Bortezomib, MLN-341, DPBA, LDP-341, NSC-681239, PS-341, Velcade, -Drug Synthesis Database

【结构式】

【药物名称】Bortezomib, MLN-341, DPBA, LDP-341, NSC-681239, PS-341, Velcade

【化学名称】3-Methyl-1(R)-[N-(pyrazin-2-ylcarbonyl)-L-phenylalanylamino]butylboronic acid
　　　　　　N-(Pyrazin-2-ylcarbonyl)-L-phenylalanyl-L-boroleucine
　　　　　　N-[1(S)-[N-[1(R)-(Dihydroxyboryl)-3-methylbutyl]carbamoyl]-2-phenylethyl]pyrazine-2-carboxamide

【CA登记号】179324-69-7

【分子式】C₁₉H₂₅BN₄O₄

【分子量】384.2465

【开发单位】Millennium (Proprietary), Millennium (Orphan Drug), ProScript (Originator), Ortho Biotech (Licensee), National Cancer Institute (Codevelopment)

【药理作用】Bone Cancer Therapy, Brain Cancer Therapy, Breast Cancer Therapy, Colorectal Cancer Therapy, Gastric Cancer Therapy, IMMUNOMODULATING AGENTS, Leukemia Therapy, Lung Cancer Therapy, Lymphocytic Leukemia Therapy, Lymphoma Therapy, Multiple Myeloma Therapy, Non-Hodgkin's Lymphoma Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Osteosarcoma Therapy, Prostate Cancer Therapy, Solid Tumors Therapy, Treatment of Transplant Rejection, Inhibitors of Signal Transduction Pathways, NF-kappaB (NFKB) Activation Inhibitors, Proteasome Inhibitor

合成路线1 合成路线2

合成路线1

参考文献中间体

【1】 Adams J,Behnke M, ChenS,et aL 1998. Potent and selective inhibiton of the protensome, dipeptidyl boronic acids Bioorg Med Chem Let-t,8:333 - 338

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	58549	(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^2,6]dec-4-yl]-1-butanamine 2,2,2-trifluoroacetate; (1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^2,6]dec-4-yl]butylamine 2,2,2-trifluoroacetate	179324-87-9	C₁₅H₂₈BNO₂.CF₃COOH	详情	详情
(II)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(V)	37256	2-pyrazinecarboxylic acid; Pyrazinoic acid	98-97-5	C₅H₄N₂O₂	详情	详情
(VI)	58552	N-[(1S)-1-benzyl-2-({(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]butyl}amino)-2-oxoethyl]-2-pyrazinecarboxamide		C₂₉H₃₉BN₄O₄	详情	详情
(VII)	66158	(2R,5S)-7-methyl-3-oxo-1-phenyl-5-((3aS,6S,7aR)-5,5,7a-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)octan-2-aminium chloride		C₂₅H₃₉BClNO₃	详情	详情
(VIII)	66159			C₁₆H₂₉BN₄O	详情	详情

合成路线2

Pinanediol leucine boronate (I) was coupled with N-Boc-L-phenylalanine (II) in the presence of TBTU to afford the dipeptide boronate (III). Acid cleavage of the Boc protecting group of (III), followed by acylation of the resultant amine (IV) with 2-pyrazinecarboxylic acid (V), furnished amide (VI). Finally, deprotection of the boronic acid (VI) was accomplished by two-phase transesterification with isobutylboronic acid.

参考文献中间体

【1】 Adams, J.; Behnke, M.; Chen, S.; Cruickshank, A.A.; Dick, L.R.; Grenier, L.; Klunder, J.M.; Ma, Y.T.; Plamondon, L.; Stein, R.L.; Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids. Bioorg Med Chem Lett 1998, 8, 4, 333.
【2】 Adams, J.; Ma, Y.-T.; Stein, R.; Baevsky, M.; Grenier, L.; Plamondon, L. (ProScript, Inc.); Boronic ester and acid cpds., synthesis and uses. JP 1998510245; US 5780454; US 6083903; WO 9613266 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	58549	(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^2,6]dec-4-yl]-1-butanamine 2,2,2-trifluoroacetate; (1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0^2,6]dec-4-yl]butylamine 2,2,2-trifluoroacetate	179324-87-9	C₁₅H₂₈BNO₂.CF₃COOH	详情	详情
(II)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(III)	58550	tert-butyl (1S)-1-benzyl-2-({(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]butyl}amino)-2-oxoethylcarbamate		C₂₉H₄₅BN₂O₅	详情	详情
(IV)	58551	(2S)-2-amino-N-{(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]butyl}-3-phenylpropanamide		C₂₄H₃₇BN₂O₃	详情	详情
(V)	37256	2-pyrazinecarboxylic acid; Pyrazinoic acid	98-97-5	C₅H₄N₂O₂	详情	详情
(VI)	58552	N-[(1S)-1-benzyl-2-({(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]butyl}amino)-2-oxoethyl]-2-pyrazinecarboxamide		C₂₉H₃₉BN₄O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(3)