贝洛替康的半合成新路线

doi:10.6023/cjoc202501018

摘要/Abstract

贝洛替康为天然产物喜树碱的衍生物, 具有临床治疗效果及潜在的应用价值. 开发了一条新的合成路线, 采用Minisci反应作为构建关键中间体的新方法, 后续经羟基消除、异丙胺加成得到贝洛替康, 三步反应总收率为16.31%, 纯度为99%. 经优化, 完成了贝洛替康的半合成新路线的概念验证.

关键词: 喜树碱, Minisci反应, 贝洛替康, 路线设计

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

引用此文

张雨恺, 梁玉峰, 齐庆蓉. 贝洛替康的半合成新路线[J]. 有机化学, 2025, 45(9): 3370-3377.

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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参考文献 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