-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】(1R,2R,3aR,3bS,5R,8S,11S,14S,16R,18R,19aS,20aS,22S,23R,24aS,25S,25aR,29R,30aS,31S,32aR)-22-Hydroxy-23-(hydroxymethyl)-16,25-dimethyl-10,15-dimethylideneperhydro-1,5:8,11,14,18-triepoxy-29,31-ethano-2,5-methanofuro[2',3':5,6]pyrano[4,3-b]pyrano[2',3':5,6]pyrano[3,2-i][1,4,8]trioxacyclopentacosin-27-one

【CA登记号】

【分子式】C₄₁H₅₈O₁₃

【分子量】758.91161

【开发单位】Eisai (Originator)

【药理作用】ONCOLYTIC DRUGS, Antimitotic Drugs, Microtubule-Stabilizing Agents

合成路线1 合成路线2

合成路线1

Dess-Martin oxidation of alcohol (I) in CH2Cl2 yields aldehyde (II), which is then subjected to a Horner-Emmons reaction with phosphonate (III) in THF in the presence of NaH to provide compound (IV). Enone (IV) is then converted into intermediate (V) by first conjugate reduction by the Stryker reagent, reduction with NaBH4 in MeOH of the resulting saturated ketone, separation of the two possible diastereomers obtained and final mesylation by means of Ms2O and Et3N. Dess-Martin oxidation of the primary alcohol (VI) affords aldehyde (VII), which is then coupled to mesylate (V) by means of NiCl2-CrCl2 in DMF/THF. The resulting product is subjected to cyclization by means of KH in DME to furnish tetrahydropyran derivative (VIII). Reduction of (VIII) with LiAlH4 in Et2O yields alcohol (IX), which is then oxidized by the Dess Martin reagent to give aldehyde (X). Coupling of (X) with compound (XI) by means of NiCl2-CrCl2 in DMF/THF affords ketone (XII).

参考文献中间体

【1】 Aicher, T.D.; et al.; Total synthesis of halichondrin B and norhalichondrin B. J Am Chem Soc 1992, 114, 8, 3162.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	48410	3-[(2S,5R)-5-(hydroxymethyl)-4-methylenetetrahydro-2-furanyl]propyl pivalate	C₁₄H₂₄O₄	详情	详情
(II)	48411	3-[(2S,5R)-5-formyl-4-methylenetetrahydro-2-furanyl]propyl pivalate	C₁₄H₂₂O₄	详情	详情
(III)	48412	dimethyl (4R)-5-iodo-4-methyl-2-oxo-5-hexenylphosphonate	C₉H₁₆IO₄P	详情	详情
(IV)	48413	3-[(2S,5S)-5-[(1Z,5R)-6-iodo-5-methyl-3-oxo-1,6-heptadienyl]-4-methylenetetrahydro-2-furanyl]propyl pivalate	C₂₁H₃₁IO₄	详情	详情
(V)	48414	3-[(2S,5S)-5-((3R,5R)-6-iodo-5-methyl-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-heptenyl)-4-methylenetetrahydro-2-furanyl]propyl pivalate	C₂₄H₄₁IO₄S	详情	详情
(VI)	48415	2-[(2S,3R,4R,4aS,6R,7R,8aS)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-[(4-methoxybenzyl)oxy]-4-methyloctahydropyrano[3,2-b]pyran-2-yl]-1-ethanol	C₃₂H₅₈O₇Si₂	详情	详情
(VII)	48416	2-[(2S,3R,4R,4aS,6R,7R,8aS)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-[(4-methoxybenzyl)oxy]-4-methyloctahydropyrano[3,2-b]pyran-2-yl]acetaldehyde	C₃₂H₅₆O₇Si₂	详情	详情
(VIII)	48417	3-((2S,5S)-5-[2-[(4R,6R)-2-([(2S,3R,4R,4aS,6R,7R,8aS)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-[(4-methoxybenzyl)oxy]-4-methyloctahydropyrano[3,2-b]pyran-2-yl]methyl)-4-methyl-3-methylene-1,2-oxazinan-6-yl]ethyl]-4-methylenetetrahydro-2-furanyl)propyl 2,2-dimethylpropanoate	C₅₂H₈₉NO₁₀Si₂	详情	详情
(IX)	48418	3-((2S,5S)-5-[2-[(4R,6R)-2-([(2S,3R,4R,4aS,6R,7R,8aS)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-[(4-methoxybenzyl)oxy]-4-methyloctahydropyrano[3,2-b]pyran-2-yl]methyl)-4-methyl-3-methylene-1,2-oxazinan-6-yl]ethyl]-4-methylenetetrahydro-2-furanyl)-1-propanol	C₄₇H₈₁NO₉Si₂	详情	详情
(X)	48419	3-((2S,5S)-5-[2-[(4R,6R)-2-([(2S,3R,4R,4aS,6R,7R,8aS)-7-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-[(4-methoxybenzyl)oxy]-4-methyloctahydropyrano[3,2-b]pyran-2-yl]methyl)-4-methyl-3-methylene-1,2-oxazinan-6-yl]ethyl]-4-methylenetetrahydro-2-furanyl)propanal	C₄₇H₇₉NO₉Si₂	详情	详情
(XI)	48420	methyl 2-[(2R,4aS,6S,7R,8S,8aS)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-6-((1S,2E)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-iodo-2-propenyl)octahydropyrano[3,2-b]pyran-2-yl]acetate	C₃₂H₆₃IO₇Si₃	详情	详情
(XII)	48421		C₇₉H₁₄₁NO₁₆Si₅	详情	详情

合成路线2

The next steps for conversion of (XII) into (XIII) are: Dess-Martin oxidation, removal of the (p-methoxyphenyl)methyl group (MPM) by means of DDQ in phosphate buffer/tert-BuOH/CH2Cl2, hydrolysis of the methyl ester with LiOH in H2O/THF and, finally, Yamaguchi lactonization. Finally, the target product is obtained by removal of the TBDMS groups of lactone enone (XIII) with tetrabutyl ammonium fluoride (TBAF) in THF to furnish alcohol (XIV), followed by treatment with p-TsOH.Py (PPTS) in CH2Cl2, activation with p-nitrobenzoyl chloride in CH2Cl2 in the presence of pyridine, reaction with TBSOTf and Et3N in CH2Cl2, and final saponification with K2CO3 in MeOH.

参考文献中间体

【1】 Aicher, T.D.; et al.; Total synthesis of halichondrin B and norhalichondrin B. J Am Chem Soc 1992, 114, 8, 3162.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	48421		C₇₉H₁₄₁NO₁₆Si₅	详情	详情
(XIII)	48422		C₆₉H₁₂₈N₂O₁₄Si₅	详情	详情
(XIV)	48423	(3S,5S,7R,8R,10S,11S,12R,16R,19S,20R,21R,22S,23S,24S,30S,33S,36R,38R)-7,21,22,24-tetrahydroxy-8-(hydroxymethyl)-11,38-dimethyl-32,39-dimethylene-4,9,13,40,41,42,43-heptaoxa-1,26-diazaheptacyclo[34.3.1.1(16,20).1(19,23).1(30,33).0(3,12).0(5,10)]tritetracont-25-ene-14,27-	C₃₉H₅₈N₂O₁₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)