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【结 构 式】 
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【药物名称】NC2-86 【化学名称】Carbamic acid 3(R),9(R)-dihydroxy-14-[4(S)-(methoxymethoxy)-3(R),5(R)-dimethyl-6-oxotetrahydropyran-2(S)-yl]-2(S),8(S),10(S)-trimethyl-1(S)-[1(S)-methylpenta-2(Z),4-dienyl]tetradeca-6(Z),11(Z)-dienyl ester 【CA登记号】 【 分 子 式 】C33H55NO8 【 分 子 量 】593.8082 |
【开发单位】University of Pittsburgh (Originator), Cellomics (Codevelopment) 【药理作用】ONCOLYTIC DRUGS, Antimitotic Drugs, Microtubule-Stabilizing Agents |
合成路线1
Protection of (S)-3-hydroxy-2-methylpropionic acid methyl ester (I) as the corresponding silyl ether, followed by reduction with DIBAL provides the aldehyde (II). Diastereoselective aldol condensation of (II) with the chiral N-propionyl oxazolidinone (III) in the presence of dibutylboron triflate leads to adduct (IV), which is then reduced with LiBH4 to give the diol (V). The diol (V) is protected as the cyclic ketal (VII) by treatment with anisaldehyde dimethylacetal (VI) in the presence of pyridinium p-toluenesulfonate (PPTS). Desilylation of (VII) using tetrabutylammonium fluoride yields the alcohol (VIII). Subsequent iodination of (VIII) with I2/PPh3, followed by displacement of alkyl iodide (IX) with PPh3 in refluxing benzene, furnishes the phosphonium salt (X).
| 【1】 Choy, N.; Shin, Y.; Nguyen, P.Q.; Curran, D.P.; Balachandran, R.; Madiraju, C.; Day, B.W.; Simplified discodermolide analogues: Synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents. J Med Chem 2003, 46, 14, 2846. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 42624 | (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropanal | C10H22O2Si | 详情 | 详情 | |
| (III) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (IV) | 64732 | 3-(5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-hydroxy-2,4-dimethylpentanoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one | C23H37NO5Si | 详情 | 详情 | |
| (V) | 64733 | 5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,4-dimethyl-1,3-pentanediol | C13H30O3Si | 详情 | 详情 | |
| (VI) | 26485 | 1-(dimethoxymethyl)-4-methoxybenzene | 2186-92-7 | C10H14O3 | 详情 | 详情 |
| (VII) | 64734 | (1,1-dimethylethyl)(dimethyl)[(2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}propyl)oxy]silane; (1,1-dimethylethyl)(dimethyl)silyl 2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}propyl ether | C21H36O4Si | 详情 | 详情 | |
| (VIII) | 64735 | 2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}-1-propanol | C15H22O4 | 详情 | 详情 | |
| (IX) | 64736 | 4-(2-iodo-1-methylethyl)-5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxane; 4-[4-(2-iodo-1-methylethyl)-5-methyl-1,3-dioxan-2-yl]phenyl methyl ether | C15H21IO3 | 详情 | 详情 | |
| (X) | 64737 | (2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}propyl)(triphenyl)phosphonium iodide | C33H36IO3P | 详情 | 详情 |
合成路线2
Mono-protection of 1,4-butanediol (XI) by means of 4-methoxybenzyl chloride, followed by Swern oxidation with DMSO/SO3-Pyr, leads to the aldehyde (XII). Condensation of (XII)with the boron enolate of the N-propionyl oxazolidinone (III) and subsequent silylation with tert-butyldimethylsilyl triflate furnishes the N-acyl oxoazolidinone (XIII), which is reduced by LiBH4 to the primary alcohol (XIV), which is then subjected to Swern oxidation to produce the aldehyde (XV). Further condensation of (XV) with acyl oxazolidinone (III) leads to adduct (XVI). The free hydroxyl group of (XVI) is alkylated with chloromethyl methyl ether to produce the O-methoxymethyl derivative (XVII), which under desilylation conditions with HF-pyridine cyclizes to the lactone (XVIII).
| 【1】 Choy, N.; Shin, Y.; Nguyen, P.Q.; Curran, D.P.; Balachandran, R.; Madiraju, C.; Day, B.W.; Simplified discodermolide analogues: Synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents. J Med Chem 2003, 46, 14, 2846. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (XI) | 46190 | (1R,2R,6S)-1-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-hydroxy-2,6-dimethyl-7-octenyl methanesulfonate | C26H47NO5S2Si | 详情 | 详情 | |
| (XII) | 64738 | 4-({[4-(methyloxy)phenyl]methyl}oxy)butanal | C12H16O3 | 详情 | 详情 | |
| (XIII) | 64739 | 3-[3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-6-({[4-(methyloxy)phenyl]methyl}oxy)hexanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one | C31H45NO6Si | 详情 | 详情 | |
| (XIV) | 64740 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-6-({[4-(methyloxy)phenyl]methyl}oxy)-1-hexanol | C21H38O4Si | 详情 | 详情 | |
| (XV) | 64741 | 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-6-({[4-(methyloxy)phenyl]methyl}oxy)hexanal | C21H36O4Si | 详情 | 详情 | |
| (XVI) | 64742 | C34H51NO7Si | 详情 | 详情 | ||
| (XVII) | 64743 | 3-[5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,4-dimethyl-3-{[(methyloxy)methyl]oxy}-8-({[4-(methyloxy)phenyl]methyl}oxy)octanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one | C36H55NO8Si | 详情 | 详情 | |
| (XVIII) | 64744 | 3,5-dimethyl-4-{[(methyloxy)methyl]oxy}-6-[3-({[4-(methyloxy)phenyl]methyl}oxy)propyl]tetrahydro-2H-pyran-2-one | C20H30O6 | 详情 | 详情 |
合成路线3
The lactone (XVIII) is reduced by means of DIBAL to the corresponding lactol (XIX). Treatment of (XIX) with MeOH and PPTS generates an anomeric mixture of methyl ketals, from which isomer (XX) can be separated by column chromatography. Catalytic hydrogenolysis of the p-methoxybenzyl moiety of (XX) leads to alcohol (XXI), which is further converted into aldehyde (XXII) by Dess-Martin oxidation. Wittig condensation between aldehyde (XXII) and phosphonium salt (X) affords the cis-olefin (XXIII). Reductive opening of the cyclic acetal (XXIII) utilizing DIBAL produces the mono-benzylated diol (XXIV), which is then oxidized to aldehyde (XXV) under Swern conditions.
| 【1】 Choy, N.; Shin, Y.; Nguyen, P.Q.; Curran, D.P.; Balachandran, R.; Madiraju, C.; Day, B.W.; Simplified discodermolide analogues: Synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents. J Med Chem 2003, 46, 14, 2846. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 64737 | (2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}propyl)(triphenyl)phosphonium iodide | C33H36IO3P | 详情 | 详情 | |
| (XVIII) | 64744 | 3,5-dimethyl-4-{[(methyloxy)methyl]oxy}-6-[3-({[4-(methyloxy)phenyl]methyl}oxy)propyl]tetrahydro-2H-pyran-2-one | C20H30O6 | 详情 | 详情 | |
| (XIX) | 64745 | 3,5-dimethyl-4-{[(methyloxy)methyl]oxy}-6-[3-({[4-(methyloxy)phenyl]methyl}oxy)propyl]tetrahydro-2H-pyran-2-ol | C20H32O6 | 详情 | 详情 | |
| (XX) | 64746 | 3,5-dimethyl-4-{[(methyloxy)methyl]oxy}-6-[3-({[4-(methyloxy)phenyl]methyl}oxy)propyl]tetrahydro-2H-pyran-2-yl methyl ether; 3,5-dimethyl-2-(methyloxy)-4-{[(methyloxy)methyl]oxy}-6-[3-({[4-(methyloxy)phenyl]methyl}oxy)propyl]tetrahydro-2H-pyran | C21H34O6 | 详情 | 详情 | |
| (XXI) | 64747 | 3-(3,5-dimethyl-6-(methyloxy)-4-{[(methyloxy)methyl]oxy}tetrahydro-2H-pyran-2-yl)-1-propanol | C13H26O5 | 详情 | 详情 | |
| (XXII) | 64748 | 3-(3,5-dimethyl-6-(methyloxy)-4-{[(methyloxy)methyl]oxy}tetrahydro-2H-pyran-2-yl)propanal | C13H24O5 | 详情 | 详情 | |
| (XXIII) | 64749 | 3,5-dimethyl-6-(5-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}-3-hexenyl)-4-{[(methyloxy)methyl]oxy}tetrahydro-2H-pyran-2-yl methyl ether; 4-[5-(3,5-dimethyl-6-(methyloxy)-4-{[(methyloxy)methyl]oxy}tetrahydro-2H-pyran-2-yl)-1-methyl-2-pentenyl]-5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxane | C28H44O7 | 详情 | 详情 | |
| (XXIV) | 64750 | 8-(3,5-dimethyl-6-(methyloxy)-4-{[(methyloxy)methyl]oxy}tetrahydro-2H-pyran-2-yl)-2,4-dimethyl-3-({[4-(methyloxy)phenyl]methyl}oxy)-5-octen-1-ol | C28H46O7 | 详情 | 详情 | |
| (XXV) | 64751 | 8-(3,5-dimethyl-6-(methyloxy)-4-{[(methyloxy)methyl]oxy}tetrahydro-2H-pyran-2-yl)-2,4-dimethyl-3-({[4-(methyloxy)phenyl]methyl}oxy)-5-octenal | C28H44O7 | 详情 | 详情 |
合成路线4
Wittig condensation of aldehyde (XXV) with the phosphonium salt (XXVI) produces the olefin adduct (XXVII). The O-silyl protecting group of (XXVII) is then removed by treatment with tetrabutylammonium fluoride to afford alcohol (XXVIII).
| 【1】 Choy, N.; Shin, Y.; Nguyen, P.Q.; Curran, D.P.; Balachandran, R.; Madiraju, C.; Day, B.W.; Simplified discodermolide analogues: Synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents. J Med Chem 2003, 46, 14, 2846. |
| 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) | 64751 | 8-(3,5-dimethyl-6-(methyloxy)-4-{[(methyloxy)methyl]oxy}tetrahydro-2H-pyran-2-yl)-2,4-dimethyl-3-({[4-(methyloxy)phenyl]methyl}oxy)-5-octenal | C28H44O7 | 详情 | 详情 | |
| (XXVI) | 64752 | [6-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5,7-dimethyl-4-({[4-(methyloxy)phenyl]methyl}oxy)-8,10-undecadienyl](triphenyl)phosphonium iodide | C45H60IO3PSi | 详情 | 详情 | |
| (XXVII) | 64753 | (1,1-dimethylethyl)(dimethyl)silyl 14-(3,5-dimethyl-6-(methyloxy)-4-{[(methyloxy)methyl]oxy}tetrahydro-2H-pyran-2-yl)-2,8,10-trimethyl-3,9-bis({[4-(methyloxy)phenyl]methyl}oxy)-1-(1-methyl-2,4-pentadienyl)-6,11-tetradecadienyl ether; (1,1-dimethylethyl){[14-(3,5-dimethyl-6-(methyloxy)-4-{[(methyloxy)methyl]oxy}tetrahydro-2H-pyran-2-yl)-2,8,10-trimethyl-3,9-bis({[4-(methyloxy)phenyl]methyl}oxy)-1-(1-methyl-2,4-pentadienyl)-6,11-tetradecadienyl]oxy}dimethylsilane | C55H88O9Si | 详情 | 详情 | |
| (XXVIII) | 64754 | 19-(3,5-dimethyl-6-(methyloxy)-4-{[(methyloxy)methyl]oxy}tetrahydro-2H-pyran-2-yl)-5,7,13,15-tetramethyl-8,14-bis({[4-(methyloxy)phenyl]methyl}oxy)-1,3,11,16-nonadecatetraen-6-ol | C49H74O9 | 详情 | 详情 |
合成路线5
Acylation of alcohol (XXVIII) with trichloroacetyl isocyanate, followed by alkaline hydrolysis of the trichloroacetyl group leads to the carbamate (XXIX). The methyl acetal function of (XXIX) is then hydrolyzed with aqueous AcOH, and the resultant lactol is further oxidized to the corresponding lactone (XXX) by means of the Dess-Martin periodinane reagent. Finally, removal of the p-methoxybenzyl protecting groups of (XXX) in the presence of DDQ provides the target compound.
| 【1】 Choy, N.; Shin, Y.; Nguyen, P.Q.; Curran, D.P.; Balachandran, R.; Madiraju, C.; Day, B.W.; Simplified discodermolide analogues: Synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents. J Med Chem 2003, 46, 14, 2846. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVIII) | 64754 | 19-(3,5-dimethyl-6-(methyloxy)-4-{[(methyloxy)methyl]oxy}tetrahydro-2H-pyran-2-yl)-5,7,13,15-tetramethyl-8,14-bis({[4-(methyloxy)phenyl]methyl}oxy)-1,3,11,16-nonadecatetraen-6-ol | C49H74O9 | 详情 | 详情 | |
| (XXIX) | 64755 | C50H75NO10 | 详情 | 详情 | ||
| (XXX) | 64756 | 14-(3,5-dimethyl-4-{[(methyloxy)methyl]oxy}-6-oxotetrahydro-2H-pyran-2-yl)-2,8,10-trimethyl-3,9-bis({[4-(methyloxy)phenyl]methyl}oxy)-1-(1-methyl-2,4-pentadienyl)-6,11-tetradecadienyl carbamate | C49H71NO10 | 详情 | 详情 |