(2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid -Drug Synthesis Database

【结构式】

【分子编号】22258

【品名】(2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid

【CA登记号】104091-08-9

【分子式】C₂₄H₂₇NO₆

【分子量】425.48152

【元素组成】C 67.75% H 6.4% N 3.29% O 22.56%

与该中间体有关的原料药合成路线共 6 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6

合成路线1

该中间体在本合成路线中的序号：(VIII)

Coupling of N-(Boc)-3-methyl-L-valine (I) with L-leucine benzyl ester (II) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-HCl (EDC) and 1-hydroxybenzotriazole (HOBt) in the presence of N-ethylmorpholine gave the N-Boc-dipeptide (III), which was deprotected with trifluoroacetic acid in CH2Cl2 to afford (IV). Subsequent coupling of (IV) with N-Fmoc-2-methyl-L-phenylalanine (V) mediated by EDC and HOBt provided the N-Fmoc-tripeptide (VI). Deprotection of the fluorenylmethoxycarbonyl group of (VI) was effected with piperidine in CH2Cl2 to yield (VII). Further coupling and deprotection cycles with N-Fmoc-O-tert-butyl-L-glutamic acid (VIII) and then with N-Fmoc-O-tert-butyl-L-aspartic acid (X) provided peptides (IX) and (XI), respectively. This latter was then coupled to mono-tert--butyl succinate (XII) to furnish (XIII).

参考文献中间体

合成目标

【1】 Attwood, M.R.; Campbell, A.D.; Bennett, J.M.; et al.; The design and synthersis of potent inhibitors of hepatitis C virus NS3-4A proteinase. Antivir Chem Chemother 1999, 10, 5, 259.
【2】 Attwood, M.R.; Hurst, D.N.; Jones, P.S.; Kay, P.B.; Raynham, T.M.; Wilson, F.X. (F. Hoffmann-La Roche AG); Antiviral peptide derivs.. JP 2000508344; WO 9822496 .

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)	22251	(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine	62965-35-9	C₁₁H₂₁NO₄	详情	详情
(II)	22252	Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate		C₁₃H₁₉NO₂	详情	详情
(III)	22253	benzyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]amino)-4-methylpentanoate		C₂₄H₃₈N₂O₅	详情	详情
(IV)	22254	benzyl (2S)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-4-methylpentanoate		C₁₉H₃₀N₂O₃	详情	详情
(V)	22255	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-methylphenyl)propionic acid		C₂₅H₂₃NO₄	详情	详情
(VI)	22256	benzyl (5S,8S,11S)-8-(tert-butyl)-1-(9H-fluoren-9-yl)-11-isobutyl-5-(2-methylbenzyl)-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate		C₄₄H₅₁N₃O₆	详情	详情
(VII)	22257	benzyl (2S)-2-[((2S)-2-[[(2S)-2-amino-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-4-methylpentanoate		C₂₉H₄₁N₃O₄	详情	详情
(VIII)	22258	(2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid	104091-08-9	C₂₄H₂₇NO₆	详情	详情
(IX)	22259	benzyl (2S,5S,8S,11S)-11-amino-5-(tert-butyl)-2-isobutyl-16,16-dimethyl-8-(2-methylbenzyl)-4,7,10,14-tetraoxo-15-oxa-3,6,9-triazaheptadecan-1-oate		C₃₈H₅₆N₄O₇	详情	详情
(X)	22260	(2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid		C₂₃H₂₅NO₆	详情	详情
(XI)	22261	1-benzyl 16-(tert-butyl) (2S,5S,8S,11S,14S)-14-amino-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13-tetraoxo-3,6,9,12-tetraazahexadecane-1,16-dioate		C₄₆H₆₉N₅O₁₀	详情	详情
(XII)	22262	4-(tert-butoxy)-4-oxobutyric acid		C₈H₁₄O₄	详情	详情
(XIII)	22263	1-benzyl 19-(tert-butyl) (2S,5S,8S,11S,14S)-14-[2-(tert-butoxy)-2-oxoethyl]-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazanonadecane-1,19-dioate		C₅₄H₈₁N₅O₁₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

参考文献中间体

合成目标

【1】 Attwood, M.R.; Hurst, D.N.; Jones, P.S.; Kay, P.B.; Raynham, T.M.; Wilson, F.X. (F. Hoffmann-La Roche AG); Antiviral peptide derivs.. JP 2000508344; WO 9822496 .

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)	22251	(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine	62965-35-9	C₁₁H₂₁NO₄	详情	详情
(II)	22252	Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate		C₁₃H₁₉NO₂	详情	详情
(III)	22253	benzyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl]amino)-4-methylpentanoate		C₂₄H₃₈N₂O₅	详情	详情
(IV)	22254	benzyl (2S)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-4-methylpentanoate		C₁₉H₃₀N₂O₃	详情	详情
(V)	22255	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-methylphenyl)propionic acid		C₂₅H₂₃NO₄	详情	详情
(VI)	22256	benzyl (5S,8S,11S)-8-(tert-butyl)-1-(9H-fluoren-9-yl)-11-isobutyl-5-(2-methylbenzyl)-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oate		C₄₄H₅₁N₃O₆	详情	详情
(VII)	22257	benzyl (2S)-2-[((2S)-2-[[(2S)-2-amino-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-4-methylpentanoate		C₂₉H₄₁N₃O₄	详情	详情
(VIII)	22258	(2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid	104091-08-9	C₂₄H₂₇NO₆	详情	详情
(IX)	22259	benzyl (2S,5S,8S,11S)-11-amino-5-(tert-butyl)-2-isobutyl-16,16-dimethyl-8-(2-methylbenzyl)-4,7,10,14-tetraoxo-15-oxa-3,6,9-triazaheptadecan-1-oate		C₃₈H₅₆N₄O₇	详情	详情
(X)	22260	(2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid		C₂₃H₂₅NO₆	详情	详情
(XI)	22261	1-benzyl 16-(tert-butyl) (2S,5S,8S,11S,14S)-14-amino-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13-tetraoxo-3,6,9,12-tetraazahexadecane-1,16-dioate		C₄₆H₆₉N₅O₁₀	详情	详情
(XII)	22262	4-(tert-butoxy)-4-oxobutyric acid		C₈H₁₄O₄	详情	详情
(XIII)	22263	1-benzyl 19-(tert-butyl) (2S,5S,8S,11S,14S)-14-[2-(tert-butoxy)-2-oxoethyl]-11-[3-(tert-butoxy)-3-oxopropyl]-5-(tert-butyl)-2-isobutyl-8-(2-methylbenzyl)-4,7,10,13,16-pentaoxo-3,6,9,12,15-pentaazanonadecane-1,19-dioate		C₅₄H₈₁N₅O₁₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XIV)

Preparation of the title compound was carried out by solid-phase peptide synthesis, starting from Wang resin bounded to N-Fmoc-phenylalanine (XII). Removal of the Fmoc group of (XII) with piperidine in DMF provided phenylalanine-resin (XIII), which was subsequently coupled with N-Fmoc-glutamic acid gamma-tert-butyl ester (XIV) in the presence of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt). Cleavage of the Fmoc group from the resulting protected dipeptide-resin furnished (XV). Sequential coupling-deprotection cycles with N-Fmoc-alanine (XVI), intermediate (XI) and Nalpha-Fmoc-Nbeta-trityl-asparagine (XIX) furnished the peptide resins (XVII), (XVIII) and (XX), respectively. (Scheme 28685901b).

参考文献中间体

合成目标

【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	40633	(2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid		C₃₁H₄₅NO₅Si	详情	详情
(XII)	19030	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine	35661-40-6	C₂₄H₂₁NO₄	详情	详情
(XIII)	13952	(S)-(-)-Phenylalanine; L-Phenylalanine	63-91-2	C₉H₁₁NO₂	详情	详情
(XIV)	22258	(2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid	104091-08-9	C₂₄H₂₇NO₆	详情	详情
(XV)	40634	(2S)-2-[[(2S)-2-amino-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid		C₁₈H₂₆N₂O₅	详情	详情
(XVI)	19926	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid		C₁₈H₁₇NO₄	详情	详情
(XVII)	40635	(2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid		C₂₁H₃₁N₃O₆	详情	详情
(XVIII)	40636	(5S,7R,10S,13S,16S)-5-[(1S)-1-amino-3-methylbutyl]-16-benzyl-13-[3-(tert-butoxy)-3-oxopropyl]-2,2,3,3,7,10-hexamethyl-8,11,14-trioxo-4-oxa-9,12,15-triaza-3-silaheptadecan-17-oic acid		C₃₇H₆₄N₄O₈Si	详情	详情
(XIX)	40637	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxo-4-(tritylamino)butyric acid		C₃₈H₃₂N₂O₅	详情	详情
(XX)	40638	(5S,8S,9S,11R,14S,17S,20S)-5-amino-20-benzyl-17-[3-(tert-butoxy)-3-oxopropyl]-9-[[tert-butyl(dimethyl)silyl]oxy]-8-isobutyl-11,14-dimethyl-3,6,12,15,18-pentaoxo-1,1,1-triphenyl-2,7,13,16,19-pentaazahenicosan-21-oic acid		C₆₀H₈₄N₆O₁₀Si	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XIV)

参考文献中间体

合成目标

【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	40633	(2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid		C₃₁H₄₅NO₅Si	详情	详情
(XII)	19030	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine	35661-40-6	C₂₄H₂₁NO₄	详情	详情
(XIII)	13952	(S)-(-)-Phenylalanine; L-Phenylalanine	63-91-2	C₉H₁₁NO₂	详情	详情
(XIV)	22258	(2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid	104091-08-9	C₂₄H₂₇NO₆	详情	详情
(XV)	40634	(2S)-2-[[(2S)-2-amino-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid		C₁₈H₂₆N₂O₅	详情	详情
(XVI)	19926	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid		C₁₈H₁₇NO₄	详情	详情
(XVII)	40635	(2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid		C₂₁H₃₁N₃O₆	详情	详情
(XVIII)	40636	(5S,7R,10S,13S,16S)-5-[(1S)-1-amino-3-methylbutyl]-16-benzyl-13-[3-(tert-butoxy)-3-oxopropyl]-2,2,3,3,7,10-hexamethyl-8,11,14-trioxo-4-oxa-9,12,15-triaza-3-silaheptadecan-17-oic acid		C₃₇H₆₄N₄O₈Si	详情	详情
(XIX)	40637	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxo-4-(tritylamino)butyric acid		C₃₈H₃₂N₂O₅	详情	详情
(XX)	40638	(5S,8S,9S,11R,14S,17S,20S)-5-amino-20-benzyl-17-[3-(tert-butoxy)-3-oxopropyl]-9-[[tert-butyl(dimethyl)silyl]oxy]-8-isobutyl-11,14-dimethyl-3,6,12,15,18-pentaoxo-1,1,1-triphenyl-2,7,13,16,19-pentaazahenicosan-21-oic acid		C₆₀H₈₄N₆O₁₀Si	详情	详情

合成路线5

该中间体在本合成路线中的序号：(XIV)

Sequential coupling-deprotection cycles with N- N-Fmoc-valine (XXI), and N-Fmoc-glutamic acid gamma-tert-butyl ester (XIV) furnished the peptide resins (XXII) and (XXIII), respectively. Finally, removal of the side-chain protecting groups and cleavage from the resin by means of 95% trifluoroacetic acid yielded the title compound.) (Scheme 28686001c)

参考文献中间体

合成目标

【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	22258	(2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid	104091-08-9	C₂₄H₂₇NO₆	详情	详情
(XX)	40638	(5S,8S,9S,11R,14S,17S,20S)-5-amino-20-benzyl-17-[3-(tert-butoxy)-3-oxopropyl]-9-[[tert-butyl(dimethyl)silyl]oxy]-8-isobutyl-11,14-dimethyl-3,6,12,15,18-pentaoxo-1,1,1-triphenyl-2,7,13,16,19-pentaazahenicosan-21-oic acid		C₆₀H₈₄N₆O₁₀Si	详情	详情
(XXI)	19932	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid		C₂₀H₂₁NO₄	详情	详情
(XXII)	40639	(2S,5S,8S,11R,13S,14S,17S,20S)-20-amino-2-benzyl-5-[3-(tert-butoxy)-3-oxopropyl]-13-[[tert-butyl(dimethyl)silyl]oxy]-14-isobutyl-8,11,21-trimethyl-4,7,10,16,19-pentaoxo-17-[2-oxo-2-(tritylamino)ethyl]-3,6,9,15,18-pentaazadocosan-1-oic acid		C₆₅H₉₃N₇O₁₁Si	详情	详情
(XXIII)	40640			C₇₄H₁₀₈N₈O₁₄Si	详情	详情

合成路线6

该中间体在本合成路线中的序号：(C)

N-Fmoc-L-leucine (X) was coupled to the resin (IX) by means of TBTU to afford, after Fmoc deprotection with piperidine/DMF, the dipeptide-resin (XI). Sequential chain elongation by coupling with the following protected amino acids: Fmoc-3-methyl-L-valine (A), Fmoc-2-methyl-L-phenylalanine (B), Fmoc-L-glutamic gamma-tert-butyl ester (C), and Fmoc-L-aspartic beta-tert-butyl ester (D), followed by the corresponding Fmoc deprotection steps, furnished the peptide resins (XII), (XIII), (XIV) and (XV), respectively.

参考文献中间体

合成目标

【1】 Jones, P.S.; Kay, P.B.; Wilson, F.X.; Raynham, T.M.; Hurst, D.N. (Hoffmann-La Roche, Inc.); alpha-Ketoamide derivs.. US 6187905 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	22255	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(2-methylphenyl)propionic acid		C₂₅H₂₃NO₄	详情	详情
(D)	22260	(2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid		C₂₃H₂₅NO₆	详情	详情
(A)	43350	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3,3-dimethylbutyric acid	132684-60-7	C₂₁H₂₃NO₄	详情	详情
(IX)	47880	(2S,3S)-3-amino-2-hydroxyheptanamide		C₇H₁₆N₂O₂	详情	详情
(X)	19934	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoic acid		C₂₁H₂₃NO₄	详情	详情
(XI)	47882	(2S,3S)-3-[[(2S)-2-amino-4-methylpentanoyl]amino]-2-hydroxyheptanamide		C₁₃H₂₇N₃O₃	详情	详情
(XII)	47883	(2S,3S)-3-[((2S)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-4-methylpentanoyl)amino]-2-hydroxyheptanamide		C₁₉H₃₈N₄O₄	详情	详情
(XIII)	47884	(2S,3S)-3-([(2S)-2-[((2S)-2-[[(2S)-2-amino-3-(2-methylphenyl)propanoyl]amino]-3,3-dimethylbutanoyl)amino]-4-methylpentanoyl]amino)-2-hydroxyheptanamide		C₂₉H₄₉N₅O₅	详情	详情
(XIV)	47885	tert-butyl (4S,7S,10S,13S,16S)-4-amino-16-[(1S)-2-amino-1-hydroxy-2-oxoethyl]-10-(tert-butyl)-13-isobutyl-7-(2-methylbenzyl)-5,8,11,14-tetraoxo-6,9,12,15-tetraazaicosan-1-oate		C₃₈H₆₄N₆O₈	详情	详情
(XV)	47886	tert-butyl (3S,6S,9S,12S,15S,18S)-3-amino-18-[(1S)-2-amino-1-hydroxy-2-oxoethyl]-6-[3-(tert-butoxy)-3-oxopropyl]-12-(tert-butyl)-15-isobutyl-9-(2-methylbenzyl)-4,7,10,13,16-pentaoxo-5,8,11,14,17-pentaazadocosan-1-oate		C₄₆H₇₇N₇O₁₁	详情	详情
(C)	22258	(2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid	104091-08-9	C₂₄H₂₇NO₆	详情	详情

Extended Information