protection, compound VI (198.0g, 345.9mmol, 1.0eq) and compound VII (105.2g, 345.9mmol, 1.0eq) were added to N,N-dimethylformamide (990mL), stirred at room temperature for half After 1 hour until all the raw materials were dissolved, diisopropylethylamine (44.7g, 345.9mmol, 1.0eq) was added to carry out the substitution reaction. The reaction time was 3-5 hours. After the completion of the reaction, precipitate at normal pressure (spin off 3/4 of the total volume of the solution), and beat the residue with DCM:PE=1:1 (v/v) (792mL). After the beating is completed, filter, collect the filter cake, and then Dissolve the filter cake with HOAc:MeOH=1:1 (v/v) (990mL), add water to the filtrate until no solid precipitates, filter, collect the filter cake, wash with water (500mL×3), and dry in vacuo to obtain a white solid VIII (226.2 g, yield: 88%, purity: 99.2%, de: 99.3%, monohetero<0.1%).
1H-NMR(400MHz,CDCl3)8.23(d,J＝8.8,2H),7.65(d,J＝8.8,2H),7.42-7.39(m,4H),6.66(s,2H),5.26(s,2H),4.59-4.55(m,1H),4.20-4.16(m,1H),3.48(t,J＝7.2,2H),3.33-3.17(m,2H),2.29-2.25(t,J＝7.2,2H),2.01-1.89(m,2H),1.74-1.31(m,9H),0.95-0.90(m,6H).LC/MS:[M+H]+＝738.1 H-NMR (400MHz, CDCl3 ) 8.23 (d, J = 8.8, 2H), 7.65 (d, J = 8.8, 2H), 7.42-7.39 (m, 4H), 6.66 (s, 2H), 5.26 ( s,2H),4.59-4.55(m,1H),4.20-4.16(m,1H),3.48(t,J=7.2,2H),3.33-3.17(m,2H),2.29-2.25(t,J =7.2,2H),2.01-1.89(m,2H),1.74-1.31(m,9H),0.95-0.90(m,6H).LC/MS:[M+H]+ ＝738.
实施例5：(9H-芴-9-基)甲基((S)-1-(((S)-1-((4-(((叔丁基二甲基甲硅烷基)氧基)甲基)苯基)氨基)-1-氧代-5-脲基-戊-2-基)氨基)-3-甲基-1-氧代丁-2-基)氨基甲酸的制备Example 5: (9H-fluoren-9-yl)methyl ((S)-1-(((S)-1-((4-(((tert-butyldimethylsilyl)oxy) Preparation of methyl)phenyl)amino)-1-oxo-5-ureido-pent-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamic acid
氮气保护下，将化合物I(540g，1.09mol，1.0eq)和化合物IX-1(258.8g，1.09mol，1.0eq)，加入到DMF(10.0L)中，室温下搅拌半小时至原料全部溶解，再将氯甲酸乙酯(470.88g，4.36mol，4.0eq)和三乙胺(660.54g，6.54mol，6.0eq)的DMF(0.8L)溶液加到反应体系中，滴加过程温度控制在-5～-15℃。滴加完毕，缓慢升至室温继续反应直至液相跟踪显示反应体系中原料I消失，停止反应。反应停止后往反应体系中加入4L的水至固体析出，过滤，收集滤饼，用水(1L×2)，石油醚(1L×3)洗涤，经干燥得到类白色固体X-1(550.7g，收率：70％，纯度：99.2％，de：99.0％)。Under the protection of nitrogen, compound I (540g, 1.09mol, 1.0eq) and compound IX-1 (258.8g, 1.09mol, 1.0eq) were added to DMF (10.0L), stirred at room temperature for half an hour until all the raw materials were dissolved , then the DMF (0.8L) solution of ethyl chloroformate (470.88g, 4.36mol, 4.0eq) and triethylamine (660.54g, 6.54mol, 6.0eq) was added to the reaction system, and the dropwise process temperature was controlled at -5～-15℃. After the dropwise addition, slowly rise to room temperature and continue the reaction until the liquid phase tracking shows that the raw material I in the reaction system disappears, and the reaction is stopped. After the reaction stopped, add 4L of water to the reaction system until the solid precipitated, filtered, collected the filter cake, washed with water (1L×2), petroleum ether (1L×3), and dried to obtain an off-white solid X-1 (550.7g, Yield: 70%, purity: 99.2%, de: 99.0%).
1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.07(d,J＝7.2,1H),7.83(d,J＝7.6,2H),7.71-7.67(m,2H),7.53-7.51(m,2H),7.43-7.40(m,1H),7.37-7.33(m,2H),7.28-7.25(m,2H),7.18-7.16(m,2H),6.01(t,J＝5.2,1H),5.44-5.40(m,2H),4.64(s,2H),4.44-4.43(m,1H),4.31-4.23(m,3H),3.96-3.92(m,1H),3.05-2.94(m,2H),2.01-1.98(m,1H),1.75-1.55(m,2H),1.46-1.37(m,2H),0.88-0.85(m,15H),0.06(s,6H).LC/MS:[M+H]+＝716.1 H NMR (400MHz,DMSO-d6 )δ9.98(s,1H),8.07(d,J=7.2,1H),7.83(d,J=7.6,2H),7.71-7.67(m,2H) ,7.53-7.51(m,2H),7.43-7.40(m,1H),7.37-7.33(m,2H),7.28-7.25(m,2H),7.18-7.16(m,2H),6.01(t, J＝5.2,1H),5.44-5.40(m,2H),4.64(s,2H),4.44-4.43(m,1H),4.31-4.23(m,3H),3.96-3.92(m,1H), 3.05-2.94(m,2H),2.01-1.98(m,1H),1.75-1.55(m,2H),1.46-1.37(m,2H),0.88-0.85(m,15H),0.06(s,6H ).LC/MS: [M+H]+ =716.
实施例6：(S)-2-((S)-2-氨基-3-甲基丁烷酰胺基)-N-(4-(((叔丁基二甲基甲硅烷基)氧基)甲基)苯基)-5-脲基戊酰胺的制备Example 6: (S)-2-((S)-2-amino-3-methylbutanamido)-N-(4-(((tert-butyldimethylsilyl)oxy) Preparation of Methyl)phenyl)-5-ureidopentanamide
室温下将化合物X-1(344g，0.48mol，1.0eq)加到N,N-二甲基甲酰胺(6.9L)中，搅拌半小时至原料全部溶解，再加入三乙胺(242.9g，2.4mol，5.0eq)，直至液相跟踪显示反应体系中原料X-1消失，停止反应。反应停止后，常压脱溶(旋掉溶液总体积的3/4)，再将剩余物加到乙酸乙酯(500mL)中，搅拌至澄清后向体系中滴加石油醚至白色浑浊液出现，再反滴加乙酸乙酯至刚溶清，室温敞口静置16～48小时，有固体析出，过滤，收集滤饼用石油醚(300mL×2)洗涤，真空干燥，得到白色固体XI-1。(172.4g，收率：71％，纯度：97.6％，de：98.0％)。Compound X-1 (344g, 0.48mol, 1.0eq) was added to N,N-dimethylformamide (6.9L) at room temperature, stirred for half an hour until all the raw materials were dissolved, then triethylamine (242.9g, 2.4mol, 5.0eq), until the liquid phase tracking shows that the raw material X-1 in the reaction system disappears, stop the reaction. After the reaction stopped, desolventize under normal pressure (spin off 3/4 of the total volume of the solution), then add the residue to ethyl acetate (500mL), stir until clear, then add petroleum ether dropwise to the system until a white turbid solution appears , then added ethyl acetate back dropwise until just dissolved, and left to stand at room temperature for 16 to 48 hours. Solids were precipitated, filtered, and the filter cake was collected and washed with petroleum ether (300mL×2), dried in vacuo to obtain a white solid XI- 1. (172.4 g, yield: 71%, purity: 97.6%, de: 98.0%).
1H-NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.14-8.12(m,1H),7.58-7.55(m,2H),7.24-7.22(m,2H),5.99(s,1H),5.43(s,2H),4.64(s,2H),4.49-4.47(m,1H),3.02-2.92(m,3H),1.73-1.70(m,1H),1.57-1.59(m,4H),1.41-1.37(m,2H),0.89-0.88(m,12H),0.78(d,J＝6.8,3H),0.06(s,6H).LC/MS:[M+H]+＝494.1 H-NMR (400MHz,DMSO-d6 )δ10.08(s,1H),8.14-8.12(m,1H),7.58-7.55(m,2H),7.24-7.22(m,2H),5.99( s,1H),5.43(s,2H),4.64(s,2H),4.49-4.47(m,1H),3.02-2.92(m,3H),1.73-1.70(m,1H),1.57-1.59( m,4H),1.41-1.37(m,2H),0.89-0.88(m,12H),0.78(d,J＝6.8,3H),0.06(s,6H).LC/MS:[M+H]+ ＝494.
实施例7：6-(2，5-二氧代-2，5-二氢-1H-吡咯-1-基)-N-((S)-1-(((S)-1-((4-(羟甲基)苯基)氨基)-1-氧代-5-脲基戊-2-基)氨基)-3-甲基-1-氧代丁-2-基)己酰胺的制备Example 7: 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-(( Preparation of 4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopent-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide
室温下将化合物XI-1(538g，1.09mol，1.0eq)和化合物V(1680.18g，5.45mol，5.0eq)加到乙腈(10.7L)中，室温下搅拌半小时至原料全部溶解，然后升温至45～50℃下反应4～6小时，得到取代物反应液，将反应液冷却至-5～0℃加入盐酸(2M，1.6L，3.27mol，3.0eq)滴加完毕，升至室温反应直至液相跟踪显示反应体系中原料消失，停止反应。反应停止后，反应液冷却至-5～0℃，滴加饱和碳酸氢钠水溶液至PH值7～8。滴加完毕，过滤，收集滤饼。滤饼用水(800mL)和乙酸乙酯(1.6L)打浆半小时，过滤，收集滤饼，真空干燥得到类白色固体VI(466.1g，收率：74％，纯度：99.1％，de：99.6％)。Add compound XI-1 (538g, 1.09mol, 1.0eq) and compound V (1680.18g, 5.45mol, 5.0eq) into acetonitrile (10.7L) at room temperature, stir at room temperature for half an hour until all the raw materials are dissolved, then raise the temperature React at 45-50°C for 4-6 hours to obtain a reaction solution of the substitute, cool the reaction solution to -5-0°C, add hydrochloric acid (2M, 1.6L, 3.27mol, 3.0eq) dropwise, and rise to room temperature for reaction Stop the reaction until the liquid phase tracking shows that the raw materials in the reaction system disappear. After the reaction stopped, the reaction solution was cooled to -5-0°C, and saturated aqueous sodium bicarbonate solution was added dropwise until the pH value was 7-8. After the dropwise addition, filter and collect the filter cake. The filter cake was beaten with water (800 mL) and ethyl acetate (1.6 L) for half an hour, filtered, the filter cake was collected, and vacuum-dried to obtain an off-white solid VI (466.1 g, yield: 74%, purity: 99.1%, de: 99.6% ).
1H-NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.03(d,J＝7.2,1H),7.78(d,J＝8.8,1H),7.49(d,J＝8.8,2H),7.17(d,J＝8.0,1H),6.95(s,2H),5.96(s,1H),5.38(s,2H),5.05(t,J＝5.6,1H),4.37-4.33(m,3H),4.13(m,1H),3.21-3.40(m,2H),2.95-2.89(m,2H),2.11-2.07(m,2H),1.92-1.90(m,1H),1.63-1.42(m,9H),1.14-1.12(m,2H),0.80-0.75(m,6H).LC/MS:[M+H]+＝573.1 H-NMR (400MHz, DMSO-d6 ) δ9.87(s, 1H), 8.03(d, J=7.2, 1H), 7.78(d, J=8.8, 1H), 7.49(d, J=8.8 ,2H),7.17(d,J=8.0,1H),6.95(s,2H),5.96(s,1H),5.38(s,2H),5.05(t,J=5.6,1H),4.37-4.33 (m,3H),4.13(m,1H),3.21-3.40(m,2H),2.95-2.89(m,2H),2.11-2.07(m,2H),1.92-1.90(m,1H),1.63 -1.42(m,9H),1.14-1.12(m,2H),0.80-0.75(m,6H).LC/MS:[M+H]+ ＝573.
实施例8：4-((S)-2-((S)-2-(6-(2，5-二氧代-2，5-二氢-1H-吡咯-1-基)己酰胺基)-3-甲基丁酰氨)-5-脲基戊基)苄基(4-硝基苯基)碳酸酯的制备Example 8: 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido Preparation of )-3-methylbutyrylamide)-5-ureidopentyl)benzyl(4-nitrophenyl)carbonate
氮气保护下，将化合物VI(1.98Kg，3.46mol，1.0eq)和化合物VII(1.05Kg，3.46mol，1.0eq)加入到N,N-二甲基甲酰胺(39.6L)中，室温下搅拌半小时至原料全部溶解，再加入二异丙基乙基胺(89.4g，6.92mol，2.0eq)进行取代反应，反应时间为3～5小时。反应完成后，常压脱溶(旋掉溶液总体积的3/4)，剩余物用DCM(8L)打浆，打浆完毕，过滤，收集滤饼，再用HOAc：MeOH＝1：1(v/v)(39.6L)溶解滤饼，往滤液中加入水直至不再有固体析出，过滤，收集滤饼用水(5L×3)洗涤，真空干燥得到白色固体VIII(2.14Kg，收率：83％，纯度：99.2％，de：99.4％，单杂<0.1％)。Under nitrogen protection, compound VI (1.98Kg, 3.46mol, 1.0eq) and compound VII (1.05Kg, 3.46mol, 1.0eq) were added to N,N-dimethylformamide (39.6L), stirred at room temperature After half an hour until all the raw materials were dissolved, diisopropylethylamine (89.4g, 6.92mol, 2.0eq) was added to carry out the substitution reaction. The reaction time was 3-5 hours. After the reaction is completed, precipitate at normal pressure (spin off 3/4 of the total volume of the solution), and the residue is beaten with DCM (8L). v) (39.6L) dissolves the filter cake, adds water to the filtrate until no solid precipitates out, filters, collects the filter cake, washes with water (5L×3), and vacuum-dries to obtain white solid VIII (2.14Kg, yield: 83%) , purity: 99.2%, de: 99.4%, simplex <0.1%).
1H-NMR(400MHz,CDCl3)8.23(d,J＝8.8,2H),7.65(d,J＝8.8,2H),7.42-7.39(m,4H),6.66(s,2H),5.26(s,2H),4.59-4.55(m,1H),4.20-4.16(m,1H),3.48(t,J＝7.2,2H),3.33-3.17(m,2H),2.29-2.25(t,J＝7.2,2H),2.01-1.89(m,2H),1.74-1.31(m,9H),0.95-0.90(m,6H).LC/MS:[M+H]+＝738.1 H-NMR (400MHz, CDCl3 ) 8.23 (d, J = 8.8, 2H), 7.65 (d, J = 8.8, 2H), 7.42-7.39 (m, 4H), 6.66 (s, 2H), 5.26 ( s,2H),4.59-4.55(m,1H),4.20-4.16(m,1H),3.48(t,J=7.2,2H),3.33-3.17(m,2H),2.29-2.25(t,J =7.2,2H),2.01-1.89(m,2H),1.74-1.31(m,9H),0.95-0.90(m,6H).LC/MS:[M+H]+ ＝738.
实施例9：(9H-芴-9-基)甲基((S)-1-(((S)-1-((4-((甲氧基甲氧基)甲基)苯基)氨基)-1-氧代-5-脲基戊-2-基)氨基)-3-甲基-1-氧代丁-2-基)氨基甲酸的制备Example 9: (9H-fluoren-9-yl)methyl((S)-1-(((S)-1-((4-((methoxymethoxy)methyl)phenyl)amino )-1-oxo-5-ureidopent-2-yl)amino)-3-methyl-1-oxobut-2-yl)carbamic acid
氮气保护下，将化合物I(2.7kg，5.44mol，1.0eq)和化合物IX-2(3638.4g，21.76mol，4.0eq)加到乙酸乙酯(13L)中，室温下搅拌半小时至原料全部溶解。再将DMTMM(6413.5g，21.76mol，4.0eq)和碳酸钾(751.9g，5.44mol，1.0eq)的乙酸乙酯(0.5L)溶液加入到反应液中，滴加过程温度控制在-5～-15℃。滴加完毕，缓慢升至室温继续反应直至液相跟踪显示反应体系中原料I消失，停止反应。反应停止后经常压脱溶，剩余固体用石油醚(3L×3)洗涤，真空干燥得到类白色固体X-1(2880.9g，收率：81.6％，纯度：99.5％，de：99.2％)。Under nitrogen protection, compound I (2.7kg, 5.44mol, 1.0eq) and compound IX-2 (3638.4g, 21.76mol, 4.0eq) were added to ethyl acetate (13L), stirred at room temperature for half an hour until all the raw materials were dissolve. DMTMM (6413.5g, 21.76mol, 4.0eq) and ethyl acetate (0.5L) solution of potassium carbonate (751.9g, 5.44mol, 1.0eq) were added to the reaction solution, and the temperature of the dropping process was controlled at -5～ -15°C. After the dropwise addition, slowly rise to room temperature and continue the reaction until the liquid phase tracking shows that the raw material I in the reaction system disappears, and the reaction is stopped. After the reaction was stopped, the solvent was removed under normal pressure, the remaining solid was washed with petroleum ether (3L×3), and dried in vacuo to obtain an off-white solid X-1 (2880.9g, yield: 81.6%, purity: 99.5%, de: 99.2%).
1H NMR(400MHz，DMSO-d6)δ9.98(s,1H),8.07(d,J＝7.2,1H),7.83(d,J＝7.6,2H),7.71-7.67(m,2H),7.53-7.51(m,2H),7.43-7.40(m,1H),7.37-7.33(m,2H),7.28-7.25(m,2H),7.18-7.16(m,2H),6.01(t,J＝5.2,1H),5.44-5.40(m,2H),4.64(s,2H),4.44-4.43(m,3H),4.31-4.23(m,3H),3.96-3.92(m,1H),3.31(s,3H),3.05-2.94(m,2H),2.01-1.98(m,1H),1.75-1.55(m,2H),1.46-1.37(m,2H),0.85(d,J＝6.8,6H).LC/MS:[M+H]+＝646.1 H NMR (400MHz, DMSO-d6 ) δ9.98(s, 1H), 8.07(d, J=7.2, 1H), 7.83(d, J=7.6, 2H), 7.71-7.67(m, 2H) ,7.53-7.51(m,2H),7.43-7.40(m,1H),7.37-7.33(m,2H),7.28-7.25(m,2H),7.18-7.16(m,2H),6.01(t, J＝5.2,1H),5.44-5.40(m,2H),4.64(s,2H),4.44-4.43(m,3H),4.31-4.23(m,3H),3.96-3.92(m,1H), 3.31(s,3H),3.05-2.94(m,2H),2.01-1.98(m,1H),1.75-1.55(m,2H),1.46-1.37(m,2H),0.85(d,J＝6.8 ,6H).LC/MS: [M+H]+ ＝646.
实施例10：(S)-2-((S)-2-氨基-3-甲基丁酰氨基)-N-(4-((甲氧基甲氧基)甲基)苯基)-5-脲基戊酰胺的制备Example 10: (S)-2-((S)-2-amino-3-methylbutyrylamino)-N-(4-((methoxymethoxy)methyl)phenyl)-5 - Preparation of ureido valeramide
室温下将化合物X-2(310.0g，0.48mol，1.0eq)加入到乙腈(1.6L)中，搅拌半小时至原料全部溶解，再加入二乙胺(70.1g，0.96mol，2.0eq)，直至液相跟踪显示反应体系中原料X-2消失，停止反应。反应停止后，常压脱溶(旋掉溶液总体积的3/4)，再将剩余物加到乙酸乙酯(500mL)中，搅拌至澄清后向体系中滴加石油醚至白色浑浊液出现，再反滴加乙酸乙酯至刚溶清，室温敞口静置16～48小时，有固体析出，过滤，收集滤饼用石油醚(300mL×2)洗涤，真空干燥，得到白色固体XI-2(173.9g，收率：84％，纯度：98.2％，de：98.1％)。Compound X-2 (310.0g, 0.48mol, 1.0eq) was added to acetonitrile (1.6L) at room temperature, stirred for half an hour until all the raw materials were dissolved, then diethylamine (70.1g, 0.96mol, 2.0eq) was added, Stop the reaction until the liquid phase tracking shows that the raw material X-2 in the reaction system disappears. After the reaction stopped, desolventize under normal pressure (spin off 3/4 of the total volume of the solution), then add the residue to ethyl acetate (500mL), stir until clear, then add petroleum ether dropwise to the system until a white turbid solution appears , then added ethyl acetate back dropwise until just dissolved, and left to stand at room temperature for 16 to 48 hours. Solids were precipitated, filtered, and the filter cake was collected and washed with petroleum ether (300mL×2), dried in vacuo to obtain a white solid XI- 2 (173.9 g, yield: 84%, purity: 98.2%, de: 98.1%).
1H-NMR(400MHz,DMSO-d6)δ10.08(s,1H),8.14-8.12(m,1H),7.58-7.55(m,2H),7.24-7.22(m,2H),5.99(s,1H),5.23(s,2H),4.64(s,2H),4.49-4.47(m,3H),3.31(s,3H),3.02-2.92(m,3H),1.73-1.70(m,1H),1.57-1.59(m,4H),1.41-1.37(m,2H),0.88(d,J＝6.8,3H),0.78(d,J＝6.8,3H).LC/MS:[M+H]+＝424.1 H-NMR (400MHz,DMSO-d6 )δ10.08(s,1H),8.14-8.12(m,1H),7.58-7.55(m,2H),7.24-7.22(m,2H),5.99( s,1H),5.23(s,2H),4.64(s,2H),4.49-4.47(m,3H),3.31(s,3H),3.02-2.92(m,3H),1.73-1.70(m, 1H), 1.57-1.59(m, 4H), 1.41-1.37(m, 2H), 0.88(d, J=6.8, 3H), 0.78(d, J=6.8, 3H).LC/MS: [M+ H]+ ＝424.
实施例11：6-(2，5-二氧代-2，5-二氢-1H-吡咯-1-基)-N-((S)-1-(((S)-1-((4-(羟甲基)苯基)氨基)-1-氧代-5-脲基戊-2-基)氨基)-3-甲基-1-氧代丁-2-基)己酰胺的制备Example 11: 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-(( Preparation of 4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopent-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide
室温下将化合物XI-2(269.0g，635.2mmol，1.0eq)和化合物V(195.8g，635.2mmol，1.0eq)溶于N,N-二甲基甲酰胺(5.38L)中，室温下搅拌半小时至原料全部溶解，然后升温至45～50℃下反应4～6小时，得到取代物反应液，将反应液冷却至-5～0℃加入三氟乙酸(217.2g，1905.6mmol，3.0eq)，滴加完毕，升至室温反应直至液相跟踪显示反应体系中原料消失，停止反应。反应停止后，反应液冷却至-5～0℃，滴加饱和碳酸氢钠水溶液至PH值7～8。滴加完毕，过滤，收集滤饼。滤饼用水(400mL)和乙酸乙酯(800mL)打浆半小时，过滤，收集滤饼，真空干燥得到类白色固体VI(310.7g，收率：85％，纯度：99.5％，de：99.3％)。Compound XI-2 (269.0g, 635.2mmol, 1.0eq) and compound V (195.8g, 635.2mmol, 1.0eq) were dissolved in N,N-dimethylformamide (5.38L) at room temperature and stirred at room temperature Half an hour until all the raw materials are dissolved, then raise the temperature to 45-50°C and react for 4-6 hours to obtain a reaction solution of the substitute, then cool the reaction solution to -5-0°C and add trifluoroacetic acid (217.2g, 1905.6mmol, 3.0eq ), the dropwise addition is completed, rise to room temperature and react until the liquid phase tracking shows that the raw materials in the reaction system disappear, and stop the reaction. After the reaction stopped, the reaction solution was cooled to -5-0°C, and saturated aqueous sodium bicarbonate solution was added dropwise until the pH value was 7-8. After the dropwise addition, filter and collect the filter cake. The filter cake was beaten with water (400mL) and ethyl acetate (800mL) for half an hour, filtered, the filter cake was collected, and vacuum-dried to obtain off-white solid VI (310.7g, yield: 85%, purity: 99.5%, de: 99.3%) .
1H-NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.03(d,J＝7.2,1H),7.78(d,J＝8.8,1H),7.49(d,J＝8.8,2H),7.17(d,J＝8.0,1H),6.95(s,2H),5.96(s,1H),5.38(s,2H),5.05(t,J＝5.6,1H),4.37-4.33(m,3H),4.13(m,1H),3.40-3.21(m,2H),2.95-2.89(m,2H),2.11-2.07(m,2H),1.92-1.90(m,1H),1.63-1.42(m,9H),1.14-1.12(m,2H),0.80-0.75(m,6H).LC/MS:[M+H]+＝573.1 H-NMR (400MHz, DMSO-d6 ) δ9.87(s, 1H), 8.03(d, J=7.2, 1H), 7.78(d, J=8.8, 1H), 7.49(d, J=8.8 ,2H),7.17(d,J=8.0,1H),6.95(s,2H),5.96(s,1H),5.38(s,2H),5.05(t,J=5.6,1H),4.37-4.33 (m,3H),4.13(m,1H),3.40-3.21(m,2H),2.95-2.89(m,2H),2.11-2.07(m,2H),1.92-1.90(m,1H),1.63 -1.42(m,9H),1.14-1.12(m,2H),0.80-0.75(m,6H).LC/MS:[M+H]+ ＝573.
实施例12：4-((S)-2-((S)-2-(6-(2，5-二氧代-2，5-二氢-1H-吡咯-1-基)己酰胺基)-3-甲基丁酰氨)-5-脲基戊基)苄基(4-硝基苯基)碳酸酯的制备Example 12: 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido Preparation of )-3-methylbutyrylamide)-5-ureidopentyl)benzyl(4-nitrophenyl)carbonate
氮气保护下，将化合物VI(5g，8.73mmol，1.0eq)和化合物VII(5.3g，17.46mmol，2.0eq)加入到N,N-二甲基甲酰胺(100mL)中，室温下搅拌半小时至原料全部溶解，再加入三乙胺(1.77g，17.46mmol，2.0eq)进行取代反应，反应时间为3～5小时。反应完成后，常压脱溶(旋掉溶液总体积的3/4)，剩余物用DCM：PE＝1：1(v/v)(25mL)打浆，打浆完毕，过滤，收集滤饼，再用HOAc：MeOH＝4：1(v/v)(100mL)溶解滤饼，往滤液中加入水直至不再有固体析出，过滤，收集滤饼用水(15mL×3)洗涤，真空干燥得到白色固体VIII(4.85g，收率：75％，纯度：99.7％，de：99.6％，单杂<0.1％)。Under nitrogen protection, compound VI (5g, 8.73mmol, 1.0eq) and compound VII (5.3g, 17.46mmol, 2.0eq) were added to N,N-dimethylformamide (100mL), stirred at room temperature for half an hour After all the raw materials were dissolved, triethylamine (1.77g, 17.46mmol, 2.0eq) was added for substitution reaction, and the reaction time was 3-5 hours. After the completion of the reaction, precipitate under normal pressure (spin off 3/4 of the total volume of the solution), and beat the residue with DCM:PE=1:1 (v/v) (25mL). After the beating is completed, filter and collect the filter cake. Dissolve the filter cake with HOAc: MeOH = 4: 1 (v/v) (100 mL), add water to the filtrate until no solid precipitates, filter, collect the filter cake, wash with water (15 mL × 3), and dry in vacuo to obtain a white solid VIII (4.85 g, yield: 75%, purity: 99.7%, de: 99.6%, monohetero<0.1%).
1H-NMR(400MHz,CDCl3)8.23(d,J＝8.8,2H),7.65(d,J＝8.8,2H),7.42-7.39(m,4H),6.66(s,2H),5.26(s,2H),4.59-4.55(m,1H),4.20-4.16(m,1H),3.48(t,J＝7.2,2H),3.33-3.17(m,2H),2.29-2.25(t,J＝7.2,2H),2.01-1.89(m,2H),1.74-1.31(m,9H),0.95-0.90(m,6H).LC/MS:[M+H]+＝738.1 H-NMR (400MHz, CDCl3 ) 8.23 (d, J = 8.8, 2H), 7.65 (d, J = 8.8, 2H), 7.42-7.39 (m, 4H), 6.66 (s, 2H), 5.26 ( s,2H),4.59-4.55(m,1H),4.20-4.16(m,1H),3.48(t,J=7.2,2H),3.33-3.17(m,2H),2.29-2.25(t,J =7.2,2H),2.01-1.89(m,2H),1.74-1.31(m,9H),0.95-0.90(m,6H).LC/MS:[M+H]+ ＝738.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.
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| CN201510451473.8ACN106380508A (en) | 2015-07-28 | 2015-07-28 | A kind of industrial production method of antibody-conjugated drug linker |
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| CN107805274B (en)* | 2017-11-08 | 2021-02-09 | 上海皓元生物医药科技有限公司 | Industrial production method of antibody-conjugated drug linker intermediate |
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