达罗他胺中间体合成中杂质的发现和结构表征

doi:10.11938/cjmr20233078

摘要/Abstract

摘要：

达罗他胺是治疗前列腺癌的重要药物，在进行其合成工艺研究时，在第一步Suzuki偶联和第二步水解脱保护反应中，发现并纯化得到3个杂质A、B和C，其中杂质A和B来自第一步反应，杂质C来自第二步反应. 通过高分辨质谱（HRMS）、核磁共振氢谱（¹H NMR）和核磁共振碳谱（¹³C NMR）表征方法，确定了杂质A和B的结构，分别为初始反应原料化合物2的脱硼酸频哪醇酯产物和初始反应原料化合物1的双偶联产物；借助HRMS、¹H NMR、¹³C NMR、¹H-¹H COSY、¹H-¹³C HSQC、¹H-¹³C HMBC和¹H-¹H NOESY方法确定了中间体化合物3和杂质C的准确结构，对其形成机理和规避方法也进行了讨论分析.

关键词: 达罗他胺中间体, 核磁共振, 药物杂质

Abstract:

Darolutamide is an important drug for the treatment of prostate cancer. When studying its synthesis process, three impurities A, B, and C were discovered and purified in the first step of Suzuki coupling and the second step of hydrolysis deprotection reactions. Impurities A and B came from the first-step reaction, and impurity C came from the second-step reaction. The structures of impurities A and B were further determined through high-resolution mass spectrometry (HRMS), ¹H nuclear magnetic resonance (NMR), and ¹³C NMR methods. It was discovered that impurities A and B were the deborated pinacol ester product of compound 2 and the double coupling product of compound 1, respectively. The accurate structures of compound 3 and impurity C were determined using HRMS, ¹H NMR, ¹³C NMR, ¹H-¹H COSY (correlation spectroscopy), ¹H-¹³C HSQC (heteronuclear singular quantum correlation), ¹H-¹³C HMBC (heteronuclear multiple bond correlation) and ¹H-¹H NOESY (nuclear overhauser effect spectroscopy). The formation mechanisms and avoidance methods of these impurities were also discussed.

Key words: darolutamide intermediate, NMR, drug impurities

中图分类号:

O482.53

马卉芳, 童悦, 王荣繁, 谢建伟. 达罗他胺中间体合成中杂质的发现和结构表征[J]. 波谱学杂志, 2024, 41(1): 56-66.

MA Huifang, TONG Yue, WANG Rongfan, XIE Jianwei. Discovery and Structural Characterization of Impurities in the Synthesis of Darolutamide Intermediate[J]. Chinese Journal of Magnetic Resonance, 2024, 41(1): 56-66.

图/表 11

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表4

参考文献 12

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名称	化合物1	化合物2	化合物3	三苯基氧磷	杂质A	杂质B	化合物4
反应液中含量	0.25%	1.10%	92.75%	0.52%	3.90%	0.61%	0.67%
固体中含量	0.35%	0	98.46%	0.07%	0.04%	0.14%	0.85%

No.	¹H NMR	¹³C NMR	HMBC(¹H→¹³C)	¹H-¹H COSY
No.	δ_H	δ_C	HMBC(¹H→¹³C)	¹H-¹H COSY
1	N/A	115.7	N/A	N/A
2	N/A	113.0	N/A	N/A
3	N/A	137.2	N/A	N/A
4	7.79 (1H, d, J=1.4 Hz)	130.2	C-2, 6, 8	N/A
5	N/A	136.2	N/A	N/A
6	7.59 (1H, dd, J=8.0, 1.5 Hz)	127.4	C-2, 3, 4, 7, 8	H-7
7	7.78 (1H, d, J=8.1 Hz)	134.1	C-1, 3, 5	H-6
8	N/A	141.1	N/A	N/A
9	6.46 (1H, d, J=1.8 Hz)	108.0	C-5, 8, 10, 11	H-10
10	7.64 (1H, d, J=1.6 Hz)	139.7	C-8, 9	H-9
11	5.15 (1H, dd, J=10.0, 2.4 Hz)	84.6	C-8, 12, 13, 15	H-12
12	1.90 (1H, m), 2.59 (1H, m)	29.5	C-11, 13, 14	H-11, 13
13	1.62 (1H, overlap), 2.12 (1H, m)	22.8	C-11, 12, 14, 15	H-12, 14
14	1.62 (1H, overlap), 1.78 (1H, m)	24.8	C-12, 13, 15	H-13, 15
15	3.64 (1H, m), 4.17 (1H, m)	67.6	C-11, 13, 14	H-14

No.	¹H NMR	¹³C NMR	HMBC(¹H→¹³C)	¹H-¹H COSY
No.	δ_H	δ_C	HMBC(¹H→¹³C)	¹H-¹H COSY
1	N/A	116.3	N/A	N/A
2	N/A	111.6	N/A	N/A
3	N/A	137.1	N/A	N/A
4	8.01 (1H, d, J=1.4 Hz)	126.7	C-2, 3, 6, 8	N/A
5	N/A	139.3	N/A	N/A
6	7.81 (1H, dd, J=8.1, 1.5 Hz)	124.1	C-2, 4, 8	H-7
7	7.68 (1H, d, J=8.1 Hz)	134.1	C-1, 3, 5	H-6
8	N/A	148.5	N/A	N/A
9	6.67 (1H, d, J=2.5 Hz)	104.2	C-8, 10	H-10
10	7.70 (1H, d, J=2.5 Hz)	129.7	C-8, 9	H-9
11	5.45 (1H, dd, J=9.6, 2.6 Hz)	88.0	C-10, 12, 13, 15	H-12
12	2.13 (1H, m), 2.19 (1H, m)	30.6	C-11, 13, 14	H-11, 13
13	1.75 (1H, overlap), 2.09 (1H, m)	22.3	C-11, 12, 14, 15	H-12, 14
14	1.67 (1H, m), 1.75 (1H, overlap)	24.9	C-12, 13, 15	H-13, 15
15	3.76 (1H, m), 4.11 (1H, m)	68.0	C-11, 13, 14	H-14

编号	反应温度/℃	反应时间/h	HPLC含量/%
编号	反应温度/℃	反应时间/h	化合物4	化合物3	杂质C
1	20	1	33.25	65.92	0.05
2	20	5	97.62	0.74	0.47
3	20	22	97.58	0.29	1.20
4	30	1	97.63	0.29	1.06
5	30	5	97.32	0.43	1.37
6	40	1	97.32	0.35	1.42
7	40	5	90.31	2.21	6.74
8	50	1	94.19	1.20	3.74
9	60	1	85.06	3.00	11.07

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