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【结 构 式】 
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【分子编号】32808 【品名】2-chloro-1,1-dimethyl-2-oxoethyl acetate 【CA登记号】40635-66-3 |
【 分 子 式 】C6H9ClO3 【 分 子 量 】164.58836 【元素组成】C 43.79% H 5.51% Cl 21.54% O 29.16% |
合成路线1
该中间体在本合成路线中的序号：(XX)The intermediate chiral phosphonamide (XXXII) has been obtained as follows: The treatment of arabitol (XIX) with the Moffat reagent (alpha-acetoxy-isobutyric acyl chloride) (XX) gives the intermediate (XXI), which, without isolation, by treatment with NaOMe and with Tbdms-Cl yields the silylated diepoxide (XXII). The condensation of (XXII) with ethoxyethynyl lithium (XXIII) by means of BF3/Et2O, HgCl2 and Ts-OH affords the bis(lactone) (XXIV), which is methylated by means of methyl iodide and LDA to provide the dimethyl analogue (XXV). The hydrolysis and desilylation of (XXV) by means of HF, followed by reprotection with benzyl trichloroacetimidate, and exhaustive methylation with NaH and methyl iodide gives the chiral nonanedioic dimethyl ester (XXVI). The reductive cleavage of the benzyl ether group with H2 over Pd(OH)2, followed by cyclization by means of PPTS yields the lactone (XXVII). The reduction of (XXVII) with L-selectride, followed by protection with propane-1,3-dithiol and BF3/Et2O affords the 1,3-dithiane (XXVIII). The reduction of the lactone group of (XXVIII) with LiAlH4, followed by reaction with PPh3 and I2 provides the chiral nonyl iodide (XXIX). The protection of the OH group of (XXIX) by means of Tbdms-OTf gives the silyl ether (XXX), which is finally condensed with lithium derived ethylphosphonamide (XXXI) to yield the intermediate chiral phosphonamide (XXXII).
| 【1】 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 11442 | (2S,4S)-1,2,3,4,5-Pentanepentol; D-Arabinol | 488-82-4 | C5H12O5 | 详情 | 详情 |
| (XX) | 32808 | 2-chloro-1,1-dimethyl-2-oxoethyl acetate | 40635-66-3 | C6H9ClO3 | 详情 | 详情 |
| (XXI) | 57258 | (1R,3R)-3-(acetyloxy)-4-chloro-1-(chloromethyl)-2-hydroxybutyl acetate | C9H14Cl2O5 | 详情 | 详情 | |
| (XXII) | 11445 | tert-Butyl(dimethyl)silyl di[(2S)oxiranyl]methyl ether; tert-Butyl[di[(2S)oxiranyl]methoxy]dimethylsilane | C11H22O3Si | 详情 | 详情 | |
| (XXIII) | 55241 | (2-ethoxyethynyl)lithium | C4H5LiO | 详情 | 详情 | |
| (XXIV) | 11448 | (5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S)-5-oxotetrahydro-2-furanyl]methyl]dihydro-2(3H)-furanone | C15H26O5Si | 详情 | 详情 | |
| (XXV) | 11449 | (3R,5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]methyl]-3-methyldihydro-2(3H)-furanone | C17H30O5Si | 详情 | 详情 | |
| (XXVI) | 11452 | dimethyl (2R,4S,6S,8R)-5-(benzyloxy)-4,6-dimethoxy-2,8-dimethylnonanedioate | C22H34O7 | 详情 | 详情 | |
| (XXVII) | 11454 | methyl (2R,4S)-4-methoxy-4-[(2S,3S,5R)-3-methoxy-5-methyl-6-oxotetrahydro-2H-pyran-2-yl]-2-methylbutanoate | C14H24O6 | 详情 | 详情 | |
| (XXVIII) | 11456 | (3R,5S,6R)-6-[(1S,3R)-3-(1,3-Dithian-2-yl)-1-methoxybutyl]-5-methoxy-3-methyltetrahydro-2H-pyran-2-one | C16H28O4S2 | 详情 | 详情 | |
| (XXIX) | 11458 | (2R,4S,5S,6S,8R)-8-(1,3-Dithian-2-yl)-1-iodo-4,6-dimethoxy-2-methyl-5-nonanol | C16H31IO3S2 | 详情 | 详情 | |
| (XXX) | 11459 | tert-Butyl([(1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl]oxy)dimethylsilane; tert-Butyl(dimethyl)silyl (1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl ether | C22H45IO3S2Si | 详情 | 详情 | |
| (XXXI) | 57259 | {1-[bis(dimethylamino)phosphoryl]ethyl}lithium | C6H16LiN2OP | 详情 | 详情 | |
| (XXXII) | 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 |
合成路线2
该中间体在本合成路线中的序号：(A)The Grignard reaction of vinyloxirane (I) with phenylmagnesium bromide and CuCN in THF gives 4-phenyl-2-buten-1-ol (II), which is submitted to a Sharpless epoxidation with t-BuOOH and Ti(Oi-Pr)4 in dichloromethane in the presence of (-)-diethyl tartrate [(-)-DET] yielding the chiral epoxide (III). The reaction of (III) with Ti(Oi-Pr)2(N3)2 in refluxing benzene affords the 3(S)-azido-4-phenylbutane-1,2(S)-diol (IV), which is epoxidized with 2-acetoxy-2-methylpropionyl chloride (A) and NaOMe in THF to give the chiral azidoepoxide (V). The reaction of (V) with isobutylamine (VI) in hot isopropanol yields the secondary amine (VII), which is condensed with 4-methoxyphenylsulfonyl chloride (VIII) in pyridine affording the sulfonamide (IX). The reduction of the azido group of (IX) with H2 over Pd/C in methanol provides (X) with a primary amino group that is finally condensed with the succinimidinyl carbonate (XI) by means of triethylamine in acetonitrile.
| 【1】 Ghosh, A.K.; Kincaid, J.F.; Cho, W.; Walters, D.E.; Krishnan, K.; Hussain, K.A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.; Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 6, 687. |
| 【2】 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 . |
| 【3】 Ghosh, A.K.; et al.; Potent HIV protease inhibitors: The development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands. J Med Chem 1993, 36, 16, 2300. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 | |
| (A) | 32808 | 2-chloro-1,1-dimethyl-2-oxoethyl acetate | 40635-66-3 | C6H9ClO3 | 详情 | 详情 |
| (I) | 32805 | 2-vinyloxirane | 930-22-3 | C4H6O | 详情 | 详情 |
| (II) | 32806 | (E)-4-phenyl-2-buten-1-ol | C10H12O | 详情 | 详情 | |
| (III) | 32807 | [(2R,3S)-3-benzyloxiranyl]methanol | 116949-62-3 | C10H12O2 | 详情 | 详情 |
| (IV) | 14544 | (2S,3S)-3-azido-4-phenyl-1,2-butanediol | C10H13N3O2 | 详情 | 详情 | |
| (V) | 14547 | (1S)-1-[(2S)oxiranyl]-2-phenylethyl azide; (2S)-2-[(1S)-1-azido-2-phenylethyl]oxirane | C10H11N3O | 详情 | 详情 | |
| (VI) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (VII) | 32809 | (2R,3S)-3-azido-1-(isobutylamino)-4-phenyl-2-butanol | C14H22N4O | 详情 | 详情 | |
| (VIII) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (IX) | 32810 | N-[(2R,3S)-3-azido-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide | C21H28N4O4S | 详情 | 详情 | |
| (X) | 32811 | N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide | C21H30N2O4S | 详情 | 详情 | |
| (XI) | 32812 | 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C11H13NO7 | 详情 | 详情 |