WO2024083099A1 - 药物中间体及其制备方法 - Google Patents

药物中间体及其制备方法 Download PDF

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WO2024083099A1
WO2024083099A1 PCT/CN2023/124877 CN2023124877W WO2024083099A1 WO 2024083099 A1 WO2024083099 A1 WO 2024083099A1 CN 2023124877 W CN2023124877 W CN 2023124877W WO 2024083099 A1 WO2024083099 A1 WO 2024083099A1
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compound
formula
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张健
林峰
邹晓东
王勇
郭辉
肖福生
贺海鹰
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Fujian Akeylink Biotechnology Co Ltd
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Fujian Akeylink Biotechnology Co Ltd
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Priority to CN202380014385.4A priority patent/CN118251404B/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms

Definitions

  • the present invention relates to a pharmaceutical intermediate and a preparation method thereof, and in particular to a compound of formula (I) and a preparation method thereof.
  • SARS-CoV-2 is a single positive-strand RNA virus with high homology to SARS-CoV and MERS-CoV. After the virus infects and enters the host cell, with the help of the host cell, its genetic material RNA first translates and expresses two polyprotein precursors (pp1a and pp1ab).
  • the polyprotein precursor undergoes intramolecular cleavage under the action of 3CL protease and PL protease to produce multiple non-structural proteins. Since 3CL protease is responsible for cleavage at least 11 sites, it is also called main protease (Mpro).
  • Nonstructural proteins are involved in the production of viral subgenomic RNA and four structural proteins (E protein, M protein, S protein and N protein), thereby completing the reproduction and release of progeny viruses; 3CL protease belongs to cysteine protease, and its active form is a homodimer.
  • 3CL protease is relatively conservative in coronaviruses, and the substrates of 3CL proteases of different coronaviruses have common characteristics; since there is no protease homologous to 3CL protease in the human body, 3CL protease has become one of the ideal anti-coronavirus targets.
  • Patent PCT/CN2022/087511 discovered a 3CL protein with good anti-new coronavirus activity.
  • 3CL protease inhibitors In order to further improve the accessibility of drugs and facilitate scale-up production, it is necessary to develop new methods for obtaining intermediates of 3CL protease inhibitors to overcome the problems associated with the known methods in PCT/CN2022/087511, including the commercial accessibility and price of reagents, the scalability of large-scale production, the safety of process production, and the overall production cost.
  • the molecular structure of the 3CL protease inhibitor is as follows:
  • the present invention provides a method for preparing a compound of formula (I).
  • R 1 is selected from H, C 1-4 alkyl and benzyl
  • R2 is an amino protecting group.
  • R 1 is selected from H, methyl, ethyl, isopropyl, tert-butyl and benzyl, preferably methyl.
  • R 2 is selected from Boc.
  • the method for preparing the compound of formula (I) further comprises the step of synthesizing the compound of formula (I) from compound D.
  • the method for preparing the compound of formula (I) further comprises the following steps:
  • the method for preparing the compound of formula (I) further comprises the step of pulping and purifying the crude product of the compound obtained after the reaction in step 5:
  • the present invention also provides an intermediate of the following formula, its hydrochloride or sulfate,
  • the intermediate compounds of the present invention can be synthesized by various methods known to those skilled in the art.
  • the present invention is prepared by the following specific embodiments, embodiments formed by combining the above with other chemical synthesis methods, and equivalent replacement methods known to those skilled in the art.
  • Preferred embodiments include but are not limited to the embodiments of the present invention.
  • Those skilled in the art can refer to the contents of the present invention to appropriately change the raw materials, process conditions and other links to achieve other corresponding purposes. The relevant changes do not deviate from the contents of the present invention. All similar replacements and modifications are obvious to those skilled in the art and are deemed to be included in the scope of the present invention.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.
  • acyl such as alkanoyl (e.g., acetyl
  • C 1-4 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 and C 2-3 alkyl groups, etc.; they can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), etc.
  • Me represents methyl
  • Boc represents tert-butyloxycarbonyl
  • TFAA represents trifluoroacetic anhydride
  • EtOAc represents ethyl acetate
  • IBX 2-iodoacetylbenzoic acid
  • EDCI represents Table 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • HOBt stands for 1-hydroxybenzotriazole.
  • the compounds are named by conventional methods in the art or The software names were used, and commercially available compounds were named using the supplier's catalog names.
  • the synthesis process of the intermediate provided by the invention has the beneficial effects of: the raw materials are cheap and readily available, the production cost is low, the potential safety hazard in the production process is eliminated, and it is more suitable for large-scale production.
  • Process safety The IBX used in the original process route posed safety hazards during the production process. The new process route replaced it with Tempo reagent, eliminating the safety hazards.
  • the new process route involves more conventional process conditions, a simpler purification process, and is more suitable for large-scale production.
  • the intermediate 1-A (70 g) and 2,2,6,6-tetramethylpiperidine nitrogen oxide (0.2 g) were dissolved in dichloromethane (700 mL), cooled to 0-5°C, sodium bicarbonate (33.81 g) and sodium bromide (2.65 g) were dissolved in water (420 mL) and added to the reaction solution, sodium hypochlorite solution (372.12 g, 8% content) and water (200 mL) were mixed evenly, and added dropwise to the reaction solution at 0-10°C, stirred for reaction for 1 hour, and after the reaction was completed, sodium sulfite (100 g) was dissolved in water (1000 mL), added to the reaction solution for quenching for 0.5 hours, separated, dichloromethane (1 L) was added to the organic phase and extracted again, the organic phases were combined, washed once with brine (1 L), and concentrated to obtain the intermediate 1-B (68 g, yield: 98%).
  • Methyltriphenylphosphonium bromide (103.47 g) was dissolved in toluene (650 mL), replaced with nitrogen three times, cooled to 0-5° C., potassium tert-butoxide (29.79 g) was added, heated to 20-25° C., stirred for reaction for 1 hour, intermediate 1-B (65 g) was added, stirred for reaction at 20-25° C. for 16 hours, after the reaction was completed, water (1000 mL) was added, extracted and separated, methyl tert-butyl ether was added to the aqueous phase and extracted again, the organic phases were combined, washed with brine (1000 mL), and the organic phase was concentrated to dryness under reduced pressure.
  • Chlorobenzene 250mL was cooled to -10-0°C, diethylzinc n-hexane solution (1mol/L, 561mL) was added, and after the addition was completed, boron trifluoride ether (119.46g) was added dropwise, and stirring was continued for 0.5 hours after the addition was completed, and the temperature was cooled to -10°C, and diiodomethane (300.57g) was added dropwise, and stirring was continued for 0.5 hours after the addition was completed, and the intermediate 1-C (50g) was dissolved in chlorobenzene (50mL), and added dropwise to the reaction solution, and after the addition was completed, the temperature was raised to 35-40°C and the reaction was carried out for 4 hours.
  • the intermediate 1-E (211.59 g) was dissolved in dichloromethane (1300 mL), trifluoroacetic anhydride (201.48 g) was added at 10-15°C, and triethylamine (64.71 g) was added continuously. After the addition was completed, the reaction was continued at 20-25°C for 1 hour. After the reaction was completed, the reaction solution was cooled to 10-15°C, water (500 mL) was added dropwise, and the liquid was separated. The organic phase was washed with 10% citric acid aqueous solution (500 mL), saturated sodium bicarbonate aqueous solution (500 mL), and saturated brine (500 mL). It was concentrated to dryness to obtain a crude product of the intermediate 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
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  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

本发明公开了一种药物中间体及其制备方法，具体公开了式(I)化合物及其制备方法。

Description

药物中间体及其制备方法
本申请要求申请日为2022/10/18的中国专利申请2022112756796的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种药物中间体及其制备方法，具体涉及式(I)化合物及其制备方法。
背景技术
2022年是人类与新冠大流行抗争的第3年，全球累计确诊病例已超6亿，累计死亡人数超600万，约70个国家新冠确诊病例超过100万例，其流行病学传播的模式、蔓延态势和大流行的程度远远超过了2009年的H1N1甲型流感。SARS-CoV-2属于单正链的RNA病毒，和SARS-CoV以及MERS-CoV具有较高的同源性。该病毒感染进入宿主细胞后，在宿主细胞的帮助下，其遗传物质RNA首先翻译表达出两条多聚蛋白前体(pp1a和pp1ab)，多聚蛋白前体在3CL蛋白酶和PL蛋白酶的作用下发生分子内的切割产生多个非结构蛋白，由于3CL蛋白酶至少负责11个位点的切割，故又称之为主蛋白酶(main protease，Mpro)。非结构蛋白参与了病毒亚基因RNA和四个结构蛋白(E蛋白、M蛋白、S蛋白和N蛋白)的产生，进而完成子代病毒的繁衍与释放；3CL蛋白酶属于半胱氨酸蛋白酶,活性形式为同源二聚体。3CL蛋白酶在冠状病毒中较为保守,并且不同冠状病毒3CL蛋白酶的底物之间具有共同特征；由于人体内不存在与3CL蛋白酶同源的蛋白酶，因此3CL蛋白酶成为理想的抗冠状病毒靶标之一。
开发能够有效抗新型冠状病毒的药物是目前临床用药所亟需的。专利PCT/CN2022/087511发现了一种具有良好的抗新型冠状病毒活性的3CL蛋 白酶抑制剂。为了进一步提高药物的可及性和更有利于放大生产，有必要开发用于获得该3CL蛋白酶抑制剂的中间体的新方法，以克服与PCT/CN2022/087511中已知方法相关的问题，包括使用试剂商业可及性及价格问题，规模化生产可放大性问题，工艺生产安全性问题，总体生产成本问题等。3CL蛋白酶抑制剂的分子结构如下：
发明内容
本发明提供了式(I)化合物的制备方法，
其特征在于，包含以化合物A为原料合成化合物D的步骤：
其中，
R1选自H、C1-4烷基和苄基；
R2为氨基保护基。
本发明的一些方案中，上述R1选自H、甲基、乙基、异丙基、叔丁基和苄基，优选甲基。
本发明的一些方案中，上述R2选自Boc。
本发明的一些方案中，式(I)化合物的制备方法还包含由化合物D合成式(I)化合物的步骤。
本发明的一些方案中，式(I)化合物的制备方法还包含如下的步骤：
本发明的一些方案中，式(I)化合物的制备方法还包括将步骤5反应后所得化合物的粗品打浆纯化的过程：
1)向粗品中加入醋酸异丙酯和正庚烷的混合溶剂，所述醋酸异丙酯和正庚烷的混合溶剂的比例为1:4～2:3，优选1:3；
2)在40～60℃下打浆1～2小时，优选50℃；
3)降温至10-20℃；
4)过滤。
本发明还提供下式中间体、其盐酸盐或硫酸盐，
定义和说明：
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方 法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。本领域技术人员可以借鉴本发明的内容适当改变原料、工艺条件等环节来实现相应的其它目的，其相关改变都没有脱离本发明的内容，所有类似的替换和改动对于本领域技术人员来说是显而易见的，都被视为包括在本发明的范围之内。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本发明中的氨基)选择合适的保护基。
术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
除非另有规定，术语“C1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C1-4烷基包括C1-2、C1-3和C2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-4烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)等。
本发明所使用的所有溶剂可经市售获得。
本发明采用下述缩略词：Me代表甲基；Boc代表叔丁氧羰基；TFAA代表三氟乙酸酐；EtOAc代表乙酸乙酯；IBX代表2-碘酰基苯甲酸；EDCI代 表1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐；HOBt代表1-羟基苯并三唑。
化合物经本领域常规命名方法或者软件命名，市售化合物采用供应商目录名称。
技术效果
本发明给出的中间体的合成工艺，有益效果为：原料价格便宜易得，生产成本低，消除了生产过程中的安全隐患，更适于规模化生产。
具体地：
1、成本更低：新路线中Boc-叔亮氨酸使用效率更高，各步收率更优，成本较高的缩合步骤更靠后，物料成本大大降低。
2、试剂更廉价易得：原工艺路线中，烯烃化步骤采用的TEBBE试剂；新工艺路线更换为更为广泛易得的Wittig试剂。
3、工艺安全：原工艺路线中使用的IBX在生产过程中均存在安全隐患，新工艺路线分别用Tempo试剂进行了替代，消除了安全隐患。
4、更适合规模化生产：新工艺路线涉及的工艺条件更常规，纯化过程更简便，更适于规模化生产。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
实施例1
合成路线：
步骤1：中间体1-B的合成
将中间体1-A(70g)和2,2,6,6-四甲基哌啶氮氧化物(0.2g)溶于二氯甲烷(700mL)中，降温至0-5℃，将碳酸氢钠(33.81g)、溴化钠(2.65g)溶于水(420mL)中，加入到反应液中，将次氯酸钠溶液(372.12g,8％含量)，水(200mL)，混合均匀，于0～10℃滴加到反应液中，搅拌反应1小时，反应结束后，将亚硫酸钠(100g)溶于水(1000mL)中，加入反应液中淬灭0.5小时，分液，有机相加入二氯甲烷(1L)再萃取一遍，合并有机相，加入食盐水(1L)洗涤一遍，浓缩得到中间体1-B(68g,收率：98％)。1H NMR(400MHz,CDCl3)δppm major[4.66(s,1H),4.00(s,1H),3.69(s,3H),2.94(s,1H),2.37–2.12(m,3H),1.80(s,1H),1.33(s,9H)].minor[4.53(s,1H),4.09(s,1H),3.69(s,3H),2.96(s,1H),2.37–2.12(m,3H),1.77(s,1H),1.41(s,9H)].MS m/z:168.0[M-Boc]+步骤2：中间体1-C的合成
将甲基三苯基溴化膦(103.47g)溶于甲苯(650mL)中，氮气置换3次，降温至0-5℃，加入叔丁醇钾(29.79g)，升温至20-25℃，搅拌反应1小时，加入中间体1-B(65g)，20-25℃搅拌反应16小时，反应结束后，加入水(1000mL)，萃取分液，水相加入甲基叔丁基醚再萃取一遍，合并有机相，用食盐水(1000mL)洗涤，有机相减压浓缩至干，浓缩物用石油醚-乙酸乙酯进行柱层析纯化，得到中间体1-C(33g,收率：51％)。1H NMR(400MHz,CDCl3)δppm major[5.15(d,J＝6.0Hz,1H),4.85(d,J＝6.0Hz,1H),4.45(s,1H),3.87(s,1H),3.72(s,3H),3.09(s,1H),2.41–2.22(m,3H),1.84(s,1H),1.37(s,9H)]. minor[5.15(d,J＝6.0Hz,1H),4.85(d,J＝6.0Hz,1H),4.31(s,1H),3.97(s,1H),3.72(s,3H),3.11(s,1H),2.37–2.12(m,3H),2.06(s,1H),1.40(s,9H)].MS m/z:166.0[M-Boc]+
步骤3：中间体1-D的合成
氯苯(250mL)中降温至-10-0℃，加入二乙基锌正己烷溶液(1mol/L,561mL)，滴加完毕后，再滴加三氟化硼乙醚(119.46g)，滴加完毕后继续搅拌0.5小时，降温至-10℃，滴加二碘甲烷(300.57g)，滴加完毕后继续搅拌0.5小时，将中间体1-C(50g)溶解于氯苯(50mL)中，滴加到反应液中，滴加完毕升温至35-40℃反应4小时，反应结束后，降温至-10～-5℃，滴加20％柠檬酸水溶液(1000mL)，滴加完毕后，加入乙酸乙酯(500mL)，继续搅拌10分钟，分液，有机相用20％柠檬酸水溶液(250mL)洗涤，合并水相，水相用乙酸乙酯(300mL*2)萃取，水相加入酒石酸钾钠水溶液[酒石酸钾钠(316g)+水(750mL)]，用氨水调节pH至9-10，加入二氯甲烷(500mL)，萃取分液，水相用二氯甲烷(300mL)再萃取一遍，合并有机相减压浓缩得到中间体1-D(24g,收率：70％)。1H NMR(400MHz,CDCl3)δppm 3.71(s,3H),3.69(s,1H),3.64(d,J＝3.6Hz,1H),1.86(s,1H),1.72–1.67(m,2H),1.52–1.47(m,2H),0.70–0.59(m,3H),0.40–0.38(m,1H).MS m/z:182.1[M+H]+
步骤4：中间体1-E的合成
将中间体1-D(137g)、(S)-N-Boc叔亮氨酸(192.32g)溶解于乙腈(1370mL)和N,N-二甲基甲酰胺(137mL)的混合溶液中，25℃条件下加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(159.41g)、N-甲基吗啉(152.93g)、1-羟基苯并三唑(102.14g)，继续反应16小时，反应完成后，减压浓缩除去大部分乙腈后，加入乙酸乙酯(1000mL)，水(1000mL)，萃取，分液，有机相用10％柠檬酸(500mL*2)洗涤，饱和碳酸氢钠(500mL)洗涤，饱和食盐水(500mL)洗涤，减压浓缩至干，浓缩物于10-15℃下加入盐酸乙酸乙酯溶液(4mol/L,1.89L)，甲醇(200mL)，加完后于20-25℃搅拌反应0.5小时，反应完成后，浓缩 除1L溶剂，于25℃下搅拌0.5小时，过滤，滤饼加入乙酸乙酯(200mL)洗涤，滤饼除溶残后得到中间体1-E(212g,收率：85％)。1H NMR(400MHz,CDCl3)δppm 8.49(s,3H),4.51(s,1H),4.42(s,1H),4.03(d,J＝4.8Hz,1H),3.70(s,3H),2.26(d,J＝10.8Hz,1H),2.07(s,1H),1.97(s,1H),1.90(d,J＝10.0Hz,1H),1.90(d,J＝10.0Hz,1H),1.80(d,J＝12.4Hz,1H),1.23(s,9H),0.81–0.64(m,3H),0.48–0.46(m,1H).MS m/z:294.9[M+H]+
步骤5：中间体1的合成
将中间体1-E(211.59g)溶解于二氯甲烷(1300mL)中，于10-15℃下加入三氟乙酸酐(201.48g)，继续加入三乙胺(64.71g)，加完后于20-25℃继续反应1小时，反应结束后，将反应液降温至10-15℃，滴加水(500mL)，分液，有机相用10％柠檬酸水溶液(500mL)洗涤，饱和碳酸氢钠水溶液(500mL)洗涤，饱和食盐水(500mL)洗涤，浓缩至干得到中间体1的粗品，向粗品中加入醋酸异丙酯(50mL)、正庚烷(500mL)于50℃下打浆1-2小时，降温至10-20℃，过滤，得到中间体1(212g,收率：85％)。1H NMR(400MHz,CDCl3)δppm 8.49(d,J＝8.8Hz,1H),4.68(d,J＝9.6Hz,1H),4.59(s,1H),4.37(s,1H),3.72(s,3H),2.10(d,J＝10.0Hz,1H),1.99(s,1H),1.92–1.86(m,2H),1.59(dd,J＝12.4Hz,2.4Hz,1H),1.10(s,9H),0.75–0.63(m,3H),0.49–0.47(m,1H).MS m/z:391.1[M+H]+.
实施例2中间体1-A的合成
氮气保护下，将S1(39g，141.6mmol，1eq)投入1000mL圆底烧瓶中，加入甲醇160g，乙酸(10.2g，170mmol，1.2eq)搅拌溶解；加入10％钯碳4.0g，将氢气压力设定0.3～0.5MPa，温度10～20℃，保温搅拌8～10hr；中控TLC 点板显示原料点消失；过滤；滤液转移至1000mL圆底烧瓶中，5～5℃滴加三乙胺，0～10℃滴加二碳酸二叔丁酯，滴毕升温至15～20℃，保温搅拌2～2.5hr，TLC中控至原料点消失；反应液减压浓缩，加入乙酸乙酯180g，饮用水100g萃洗分层；水相用乙酸乙酯复萃；合并有机相，依次用12％碳酸氢钠水溶液，和30％氯化钠水溶液洗涤；有机相用无水硫酸钠干燥2hr，过滤；减压浓缩干，浓缩结束加入正庚烷80.4g室温打浆2-3hr，过滤，收集滤饼40-45℃真空干燥，得到目标产物中间体1-A(33.0g，收率：85.9％)，1H NMR(400MHz,DMSO-d6,298K,δin ppm):5.03(m,1H,CH),3.94(m,1H,CH),3.71(s,9H,C(CH3)3),3.64(d,3H,CH3),3.60(d,1H,CH),3.34(m,2H,CH2),2.41(m,1H,OH),1.86(m,1H,CH),1.63(m,2H,CH2)。

Claims (7)

  1. 式(I)化合物的制备方法，
    其特征在于，包含以化合物A为原料合成化合物D的步骤：
    其中，
    R1选自H、C1-4烷基和苄基；
    R2为氨基保护基。
  2. 根据权利要求1所述式(I)化合物的制备方法，其中R1选自H、甲基、乙基、异丙基、叔丁基和苄基，优选甲基。
  3. 根据权利要求1所述式(I)化合物的制备方法，其中R2选自Boc。
  4. 根据权利要求1所述式(I)化合物的制备方法，其还包含由化合物D合成式(I)化合物的步骤。
  5. 根据权利要求1所述式(I)化合物的制备方法，其包含如下的步骤：
  6. 权利要求5所述式(I)化合物的制备方法，其中，还包括将步骤5反 应后所得化合物的粗品打浆纯化的过程：
    1)向粗品中加入醋酸异丙酯和正庚烷的混合溶剂，所述醋酸异丙酯和正庚烷的混合溶剂的比例为1:4～2:3，优选1:3；
    2)在40～60℃下打浆1～2小时，优选50℃；
    3)降温至10-20℃；
    4)过滤。
  7. 下式中间体、其盐酸盐或硫酸盐，
PCT/CN2023/124877 2022-10-18 2023-10-17 药物中间体及其制备方法 Ceased WO2024083099A1 (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025218702A1 (zh) * 2024-04-17 2025-10-23 福建广生中霖生物科技有限公司 一种药物中间体的盐、晶型及其制备方法和应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021223718A1 (zh) * 2020-05-06 2021-11-11 中国科学院上海药物研究所 醛基类化合物及其制备方法、药物组合物和用途
CN114133350A (zh) * 2021-12-16 2022-03-04 浙江乐普药业股份有限公司 一种抗新冠药物Paxlovid中间体的制备方法
CN114149415A (zh) * 2021-07-26 2022-03-08 中国药科大学 一种拟肽类化合物及其衍生物、制备方法、药物组合物和应用
CN114507221A (zh) * 2022-04-21 2022-05-17 北京科翔中升医药科技有限公司 一种三嗪类化合物及其在制备抗病毒药物上的用途
CN114605419A (zh) * 2021-12-30 2022-06-10 威科检测集团有限公司 一种具有抗新冠病毒活性的吡咯烷类化合物及其在药物中的应用
CN114685468A (zh) * 2020-12-25 2022-07-01 成都硕德药业有限公司 用于治疗子宫肌瘤的药物的中间体化合物及其制备方法
CN114790198A (zh) * 2022-06-24 2022-07-26 北京科翔中升医药科技有限公司 一种三嗪类化合物及其制备方法和应用

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ543102A (en) * 2003-04-24 2008-12-24 Incyte Corp Aza spiro alkane derivatives as inhibitors of metalloproteases
CN106938980B (zh) * 2017-05-04 2019-11-29 无锡捷化医药科技有限公司 一种5-苄基-5-n杂螺[2.4]庚烷-1-羧酸的制备方法
US11351149B2 (en) * 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
EP4209494B1 (en) * 2021-04-16 2024-10-09 Fujian Akeylink Biotechnology Co., Ltd. Ring-modified proline short peptide compound and use thereof
WO2023043816A1 (en) * 2021-09-17 2023-03-23 Aligos Therapeutics, Inc. Anti-viral compounds for treating coronavirus, picornavirus, and norovirus infections
WO2023116811A1 (zh) * 2021-12-22 2023-06-29 福建广生中霖生物科技有限公司 含β-胺基酮的短肽化合物及其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021223718A1 (zh) * 2020-05-06 2021-11-11 中国科学院上海药物研究所 醛基类化合物及其制备方法、药物组合物和用途
CN114685468A (zh) * 2020-12-25 2022-07-01 成都硕德药业有限公司 用于治疗子宫肌瘤的药物的中间体化合物及其制备方法
CN114149415A (zh) * 2021-07-26 2022-03-08 中国药科大学 一种拟肽类化合物及其衍生物、制备方法、药物组合物和应用
CN114133350A (zh) * 2021-12-16 2022-03-04 浙江乐普药业股份有限公司 一种抗新冠药物Paxlovid中间体的制备方法
CN114605419A (zh) * 2021-12-30 2022-06-10 威科检测集团有限公司 一种具有抗新冠病毒活性的吡咯烷类化合物及其在药物中的应用
CN114507221A (zh) * 2022-04-21 2022-05-17 北京科翔中升医药科技有限公司 一种三嗪类化合物及其在制备抗病毒药物上的用途
CN114790198A (zh) * 2022-06-24 2022-07-26 北京科翔中升医药科技有限公司 一种三嗪类化合物及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4606813A4

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025218702A1 (zh) * 2024-04-17 2025-10-23 福建广生中霖生物科技有限公司 一种药物中间体的盐、晶型及其制备方法和应用

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