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【结 构 式】 
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【分子编号】33696 【品名】3-[([1-[(1-[[(3-hydroxypropyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)amino]-1-propanol 【CA登记号】 |
【 分 子 式 】C20H40N2O2S2 【 分 子 量 】404.68188 【元素组成】C 59.36% H 9.96% N 6.92% O 7.91% S 15.85% |
合成路线1
该中间体在本合成路线中的序号：5) A second coupling reaction was the addition of the phosphonamide (XX) to the aldehyde (LI) by means of butyllithium in THF to give the dithianylolefin (LII), which was treated first with TFIB and methanol and then with acetic acid, yielding the free aldeyde (LIII). The condensation of (LIII) with methyl 2-(2,4-dimethoxybenzyloxy)acetate (LIV) by means of lithium diisopropylamide in THF, followed by a treatment with LiOH affords the hydroxy acid (LV), which is protected with TES trifluoromethylsulfonate and treated with 2,6-dimethylpyridine to give the free amino acid (LVI), the open-chain precursor of FK-506.
| 【1】 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 33696 | 3-[([1-[(1-[[(3-hydroxypropyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)amino]-1-propanol | C20H40N2O2S2 | 详情 | 详情 | ||
| (XX) | 11491 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide | C28H61N2O4PS2Si | 详情 | 详情 | |
| (LI) | 11490 | 1-(tert-butyl) 2-[(1S,2S,3S,5S,6S)-6-formyl-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl] (2S)-1,2-piperidinedicarboxylate | C58H101NO9Si2 | 详情 | 详情 | |
| (LII) | 11492 | 2-[(1S,2S,3S,5S,6S,7E,10S,12S,13R,14S,16R)-6-allyl-16-(1,3-dithian-2-yl)-12,14-dimethoxy-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10-trimethyl-3,13-bis[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C85H155NO11S2Si3 | 详情 | 详情 | |
| (LIII) | 11493 | 2-[(1S,2S,3S,5S,6S,7E,10S,12S,14R,15S,16R)-6-allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-12,14-dimethoxy-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-17-oxo-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C79H143NO12Si3 | 详情 | 详情 | |
| (LIV) | 57274 | methyl 2-[(2,4-dimethoxybenzyl)oxy]acetate | C12H16O5 | 详情 | 详情 | |
| (LV) | 11494 | 2-[(1S,2S,3S,6S,7E,10S,12S,13R,14S,16R)-6-allyl-13-[[tert-butyl(dimethyl)silyl]oxy]-18-[(2,4-dimethoxybenzyl)oxy]-17-hydroxy-12,14,19-trimethoxy-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-19-oxo-3-[(triisopropylsilyl)oxy]-7-nonadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C91H159NO17Si3 | 详情 | 详情 | |
| (LVI) | 11495 | (4R,6S,7R,8S,10S,12E,14R,15S,17S,18S,19S,20E)-14-Allyl-7-[[tert-butyl(dimethyl)silyl]oxy]-2-[(2,4-dimethoxybenzyl)oxy]-6,8-dimethoxy-15-[(4-methoxybenzyl)oxy]-21-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,10,12,18,20-pentamethyl-19-[[(2S)piperidinylcarbonyl]oxy]-3-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoic acid | C91H163NO16Si4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Treatment of cyclohexanecarboxaldehyde (I) with sulfur monochloride produced the dimeric disulfide (II). After condensation of (II) with 3-amino-1-propanol (III), reduction with NaBH4 afforded diamine (IV). Subsequent N-methylation of (IV) to give (VI) was achieved by condensation with formaldehyde, followed by NaBH4 reduction of the resulting oxazine (V). Reductive cleavage of the disulfide group of (VI) using LiAlH4 provided thiol (VII). Optionally, nitrosation of the sulfhydryl group of (VII) by means of tert-butyl nitrite gave rise to the nitrosothio derivative (VIII). Further coupling of this compound with diclofenac (IX) in the presence of DCC and DMAP furnished the title ester. Alternatively, the title compound was prepared by esterification of mercapto alcohol (VII) with diclofenac, followed by S-nitrosation of the resulting ester (X).
| 【1】 Bandarage, U.K.; et al.; Nitrosothiol esters of diclofonecac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs. J Med Chem 2000, 43, 21, 4005. |
| 【2】 Bandarage, U.K.; et al.; NMI-377, a nitric oxide-donating diclofenac derivative with gastroprotective properties. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 81. |
| 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) | 33694 | cyclohexanecarbaldehyde | 2043-61-0 | C7H12O | 详情 | 详情 |
| (II) | 33695 | 1-[(1-formylcyclohexyl)disulfanyl]cyclohexanecarbaldehyde | C14H22O2S2 | 详情 | 详情 | |
| (III) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
| (IV) | 33696 | 3-[([1-[(1-[[(3-hydroxypropyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)amino]-1-propanol | C20H40N2O2S2 | 详情 | 详情 | |
| (V) | 33697 | bis[1-(1,3-oxazinan-3-ylmethyl)cyclohexyl] disulfide; 3-[(1-[[1-(1,3-oxazinan-3-ylmethyl)cyclohexyl]disulfanyl]cyclohexyl)methyl]-1,3-oxazinane | C22H40N2O2S2 | 详情 | 详情 | |
| (VI) | 33698 | 3-[([1-[(1-[[(3-hydroxypropyl)(methyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)(methyl)amino]-1-propanol | C22H44N2O2S2 | 详情 | 详情 | |
| (VII) | 33699 | 3-[methyl[(1-sulfanylcyclohexyl)methyl]amino]-1-propanol | C11H23NOS | 详情 | 详情 | |
| (VIII) | 33700 | 1-[[(3-hydroxypropyl)(methyl)amino]methyl]-N-oxocyclohexanesulfenamide | C11H22N2O2S | 详情 | 详情 | |
| (IX) | 33701 | Diclofenac; 2-[2-(2,6-Dichloroanilino)phenyl]acetic acid | C14H11Cl2NO2 | 详情 | 详情 | |
| (X) | 33702 | 3-[methyl[(1-sulfanylcyclohexyl)methyl]amino]propyl 2-[2-(2,6-dichloroanilino)phenyl]acetate | C25H32Cl2N2O2S | 详情 | 详情 |