A New Semi-synthesis Route of Belotecan

doi:10.6023/cjoc202501018

Chinese Journal of Organic Chemistry ›› 2025, Vol. 45 ›› Issue (9): 3370-3377.DOI: 10.6023/cjoc202501018 Previous Articles Next Articles

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贝洛替康的半合成新路线

张雨恺^a, 梁玉峰^b^,^*(), 齐庆蓉^a^,^*()

^a 四川大学华西药学院靶向药物与释药系统教育部重点实验室靶向药物与释药系统四川省重点实验室四川省小分子药物精准化工程技术研究中心四川省植物来源药物工程实验室成都 610041
^b 四川科伦博泰生物医药有限公司成都 610041

收稿日期:2025-03-21 修回日期:2025-04-26 发布日期:2025-05-30

A New Semi-synthesis Route of Belotecan

Yukai Zhang^a, Yufeng Liang^b^,^*(), Qingrong Qi^a^,^*()

^a Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041
^b Sichuan Kelunbotai Biopharmaceutical Co., Ltd, Chengdu 610041

Received:2025-03-21 Revised:2025-04-26 Published:2025-05-30
Contact: *E-mail: qiqinrong@scu.edu.cn; liangyf@kelun.com
About author:
^★ Academic Papers of the 27^th Annual Meeting of the China Association for Science and Technology.

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Abstract

Belotecan is the derivative of the natural product camptothecin, which has clinical therapeutic effect and potential application value. A new process route was developed utilizing the Minisci reaction as a new method for constructing the key intermediate, which is subsequently followed by hydroxyl elimination and addition of isopropylamine, to obtain Belotecan in three steps with 16.31% total yield and 99% purity. After optimization, this study accomplished the proof of concept for a novel semi-synthetic route to belotecan.

Key words: camptothecin, Minisci reaction, Belotecan, route design

Cite this article

Yukai Zhang, Yufeng Liang, Qingrong Qi. A New Semi-synthesis Route of Belotecan[J]. Chinese Journal of Organic Chemistry, 2025, 45(9): 3370-3377.

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Fig. & Tab. 9

References 29

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Entry	FeSO₄•7H₂O/equiv.	Acrolein/equiv.	H₂O₂/equiv.	Conversion^b/%	CPT and impurities^b/%
1	3.5	15	8	75.93	13.78
2	2	15	8	63.62	17.42
3	2	8	8	69.20	15.35
4	2	4	8	37.03	48.31
5	1.75	15	8	68.75	19.17
6	1.75	11.25	8	64.93	28.42
7	1.75	7.5	8	45.81	48.39
8	1.65	8	8	54.43	29.82
9	1.32	8	8	29.89	61.32
10	1	8	8	29.98	61.32
11	0.875	15	8	22.11	73.20
12	0.875	7.5	8	27.50	66.27
13	0.875	3.75	8	12.63	86.79
14	2	8	6	50.84	34.42
15	2	8	4	44.14	46.65
16	2	8	2	26.06	67.89

Entry	FeSO₄•7H₂O/equiv.	Acrolein/equiv.	H₂O₂/equiv.	Conversion^b/%	CPT and impurities^b/%
1	3.5	15	8	75.93	13.78
2	2	15	8	63.62	17.42
3	2	8	8	69.20	15.35
4	2	4	8	37.03	48.31
5	1.75	15	8	68.75	19.17
6	1.75	11.25	8	64.93	28.42
7	1.75	7.5	8	45.81	48.39
8	1.65	8	8	54.43	29.82
9	1.32	8	8	29.89	61.32
10	1	8	8	29.98	61.32
11	0.875	15	8	22.11	73.20
12	0.875	7.5	8	27.50	66.27
13	0.875	3.75	8	12.63	86.79
14	2	8	6	50.84	34.42
15	2	8	4	44.14	46.65
16	2	8	2	26.06	67.89

Entry	Reagent	Temp./℃	Conversion^d/%	2d^d/%	Eliminate product^d/%	Impurity^d/%
1	TsCl	r.t.	32.80	13.95	Trace	32.04
2	Ms₂O	r.t.	42.18	49.73	5.06	Trace
3	TsCl	60	ND.	17.41	8.81	72.29
4	Ms₂O	60	ND.	43.31	34.24	20.52
5	TsCl^b	60	ND.	20.57	61.09	18.33
6	T3P^c	60	ND	ND.	87.29	7.18
7	T4P^c	60	ND	ND.	88.72	5.35

Entry	Reagent	Temp./℃	Conversion^d/%	2d^d/%	Eliminate product^d/%	Impurity^d/%
1	TsCl	r.t.	32.80	13.95	Trace	32.04
2	Ms₂O	r.t.	42.18	49.73	5.06	Trace
3	TsCl	60	ND.	17.41	8.81	72.29
4	Ms₂O	60	ND.	43.31	34.24	20.52
5	TsCl^b	60	ND.	20.57	61.09	18.33
6	T3P^c	60	ND	ND.	87.29	7.18
7	T4P^c	60	ND	ND.	88.72	5.35

Entry	Base	Solvent	Temp./℃	Reaction time	Conversion^c/%
1	Isopropylamine	Tetrahydrofuran	60	Overnight	87.29
2	Isopropylamine	2-Methyltetrahydrofuran	60	Overnight	26.71
3	Isopropylamine	Ethyl acetate	60	Overnight	68.99
4	Isopropylamine	Dimethyl sulfoxide	60	Overnight	23.50
5	Isopropylamine	1,4-Dioxane	60	Overnight	84.18
6	Isopropylamine	N,N-Dimethylacetamide	60	Overnight	76.07
7	Isopropylamine	N,N-Dimethylformamide	60	Overnight	86.09
8	Isopropylamine	N-Methylpyrrolidone	60	Overnight	54.27
9	Isopropylamine	Tetrahydrofuran	r.t.	Overnight	6.56
10	Isopropylamine	Tetrahydrofuran	50	Overnight	34.64
11	Isopropylamine	Tetrahydrofuran	70^b	5 h	85.44
12	Isopropylamine	Tetrahydrofuran	95^b	3 h	86.31
13	Triethylamine	Tetrahydrofuran	60	Overnight	88.12
14	Diethylamine	Tetrahydrofuran	60	Overnight	90.17
15	Diethylamine	Tetrahydrofuran	70^b	5 h	87.52
16	N,N-Diisopropylethylamine	Tetrahydrofuran	60	Overnight	88.42
17	Pyridine	Tetrahydrofuran	60	Overnight	21.44
18	4-Dimethylaminopyridine	Tetrahydrofuran	60	Overnight	50.33
19	N/A	Tetrahydrofuran	60	Overnight	59.98

贝洛替康的半合成新路线

A New Semi-synthesis Route of Belotecan

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