ER-112022, -Drug Synthesis Database

【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 合成路线2 合成路线3

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.

参考文献中间体

【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).

参考文献中间体

【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.

参考文献中间体

【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

Drug NewChemical Entity Original Patent(1)