抗新冠病毒药莫诺匹拉韦合成新方法研究

doi:10.6023/cjoc202203044

有机化学 ›› 2022, Vol. 42 ›› Issue (9): 2988-2993.DOI: 10.6023/cjoc202203044 上一篇下一篇

研究简报

抗新冠病毒药莫诺匹拉韦合成新方法研究

刘铮^a, 杨景^b, 刘丰五^b^,^c^,^*()

a 吉林大学化学学院长春 130012
b 郑州大学药物研究院郑州 450001
c 郑州大学药学院郑州 450001

收稿日期:2022-03-22 修回日期:2022-05-18 发布日期:2022-06-08
通讯作者: 刘丰五

New Routes to Antiviral Molnupiravir against SARS-CoV-2 Infection

Zheng Liu^a, Jing Yang^b, Fengwu Liu^b^,^c()

a College of Chemistry, Jilin University, Changchun 130012
b Institute for Drug Research, Zhengzhou University, Zhengzhou 450001
c School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001

Received:2022-03-22 Revised:2022-05-18 Published:2022-06-08
Contact: Fengwu Liu

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摘要/Abstract

莫诺匹拉韦是已被英美等国批准使用的抗SARS-CoV-2感染的口服药物. 目前报道的莫诺匹拉韦合成方法存在诸多不足, 如反应步骤多、反应收率低、成本高等. 报道了以价格低廉的胞嘧啶核苷为起始物, 直接酰化高效率合成莫诺匹拉韦的路线. 研究发现, 在不同比例的水/四氢呋喃溶液中依次通过胞苷的羟基选择性异丁酰化和选择性2',3'位脱异丁酰基反应, 可以顺利得到5'-O-异丁酰基胞嘧啶核苷, 再通过N⁴-羟基化反应即可得到目标产物. 该方法操作简单、反应选择性高, 最终以总收率82%制备了抗新冠病毒原料药莫诺匹拉韦.

关键词: 莫诺匹拉韦, 抗病毒药, 新冠病毒, 选择性异丁酰化, 胞嘧啶核苷

Molnupiravir is an oral drug against SARS-CoV-2 infection approved by Britain and America in 2021. Currently, the reported synthetic methods of molnupiravir have disadvantages, such as long steps, limited yield and high cost. Efficient methods for the synthesis of molnupirovir through direct acylation of low-price cytidine are developed. In different proportions of aqueous tetrahydrofuran solution, selective isobutyrylation of hydroxyl of cytidine and further 2',3'-deprotection of 2',3',5'-tri-O-isobutyrylcytidine could be realized, which successfully gave 5'-O-isobutyrylcytidine. Finally, N⁴-hydroxylation of 5'-O-isobutyrylcytidine yielded molnupirovir. Using this straightforward and high-yielding three-step approach, molnupirovir was obtained from cytidine in 82% overall yield.

Key words: molnupiravir, antiviral, SARS-CoV-2, selective isobutyrylation, cytidine

引用此文

刘铮, 杨景, 刘丰五. 抗新冠病毒药莫诺匹拉韦合成新方法研究[J]. 有机化学, 2022, 42(9): 2988-2993.

Zheng Liu, Jing Yang, Fengwu Liu. New Routes to Antiviral Molnupiravir against SARS-CoV-2 Infection[J]. Chinese Journal of Organic Chemistry, 2022, 42(9): 2988-2993.

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图/表 5

图式1. 以尿苷为原料合成莫诺匹拉韦的方法

Scheme 1. Route to molnupiravir from uridine Reagents and conditions: (i) (a) acetone, H2SO4; (b) NEt3; (ii) isobutyric anhydride, NEt3, DMAP, 99%; (iii) 1,2,4-triazole, POCl3, NEt3, acetonitrile, 29%; (iv) NH2OH, iPrOH, 60%; (v) HCO2H, EtOH, MTBE

图式2. 以胞苷为原料合成莫诺匹拉韦的两条路线

Scheme 2. Two routes to molnupiravir from cytidine Reagents and conditions: (A-i) Me2C(OMe)2, Acetone, H2SO4, r.t., 3 h, 94%; (A-ii) Isobutyric anhydride, DMAP, DBU, CH3CN, r.t., 2 h, 78%; (A-iii) (NH2OH)2•H2SO4, 70% iPrOH in H2O, 78 ℃, 17 h, 96%; (A-iv) HCO2H, r.t., 5 h, 60%; (A-v) (NH2OH)2•H2SO4, 40% iPrOH in H2O,78 ℃, 17 h, 53%; (B-i) Isobutyric acetoxime ester, Novozyme 435 (200% in weight), 78%; (B-ii) (NH2OH)2•H2SO4, iPrOH, 78 ℃, 20 h, 96%

Entry	V(ⁱPrOH)∶ V(H₂O)	(NH₂OH)₂•H₂SO₄/ equiv.	T/℃	Time/h	3∶4
1	7∶3	3.2	78	1.0	3∶2^b
2	7∶3	1.0	78	1.0	3∶7
3	1∶1	3.2	78	1.0	1∶1
4	1∶0	3.2	78	1.0	1∶4
5	7∶3	3.2	40	1.0	1∶4
6	7∶3	6.0	78	24	9∶1
7	7∶3	6.0	78	48	9∶1
8	7∶3	10.0	78	24	9∶1

表1. 羟胺化反应条件优化a

Table 1. Optimization of hydroxamination conditions

图式3. 以胞苷为原料合成莫诺匹拉韦的两条新路线

Scheme 3. Two new routes to molnupiravir from cytidine Reagent and conditions: (1-i) isobutyryl chloride (4.6 equiv.), pyridine, r.t., 6.5 h; (1-ii) CH3ONa (3.0 equiv.), THF, 8 ℃, 1 h; (1-iii) (NH2OH)2• H2SO4 (6.0 equiv.), iPrOH/H2O (V∶V=7∶3), 78 ℃, 24 h; (2-i) isobutyric anhydride, NEt3, THF/H2O (V∶V=5∶2), r.t., 2.5 h; (2-ii) TBAF (1 mol/L) in THF/H2O (V∶V=9∶1), r.t., 24 h; (2-iii) (NH2OH)2•H2SO4 (3.2 equiv.), iPrOH/H2O (V∶V=7∶3), 78 ℃, 24 h

Entry	Solvent	Reagent	Amount/ equiv.	T/℃	Time/h	Yield^a/%
1	THF	CH₃ONa	3.0	8	2.5	70
2	THF	CH₃ONa	5.0	8	1.5	52
3	THF	CH₃ONa	3.0	30	1.0	24
4	THF	CH₃ONa	5.0	30	1.0	15
5	THF/H₂O (V∶V=9∶1)	TBAF	7.0^b	20	24	90

表2. 2',3',5'-三-O-异丁酰基胞嘧啶核苷制备5'-O-异丁酰基胞嘧啶核苷条件优化

Table 2. Optimization of reaction conditions for preparation of 5'-O-isobutyrylcytidine from 2',3',5'-tri-O-isobutyrylcytidine

参考文献 8

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抗新冠病毒药莫诺匹拉韦合成新方法研究

New Routes to Antiviral Molnupiravir against SARS-CoV-2 Infection

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