Synthetic Process Optimization for the Second-Generation Boron Drug 4-Borono-L-phenylalanine (L-BPA) in Boron Neutron Capture Therapy (BNCT)

doi:10.6023/cjoc202507005

Abstract

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

Cite this article

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.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 10

References 26

[1]	Siegel R. L.; Miller K. D.; Wagle N. S.; Jemal A. CA Cancer J. Clin. 2023, 73, 17.
[2]	Luo T.; Huang W.; Chu F.; Zhu T.; Feng B.; Huang S.; Hou J.; Zhu L.; Zhu S.; Zeng W. Mol. Pharm. 2023, 20, 4942. doi: 10.1021/acs.molpharmaceut.3c00701
[3]	Suzuki M. Int. J. Clin. Oncol. 2020, 25, 43. doi: 10.1007/s10147-019-01480-4
[4]	Takahara K.; Miyatake S. I.; Azuma H.; Shiroki R. Int. J. Urol. 2022, 29, 610. doi: 10.1111/iju.14855 pmid: 35240726
[5]	Wongthai P.; Hagiwara K.; Miyoshi Y.; Wiriyasermkul P.; Wei L.; Ohgaki R.; Kato I.; Hamase K.; Nagamori S.; Kanai Y. Cancer Sci. 2015, 106, 279. doi: 10.1111/cas.2015.106.issue-3
[6]	Detta A.; Cruickshank G. S. Cancer Res. 2009, 69, 2126.
[7]	Seneviratne D.; Advani P.; Trifiletti D. M.; Trifiletti D. M.; Chumsri S.; Beltran C. J.; Bush A. F.; Vallow L. A. Cancers 2022, 14, 3009. doi: 10.3390/cancers14123009
[8]	Coghi P.; Li J.; Hosmane N. S.; Zhu Y. Med. Res. Rev. 2023, 43, 1809. doi: 10.1002/med.v43.5
[9]	Miyatake S.-I.; Kawabata S.; Kajimoto Y.; Aoki A.; Yokoyama K.; Yamada M.; Kuroiwa T.; Tsuji M.; Imahori Y.; Kirihata M.; Sakurai Y.; Masunaga S.-I.; Nagata K.; Maruhashi A.; Ono K. J. Neurosurg. 2005, 103, 1000. doi: 10.3171/jns.2005.103.6.1000
[10]	Snyder H. R.; Reedy A. J.; Lennarz W. J. J. Am. Chem. Soc. 1958, 80, 835. doi: 10.1021/ja01537a021
[11]	Nakamura H.; Fujiwara M.; Yamamoto Y. J. Org. Chem. 1998, 63, 7529. doi: 10.1021/jo980818r
[12]	Zaidlewicz M.; Sokol W.; Wolan A.; Cytarska J.; Kaczmarek A. T.; Dzielendziak A.; Kwinto A. P. Pure Appl. Chem. 2003, 75, 1349. doi: 10.1351/pac200375091349
[13]	Hattori Y.; Asano T.; Kirihata M.; Yamaguchi Y.; Wakamiya T. Tetrahedron Lett. 2008, 49, 4977. doi: 10.1016/j.tetlet.2008.05.108
[14]	Richardson M. B.; Brown D. B.; Vasquez C. A.; Ziller J. W.; Johnston K. M.; Weiss G. A. J. Org. Chem. 2018, 83, 4525. doi: 10.1021/acs.joc.8b00270 pmid: 29577718
[15]	Ousmer M.; Boucard V.; Lubin-Germain N.; Uziel J.; Augé J. Eur. J. Org. Chem. 2006, 5, 1216.
[16]	Boyle T. P.; Bremner J. B.; Coates J. A.; Deadman J.; Keller P. A.; Pyne S. G.; Somphol K. Eur. J. Med. Chem. 2009, 44, 1001. doi: 10.1016/j.ejmech.2008.07.001
[17]	Broutin P.-E.; Čerňa I.; Campaniello M.; Leroux F.; Colobert F. Org. Lett. 2004, 6, 4419. doi: 10.1021/ol048303b
[18]	Tang S.; Wang Z.; Zhu M.; Zhao X.; Hu X.; Zhang H. Chin. Chem. Lett. 2025, 36, 110503. doi: 10.1016/j.cclet.2024.110503
[19]	Zhu F.; Jia Z.; Zhang F.; Wu X.-F. Green Synth. Catal. 2025, DOI: 10.1016/j.gresc.2025.06.013.
[20]	Wang W. Chin. J. Org. Chem. 2023, 43, 3146 (in Chinese). doi: 10.6023/cjoc202308001
	(王文芳, 有机化学, 2023, 43, 3146.) doi: 10.6023/cjoc202308001
[21]	Zhu W.; Ma D. Org. Lett. 2006, 8, 261. doi: 10.1021/ol052633u
[22]	Dumas A.; Spicer C. D.; Gao Z.; Takehana T.; Lin Y. A.; Yasukohchi T.; Davis B. G. Angew. Chem. Int. Ed. 2013, 52, 3916. doi: 10.1002/anie.v52.14
[23]	Tran H.; McCallum T.; Morin M.; Barriault L. Org. Lett. 2016, 18, 4308. doi: 10.1021/acs.orglett.6b02021 pmid: 27522864
[24]	Modemann D. J.; Zlatopolskiy B. D.; Urusova E. A.; Zischler J.; Craig A.; Ermert J.; Guliyev M.; Endepols H.; Neumaier B. Synthesis 2019, 51, 664. doi: 10.1055/s-0037-1611370
[25]	Sap J. B. I.; Meyer C. F.; Ford J.; Straathof N. J. W.; Dürr A. B.; Lelos M. J.; Paisey S. J.; Mollner T. A.; Hell S. M.; Trabanco A. A.; Genicot C.; Ende C. W.; Paton R. S.; Tredwell M.; Gouverneur V. Nature 2022, 606, 102. doi: 10.1038/s41586-022-04669-2
[26]	Hebel M. Riegger A.; Zegota M. M.; Kizilsavas G.; Gačanin J.; Pieszka M.; Luckerath T.; Coelho J. A. S.; Wagner M.; Gois P. M. P.; Ng D. Y. W.; Weil T. J. Am. Chem. Soc. 2019, 141, 14026. doi: 10.1021/jacs.9b03107

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.

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.

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

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

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