Olcegepant, BIBN-4096, BIBN-4096BS, -Drug Synthesis Database

【结构式】

【药物名称】Olcegepant, BIBN-4096, BIBN-4096BS

【化学名称】N-[2-[5-Amino-1(S)-[4-(4-pyridinyl)piperazin-1-ylcarbonyl]pentylamino]-1(R)-(3,5-dibromo-4-hydroxybenzyl)-2-oxoethyl]-4-(2-oxo-1,2,3,4-tetrahydroquinazolin-3-yl)piperidine-1-carboxamide

【CA登记号】204697-65-4

【分子式】C₃₈H₄₇Br₂N₉O₅

【分子量】869.66359

【开发单位】Boehringer Ingelheim (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, Calcitonin Gene-Related Peptides (CGRP) Antagonists

合成路线1 合成路线2

合成路线1

The reductive amination of 2-nitrobenzaldehyde (I) with 4-amino-1-benzylpiperidine (II) in the presence of NaBH4 gave amine (III). Subsequent hydrogenation of the nitro group of (III) over Rh/C afforded (IV), which was converted to oxoquinazoline (V) upon treatment with carbonyl diimidazole in hot DMF. Hydrogenolysis of the benzyl protecting group of (V) yielded intermediate (VI).

参考文献中间体

【1】 Eberlein, W.; Wienen, W.; Doods, H.; Rudolf, K.; Entzeroth, M.; Pieper, H.; Engel, W.; Hallermayer, G. (Dr. Karl Thomae GmbH); Modified aminoacids, pharmaceuticals containing these cpds. and methods for their production. JP 2000505100; WO 9811128 .

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)	11370	2-Nitrobenzaldehyde	552-89-6	C₇H₅NO₃	详情	详情
(II)	34808	1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine	50541-93-0	C₁₂H₁₈N₂	详情	详情
(III)	39269	1-benzyl-N-(2-nitrobenzyl)-4-piperidinamine; N-(1-benzyl-4-piperidinyl)-N-(2-nitrobenzyl)amine		C₁₉H₂₃N₃O₂	详情	详情
(IV)	39270	N-(2-aminobenzyl)-N-(1-benzyl-4-piperidinyl)amine; N-(2-aminobenzyl)-1-benzyl-4-piperidinamine		C₁₉H₂₅N₃	详情	详情
(V)	39271	3-(1-benzyl-4-piperidinyl)-3,4-dihydro-2(1H)-quinazolinone		C₂₀H₂₃N₃O	详情	详情
(VI)	39272	3-(4-piperidinyl)-3,4-dihydro-2(1H)-quinazolinone		C₁₃H₁₇N₃O	详情	详情

合成路线2

Coupling of Nalpha-Cbz-Nepsilon-Boc-L-lysine (VII) with N-(4-pyridinyl)piperazine (VIII) using TBTU and HOBt afforded amide (IX). After deprotection of the carbobenzoxy group by of (IX) hydrogenation over Pd/C, the resulting amino derivative (X) was coupled with N-Fmoc-3,5-dibromo-D-tyrosine (XI) to furnish the protected dipeptide amide (XII). Removal of the Fmoc protecting group of (XII) was then achieved by treatment with diethylamine in hot MeOH yielding (XIII). After treatment of piperidinyl oxoquinazoline (VI) with carbonyl ditriazole, the resulting intermediate was coupled with amine (XIII) to produce urea (XIV). Finally, removal of the Boc group of (XIV) using trifluoroacetic acid provided the title compound.

参考文献中间体

【1】 Eberlein, W.; Wienen, W.; Doods, H.; Rudolf, K.; Entzeroth, M.; Pieper, H.; Engel, W.; Hallermayer, G. (Dr. Karl Thomae GmbH); Modified aminoacids, pharmaceuticals containing these cpds. and methods for their production. JP 2000505100; WO 9811128 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	39273	(2S)-2-[[(benzyloxy)carbonyl]amino]-6-[(tert-butoxycarbonyl)amino]hexanoic acid		C₁₉H₂₈N₂O₆	详情	详情
(VIII)	39274	1-(4-pyridinyl)piperazine	1008-91-9	C₉H₁₃N₃	详情	详情
(IX)	39275	benzyl (1S)-5-[(tert-butoxycarbonyl)amino]-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl]pentylcarbamate		C₂₈H₃₉N₅O₅	详情	详情
(X)	39276	tert-butyl (5S)-5-amino-6-oxo-6-[4-(4-pyridinyl)-1-piperazinyl]hexylcarbamate		C₂₀H₃₃N₅O₃	详情	详情
(XI)	39277	(2R)-3-(3,5-dibromo-4-hydroxyphenyl)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid		C₂₄H₁₉Br₂NO₅	详情	详情
(XII)	39278	9H-fluoren-9-ylmethyl (1R)-2-[((1S)-5-[(tert-butoxycarbonyl)amino]-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl]pentyl)amino]-1-(3,5-dibromo-4-hydroxybenzyl)-2-oxoethylcarbamate		C₄₄H₅₀Br₂N₆O₇	详情	详情
(XIII)	39279	tert-butyl (5S)-5-[[(2R)-2-amino-3-(3,5-dibromo-4-hydroxyphenyl)propanoyl]amino]-6-oxo-6-[4-(4-pyridinyl)-1-piperazinyl]hexylcarbamate		C₂₉H₄₀Br₂N₆O₅	详情	详情
(XIV)	39272	3-(4-piperidinyl)-3,4-dihydro-2(1H)-quinazolinone		C₁₃H₁₇N₃O	详情	详情
(XV)	39280	tert-butyl (5S)-5-([(2R)-3-(3,5-dibromo-4-hydroxyphenyl)-2-[([4-[2-oxo-1,4-dihydro-3(2H)-quinazolinyl]-1-piperidinyl]carbonyl)amino]propanoyl]amino)-6-oxo-6-[4-(4-pyridinyl)-1-piperazinyl]hexylcarbamate		C₄₃H₅₅Br₂N₉O₇	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)