N-4909, -Drug Synthesis Database

【结构式】

【药物名称】N-4909

【化学名称】N2-[3(S)-Hydroxy-13-methyltetradecanoyl]-L-glutaminyl-L-leucyl-D-leucyl-L-valyl-L-aspartyl-D-leucyl-L-isoleucine O-3.1-C-1.8-lactone

【CA登记号】

【分子式】C₅₃H₉₄N₈O₁₂

【分子量】1035.38653

【开发单位】Nisshin Pharma (Originator)

【药理作用】Lipoprotein Disorders, Treatment of , METABOLIC DRUGS

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

Condensation of (R)-benzyl 3-hydroxy-13-methyl tetradecanoate (I) with N-Boc-L-isoleucine (II) in the presence of dicyclohexyl carbodiimide and dimethylaminopyridine furnished the corresponding ester (III). After deprotection of the benzyl group of (III) by hydrogenation over Pd/C, the resulting carboxylic acid (IV) was attached to an oxime resin using O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) to give the resin-coupled product (V).

参考文献中间体

【1】 Yanai, M.; Suguroi, T.; Solid-phase synthesis of cyclooctadepsipeptide N-4909 using a cyclization-cleavage method with oxime resin. J Antibiot 1999, 52, 9, 835.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV),(V)	31816	(3S)-3-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoyl]oxy)-13-methyltetradecanoic acid		C₂₆H₄₉NO₆	详情	详情
(I)	31814	benzyl (3R)-3-hydroxy-13-methyltetradecanoate		C₂₂H₃₆O₃	详情	详情
(II)	30009	(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid	13139-16-7	C₁₁H₂₁NO₄	详情	详情
(III)	31815	benzyl (3S)-3-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoyl]oxy)-13-methyltetradecanoate		C₃₃H₅₅NO₆	详情	详情

合成路线2

Removal of the Boc protecting group of (V) with trifluoroacetic acid was followed by coupling with N-Boc-D-leucine (VI) in the presence of HATU to provide (VII). The deprotection-coupling procedure was repeated using N-Boc-L-aspartic acid gamma-benzyl ester (VIII), N-Boc-L-valine (X), and N-Boc-D-Leucine yielding the depsipeptide resins (IX), (XI) and (XII), respectively.

参考文献中间体

【1】 Yanai, M.; Suguroi, T.; Solid-phase synthesis of cyclooctadepsipeptide N-4909 using a cyclization-cleavage method with oxime resin. J Antibiot 1999, 52, 9, 835.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	31816	(3S)-3-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoyl]oxy)-13-methyltetradecanoic acid		C₂₆H₄₉NO₆	详情	详情
(VI)	31819	(2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid	16937-99-8	C₁₁H₂₁NO₄	详情	详情
(VII)	31817	(6R,9S,12S)-6-isobutyl-2,2-dimethyl-9-[(1S)-1-methylpropyl]-12-(10-methylundecyl)-4,7,10-trioxo-3,11-dioxa-5,8-diazatetradecan-14-oic acid		C₃₂H₆₀N₂O₇	详情	详情
(VIII)	25219	(2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid	7536-58-5	C₁₆H₂₁NO₆	详情	详情
(IX)	31821	(6S,9R,12S,15S)-6-[2-(benzyloxy)-2-oxoethyl]-9-isobutyl-2,2-dimethyl-12-[(1S)-1-methylpropyl]-15-(10-methylundecyl)-4,7,10,13-tetraoxo-3,14-dioxa-5,8,11-triazaheptadecan-17-oic acid		C₄₃H₇₁N₃O₁₀	详情	详情
(X)	19733	(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid		C₁₀H₁₉NO₄	详情	详情
(XI)	31822	(6S,9S,12R,15S,18S)-9-[2-(benzyloxy)-2-oxoethyl]-12-isobutyl-6-isopropyl-2,2-dimethyl-15-[(1S)-1-methylpropyl]-18-(10-methylundecyl)-4,7,10,13,16-pentaoxo-3,17-dioxa-5,8,11,14-tetraazaicosan-20-oic acid		C₄₈H₈₀N₄O₁₁	详情	详情
(XII)	31823	(6S,9S,12S,15R,18S,21S)-12-[2-(benzyloxy)-2-oxoethyl]-6,15-diisobutyl-9-isopropyl-2,2-dimethyl-18-[(1S)-1-methylpropyl]-21-(10-methylundecyl)-4,7,10,13,16,19-hexaoxo-3,20-dioxa-5,8,11,14,17-pentaazatricosan-23-oic acid		C₅₄H₉₁N₅O₁₂	详情	详情

合成路线3

The deprotection-coupling procedure was repeated using N-Boc-L-leucine (XIII), and N-Boc-L-glutamine (XV), yielding the depsipeptide resins (XII) and (XIV), respectively. Further cleavage of the Boc group provided the deprotected depsipeptide resin (XVII).

参考文献中间体

【1】 Yanai, M.; Suguroi, T.; Solid-phase synthesis of cyclooctadepsipeptide N-4909 using a cyclization-cleavage method with oxime resin. J Antibiot 1999, 52, 9, 835.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	31823	(6S,9S,12S,15R,18S,21S)-12-[2-(benzyloxy)-2-oxoethyl]-6,15-diisobutyl-9-isopropyl-2,2-dimethyl-18-[(1S)-1-methylpropyl]-21-(10-methylundecyl)-4,7,10,13,16,19-hexaoxo-3,20-dioxa-5,8,11,14,17-pentaazatricosan-23-oic acid		C₅₄H₉₁N₅O₁₂	详情	详情
(XIII)	31818	N-(tert-butoxycarbonyl)leucine		C₁₁H₂₁NO₄	详情	详情
(XIV)	31824	(6S,9R,12S,15S,18R,21S,24S)-15-[2-(benzyloxy)-2-oxoethyl]-6,9,18-triisobutyl-12-isopropyl-2,2-dimethyl-21-[(1S)-1-methylpropyl]-24-(10-methylundecyl)-4,7,10,13,16,19,22-heptaoxo-3,23-dioxa-5,8,11,14,17,20-hexaazahexacosan-26-oic acid		C₆₀H₁₀₂N₆O₁₃	详情	详情
(XV)	31820	(2S)-5-amino-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid	13726-85-7	C₁₀H₁₈N₂O₅	详情	详情
(XVI)	31825	(6S,9S,12R,15S,18S,21R,24S,27S)-6-(3-amino-3-oxopropyl)-18-[2-(benzyloxy)-2-oxoethyl]-9,12,21-triisobutyl-15-isopropyl-2,2-dimethyl-24-[(1S)-1-methylpropyl]-27-(10-methylundecyl)-4,7,10,13,16,19,22,25-octaoxo-3,26-dioxa-5,8,11,14,17,20,23-heptaazano		C₆₅H₁₁₀N₈O₁₅	详情	详情
(XVII)	31826	(3S,6S,9R,12S,15S,18R,21S,24S)-24,27-diamino-12-[2-(benzyloxy)-2-oxoethyl]-9,18,21-triisobutyl-15-isopropyl-6-[(1S)-1-methylpropyl]-3-(10-methylundecyl)-5,8,11,14,17,20,23,27-octaoxo-4-oxa-7,10,13,16,19,22-hexaazaheptacosan-1-oic acid		C₆₀H₁₀₂N₈O₁₃	详情	详情

合成路线4

Then, liberation from the resin by means of Et3N-AcOH proceded with concomitant cyclization to form the cyclic depsipeptide (XVIII). The benzyl ester group was finally deprotected by hydrogenolysis in the presence of Pd/C.

参考文献中间体

【1】 Yanai, M.; Suguroi, T.; Solid-phase synthesis of cyclooctadepsipeptide N-4909 using a cyclization-cleavage method with oxime resin. J Antibiot 1999, 52, 9, 835.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	31826	(3S,6S,9R,12S,15S,18R,21S,24S)-24,27-diamino-12-[2-(benzyloxy)-2-oxoethyl]-9,18,21-triisobutyl-15-isopropyl-6-[(1S)-1-methylpropyl]-3-(10-methylundecyl)-5,8,11,14,17,20,23,27-octaoxo-4-oxa-7,10,13,16,19,22-hexaazaheptacosan-1-oic acid		C₆₀H₁₀₂N₈O₁₃	详情	详情
(XVIII)	31827	benzyl 2-[(3S,6R,9S,12S,15R,18S,21S,25S)-21-(3-amino-3-oxopropyl)-6,15,18-triisobutyl-12-isopropyl-3-[(1S)-1-methylpropyl]-25-(10-methylundecyl)-2,5,8,11,14,17,20,23-octaoxo-1-oxa-4,7,10,13,16,19,22-heptaazacyclopentacosan-9-yl]acetate		C₆₀H₁₀₀N₈O₁₂	详情	详情

Extended Information