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

doi:10.6023/cjoc202203044

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (9): 2988-2993.DOI: 10.6023/cjoc202203044 Previous Articles Next Articles

NOTES

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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Abstract

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

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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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Fig. & Tab. 5

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

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

Table 1. Optimization of hydroxamination conditions

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

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

References 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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