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【结 构 式】

【药物名称】Vancomycin hydrochloride, Vancomycin Enterocaps, Vancomycin CP, Vancocine, Vanconcina A.P., Vancocin

【化学名称】(3S,6R,7R,22R,23S,26S,36R,38aR)-3-(Carbamoylmethyl)-10,19-dichloro-44-[2-O-[3-C-amino-3-C-methyl-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl]-beta-D-glucopyranosyloxy]-7,22,28,30,32-pentahydroxy-6-(N-methyl-D-leucylamino)-2,5,24,38,39-pentaoxo-1,2,3,4,5,6,7,22,23,24,25,26,36,37,38,38a-hexadecahydro-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid hydrochloride

【CA登记号】1404-93-9, 1404-90-6 (free base)

【 分 子 式 】C66H76Cl3N9O24

【 分 子 量 】1485.74652

【开发单位】Shionogi (Orphan Drug), Lilly (Originator), Shionogi (Licensee)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Glycopeptides

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7合成路线8合成路线9

合成路线1

A formal total synthesis of vancomycin has been reported. The known aglycon of vancomycin (I) was protected at the amino group as the allyloxy- carbonyl derivative (III) using allyloxycarbonyl succinimide (II). Then, carboxylate group was converted to allyl ester (V) with allyl bromide (IV) and KHCO3.

参考文献 中间体
【1】 Thompson, C.; et al.; Synthesis of vancomycin from the aglycon. J Am Chem Soc 1999, 121, 6, 1237.
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) 25729 (1S,2R,18R,19R,22S,25R,28R,40R)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37,50-hexahydroxy-19-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylic acid C53H52Cl2N8O17 详情 详情
(II) 25730 allyl 2,5-dioxo-1-pyrrolidinecarboxylate C8H9NO4 详情 详情
(III) 25731 (1S,2R,18R,19R,22S,25R,28R,40R)-19-([(2R)-2-[[(allyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37,50-hexahydroxy-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylic acid C57H56Cl2N8O19 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 25732 allyl (1S,2R,18R,19R,22S,25R,28R,40R)-19-([(2R)-2-[[(allyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37,50-hexahydroxy-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylate C60H60Cl2N8O19 详情 详情

合成路线2

Selective protection of the phenol group of (V) with p-methoxybenzyl chloride (VI) gave benzyl ether (VII), and the remaining phenol groups of (VII) were further alkylated with allyl bromide to afford (VIII).

参考文献 中间体
【1】 Thompson, C.; et al.; Synthesis of vancomycin from the aglycon. J Am Chem Soc 1999, 121, 6, 1237.
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) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 25732 allyl (1S,2R,18R,19R,22S,25R,28R,40R)-19-([(2R)-2-[[(allyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37,50-hexahydroxy-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylate C60H60Cl2N8O19 详情 详情
(VI) 11910 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether 824-94-2 C8H9ClO 详情 详情
(VII) 25733 allyl (1S,2R,18R,19R,22S,25R,28R,40R)-19-([(2R)-2-[[(allyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37-pentahydroxy-50-[(4-methoxybenzyl)oxy]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylate C68H68Cl2N8O20 详情 详情
(VIII) 25734 allyl (1S,2R,18R,19R,22S,25R,28R,40R)-32,37-bis(allyloxy)-19-([(2R)-2-[[(allyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18-dihydroxy-50-[(4-methoxybenzyl)oxy]-20,23,26,42,44-pentaoxo-35-(vinyloxy)-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylate C76H78Cl2N8O20 详情 详情

合成路线3

After acetylation of the benzylic alcohols of (VIII), deprotection of the p-methoxybenzyl group with TFA furnished the protected aglycon (IX). Glycosylation with the protected glucopyranose sulfoxide (X) was effected in the presence of triflic anhydride, 2,6-di-tert-butyl-4-methylpyridine, and boron trifluoride etherate to produce (XI).

参考文献 中间体
【1】 Thompson, C.; et al.; Synthesis of vancomycin from the aglycon. J Am Chem Soc 1999, 121, 6, 1237.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 25734 allyl (1S,2R,18R,19R,22S,25R,28R,40R)-32,37-bis(allyloxy)-19-([(2R)-2-[[(allyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18-dihydroxy-50-[(4-methoxybenzyl)oxy]-20,23,26,42,44-pentaoxo-35-(vinyloxy)-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylate C76H78Cl2N8O20 详情 详情
(IX) 25735 allyl (1S,2R,18R,19R,22S,25R,28R,40R)-2,18-bis(acetoxy)-32,37-bis(allyloxy)-19-([(2R)-2-[[(allyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-22-(2-amino-2-oxoethyl)-5,15-dichloro-50-hydroxy-20,23,26,42,44-pentaoxo-35-(vinyloxy)-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylate C72H74Cl2N8O21 详情 详情
(X) 25736 (2R,3S,4R,5R,6S)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-(phenylsulfinyl)tetrahydro-2H-pyran-3-yl 4-azidobutanoate C22H27N3O10S 详情 详情
(XI) 25737 (3S,6R,7R,22R,23S,26S,36R,38aR)-7,22-Diacetoxy-28,30,32-triallyloxy-6-[N-(allyloxycarbonyl)-N-methyl-D-leucylamino]-3-(carbamoylmethyl)-10,19-dichloro-44-[3,4,6-tri-O-acetyl-6-O-(4-azidobutyryl)-beta-L-glucopyranosyloxy]-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid allyl ester; (3S,6R,7R,22R,23S,26S,36R,38aR)-7,22-Diacetoxy-28,30,32-triallyloxy-6-[N-(allyloxycarbonyl)-N-methyl-D-leucylamino]-3-(carbamoylmethyl)-10,19-dichloro-44-[3,4,6-tri-O-acetyl-6-O-(4-azidobutyryl)-beta-L-glucopyranosyloxy]-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid allyl ester C88H95Cl2N11O30 详情 详情

合成路线4

Then, the azidobutirate ester of (XI) was selectively removed with PPh3, and the resulting intermediate (XII) was condensed with the protected vancosamine sulfoxide (XIII) to give the protected vancomycin (XIV).

参考文献 中间体
【1】 Thompson, C.; et al.; Synthesis of vancomycin from the aglycon. J Am Chem Soc 1999, 121, 6, 1237.
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) 25737 (3S,6R,7R,22R,23S,26S,36R,38aR)-7,22-Diacetoxy-28,30,32-triallyloxy-6-[N-(allyloxycarbonyl)-N-methyl-D-leucylamino]-3-(carbamoylmethyl)-10,19-dichloro-44-[3,4,6-tri-O-acetyl-6-O-(4-azidobutyryl)-beta-L-glucopyranosyloxy]-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid allyl ester; (3S,6R,7R,22R,23S,26S,36R,38aR)-7,22-Diacetoxy-28,30,32-triallyloxy-6-[N-(allyloxycarbonyl)-N-methyl-D-leucylamino]-3-(carbamoylmethyl)-10,19-dichloro-44-[3,4,6-tri-O-acetyl-6-O-(4-azidobutyryl)-beta-L-glucopyranosyloxy]-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid allyl ester C88H95Cl2N11O30 详情 详情
(XII) 25738 (3S,6R,7R,22R,23S,26S,36R,38aR)-7,22-Diacetoxy-28,30,32-triallyloxy-6-[N-(allyloxycarbonyl)-N-methyl-D-leucylamino]-3-(carbamoylmethyl)-10,19-dichloro-44-[3,4,6-tri-O-acetyl-beta-L-glucopyranosyloxy]-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid allyl ester; (3S,6R,7R,22R,23S,26S,36R,38aR)-7,22-Diacetoxy-28,30,32-triallyloxy-6-[N-(allyloxycarbonyl)-N-methyl-D-leucylamino]-3-(carbamoylmethyl)-10,19-dichloro-44-[3,4,6-tri-O-acetyl-beta-L-glucopyranosyloxy]-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid allyl ester C84H90Cl2N8O29 详情 详情
(XIII) 25739 (2S,3S,4S)-4-[[(allyloxy)carbonyl]amino]-2,4-dimethyl-6-(phenylsulfinyl)tetrahydro-2H-pyran-3-yl acetate C19H25NO6S 详情 详情
(XIV) 25740 (3S,6R,7R,22R,23S,26S,36R,38aR)-7,22-Diacetoxy-28,30,32-triallyloxy-6-[N-(allyloxycarbonyl)-N-methyl-D-leucylamino]-3-(carbamoylmethyl)-10,19-dichloro-44-[3,4,6-tri-O-acetyl-2-O-[3-(allyloxycarbonylamino)-2,3,6,trideoxy-3-C-methyl-beta-L-glucopyranosyloxy]-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid allyl ester; (3S,6R,7R,22R,23S,26S,36R,38aR)-7,22-Diacetoxy-28,30,32-triallyloxy-6-[N-(allyloxycarbonyl)-N-methyl-D-leucylamino]-3-(carbamoylmethyl)-10,19-dichloro-44-[3,4,6-tri-O-acetyl-2-O-[3-(allyloxycarbonylamino)-2,3,6,trideoxy-3-C-methyl-beta-L-glucopyranosyloxy]-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid allyl ester C96H109Cl2N9O32 详情 详情

合成路线5

Subsequent deacetylation with hydrazine produced (XV), from which the allyl and allyloxycarbonyl groups were finally removed by treatment with tributyltin hydride and palladium catalyst.

参考文献 中间体
【1】 Thompson, C.; et al.; Synthesis of vancomycin from the aglycon. J Am Chem Soc 1999, 121, 6, 1237.
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) 25740 (3S,6R,7R,22R,23S,26S,36R,38aR)-7,22-Diacetoxy-28,30,32-triallyloxy-6-[N-(allyloxycarbonyl)-N-methyl-D-leucylamino]-3-(carbamoylmethyl)-10,19-dichloro-44-[3,4,6-tri-O-acetyl-2-O-[3-(allyloxycarbonylamino)-2,3,6,trideoxy-3-C-methyl-beta-L-glucopyranosyloxy]-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid allyl ester; (3S,6R,7R,22R,23S,26S,36R,38aR)-7,22-Diacetoxy-28,30,32-triallyloxy-6-[N-(allyloxycarbonyl)-N-methyl-D-leucylamino]-3-(carbamoylmethyl)-10,19-dichloro-44-[3,4,6-tri-O-acetyl-2-O-[3-(allyloxycarbonylamino)-2,3,6,trideoxy-3-C-methyl-beta-L-glucopyranosyloxy]-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid allyl ester C96H109Cl2N9O32 详情 详情
(XV) 25741 (3S,6R,7R,22R,23S,26S,36R,38aR)-28,30,32-Triallyloxy-6-[N-(allyloxycarbonyl)-N-methyl-D-leucylamino]-44-[2-O-[3-(allyloxycarbonylamino)-2,3,6-trideoxy-3-C-methyl-beta-L-glucopyranosyloxy]-3-(carbamoylmethyl)-10,19-dichloro-7,22-dihyroxy-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid allyl ester; (3S,6R,7R,22R,23S,26S,36R,38aR)-28,30,32-Triallyloxy-6-[N-(allyloxycarbonyl)-N-methyl-D-leucylamino]-44-[2-O-[3-(allyloxycarbonylamino)-2,3,6-trideoxy-3-C-methyl-beta-L-glucopyranosyloxy]-3-(carbamoylmethyl)-10,19-dichloro-7,22-dihyroxy-2,3,4,5,6,7,23,24,25,26,36,37,38,38a-tetradecahydro-1H,22H-8,11:18,21-dietheno-23,36-(iminomethano)-13,16:31,35-dimetheno-[1,6,9]oxadiazacyclohexadecino[4,5-m][10,2,16]benzoxadiazacyclotetracosine-26-carboxylic acid allyl ester C85H97Cl2N9O28 详情 详情

合成路线6

The cyclization of tripeptide derivative (I) (assembled in three steps from the corresponding amino acids) by means of K2CO3/CaCO3 gives the macrocyclic peptide (II), which was reduced at its NO2 group with H2 over Pd/C and treated with tert-butyl nitrite, HBF4 and CuCl2 to obtain the corresponding chloro derivative (III). The condensation of (III) with the boronic acid derivative (IV) by means of a Pd catalyst affords the biphenyl derivative (V), which is desilylated with Bu4NF, giving the secondary alcohol (VI). The hydrolysis of the methyl ester of (VI) with LiOH yields the corresponding carboxylic acid (VII).

参考文献 中间体
【1】 Boger, D.L.; et al.; Diasteroselective total synthesis of the vancomycin aglycon with ordered atropisomer equilibrations. J Am Chem Soc 1999, 121, 13, 3226.
【2】 Boger, D.L.; et al.; Total synthesis of the vancomycin aglycon. J Am Chem Soc 1999, 121, 43, 10004.
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) 42041 methyl (6R,9R)-9-(3-bromo-4-methoxyphenyl)-12-[(R)-[[tert-butyl(dimethyl)silyl]oxy](4-fluoro-3-nitrophenyl)methyl]-6-(3,5-dihydroxy-4-methoxyphenyl)-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oate C39H50BrFN4O13Si 详情 详情
(II) 42042 　 C39H49BrN4O13Si 详情 详情
(III) 42043 　 C39H49BrClN3O11Si 详情 详情
(IV) 42044 2-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4,6-dimethoxyphenylboronic acid C22H30BNO9 详情 详情
(V) 40566 methyl (8R,11R,14S,15R)-11-(2'-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-15-[[tert-butyl(dimethyl)silyl]oxy]-18-chloro-5-hydroxy-4-methoxy-9,12-diox; methyl (8R,11R,14S,15R)-11-(2'-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-15-[[tert-butyl(dimethyl)silyl]oxy]-18-chloro-5-hydroxy-4-methoxy-9,12-diox; methyl (8R,11R,14S,15R)-11-(2'-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-15-[[tert-butyl(dimethyl)silyl]oxy]-18-chloro-5-hydroxy-4-methoxy-9,12-diox C61H77ClN4O18Si 详情 详情
(VI) 40567 methyl (8R,11R,14S,15R)-11-(2'-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.; methyl (8R,11R,14S,15R)-11-(2'-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.; methyl (8R,11R,14S,15R)-11-(2'-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14. C55H63ClN4O18 详情 详情
(VII) 40568 (8R,11R,14S,15R)-11-(2'-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3; (8R,11R,14S,15R)-11-(2'-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3; (8R,11R,14S,15R)-11-(2'-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3 C54H61ClN4O18 详情 详情

合成路线7

Selective deprotection of the benzyloxycarbonylamino group of (VII) with H2 over Pd/C gives the corresponding amino derivative (VIII), which is cyclized by means of EDC and HOBT, yielding the bicyclic peptide (IX). Elimination of the Boc protecting group of (IX) with formic acid affords the primary amine (X) , which is acylated with the tripeptide intermediate (XI) by means of EDC and HOAt, providing the adduct (XII).

参考文献 中间体
【1】 Boger, D.L.; et al.; Diasteroselective total synthesis of the vancomycin aglycon with ordered atropisomer equilibrations. J Am Chem Soc 1999, 121, 13, 3226.
【2】 Boger, D.L.; et al.; Total synthesis of the vancomycin aglycon. J Am Chem Soc 1999, 121, 43, 10004.
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) 40568 (8R,11R,14S,15R)-11-(2'-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3; (8R,11R,14S,15R)-11-(2'-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3; (8R,11R,14S,15R)-11-(2'-[(1S)-1-[[(benzyloxy)carbonyl]amino]-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3 C54H61ClN4O18 详情 详情
(VIII) 40569 (8R,11R,14S,15R)-11-(2'-[(1S)-1-amino-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3,7)]henicosa-1(18),3(21; (8R,11R,14S,15R)-11-(2'-[(1S)-1-amino-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3,7)]henicosa-1(18),3(21; (8R,11R,14S,15R)-11-(2'-[(1S)-1-amino-2-[(2-methoxyethoxy)methoxy]ethyl]-4',6,6'-trimethoxy[1,1'-biphenyl]-3-yl)-8-[(tert-butoxycarbonyl)amino]-18-chloro-5,15-dihydroxy-4-methoxy-9,12-dioxo-2-oxa-10,13-diazatricyclo[14.2.2.1(3,7)]henicosa-1(18),3(21 C46H55ClN4O16 详情 详情
(IX) 40570 tert-butyl (1R,13S,16S,17R,28R)-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-15,29,31-trioxo-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(3; tert-butyl (1R,13S,16S,17R,28R)-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-15,29,31-trioxo-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(3; tert-butyl (1R,13S,16S,17R,28R)-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-15,29,31-trioxo-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(3 C46H53ClN4O15 详情 详情
(X) 40571 (1R,13S,16S,17R,28R)-28-amino-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(35),24,26,33-dodeca; (1R,13S,16S,17R,28R)-28-amino-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(35),24,26,33-dodeca; (1R,13S,16S,17R,28R)-28-amino-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriaconta-2(36),3,5,7,9,11,18,20,23(35),24,26,33-dodeca C41H45ClN4O13 详情 详情
(XI) 42051 (6R,9R,12S)-12-(cyanomethyl)-9-[(R)-(4-fluoro-3-nitrophenyl)(hydroxy)methyl]-6-isobutyl-2,2,5-trimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid C25H34FN5O9 详情 详情
(XII) 42052 tert-butyl (1R)-1-([[(1R,2R)-1-([[(1S)-2-[[(1R,13S,16S,17R,28R)-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-15,29,31-trioxo-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriac C66H77ClFN9O21 详情 详情

合成路线8

The cyclization of (XII) by means of CsF in DMSO gives the tris macrocyclic compound (XIII), which is reduced at the NO2 group with H2 over Pd/C, yielding the amino derivative (XIV). The diazotation of (XIV) with t-Bu-ONO and HBF4, followed by reaction with CuCl2/CuCl, affords the corresponding chloro derivative (XV), which is silylated with Tbdms-N(Me)-COCF3 to provide the bis silyl ether (XVI).

参考文献 中间体
【1】 Boger, D.L.; et al.; Diasteroselective total synthesis of the vancomycin aglycon with ordered atropisomer equilibrations. J Am Chem Soc 1999, 121, 13, 3226.
【2】 Boger, D.L.; et al.; Total synthesis of the vancomycin aglycon. J Am Chem Soc 1999, 121, 43, 10004.
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) 42052 tert-butyl (1R)-1-([[(1R,2R)-1-([[(1S)-2-[[(1R,13S,16S,17R,28R)-20-chloro-17,25-dihydroxy-5,8,10,24-tetramethoxy-13-[[(2-methoxyethoxy)methoxy]methyl]-15,29,31-trioxo-22-oxa-14,30,32-triazahexacyclo[14.14.2.2(18,21).1(2,6).1(23,27).0(7,12)]hexatriac C66H77ClFN9O21 详情 详情
(XIII) 42053 tert-butyl (1R)-1-([[(1S,2R,18R,19R,22S,25R,28R,40S)-5-chloro-22-(cyanomethyl)-2,18-dihydroxy-32,35,37,50-tetramethoxy-40-[[(2-methoxyethoxy)methoxy]methyl]-15-nitro-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6). C66H76ClN9O21 详情 详情
(XIV) 42054 tert-butyl (1R)-1-([[(1S,2R,18R,19R,22S,25R,28R,40S)-15-amino-5-chloro-22-(cyanomethyl)-2,18-dihydroxy-32,35,37,50-tetramethoxy-40-[[(2-methoxyethoxy)methoxy]methyl]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6). C66H78ClN9O19 详情 详情
(XV) 42055 tert-butyl (1R)-1-([[(1S,2R,18R,19R,22S,25R,28R,40S)-5,15-dichloro-22-(cyanomethyl)-2,18-dihydroxy-32,35,37,50-tetramethoxy-40-[[(2-methoxyethoxy)methoxy]methyl]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14 C66H76Cl2N8O19 详情 详情
(XVI) 42056 tert-butyl (1R)-1-([[(1S,2R,18R,19R,22S,25R,28R,40S)-2,18-bis[[tert-butyl(dimethyl)silyl]oxy]-5,15-dichloro-22-(cyanomethyl)-32,35,37,50-tetramethoxy-40-[[(2-methoxyethoxy)methoxy]methyl]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoct C78H104Cl2N8O19Si2 详情 详情

合成路线9

Elimination of the Mem protecting group of (XVI) by treatment with borane (XVII) gives the primary alcohol (XVIII), which is oxidated to the corresponding acid with DMP and NaClO2 and simultaneously methylated with Tms-CHN2 to yield the methyl ester (XIX). The controlled hydrolysis of the cyano group of (XIX) with H2O2 and K2CO3 affords the corresponding amide (XX), which is finally desilylated with TBAF and demethylated with AlBr3 to furnish the target aglycon.

参考文献 中间体
【1】 Boger, D.L.; et al.; Diasteroselective total synthesis of the vancomycin aglycon with ordered atropisomer equilibrations. J Am Chem Soc 1999, 121, 13, 3226.
【2】 Boger, D.L.; et al.; Total synthesis of the vancomycin aglycon. J Am Chem Soc 1999, 121, 43, 10004.
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) 42056 tert-butyl (1R)-1-([[(1S,2R,18R,19R,22S,25R,28R,40S)-2,18-bis[[tert-butyl(dimethyl)silyl]oxy]-5,15-dichloro-22-(cyanomethyl)-32,35,37,50-tetramethoxy-40-[[(2-methoxyethoxy)methoxy]methyl]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoct C78H104Cl2N8O19Si2 详情 详情
(XVII) 42057 2-Bromo-1,3,2-benzodioxaborole; B-Bromocatecholborane 51901-85-0 C6H4BBrO2 详情 详情
(XVIII) 42058 tert-butyl (1R)-1-([[(1S,2R,18R,19R,22S,25R,28R,40S)-2,18-bis[[tert-butyl(dimethyl)silyl]oxy]-5,15-dichloro-22-(cyanomethyl)-40-(hydroxymethyl)-32,35,37,50-tetramethoxy-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3, C74H96Cl2N8O17Si2 详情 详情
(XIX) 42059 methyl (1S,2R,18R,19R,22S,25R,28R,40S)-19-([(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoyl]amino)-2,18-bis[[tert-butyl(dimethyl)silyl]oxy]-5,15-dichloro-22-(cyanomethyl)-32,35,37,50-tetramethoxy-20,23,26,42,44-pentaoxo-7,13-dioxa-21,2 C75H96Cl2N8O18Si2 详情 详情
(XX) 42060 methyl (1S,2R,18R,19R,22S,25R,28R,40S)-22-(2-amino-2-oxoethyl)-19-([(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoyl]amino)-2,18-bis[[tert-butyl(dimethyl)silyl]oxy]-5,15-dichloro-32,35,37,50-tetramethoxy-20,23,26,42,44-pentaoxo-7,13-dio C75H98Cl2N8O19Si2 详情 详情
Extended Information