• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【药物名称】ER-112022

【化学名称】Bis[(5Z,5'Z)-5-Dodecenoic acid] (1R,32R)-6,27-bis(3-oxotetradecanamido)-1,32-diheptyl-9,24-dihydroxy-9,24-dioxido-14,19-dioxo-4,8,10,23,25,29-hexaoxa-13,20-diaza-9,24-diphosphadotriacontane-1,32-diyl ester disodium salt

【CA登记号】287180-46-5

【 分 子 式 】C88H162N4Na2O20P2

【 分 子 量 】1704.21434

【开发单位】Eisai (Originator)

【药理作用】ANTIINFECTIVE THERAPY, Treatment of Septic Shock

合成路线1

2-Amino-1,3-propanediol (I) was reacted with in situ generated trifluoromethanesulfonyl azide, and the resulting 2-azido compound was purified by chromatography after conversion to the diacetate ester (II). Deacetylation of (II) with sodium methoxide gave 2-azido-1,3-propanediol (III), which was condensed with tosylate (IV) in the presence of NaH to produce the dihydroxyether (V). The primary alcohol group of (V) was then protected as the mono-silyl derivative (VI) employing tert-butyldiphenylsilyl chloride. After acylation of the free hydroxyl group of (VI) with the unsaturated acid (VII), the resulting ester (VIII) was desilylated by using HF in acetonitrile to yield alcohol (IX). The phosphorylating reagent (XII) was prepared by treatment of allyl phosphorodiamidite (X) with N-Boc-ethanolamine (XI). Phosphitylation of alcohol (IX) with phosphoramidite (XII), followed by oxidation of the intermediate phosphite ester with oxone , furnished phosphate (XIII). The azido group of (XIII) was then reduced to the corresponding amine (XIV) by employing (PhS)2Sn.

1 Rossignol, D.P.; Ishizaka, S.T.; Nault, A.; Lewis, M.; Rose, J.; McGuiness, P.; Hawkins, L.D. (Eisai Co., Ltd.); Immunological adjuvant cpd.. EP 1147117; US 6290973; WO 0044758 .
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) 23333 2-amino-1,3-propanediol; serinol 534-03-2 C3H9NO2 详情 详情
(II) 49119 3-(acetoxy)-2-azidopropyl acetate C7H11N3O4 详情 详情
(III) 49120 2-azido-1,3-propanediol C3H7N3O2 详情 详情
(IV) 49121 (3R)-3-hydroxydecyl 4-methylbenzenesulfonate C17H28O4S 详情 详情
(V) 49122 (3R)-1-(2-azido-3-hydroxypropoxy)-3-decanol C13H27N3O3 详情 详情
(VI) 49123 (3R)-1-(2-azido-3-[[tert-butyl(diphenyl)silyl]oxy]propoxy)-3-decanol C29H45N3O3Si 详情 详情
(VII) 49124 (Z)-5-dodecenoic acid C12H22O2 详情 详情
(VIII) 49125 (1R)-1-[2-(2-azido-3-[[tert-butyl(diphenyl)silyl]oxy]propoxy)ethyl]octyl (Z)-5-dodecenoate C41H65N3O4Si 详情 详情
(IX) 49126 (1R)-1-[2-(2-azido-3-hydroxypropoxy)ethyl]octyl (Z)-5-dodecenoate C25H47N3O4 详情 详情
(X) 49127   C15H33N2OP 详情 详情
(XI) 32500 tert-butyl 2-hydroxyethylcarbamate 26690-80-2 C7H15NO3 详情 详情
(XII) 49128   C16H33N2O4P 详情 详情
(XIII) 49129 (1R)-9-(allyloxy)-6-azido-1-heptyl-16,16-dimethyl-9,14-dioxo-4,8,10,15-tetraoxa-13-aza-9lambda(5)-phosphaheptadec-1-yl (Z)-5-dodecenoate C35H65N4O9P 详情 详情
(XIV) 49130 (1R)-9-(allyloxy)-6-amino-1-heptyl-16,16-dimethyl-9,14-dioxo-4,8,10,15-tetraoxa-13-aza-9lambda(5)-phosphaheptadec-1-yl (Z)-5-dodecenoate C35H67N2O9P 详情 详情

合成路线2

After conversion of amine (XIV) to the ketoamide (XV), the N-Boc group was cleaved with trifluoroacetic acid to provide the primary amine (XVI). Condensation of adipic acid (XVII) with amine (XVI) in the presence of EDC gave rise to the diamide (XVIII).

1 Rossignol, D.P.; Ishizaka, S.T.; Nault, A.; Lewis, M.; Rose, J.; McGuiness, P.; Hawkins, L.D. (Eisai Co., Ltd.); Immunological adjuvant cpd.. EP 1147117; US 6290973; WO 0044758 .
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) 49130 (1R)-9-(allyloxy)-6-amino-1-heptyl-16,16-dimethyl-9,14-dioxo-4,8,10,15-tetraoxa-13-aza-9lambda(5)-phosphaheptadec-1-yl (Z)-5-dodecenoate C35H67N2O9P 详情 详情
(XV) 49131 (1R)-9-(allyloxy)-1-heptyl-16,16-dimethyl-9,14-dioxo-6-[(3-oxotetradecanoyl)amino]-4,8,10,15-tetraoxa-13-aza-9lambda(5)-phosphaheptadec-1-yl (Z)-5-dodecenoate C49H91N2O11P 详情 详情
(XVI) 49132 (1R)-9-(2-aminoethoxy)-1-heptyl-9-oxo-6-[(3-oxotetradecanoyl)amino]-4,8,10-trioxa-9lambda(5)-phospha-12-tridecen-1-yl (Z)-5-dodecenoate C44H83N2O9P 详情 详情
(XVII) 49133 Hexanedioic acid; Hexanedioic acid; 1,6-Hexanedioic acid; 1,4-Butanedicarboxylic acid; Adipic acid 124-04-9 C6H10O4 详情 详情
(XVIII) 49134 (1R,32R,38Z)-9,24-bis(allyloxy)-1,32-diheptyl-9,14,19,24,34-pentaoxo-6,27-bis[(3-oxotetradecanoyl)amino]-4,8,10,23,25,29,33-heptaoxa-13,20-diaza-9lambda(5),24lambda(5)-diphospha-38-pentatetraconten-1-yl (Z)-5-dodecenoate C94H172N4O20P2 详情 详情

合成路线3

The allyl phosphate groups were then deprotected by using phenylsilane and Pd catalyst, and the resulting diphosphoric acid was finally isolated as the corresponding disodium salt by lyophilization of its solution in aqueous NaOH.

1 Rossignol, D.P.; Ishizaka, S.T.; Nault, A.; Lewis, M.; Rose, J.; McGuiness, P.; Hawkins, L.D. (Eisai Co., Ltd.); Immunological adjuvant cpd.. EP 1147117; US 6290973; WO 0044758 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 49134 (1R,32R,38Z)-9,24-bis(allyloxy)-1,32-diheptyl-9,14,19,24,34-pentaoxo-6,27-bis[(3-oxotetradecanoyl)amino]-4,8,10,23,25,29,33-heptaoxa-13,20-diaza-9lambda(5),24lambda(5)-diphospha-38-pentatetraconten-1-yl (Z)-5-dodecenoate C94H172N4O20P2 详情 详情
Extended Information