|
【结 构 式】 
|
【分子编号】16696 【品名】Diethyl L-(+)-Tartrate; diethyl (2S,3S)-2,3-dihydroxybutanedioate 【CA登记号】87-91-2 |
【 分 子 式 】C8H14O6 【 分 子 量 】206.19556 【元素组成】C 46.6% H 6.84% O 46.56% |
合成路线1
该中间体在本合成路线中的序号：(I)A new synthesis of (3R,4S)-1-benzyl-4-phenyl-3-(triethylsilyloxy)azetidin-2-one (XIII), a precursor of the side chain of paclitaxel, has been described: The reaction of ethyl L-tartrate (I) with benzaldehyde and TsOH followed, by reduction with LiAlH4 and AlCl3 gives the monobenzylated tretraol (II), which is submitted to an oxidative cleavage of the alpha-diol bond with NaIO4 to yield the aldehyde (III). Reaction of (III) with benzylamine affords the imine (IV), which is submitted to a Grignard addition of phenylmagnesium bromide in ether providing a 1:9 mixture of aminoalcohols (VI) and (VII) separated by chromatography. Oxidation of the desired major isomer (VII) with CrO3/H2SO4 gives the corresponding acid (VIII), which is then esterified with TMS-Cl in refluxing methanol to the methyl ester (IX). Deprotection of compound (IX) by hydrogenolysis with reluxing HCO2H over Pd/C yields 3(S)-amino-2(R)-hydroxy-3-phenylpropionic acid methyl ester (X), which is silylated at the OH group of with TES-Cl and TEA in ether/THF to afford the silyl ether (XI). Cyclization of (XI) by means of LHMDS in THF provides the beta-lactam (XII), which is finally benzoylated with benzoyl chloride and TEA in the usual way.
| 【1】 Kim, H.-K.; Kim, S.-C.; Synthesis of new Taxol side chain precursor from L-tartaric ester. Bull Korean Chem Soc 2000, 21, 10, 1047. |
| 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) | 16696 | Diethyl L-(+)-Tartrate; diethyl (2S,3S)-2,3-dihydroxybutanedioate | 87-91-2 | C8H14O6 | 详情 | 详情 |
| (II) | 43826 | (2S,3S)-3-(benzyloxy)-1,2,4-butanetriol | C11H16O4 | 详情 | 详情 | |
| (III) | 43827 | (2S)-2-(benzyloxy)-3-hydroxypropanal | C10H12O3 | 详情 | 详情 | |
| (IV) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (V) | 43828 | (2R)-3-(benzylimino)-2-(benzyloxy)-1-propanol | C17H19NO2 | 详情 | 详情 | |
| (VI) | 43829 | (2R,3R)-3-(benzylamino)-2-(benzyloxy)-3-phenyl-1-propanol | C23H25NO2 | 详情 | 详情 | |
| (VII) | 43830 | (2R,3S)-3-(benzylamino)-2-(benzyloxy)-3-phenyl-1-propanol | C23H25NO2 | 详情 | 详情 | |
| (VIII) | 43831 | (2R,3S)-3-(benzylamino)-2-(benzyloxy)-3-phenylpropionic acid | C23H23NO3 | 详情 | 详情 | |
| (IX) | 43832 | methyl (2R,3S)-3-(benzylamino)-2-(benzyloxy)-3-phenylpropanoate | C24H25NO3 | 详情 | 详情 | |
| (X) | 43833 | methyl (2R,3S)-3-amino-2-hydroxy-3-phenylpropanoate | C10H13NO3 | 详情 | 详情 | |
| (XI) | 43834 | methyl (2R,3S)-3-amino-3-phenyl-2-[(triethylsilyl)oxy]propanoate | C16H27NO3Si | 详情 | 详情 | |
| (XII) | 10685 | (3R,4S)-4-Phenyl-3-[(triethylsilyl)oxy]-2-azetidinone | C15H23NO2Si | 详情 | 详情 | |
| (XIII) | 10490 | (3R,4S)-1-Benzoyl-4-phenyl-3-[(triethylsilyl)oxy]-2-azetanone | C22H27NO3Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Reaction of D-tartaric acid (I) with EtOH in the presence of an acid catalyst gives diethyl D-tartrate (II), which is treated with isobutyraldehyde and anhydrous CuSO4 in the presence of methanesulfonic acid yielding diethyl 2,3-O-isobutylidene-D-tartrate (III). The 1,3-dioxolane diester (III) was then reduced with LAH to afford (4R,5R)-4,5-bis(hydroxymethyl)-2-isopropyl-1,3-dioxolane (IV), which is treated with methanesulfonyl chloride in pyridine yielding (4R,5R)-4,5-bis(methylsulfonyloxymethyl)-2-isopropyl-1,3-dioxolane (V). The bis(methanesulfonate) (V) is reacted with NaN3 in DMF to give (4R,5R)-4,5-bis(azidomethyl)-2-isopropyl-1,3-dioxolane (VI), which is reduced with hydrogen in the presence of 10% Pd/C in EtOH to afford (4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane (VII). The diamine (VII) is reacted with an equimolar amount of in situ generated K2PtI4 to afford cis-diiodo[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane] platinum(II) (VIII), which is finally treated with malonic acid disilver salt in H2O to obtain (IX).
| 【1】 Kim, Y.; Rim, J.; Yoo, K.; Kim, G.; Gam, J.; Kim, K.H.; Kim, D.-K.; Song, S.; Synthesis of carbon-14 labelled cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane] platinum(II) (SKI 2053R). J Label Compd Radiopharm 1994, 34, 2, 157-64. |
| 【2】 Kim, D.-K.; Kim, K.H.; SKI-2053R. Drugs Fut 1995, 20, 11, 1128. |
| 【3】 Kim, D.-K.; Cho, Y.-B.; Park, J.-G.; Tai, J.-H.; Kim, K.H.; Hong, W.-S.; Kim, H.-T.; Kim, G.; Gam, J.; Synthesis and antitumor activity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes. J Med Chem 1994, 37, 10, 1471-85. |
| 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) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
| (II) | 16696 | Diethyl L-(+)-Tartrate; diethyl (2S,3S)-2,3-dihydroxybutanedioate | 87-91-2 | C8H14O6 | 详情 | 详情 |
| (III) | 16697 | diethyl (4S,5S)-2-isopropyl-1,3-dioxolane-4,5-dicarboxylate | C12H20O6 | 详情 | 详情 | |
| (IV) | 16698 | [(4R,5R)-5-(hydroxymethyl)-2-isopropyl-1,3-dioxolan-4-yl]methanol | C8H16O4 | 详情 | 详情 | |
| (V) | 16699 | (4R,5R)-2-isopropyl-4,5-bis([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-1,3-dioxolane | C14H28O4S2 | 详情 | 详情 | |
| (VI) | 16700 | 1-[[(4R,5R)-2-isopropyl-5-(triazanylmethyl)-1,3-dioxolan-4-yl]methyl]triazane | C8H22N6O2 | 详情 | 详情 | |
| (VII) | 16701 | [(4R,5R)-5-(aminomethyl)-2-isopropyl-1,3-dioxolan-4-yl]methylamine; [(4R,5R)-5-(aminomethyl)-2-isopropyl-1,3-dioxolan-4-yl]methanamine | C8H18N2O2 | 详情 | 详情 | |
| (VIII) | 16702 | cis-diiodo[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum; cis-[(4R,5R)-2-isopropyl-1,3-dioxolane-4,5-dimethanamine-N,N']diiodoplatinum | C8H16I2N2O2Pt | 详情 | 详情 | |
| (IX) | 16703 | malonic acid disilver salt | C3H2Ag2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of D-tartaric acid (I) with refluxing acetone and sulfuric acid gives the isopropylidene ketal (II), which is reduced with LiAlH4 to yield 2,3-O-isopropylidene-D-threitol (III). The monosilylation of (III) with Tbdms-Cl and NaH affords the monosilyl ether (IV), which is submitted to a Swern oxidation to provide the aldehyde (V). The reaction of (V) with CBr4, PPh3 and BuLi in dichloromethane gives the acetylene (VI), which is desilylated with TBAF in THF to yield the carbinol (VII). The carbinol (VII) is treated with CBr4 and PPh3 in dichloromethane to afford the bromide (VIII), which is condensed with N-benzyl-N-(trimethylsilyl)amine (IX) by means of K2CO3 in refluxing acetonitrile, providing the tertiary amine (X). The cyclization of (X) by means of ultraviolet light in isopropanol/dichloromethane gives the methylenepiperidine (XI), which is submitted to hydroboration with 9-BBN and NaOH in THF to yield the carbinol (XII) as a single diastereomer. The cleavage of the ketal group of (XII) by treatment with HCl in methanol affords the chiral 1-benzyl-5-(hydroxymethyl)piperidine-3,4-diol (XIII), which is finally debenzylated by means of H2 over Pd(OH)2 in ethanol to furnish the target isofagomine.
| 【1】 Feit, P.W.; 1,4-Bismethanesulfonates of the stereoisomeric butanetetraols and related compounds. J Med Chem 1964, 7, 14. |
| 【2】 Iida, H.; et al.; Total synthesis of (+)-nojirimycin and (+)-1-deoxynojirimycin. J Org Chem 1987, 52, 15, 3337. |
| 【3】 Pandey, G.; Kapur, M.; A general strategy towards the synthesis of 1-N-iminosugar type glycosidase inhibitors: Demonstration by the synthesis of D- as well as L-glucose type iminosugars (isofagomines). Tetrahedron Lett 2000, 41, 45, 8821. |
| 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) | 16696 | Diethyl L-(+)-Tartrate; diethyl (2S,3S)-2,3-dihydroxybutanedioate | 87-91-2 | C8H14O6 | 详情 | 详情 |
| (II) | 52910 | diethyl (4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate | C11H18O6 | 详情 | 详情 | |
| (III) | 52911 | [(4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol | C7H14O4 | 详情 | 详情 | |
| (IV) | 52912 | [(4R,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol | C13H28O4Si | 详情 | 详情 | |
| (V) | 52913 | (4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | C13H26O4Si | 详情 | 详情 | |
| (VI) | 52914 | tert-butyl{[(4R,5R)-5-ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}dimethylsilane; tert-butyl(dimethyl)silyl [(4R,5R)-5-ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl ether | C14H26O3Si | 详情 | 详情 | |
| (VII) | 52915 | [(4R,5R)-5-ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl]methanol | C8H12O3 | 详情 | 详情 | |
| (VIII) | 52916 | (4S,5R)-4-(bromomethyl)-5-ethynyl-2,2-dimethyl-1,3-dioxolane | C8H11BrO2 | 详情 | 详情 | |
| (IX) | 52917 | N-benzyl-N-[(trimethylsilyl)methyl]amine; phenyl-N-[(trimethylsilyl)methyl]methanamine | C11H19NSi | 详情 | 详情 | |
| (X) | 52918 | N-benzyl-N-{[(4R,5R)-5-ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-N-[(trimethylsilyl)methyl]amine; N-benzyl[(4R,5R)-5-ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl]-N-[(trimethylsilyl)methyl]methanamine | C19H29NO2Si | 详情 | 详情 | |
| (XI) | 52919 | (3aR,7aR)-5-benzyl-2,2-dimethyl-7-methylenehexahydro[1,3]dioxolo[4,5-c]pyridine | C16H21NO2 | 详情 | 详情 | |
| (XII) | 52920 | [(3aR,7R,7aR)-5-benzyl-2,2-dimethylhexahydro[1,3]dioxolo[4,5-c]pyridin-7-yl]methanol | C16H23NO3 | 详情 | 详情 | |
| (XIII) | 52921 | (3R,4R,5R)-1-benzyl-5-(hydroxymethyl)-3,4-piperidinediol | C13H19NO3 | 详情 | 详情 |