CN115611757A - mRNA传递剂的合成 - Google Patents
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Abstract
本发明涉及mRNA传递剂的合成，具体为在三氟甲磺酸镱作用下，相关氨基化合物和环氧乙烷发生反应。
Description
技术领域
本发明属于化学合成领域，具体涉及mRNA传递剂的合成
背景技术
COVID-19大流行将mRNA疫苗推向了生物技术和制药工业的中心阶段。疫苗开发的速度也超出了预期，在SARS-CoV-2序列公开10个月后就有疫苗面世。这一成功不仅证明了生物技术和制药工业有能力应对紧迫和未得到满足的全球需求，而且也证明了mRNA作为一种药物形式的固有能力，与常规灭活疫苗相比，mRNA疫苗具有成本低、生产效率高、安全性高的优势，且拥有合成任何一种蛋白的潜能，因此，对于传统疫苗无力应对的新型传染性病毒有巨大应用潜力。然而，由于mRNA分子的不稳定性、先天免疫原性高及体内递送效率低等原因，mRNA疫苗的应用一直受到限制。要实现mRNA疫苗的广泛应用，需重点解决递送技术。mRNA疫苗需要有合适的递送载体(递送剂，又称为传递剂)将其递送至体内，才能有更好的免疫效果，因此开发高效无毒的递送系统是mRNA疫苗成功的关键。美国乔治梅森大学生物工程系主任Michael D.Buschmann教授阐述了mRNA传递系统的发展，总结SARS-CoV-2mRNA疫苗的临床前和临床研究结果，重点介绍了目前SARS-CoV-2疫苗临床试验中使用的脂质纳米粒，并且对脂质纳米粒在mRNA疫苗中的作用进行了分析。
在COVID-19之前，mRNA疫苗已用于临床前和临床研究，包括流感、寨卡病毒、艾滋病毒、埃博拉病毒、狂犬病、疟疾、生殖器疱疹、弓形虫病等。在目前针对新型冠状病毒COVID19疫苗竞赛中，基于mRNA疫苗已初见成效，目前正在进行的mRNA疫苗人体试验共有八个，分别是由BioNTech/Pfizer、Moderna、CureVac、Sanofi/TranslateBio、Arcturus/DukeNUS新加坡医学院、伦敦帝国理工学院、泰国Chula-longkorn大学和ProvidenceTherapeutics领导。值得注意的是，其中两项试验公布了中期第3阶段试验结果，报告了两次30μg或100μg剂量后编码棘突蛋白免疫原的mRNA序列(以脂质纳米颗粒形式递送)以及SARS-CoV-2感染率降低94％以上的疗效。
递送技术平台是mRNA疫苗的关键之一，已经有大量的mRNA制剂系统见诸报道，其中的很多已经进入临床试验阶段。这些制剂技术都是通过形成特殊的mRNA载体，来实现mRNA疫苗的递送，这些载体技术包括：鱼精蛋白载体技术、纳米颗粒脂质体载体技术、多聚体载体技术。
目前，纳米颗粒脂质体载体技术在当前SARS-CoV-2疫苗开发和生产过程中使用最为广泛。纳米颗粒脂质体载体技术使用的递送剂通常包含如下式I结构的化合物或其盐或其异构体。
专利CN109476718进一步描述了这类纳米颗粒脂质体递送剂的通式结构，具体通式结构如下式II。
专利CN109476718的说明书和实施例中进一步提及了些代表性的递送剂的结构，诸如以下结构的一些化合物：
对于n＝1的一些传递剂的合成，该专利采取的策略是化合物式III和化合物式IV发生缩合反应制备得到化合物式V；然后化合物式V和氨基乙醇发生亲核取代反应，化合物式V中的溴被氨基乙醇中的氨基亲核取代，得到化合物式VI；最后，化合物式VI和化合物式VII发生亲核取代反应，制备得到化合物式VIII。该条合成路线虽然可以实现递送剂的合成，但是由于第二步反应的产物化合物式VI含有裸露的氨基，在反应液中可以继续和化合物式V发生亲核取代反应产生二聚杂质；同时第三步反应，最后的产物式VIII非常容易继续和化合物式VII反应生成季铵溴盐杂质。这些反应路线的缺陷直接导致了该条合成路线在产业化过程中会遇到瓶颈。
发明内容
本发明的目的在于提供一条新的制备mRNA传递剂的方法，用以合成化合物式XI的化合物。
该方法合成路线为氨基化合物式X在溶剂和添加物存在下与环氧乙烷发生反应，方便地实现化合物式XI的制备。
反应所使用的溶剂包括乙腈、二氧六环、THF、DMF、DMSO,2-Me-THF。
反应所使用的添加物为三氟甲磺酸镱。
化合物式X和式XI中R1为H,C1-C10的烷基；R2为H,C1-C10的烷基。
化合物式X和式XI中，n为2-10，z为1-10，p为2-10,q为1-11。
具体实施方式
以下典型实施例用来说明本发明，在本领域内的技术人员对本发明所做的简单替换和改进等均属于本发明所保护的技术方案之内。
实施例一：8,8'-((2-羟乙基)氮烷二基)二辛酸二壬酯的制备
四口烧瓶中依次加入8,8'-二氮亚烷基二辛酸二壬酯(10.0g,18.05mmol)和乙腈(50mL),加入完毕后体系降温至-80℃,向反应体系中鼔入环氧乙烷(20g,0.45mol)；随后，向反应体系中加入三氟甲磺酸镱(1.12g,1.81mmol)。加入完毕后，反应体系搅拌下自然升至室温反应，TLC点板跟踪反应至起始物料8,8'-二氮亚烷基二辛酸二壬酯基本消失。反应完毕后体系中加入水(100mL)淬灭反应，反应体系乙酸乙酯萃取(3×80mL)，合并有机相，有机相无水硫酸钠干燥，过滤，滤液减压去除溶剂，残余物柱层析纯化(CH2Cl2/MeOH＝30:1)得8,8'-((2-羟乙基)氮烷二基)二辛酸二壬酯(9.18g,85.1％)。1H NMR(600MHz,CDCl3)δ0.90(m,6H),1.02-1.75(m，49H),2.31(m,4H),2.72-2.41(m，6H),3.61(m，2H),4.07(m，4H)Mass:599[M+H]+。
Claims (5)
1.制备mRNA传递剂式XI化合物的方法,具体为氨基化合物式X在溶剂和添加物存在下与环氧乙烷发生反应，方便地实现化合物式XI的制备。反应式如下：
2.如权利要求1所示的反应，反应所使用的溶剂为乙腈、二氧六环、THF、DMF、DMSO,2-Me-THF。
3.如权利要求1所示的反应，反应所使用的添加物为三氟甲磺酸镱。
4.如权利要求1所示的化合物，式X和式XI中R1为H,C1-C10的烷基；式X和式XI中R2为H,C1-C10的烷基。
5.如权利要求1所示的化合物，式X和式XI中，n为2-10，z为1-10，p为2-10,q为1-11。
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110804660.5A CN115611757A (zh) | 2021-07-16 | 2021-07-16 | mRNA传递剂的合成 |
| PCT/CN2021/131832 WO2023284217A1 (zh) | 2021-07-16 | 2021-11-19 | mRNA传递剂的合成 |
| US17/630,569 US20230357132A1 (en) | 2021-07-16 | 2021-11-19 | SYNTHESIS OF mRNA DELIVERY AGENT |
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| CN202110804660.5A CN115611757A (zh) | 2021-07-16 | 2021-07-16 | mRNA传递剂的合成 |
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| CN115611757A true CN115611757A (zh) | 2023-01-17 |
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| CN202110804660.5A Pending CN115611757A (zh) | 2021-07-16 | 2021-07-16 | mRNA传递剂的合成 |
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| US (1) | US20230357132A1 (zh) |
| CN (1) | CN115611757A (zh) |
| WO (1) | WO2023284217A1 (zh) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998005625A1 (en) * | 1996-08-02 | 1998-02-12 | Bracco S.P.A. | Diagnostic imaging contrast agent with improved in-serum-relaxivity |
| CN109476718A (zh) * | 2016-05-18 | 2019-03-15 | 莫得纳特斯公司 | 编码免疫调节多肽的mrna的组合及其用途 |
| WO2019089828A1 (en) * | 2017-10-31 | 2019-05-09 | Acuitas Therapeutics, Inc. | Lamellar lipid nanoparticles |
| WO2021050864A1 (en) * | 2019-09-11 | 2021-03-18 | Modernatx, Inc. | Human cytomegalovirus vaccine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111744019B (zh) * | 2020-07-01 | 2023-08-04 | 深圳瑞吉生物科技有限公司 | 基于甘露糖的mRNA靶向递送系统及其应用 |
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2021
- 2021-07-16 CN CN202110804660.5A patent/CN115611757A/zh active Pending
- 2021-11-19 WO PCT/CN2021/131832 patent/WO2023284217A1/zh unknown
- 2021-11-19 US US17/630,569 patent/US20230357132A1/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998005625A1 (en) * | 1996-08-02 | 1998-02-12 | Bracco S.P.A. | Diagnostic imaging contrast agent with improved in-serum-relaxivity |
| CN109476718A (zh) * | 2016-05-18 | 2019-03-15 | 莫得纳特斯公司 | 编码免疫调节多肽的mrna的组合及其用途 |
| WO2019089828A1 (en) * | 2017-10-31 | 2019-05-09 | Acuitas Therapeutics, Inc. | Lamellar lipid nanoparticles |
| WO2021050864A1 (en) * | 2019-09-11 | 2021-03-18 | Modernatx, Inc. | Human cytomegalovirus vaccine |
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| US20230357132A1 (en) | 2023-11-09 |
| WO2023284217A1 (zh) | 2023-01-19 |
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