BILN-303-SE, -Drug Synthesis Database

【结构式】

【药物名称】BILN-303-SE

【化学名称】Acetyl-L-aspartyl-D-glutamyl-L-(2-cyclohexyl)glycyl-L-valyl-4(R)-(2-naphthylmethoxy)-L-prolyl-L-norvaline

【CA登记号】220425-58-1

【分子式】C₄₅H₆₂N₆O₁₃

【分子量】895.02829

【开发单位】Boehringer Ingelheim (Originator)

【药理作用】Anti-Hepatitis C Virus Drugs, Anti-Hepatitis Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs, HCV NS3 Protease Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

Alkylation of N-Boc-4-(R)-hydroxyproline (I) with 2-(bromomethyl)-naphthalene (II) in the presence of NaH afforded the (naphthylmethyl) ether (III). N-Boc-norvaline (IV) was converted to the benzyl ester (V) by treatment with benzyl bromide and DBU. Subsequent acid cleavage of the Boc group of (V) yielded norvaline benzyl ester (VI). This was coupled with proline derivative (III) using HATU to give the protected dipeptide (VII).

参考文献中间体

【1】 Rancourt, J.; Tsantrizos, Y.; Simoneau, B.; Wernic, D.; Poupart, M.-A.; Llinas-Brunet, M. (Boehringer Ingelheim (Canada) Ltd.); Hepatitis C inhibitor peptides. EP 1003775; WO 9907733 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(I)	16094	(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid	16094	C₁₀H₁₇NO₅	详情	详情
(II)	35612	2-(bromomethyl)naphthalene	939-26-4	C₁₁H₉Br	详情	详情
(III)	35613	(2S,4R)-1-(tert-butoxycarbonyl)-4-(2-naphthylmethoxy)-2-pyrrolidinecarboxylic acid		C₂₁H₂₅NO₅	详情	详情
(IV)	35614	(2S)-2-[(tert-butoxycarbonyl)amino]pentanoic acid	53308-95-5	C₁₀H₁₉NO₄	详情	详情
(V)	35615	benzyl (2S)-2-[(tert-butoxycarbonyl)amino]pentanoate		C₁₇H₂₅NO₄	详情	详情
(VI)	35616	benzyl (2S)-2-aminopentanoate		C₁₂H₁₇NO₂	详情	详情
(VII)	35617	tert-butyl (2S,4R)-2-[([(1S)-1-[(benzyloxy)carbonyl]butyl]amino)carbonyl]-4-(2-naphthylmethoxy)-1-pyrrolidinecarboxylate		C₃₃H₄₀N₂O₆	详情	详情

合成路线2

After Boc group deprotection in (VII) by means of HCl in dioxan, coupling with N-Boc-valine (VIII) provided tripeptide (IX). Further deprotection and coupling cycles with N-Boc-cyclohexylglycine (X) and N-Boc-glutamic acid benzyl ester (XII) furnished peptides (XI) and (XIII), respectively.

参考文献中间体

【1】 Rancourt, J.; Tsantrizos, Y.; Simoneau, B.; Wernic, D.; Poupart, M.-A.; Llinas-Brunet, M. (Boehringer Ingelheim (Canada) Ltd.); Hepatitis C inhibitor peptides. EP 1003775; WO 9907733 .

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)	35617	tert-butyl (2S,4R)-2-[([(1S)-1-[(benzyloxy)carbonyl]butyl]amino)carbonyl]-4-(2-naphthylmethoxy)-1-pyrrolidinecarboxylate		C₃₃H₄₀N₂O₆	详情	详情
(VIII)	19733	(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid		C₁₀H₁₉NO₄	详情	详情
(IX)	35618	benzyl (2S)-2-([[(2S,4R)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]-4-(2-naphthylmethoxy)pyrrolidinyl]carbonyl]amino)pentanoate		C₃₈H₄₉N₃O₇	详情	详情
(X)	35619	(2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid		C₁₃H₂₃NO₄	详情	详情
(XI)	35620	benzyl (2S)-2-([[(2S,4R)-1-[(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]amino)-3-methylbutanoyl]-4-(2-naphthylmethoxy)pyrrolidinyl]carbonyl]amino)pentanoate		C₄₆H₆₂N₄O₈	详情	详情
(XII)	25141	(2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid	13574-13-5	C₁₇H₂₃NO₆	详情	详情
(XIII)	35621	benzyl (4R)-5-([(1S)-2-[((1S)-1-[[(2S,4R)-2-[([(1S)-1-[(benzyloxy)carbonyl]butyl]amino)carbonyl]-4-(2-naphthylmethoxy)pyrrolidinyl]carbonyl]-2-methylpropyl)amino]-1-cyclohexyl-2-oxoethyl]amino)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoate		C₅₈H₇₅N₅O₁₁	详情	详情

合成路线3

A new deprotection and coupling cycle with N-Boc-aspartic acid benzyl ester (XIV) yielded peptide (XV). After acid deprotection of the Boc group from hexapeptide (XV), its acetylation with Ac2O and pyridine produced the corresponding acetamide. Finally, hydrogenolysis of the benzyl ester groups in the presence of Pd/C and NH4OAc yielded the title compound.

参考文献中间体

【1】 Rancourt, J.; Tsantrizos, Y.; Simoneau, B.; Wernic, D.; Poupart, M.-A.; Llinas-Brunet, M. (Boehringer Ingelheim (Canada) Ltd.); Hepatitis C inhibitor peptides. EP 1003775; WO 9907733 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	35621	benzyl (4R)-5-([(1S)-2-[((1S)-1-[[(2S,4R)-2-[([(1S)-1-[(benzyloxy)carbonyl]butyl]amino)carbonyl]-4-(2-naphthylmethoxy)pyrrolidinyl]carbonyl]-2-methylpropyl)amino]-1-cyclohexyl-2-oxoethyl]amino)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoate		C₅₈H₇₅N₅O₁₁	详情	详情
(XIV)	25219	(2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid	7536-58-5	C₁₆H₂₁NO₆	详情	详情
(XV)	35622			C₆₉H₈₆N₆O₁₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)