硼中子俘获治疗(BNCT)二代硼药4-硼酸-L-苯丙氨酸(L-BPA)的合成工艺优化

doi:10.6023/cjoc202507005

摘要/Abstract

针对硼中子俘获治疗(BNCT)的第二代临床硼药4-硼酸-L-苯丙氨酸(L-BPA)高效合成难题, 设计了新型硼化策略. 以L-苯丙氨酸衍生物为原料, CuI为催化剂、NaH为碱, 在温和条件下与频哪醇硼烷(HBpin)偶联. 该反应可制备医药级高纯度L-BPA(纯度>99.5%), 维持氨基酸L-构型的高对映体过量(ee)>99%; 有效解决传统工艺同位素利用度低、手性丢失及低产率难题, 且同步提升硼利用效率, 大幅降低合成物料成本. 此研究有望推动L-BPA临床应用及BNCT技术临床转化.

关键词: 硼中子俘获治疗, 含硼药物, 碘化亚铜, 4-硼酸-L-苯丙氨酸(L-BPA), 硼化

To address the challenge of efficient synthesis of 4-borono-L-phenylalanine (L-BPA), a novel borylation strategy was designed. L-BPA is the second-generation clinical boron containing drug for boron neutron capture therapy (BNCT). Using an L-phenylalanine derivative as the starting material, CuI as the catalyst, and NaH as the base, a coupling reaction with pinacolborane (HBpin) was achieved under mild conditions. This reaction enables the preparation of pharmaceutical-grade high-purity L-BPA (purity>99.5%) while maintaining a high enantiomeric excess (ee)>99% of the L-configuration of the amino acid. It effectively overcomes the key issues of low isotope utilization, chiral loss, and low yield in traditional processes, while simultaneously improving boron utilization efficiency and significantly reducing raw material costs for synthesis. This study is anticipated to promote the clinical application of L-BPA and the clinical translation of BNCT technology.

Key words: boron neutron capture therapy, boron-containing drugs, copper iodide, 4-borono-L-phenylalanine (L-BPA), borylation

引用此文

李伟豪, 胡子龙, 阮兴杰, 侯薇薇, 钮玉辉, 王盛, 胡明友. 硼中子俘获治疗(BNCT)二代硼药4-硼酸-L-苯丙氨酸(L-BPA)的合成工艺优化[J]. 有机化学, 2026, 46(2): 570-577.

Weihao Li, Zilong Hu, Xingjie Ruan, Weiwei Hou, Yuhui Niu, Sheng Wang, Mingyou Hu. Synthetic Process Optimization for the Second-Generation Boron Drug 4-Borono-L-phenylalanine (L-BPA) in Boron Neutron Capture Therapy (BNCT)[J]. Chinese Journal of Organic Chemistry, 2026, 46(2): 570-577.

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图/表 10

图1.

Figure 1. BNCT技术示意图 (a) BNCT principles that ameliorate tumour cells; (b) schematic illustration of 10B (n,α) 7Li capture reaction; (c) structure of L-BPA Schematic illustration of BNCT technology

图2. 已知合成L-BPA的方法

Figure 2. Previous synthetic methods for L-BPA

图3. 本工作合成L-BPA的新方法

Figure 3. Novel synthetic methods for L-BPA in this work

图4.

Figure 4. 中间体BPA-S3和BPA-S4的合成路线 Reaction reagents and conditions: (a) I2, NaIO3, AcOH/H2SO4, 70 ℃, 20 h, then NaIO4, 70 ℃, 4 h, 59%; (b) NaHCO3, Boc2O, THF/H2O, r.t., 4 h, 93%; (c) Boc2O, DMAP, tBuOH, r.t., 5 h, 82%; (d) Boc2O, DMAP, THF, 50 ℃, 4 h, 79%. Synthetic route of intermediates BPA-S3 and BPA-S4

Entry	Catalyst	Additive	Solvent	Temperature/^oC	Yield/%
1	Pd(dppf)Cl₂	Et₃N	Dioxane	100	N.R.
2	Ni(dppf)Cl₂	Et₃N	Toluene	100	N.R.
3	Pd(OAc)₂/DPEphos^b	Et₃N	Dioxane	100	N.R.
4	CrCl₃/dtbpy^b	Mg	THF	90	N.R
5	Cp₂TiCl₂	MeOLi	Neat	100	N.R
6	Pd(dppf)Cl₂	TMEDA	Dioxane	100	N.R
7	Pd(dppf)Cl₂	^tBuOK	Dioxane	100	N.R
8	Pd(dppf)Cl₂	Et₃N	DMSO	100	N.R.
9	CuI	NaH	THF	r.t.	64
10	CuI^c	NaH	THF	r.t.	80
11	CuI^c	NaH	THF	40	75
12	CuI^c	NaH	THF	55	73
13	CuI^c	NaH	THF	Reflux	74
14	CuI^c	^tBuOK	THF	r.t.	23
15	CuI^c	Cs₂CO₃	THF	r.t.	19
16	CuI^c^,^d	NaH	THF	r.t.	50
17	CuI＋Fe(acac)₃^e	NaH	THF	－10	N.R.
18^f	Pd(dppf)Cl₂	Et₃N	Dioxane	100	N.R.
19^f	Pd(OAc)₂/DPEphos^b	Et₃N	Dioxane	100	N.R.
20^f	CuI^c	NaH	THF	r.t.	N.R.

表1. 反应条件优化a

Table 1. Optimization of the reaction conditions

图5.

Figure 5. L-BPA的合成路线 Reaction reagents and conditions: (a) HBpin, activated CuI, NaH, THF, r.t., 8 h, N2, 75%; (b) aq. HCl (4 mol/L), acetone, reflux, 5 h, 72% Synthetic route of L-BPA

图6. L-BPA的纯度高效液相色谱图

Figure 6. HPLC purity of L-BPA

图7. L-BPA的手性高效液相色谱图

Figure 7. Chiral HPLC of L-BPA

Entry	Synthetic route of L-BPA (¹⁰B)	Synthetic step	Boron utilization rate/%	Total material cost/ (10⁴ yuan•kg^－1)
1	Synthetic method reported by the Snyder group^[10]	7	9	20.4
2	Synthetic method reported by the Yamamoto group^[11]	6	12	17.3
3	Synthetic method reported by the Zaidlewicz group^[12]	6	51	7.5
4	Synthetic method reported by the Wakamiya group^[13]	7	36	8.1
5	Synthetic method in this work	6	54	6.3

表2. L-BPA (10B)路线成本核算

Table 2. L-BPA (10B) route cost accounting

t/min	Mobile phase A/%	Mobile phase B/%
0	10	90
3	10	90
28	30	70
35	30	70
35.1	10	90
45	10	90

表3. 流动相A和流动相B的梯度洗脱条件

Table 3. Mobile phase composition of gradient elution

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