CN114751894A - 一种治疗新冠肺炎口服药物的制备方法 - Google Patents
一种治疗新冠肺炎口服药物的制备方法 Download PDFInfo
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 29
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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Abstract
本发明揭示了一种治疗新冠肺炎的口服药物S‑217622的制备方法，其步骤包括：以[N‑(2.4.5‑三氟苯基)甲基]氨基甲酰硫氰酸乙酯氢碘酸盐和N‑(氯甲酰基)异氰酸酯发生环合反应，进而依次与3‑氯甲基‑1‑甲基‑1H‑1,2,4‑三唑盐酸盐和6‑氯‑2‑甲基‑2H‑吲唑‑5‑胺分别发生取代反应和缩合反应制得目标化合物S‑217622。该制备方法工艺简洁，条件温和，安全环保，为该产品的工业化生产提供了一条新的途径。
Description
技术领域
本发明属于有机合成路线设计及其原料药和中间体制备技术领域，特别涉及一种治疗新冠肺炎口服药物S-217622的制备方法。
背景技术
S-217622是由日本盐野义公司开发的一种治疗新冠肺炎口服药物，具有高效抑制新冠病毒3CL酶并发挥抗病毒的作用。临床前试验表明，S-217622在体外对3CL酶活性作用较强，IC50值为0.013μM，EC50值为0.37μM。动物试验表明，S-217622在大鼠、猴子及狗中口服给药具有高吸收率和低清除率，其在猴子和狗中的半衰期分别约为10和30小时。同时，体外试验还证实S-217622对多种新冠病毒变异株均具有较强的抗病毒活性，针对奥密克戎变异株的EC50值约为0.29μM，未发生明显减低。目前，该药已经完成IIb期临床试验，基于其临床试验结果，盐野义公司已经向日本厚生劳动省申请生产及上市许可。
S-217622(I)的化学名为：(6E)-6-[(6-氯-2-甲基-2H-吲唑-5-基)亚氨基]二氢-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮，其结构式如下：
分析S-217622的分子结构组成可以发现，该化合物是由“三嗪”母核和“吲唑基”、“三唑基”以及“三氟苄基”三个“侧链”所构成。
基于上述分析，借鉴“逆向合成法”思路，盐野义公司的研究文献“Discovery ofS-217622,a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor ClinicalCandidate for Treating COVID-19”(bioRxiv，Posted January 26,2022)公开了一种S-217622的合成路线：
首先，通过“三嗪母核”3-(1,1-二甲基乙基)-6-(乙巯基)-1,3,5-三嗪-2,4(1H,3H)-二酮与“氟代苄基侧链”2,4,5-三氟苄基溴在缚酸剂存在下发生取代得到中间体1；其次，中间体1在强酸条件下脱保护得到中间体2；接着中间体2与“三唑基侧链”3-(氯甲基)-1-甲基-1H-1,2,4-三唑在缚酸剂存在下再次发生取代反应得到中间体3；最后，中间体3与“吲唑基侧链”6-氯-2-甲基-2H-吲唑-5-胺在强碱条件下发生缩合反应从而制得目标产物S-217622(I)。
考察上述合成路线，为了选择性地进行两次卤代侧链与母核之间的取代反应，因而不可避免地需要采取保护及脱保护步骤，从而降低了整个反应收率，没有能够最大限度地满足“原子经济性”原则。同时，由于该反应路线两次重复使用相同机理的取代反应，势必会产生选择性下降和副反应增多的情况。
由此可以看出，为了更加高效地实现新冠药物S-217622的制备，采用现代合成技术，寻找更加经济实用的反应路线，形成一条经济、环保、绿色和可替代的工艺路线，对于丰富S-217622的制备技术和该原料药经济技术发展至关重要。
发明内容
本发明的目的在于采用现代合成技术的发展成果，按照绿色化学的合成理念，提供一种改进的(6E)-6-[(6-氯-2-甲基-2H-吲唑-5-基)亚氨基]二氢-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(S-217622，I)的制备方法。该制备方法简便、经济和环保，有利于该药品的工业化生产，并能促进该原料药的经济技术的发展。
为了实现上述目的，本发明所提供的主要技术方案如下：一种S-217622(I)的制备方法，
该方法包括如下步骤：[N-(2.4.5-三氟苯基)甲基]氨基甲酰硫氰酸乙酯氢碘酸盐(II)和N-(氯甲酰基)异氰酸酯在碱促进剂作用下发生环合反应生成6-乙巯基-1-(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(III)；所述6-乙巯基-1-(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(III)与3-氯甲基-1-甲基-1H-1,2,4-三唑盐酸盐在缚酸剂作用下发生取代反应得到6-乙巯基-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(IV)，所述6-乙巯基-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(IV)与6-氯-2-甲基-2H-吲唑-5-胺发生缩合反应生成(6E)-6-[(6-氯-2-甲基-2H-吲唑-5-基)亚氨基]二氢-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(S-217622，I)。
反应路线示意图如下：
此外，本发明还提供如下附属技术方案：
所述环合反应的原料[N-(2.4.5-三氟苯基)甲基]氨基甲酰硫氰酸乙酯氢碘酸盐(II)和N-(氯甲酰基)异氰酸酯的投料摩尔比为1:1～2，优选1:1.5。
所述环合反应的碱促进剂为三乙胺、吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶、N-甲基吗啉、N-乙基吗啉、二异丙基乙胺、1,5-二氮杂二环[4.3.0]-壬-5-烯、1,8-二氮杂双环[5.4.0]-十一-7-烯或1,4-二氮杂二环[2.2.2]辛烷，优选二异丙基乙胺或1,8-二氮杂双环[5.4.0]-十一-7-烯。
所述环合反应的碱促进剂与原料[N-(2.4.5-三氟苯基)甲基]氨基甲酰硫氰酸乙酯氢碘酸盐(II)的投料摩尔比为2～4:1，优选3:1。
所述环合反应的溶剂为四氢呋喃、乙腈、二氧六环、二甲亚砜、N,N-二甲基甲酰胺或乙腈，优选N,N-二甲基甲酰胺或乙腈。
所述环合反应的温度为-10～35℃，优选25～30℃。
所述取代反应原料6-乙巯基-1-(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(III)与3-氯甲基-1-甲基-1H-1,2,4-三唑盐酸盐的投料摩尔比为1:1～2，优选1:1.5。
所述取代反应的缚酸剂为氢化钠、氢化钾、氢氧化钠、氢氧化钾、叔丁醇钠、叔丁醇钾、甲醇钠、乙醇钠、碳酸钠、碳酸钾或碳酸铯，优选碳酸钾或碳酸铯。
所述取代反应的溶剂为甲苯、二甲苯、二氧六环、二甲亚砜、N,N-二甲基甲酰胺或乙腈，优选乙腈或N,N-二甲基甲酰胺。
所述取代反应的温度为50～100℃，优选75～85℃。
所述缩合反应原料6-乙巯基-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(IV)和6-氯-2-甲基-2H-吲唑-5-胺的投料摩尔比为1:1～2，优选1:1.5。
所述缩合反应的溶剂为四氢呋喃、乙腈、二氧六环、异丙醇、正丁醇或叔丁醇，优选叔丁醇。
所述缩合反应的温度为50～120℃，优选80～90℃。
有益效果
本发明所涉及的抗新冠肺炎药物S-217622的制备方法，通过易得的原料，依次经过常见单元反应如环合反应、取代反应和缩合反应等，使其制备过程更加简洁，条件温和且安全环保。尤其是通过一步环合反应，减少了保护及脱保护步骤，从而增增加了反应的选择性，提高了产品质量和收率，适合工业化生产。
具体实施方式
以下结合数个较佳实施例对本发明技术方案作进一步非限制性的详细说明。其中所涉及的起始原料[N-(2.4.5-三氟苯基)甲基]氨基甲酰硫氰酸乙酯氢碘酸盐(II)的制备可参考“Bioorganic&Medicinal Chemistry,”17(11),3987-3994；2009或“ActaPharmaceuticaSinica”38(8),586-591；2003对类似化合物的制备方法进行合成。
实施例一：
室温下，于反应瓶中加入1-(2,4,5-三氟苯基)甲基硫代脲(11.0g,50mmol)和甲醇(100mL)，搅拌下溶解后，加入碘乙烷(9.36g，60mmol)，继续搅拌滴反应6～8小时。减压浓缩，所得残余物用乙酸乙酯重结晶制得[N-(2.4.5-三氟苯基)甲基]氨基甲酰硫氰酸乙酯氢碘酸盐(II)10.6g，收率为56.4％，EI-MS m/z:249[M+H]+。
实施例二：
于反应瓶中加入[N-(2.4.5-三氟苯基)甲基]氨基甲酰硫氰酸乙酯氢碘酸盐(II)(7.52g,20mmol)、二异丙基乙胺(7.74g,60mmol)和二氯甲烷(100mL)，搅拌至溶解。冰浴降温至0～5℃，缓慢滴加N-(氯甲酰基)异氰酸酯(3.2g，30mmol)的二氯甲烷(15mL)溶液，滴加完成后缓慢升至室温，搅拌反应1～2小时，TLC检测反应完成。静置析晶，过滤，滤饼用二氯甲烷洗涤，乙酸乙酯重结晶得类白色固体6-乙巯基-1-(2,,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(III)5.5g，收率为86.8％，EI-MS m/z:318[M+H]+；1H NMR(DMSO d6)δ11.60(brs,1H),7.09(m,2H),5.07(s,2H),3.13(q,J＝7.4Hz,2H),1.29(t,J＝7.4Hz,3H)。
实施例三：
于三口瓶中将6-乙巯基-1-(2,,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(III)(5.73g，20mmol)和3-氯甲基-1-甲基-1H-1,2,4-三唑盐酸盐(5.04g，30mmol)溶于乙腈(100mL)中，分批加入缚酸剂碳酸铯(16.3g，50mmol)，升温至回流，反应2～4小时。冷却至室温，用饱和氯化铵溶液淬灭反应，乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥，减压蒸馏回收溶剂，残余物用乙酸乙酯重结晶得白色固体6-乙巯基-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(IV)4.8g，收率为58.1％，EI-MS m/z:413[M+H]+；1H NMR(DMSO d6)δ7.93(s,1H),7.14(m,1H),6.95(m,1H),5.23(s,2H),5.16(s,2H),3.84(s,3H),3.20(q,,J＝7.4Hz,2H),1.34(t,J＝7.4Hz,3H)。
实施例四：
于反应瓶中加入6-乙巯基-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(IV)(4.14g,10mmol)、6-氯-2-甲基-2H-吲唑-5-胺(2.72g，15mmol)、醋酸(6.0g，0.1mol)和叔丁醇50mL，回流下搅拌反应6～8小时，TLC检测反应完成。冷却至室温，将反应液倾至饱和碳酸钠水溶液，用乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥，减压蒸馏回收溶剂，所得残余物用乙醇重结晶得浅棕色固体(6E)-6-[(6-氯-2-甲基-2H-吲唑-5-基)亚氨基]二氢-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(S-217622，I)4.10g，收率为77.1％，EI-MS m/z:532[M+H]+；1H NMR(DMSO d6)δ9.31(s,1H),8.40(s,1H),7.73(s,1H),7.53(m,1H),7.67(m,1H),7.44(m,1H),5.26(s,2H),5.04(s,2H),4.15(s,3H),3.90(s,3H)。
需要指出的是，上述较佳实施例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
Claims (10)
1.一种治疗新冠肺炎口服药物S-217622(其化学名为(6E)-6-[(6-氯-2-甲基-2H-吲唑-5-基)亚氨基]二氢-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮)的制备方法：
其特征在于其制备方法包括如下步骤：[N-(2.4.5-三氟苯基)甲基]氨基甲酰硫氰酸乙酯氢碘酸盐和N-(氯甲酰基)异氰酸酯在碱促进剂作用下发生环合反应生成6-乙巯基-1-(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮；所述6-乙巯基-1-(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮与3-氯甲基-1-甲基-1H-1,2,4-三唑盐酸盐在缚酸剂作用下发生取代反应得到6-乙巯基-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮，所述6-乙巯基-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮与6-氯-2-甲基-2H-吲唑-5-胺发生缩合反应生成(6E)-6-[(6-氯-2-甲基-2H-吲唑-5-基)亚氨基]二氢-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮(S-217622)。
2.根据权利要求1所述S-217622的制备方法，其特征在于：所述环合反应的原料[N-(2.4.5-三氟苯基)甲基]氨基甲酰硫氰酸乙酯氢碘酸盐和N-(氯甲酰基)异氰酸酯的投料摩尔比为1:1～2。
3.根据权利要求1所述S-217622的制备方法，其特征在于：所述环合反应的碱促进剂为三乙胺、吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶、N-甲基吗啉、N-乙基吗啉、二异丙基乙胺、1,5-二氮杂二环[4.3.0]-壬-5-烯、1,8-二氮杂双环[5.4.0]-十一-7-烯或1,4-二氮杂二环[2.2.2]辛烷。
4.根据权利要求1所述S-217622的制备方法，其特征在于：所述环合反应的碱促进剂与原料[N-(2.4.5-三氟苯基)甲基]氨基甲酰硫氰酸乙酯氢碘酸盐的投料摩尔比为2～4:1。
5.根据权利要求1所述S-217622的制备方法，其特征在于：所述环合反应的溶剂为四氢呋喃、乙腈、二氧六环、二甲亚砜、N,N-二甲基甲酰胺或乙腈；所述环合反应的温度为-10～35℃。
6.根据权利要求1所述S-217622的制备方法，其特征在于：所述取代反应原料6-乙巯基-1-(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮与3-氯甲基-1-甲基-1H-1,2,4-三唑盐酸盐的投料摩尔比为1:1～2。
7.根据权利要求1所述S-217622的制备方法，其特征在于：所述取代反应的缚酸剂为氢化钠、氢化钾、氢氧化钠、氢氧化钾、叔丁醇钠、叔丁醇钾、甲醇钠、乙醇钠、碳酸钠、碳酸钾或碳酸铯。
8.根据权利要求1所述S-217622的制备方法，其特征在于：所述取代反应的溶剂为甲苯、二甲苯、二氧六环、二甲亚砜、N,N-二甲基甲酰胺或乙腈；所述取代反应的温度为50～100℃。
9.根据权利要求1所述S-217622的制备方法，其特征在于：所述缩合反应原料6-乙巯基-3-[(1-甲基-1H-1,2,4-三唑-3-基)甲基]-1-[(2,4,5-三氟苯基)甲基]-1,3,5-三嗪-2,4(1H,3H)-二酮和6-氯-2-甲基-2H-吲唑-5-胺的投料摩尔比为1:1～2。
10.根据权利要求1所述S-217622的制备方法，其特征在于：所述缩合反应的溶剂为四氢呋喃、乙腈、二氧六环、异丙醇、正丁醇或叔丁醇；所述缩合反应的温度为50～120℃。
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| CN115650959A (zh) * | 2022-05-20 | 2023-01-31 | 南京济群医药科技股份有限公司 | 化合物的制备方法或纯化方法 |
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| CN115650959A (zh) * | 2022-05-20 | 2023-01-31 | 南京济群医药科技股份有限公司 | 化合物的制备方法或纯化方法 |
| CN115650959B (zh) * | 2022-05-20 | 2023-10-20 | 南京济群医药科技股份有限公司 | 化合物的制备方法或纯化方法 |
| CN115141184A (zh) * | 2022-06-23 | 2022-10-04 | 杭州国瑞生物科技有限公司 | 一种恩赛特韦的制备方法 |
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