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【结 构 式】

【分子编号】50768

【品名】(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-7-amino-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]tetradecahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosine-1,4,8,13,16,18,21(17H)-heptone

【CA登记号】

【 分 子 式 】C42H65N5O11

【 分 子 量 】816.0052

【元素组成】C 61.82% H 8.03% N 8.58% O 21.57%
与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(XXIX)

Removal of the tert-butyldimethylsilyl group of (XXIV) by means of HOAc/THF/H2O yields alcohol (XXV), which is then converted into carboxylic acid (XXVI) by first Swern oxidation with trifluoroacetic anhydride, Et3N and DMSO, followed by reaction with KMnO4 in tert-butyl alcohol with sodium hydrogen phosphate. Cyclization of linear peptide (XXVI) is then performed by first removal of the Z protecting group by hydrogenation over Pd/C in MeOH/AcOEt, followed by treatment of the amine with diphenylphosphoryl azide (DPPA) and NaHCO3 in DMF, yielding protected macrolide (XXVII). Removal of the MOM protecting group of (XXVII) by means of dimethylboron bromide in CH2Cl2 affords compound (XXVIII), which is converted into intermediate (XXIX) by Swern oxidation with trifluoroacetic anhydride, Et3N and DMSO, followed by Boc removal with HCl.

参考文献 中间体
合成目标
【1】 Li, W.-R.; et al.; Total synthesis and structural investigations of didemnins A, B, and C. J Am Chem Soc 1990, 112, 21, 7659.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIV) 50763 (1S,2S,3R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-isopropyl-2-(methoxymethoxy)-3-methylbutyl (3S,4R,5S)-4-([(2S,3R)-3-[[(2S)-2-[[[(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)pyrrolidinyl]carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy]-2-[(tert-butoxycarbonyl)amino]butanoyl]amino)-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate C72H123N5O16Si2 详情 详情
(XXV) 50764 (1S,2S,3R)-4-hydroxy-1-isopropyl-2-(methoxymethoxy)-3-methylbutyl (3S,4R,5S)-4-([(2S,3R)-3-[[(2S)-2-[[[(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)pyrrolidinyl]carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy]-2-[(tert-butoxycarbonyl)amino]butanoyl]amino)-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate C66H109N5O16Si 详情 详情
(XXVI) 50765 (3S,6R,7S,10R,11S,15S,16S,17S)-1-[(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)pyrrolidinyl]-7-[(tert-butoxycarbonyl)amino]-15-isopropyl-3-(4-methoxybenzyl)-16-(methoxymethoxy)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13-tetraoxo-11-[(triisopropylsilyl)oxy]-5,14-dioxa-2,9-diazaoctadecan-18-oic acid C66H107N5O17Si 详情 详情
(XXVII) 50766 tert-butyl (3S,6R,7S,10R,11S,15S,16S,17S,20S,25aS)-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-16-(methoxymethoxy)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,18,21-hexaoxo-11-[(triisopropylsilyl)oxy]docosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-ylcarbamate C58H99N5O14Si 详情 详情
(XXVIII) 50767 tert-butyl (3S,6R,7S,10R,11S,15S,16S,17S,20S,25aS)-16-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,18,21-hexaoxo-11-[(triisopropylsilyl)oxy]docosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-ylcarbamate C56H95N5O13Si 详情 详情
(XXIX) 50768 (3S,6R,7S,10R,11S,15S,17S,20S,25aS)-7-amino-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]tetradecahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosine-1,4,8,13,16,18,21(17H)-heptone C42H65N5O11 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XXV)

Removal of the N-Boc protecting group of (XXIV) by means of HCl in dioxane generated the macrocyclic amine (XXV). The protected aminoacid (XXVII) was prepared by treatment of D-leucine (XXVI) with Boc2O, followed by N-methylation under phase-transfer conditions. Coupling of N-Boc-N-methyl-D-leucine (XXVII) with amine (XXV) provided amide (XXVIII). Then, acidic Boc group cleavage in (XXVIII) furnished didemnin A (XXIX)

参考文献 中间体
合成目标
【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354.
【2】 Giralt Lledo, E.; Albericio Palomera, F.; Lloyd-Williams, P.; Gonzalez Valcarcel, I.; Jou Prat, G.; Gomez Gonzalez, A.; Manzanares Secades, I. (PharmaMar, SA); Process for the preparation of didemnine A. ES 2102322 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIV) 62539 tert-butyl (3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-ylc C47H73N5O13 详情 详情
(XXV) 50768 (3S,6R,7S,10R,11S,15S,17S,20S,25aS)-7-amino-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]tetradecahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosine-1,4,8,13,16,18,21(17H)-heptone C42H65N5O11 详情 详情
(XXVI) 16010 D-leucine 328-38-1 C6H13NO2 详情 详情
(XXVII) 50788 (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid C12H23NO4 详情 详情
(XXVIII) 62540 tert-butyl (1R)-1-[({(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotric C54H86N6O14 详情 详情
(XXIX) 50796 (2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide C49H78N6O12 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XXV)

N-Boc-L-Threonine (LVI) was protected as the corresponding phenacyl ester (LVII) by treatment with 2-bromoacetophenone and Et3N. Esterification of (LVII) with the modified tyrosine building block (II) yielded the protected didepsipeptide (LVIII). Removal of the phenacyl ester group of (LVIII) under reductive conditions provided the carboxylic acid (VI). Coupling of acid (VI) with the depsipeptide segment (XXI), followed by deprotection by hydrogenolysis furnished the linear precursor (XXIII). Macrocyclization of (XXIII) using HATU and subsequent acidic Boc group cleavage led to the macrocyclic amine (XXV)

参考文献 中间体
合成目标
【1】 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(II) 50747 (2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid C19H21NO5 详情 详情
(VI) 52709 (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoic acid C28H36N2O9 详情 详情
(XXI) 62536 benzyl (2S)-1-{(2S)-2-[((4S)-4-{[(3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate C34H53N3O8 详情 详情
(XXIII) 62538 (2S)-1-{(2S,7S,11S,12R,15S,16R,19S)-15-[(tert-butoxycarbonyl)amino]-11-hydroxy-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16-dimethyl-12-[(1S)-1-methylpropyl]-4,6,9,14,18-pentaoxo-8,17-dioxa-3,13,20-triazahenicos-1-anoyl}-2-pyrrolidinecarboxylic C47H75N5O14 详情 详情
(XXV) 50768 (3S,6R,7S,10R,11S,15S,17S,20S,25aS)-7-amino-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]tetradecahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosine-1,4,8,13,16,18,21(17H)-heptone C42H65N5O11 详情 详情
(LVI) 50745 N-BOC-L-threonine; Boc-Threonine; N-tert-Butoxycarbonyl-L-threonine; N-(tert-Butoxycarbonyl)-L-threonine; BOC-L-Threonine 2592-18-9 C9H17NO5 详情 详情
(LVII) 62565 2-oxo-2-phenylethyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate C17H23NO6 详情 详情
(LVIII) 62566 2-oxo-2-phenylethyl (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoate C36H42N2O10 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XXV)

N-Benzyloxycarbonyl-N-methyl-D-leucine (LX) was prepared by methylation of the N-protected D-leucine (LIX) with iodomethane in the presence of NaH. Acylation of macrocyclic amine (XXV) with the N-protected aminoacid (LX) furnished the N-carbobenzoxy didemnin A (LXI). The title compound was then obtained by hydrogenolysis of the N-carbobenzoxy group of (LXI), followed by acylation with pyruvyl proline (XXXII) by means of diisopropyl carbodiimide

参考文献 中间体
合成目标
【1】 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXV) 50768 (3S,6R,7S,10R,11S,15S,17S,20S,25aS)-7-amino-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]tetradecahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosine-1,4,8,13,16,18,21(17H)-heptone C42H65N5O11 详情 详情
(XXXII) 62542 (2S)-1-pyruvoyl-2-pyrrolidinecarboxylic acid C8H11NO4 详情 详情
(LIX) 22838 (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid C14H19NO4 详情 详情
(LXI) 50810 benzyl (1R)-1-[([(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin C57H84N6O14 详情 详情
Extended Information