-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-[4-(beta-D-Glucopyranuronosyloxy)-3-nitrobenzyloxycarbonyl]-glycyl-L-isoleucyl-L-leucyl-glycyl-L-phenylalanyl-L-valyl-L-phenylalanyl-L-threonyl-L-leucine

【CA登记号】403852-50-6

【分子式】C₆₃H₈₈N₁₀O₂₂

【分子量】1337.45761

【开发单位】Wayne State University (Originator)

【药理作用】Cancer Immunotherapy, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, ONCOLYTIC 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5

合成路线1

Reaction of methyl 2,3,4-tri-O-acetyl-beta-D-glucuronyl-3-nitrobenzyl alcohol (I) with N,N'-disuccinimidyl carbonate affords the mixed carbonate ester (II), which is further coupled to glycine (III), producing carbamate (IV). Alcoholysis of (IV) with NaOMe in MeOH yields the deacetylated conjugate (V). This is then activated as the pentafluorophenyl ester (VI) upon treatment with pentafluorophenol and DCC.

参考文献中间体

【1】 Rawale, S.; Hrihorczuk, L.M.; Wei, W.-Z.; Zemlicka, J.; Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by Beta-glucuronidase. J Med Chem 2002, 45, 4, 937.

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)	65153	methyl (2S,3R,4S,5R,6S)-3,4,5-tris(acetyloxy)-6-[4-(hydroxymethyl)-2-nitrophenoxy]tetrahydro-2H-pyran-2-carboxylate		C₂₀H₂₃NO₁₃	详情	详情
(II)	65155	methyl (2S,3R,4S,5R,6S)-3,4,5-tris(acetyloxy)-6-{4-[({[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}oxy)methyl]-2-nitrophenoxy}tetrahydro-2H-pyran-2-carboxylate		C₂₅H₂₆N₂O₁₇	详情	详情
(III)	20436	glycine	56-40-6	C₂H₅NO₂	详情	详情
(IV)	65156	2-({[(3-nitro-4-{[(2S,3R,4S,5R,6S)-3,4,5-tris(acetyloxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl]oxy}benzyl)oxy]carbonyl}amino)acetic acid		C₂₃H₂₆N₂O₁₆	详情	详情
(V)	65154	2-({[(3-nitro-4-{[(2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl]oxy}benzyl)oxy]carbonyl}amino)acetic acid		C₁₇H₂₀N₂O₁₃	详情	详情
(VI)	65157	methyl (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-nitro-4-{[({[2-oxo-2-(2,3,4,5,6-pentafluorophenoxy)ethyl]amino}carbonyl)oxy]methyl}phenoxy)tetrahydro-2H-pyran-2-carboxylate		C₂₃H₁₉F₅N₂O₁₃	详情	详情

合成路线2

Coupling between N-Boc-O-benzyl-L-threonine (VII) and L-leucine benzyl ester (VIII) by means of DCC/HOBt gives the protected dipeptide (IX). Subsequent N-Boc group cleavage in (IX) upon treatment with formic acid yields (X). Further coupling of dipeptide (X) with N-Boc-L-phenylalanine (XI), followed by formic acid deprotection, leads to the benzyl-protected tripeptide (XII).

参考文献中间体

【1】 Rawale, S.; Hrihorczuk, L.M.; Wei, W.-Z.; Zemlicka, J.; Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by Beta-glucuronidase. J Med Chem 2002, 45, 4, 937.

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)	50782	(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid		C₁₆H₂₃NO₅	详情	详情
(VIII)	22252	Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate		C₁₃H₁₉NO₂	详情	详情
(IX)	65160	benzyl (2S)-2-({(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butanoyl}amino)-4-methylpentanoate		C₂₉H₄₀N₂O₆	详情	详情
(X)	65158	benzyl (2S)-2-{[(2S,3R)-2-amino-3-(benzyloxy)butanoyl]amino}-4-methylpentanoate		C₂₄H₃₂N₂O₄	详情	详情
(XI)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(XII)	65159	benzyl (2S)-2-{[(2S,3R)-2-{[(2S)-2-amino-3-phenylpropanoyl]amino}-3-(benzyloxy)butanoyl]amino}-4-methylpentanoate		C₃₃H₄₁N₃O₅	详情	详情

合成路线3

In a similar fashion, N-Boc-L-phenylalanine (XI) is coupled with L-valine benzyl ester (XIII) to furnish the protected dipeptide (XIV). Debenzylation of (XIV) with H2 and Pd/C leads to acid (XV), which is then condensed with tripeptide (XII) to yield, after deprotection with formic acid, the pentapeptide derivative (XVI).

参考文献中间体

【1】 Rawale, S.; Hrihorczuk, L.M.; Wei, W.-Z.; Zemlicka, J.; Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by Beta-glucuronidase. J Med Chem 2002, 45, 4, 937.

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)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(XII)	65159	benzyl (2S)-2-{[(2S,3R)-2-{[(2S)-2-amino-3-phenylpropanoyl]amino}-3-(benzyloxy)butanoyl]amino}-4-methylpentanoate		C₃₃H₄₁N₃O₅	详情	详情
(XIII)	41936	benzyl (2S)-2-amino-3-methylbutanoate		C₁₂H₁₇NO₂	详情	详情
(XIV)	65162	benzyl (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-methylbutanoate		C₂₆H₃₄N₂O₅	详情	详情
(XV)	65163	(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-methylbutanoic acid		C₁₉H₂₈N₂O₅	详情	详情
(XVI)	65161	benzyl (2S,5S,8S,11S,14S)-14-amino-8-benzyl-5-[(1R)-1-(benzyloxy)ethyl]-2-isobutyl-11-isopropyl-4,7,10,13-tetraoxo-15-phenyl-3,6,9,12-tetraazapentadecan-1-oate		C₄₇H₅₉N₅O₇	详情	详情

合成路线4

Coupling of N-Boc-L-leucine (XVII) with glycine benzyl ester (XVIII), followed by acidic N-Boc group cleavage, affords the dipeptide benzyl ester (XIX), which is submitted to coupling with N-Boc-L-isoleucine (XX) and further benzyl ester hydrogenolysis to give rise to the N-Boc tripeptide (XXI). Then, assembly between (XXI) and pentapeptide (XVI) is accomplished by means of EDC/HOBt, providing the protected peptide (XXII). Hydrogenolysis of the benzyl groups of (XXII), followed by Boc group cleavage with trifluoroacetic acid, leads to the fully deprotected octapeptide (XXIII).

参考文献中间体

【1】 Rawale, S.; Hrihorczuk, L.M.; Wei, W.-Z.; Zemlicka, J.; Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by Beta-glucuronidase. J Med Chem 2002, 45, 4, 937.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	65161	benzyl (2S,5S,8S,11S,14S)-14-amino-8-benzyl-5-[(1R)-1-(benzyloxy)ethyl]-2-isobutyl-11-isopropyl-4,7,10,13-tetraoxo-15-phenyl-3,6,9,12-tetraazapentadecan-1-oate		C₄₇H₅₉N₅O₇	详情	详情
(XVII)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	详情	详情
(XVIII)	13601	benzyl 2-aminoacetate; Glycine benzyl ester hydrochloride	1738-68-7	C₉H₁₁NO₂	详情	详情
(XIX)	65167	benzyl 2-{[(2S)-2-amino-4-methylpentanoyl]amino}acetate		C₁₅H₂₂N₂O₃	详情	详情
(XX)	30009	(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid	13139-16-7	C₁₁H₂₁NO₄	详情	详情
(XXI)	65166	(6S,9S)-9-isobutyl-2,2-dimethyl-6-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid		C₁₉H₃₅N₃O₆	详情	详情
(XXII)	65165	benzyl (6S,9S,15S,18S,21S,24S,27S)-15,21-dibenzyl-24-[(1R)-1-(benzyloxy)ethyl]-9,27-diisobutyl-18-isopropyl-2,2-dimethyl-6-[(1S)-1-methylpropyl]-4,7,10,13,16,19,22,25-octaoxo-3-oxa-5,8,11,14,17,20,23,26-octaazaoctacosan-28-oate		C₆₆H₉₂N₈O₁₂	详情	详情
(XXIII)	65164	(2S,5S,8S,11S,14S,20S,23S,24S)-23-amino-8,14-dibenzyl-5-[(1R)-1-hydroxyethyl]-2,20-diisobutyl-11-isopropyl-24-methyl-4,7,10,13,16,19,22-heptaoxo-3,6,9,12,15,18,21-heptaazahexacosan-1-oic acid		C₄₇H₇₂N₈O₁₀	详情	详情

合成路线5

Condensation of pentafluorophenyl ester (VI) with octapeptide (XXIII) gives rise to the nonapeptide conjugate (XXIV). The methyl ester group of (XXIV) is finally hydrolyzed by means of barium hydroxide in MeOH to produce the target compound.

参考文献中间体

【1】 Rawale, S.; Hrihorczuk, L.M.; Wei, W.-Z.; Zemlicka, J.; Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by Beta-glucuronidase. J Med Chem 2002, 45, 4, 937.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	65157	methyl (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-(2-nitro-4-{[({[2-oxo-2-(2,3,4,5,6-pentafluorophenoxy)ethyl]amino}carbonyl)oxy]methyl}phenoxy)tetrahydro-2H-pyran-2-carboxylate	C₂₃H₁₉F₅N₂O₁₃	详情	详情
(XXIII)	65164	(2S,5S,8S,11S,14S,20S,23S,24S)-23-amino-8,14-dibenzyl-5-[(1R)-1-hydroxyethyl]-2,20-diisobutyl-11-isopropyl-24-methyl-4,7,10,13,16,19,22-heptaoxo-3,6,9,12,15,18,21-heptaazahexacosan-1-oic acid	C₄₇H₇₂N₈O₁₀	详情	详情
(XXIV)	65168	(8S,11S,17S,20S,23S,26S,29S)-17,23-dibenzyl-26-[(1R)-1-hydroxyethyl]-11,29-diisobutyl-20-isopropyl-8-[(1S)-1-methylpropyl]-1-(3-nitro-4-{[(2S,3R,4S,5S,6S)-3,4,5-trihydroxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl]oxy}phenyl)-3,6,9,12,15,18,21,24,	C₆₄H₉₀N₁₀O₂₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)