Hydrogen Peroxide → (S)-(9H-fluoren-9-yl)methyl (2-((di-tert-butoxyphosphoryl)oxy)-1-(3-fluoro-5-iodophenyl)ethyl)carbamate

HRID 596041

Reaktionsgleichung

Reaktionsgleichung von HRID 596041
[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:29])[O:14][CH2:15][CH:16]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][OH:11])[CH:5]=[C:6]([I:8])[CH:7]=1.N1C=CN=C1.Cl.N1C=CN=C1.C(N(C(C)C)[P:45]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])(C)C.OO.S([O-])([O-])(=[O:63])=S.[Na+].[Na+]>C(OCC)(=O)C.CN(C=O)C>[C:52]([O:51][P:45]([O:11][CH2:10][C@@H:9]([NH:12][C:13](=[O:29])[O:14][CH2:15][CH:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4]1[CH:5]=[C:6]([I:8])[CH:7]=[C:2]([F:1])[CH:3]=1)([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:63])([CH3:53])([CH3:54])[CH3:55]

Komponenten

9

Edukt 6

HCID 784Hydrogen PeroxideHCID 795ImidazoleHCID 24477Sodium ThiosulfateHCID 853005Di-tert-butyl N,N-DiisopropylphosphoramiditeHCID 10197644Imidazolium chlorideHCID 118054608(S)-(9H-fluoren-9-yl)methyl (1-(3-fluoro-5-iodophenyl)-2-hydroxyethyl)carbamate

Produkt 1

HCID 118054603(S)-(9H-fluoren-9-yl)methyl (2-((di-tert-butoxyphosphoryl)oxy)-1-(3-fluoro-5-iodophenyl)ethyl)carbamateAusbeute 86 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

To (S)-(9H-fluoren-9-yl)methyl (1-(3-fluoro-5-iodophenyl)-2-hydroxyethyl)carbamate (5260 mg, 10.45 mmol) was added imidazole (818 mg, 12.02 mmol), imidazole HCl (1857 mg, 17.77 mmol), and DMF (Volume: 50 mL). The reaction was stirred to dissolve under argon for 2-3 minutes. Then di-tert-butyl diisopropylphosphoramidite (4928 mg, 17.77 mmol) was added drop wise over 2-3 minutes and stirred at room temperature for 2 hours. The reaction was followed by neutral LCMS and by TLC eluting with 1:1 ethyl acetate/heptane. The crude reaction was placed in a water bath, hydrogen peroxide 30% (5.34 mL, 52.3 mmol) was added slowly, and the mixture was stirred at room temperature for 30 minutes, followed by LCMS. The crude reaction was placed in an ice bath and excess saturated sodium thiosulphate was added (carefully) drop wise over 5-10 minutes. To the crude reaction mixture was added 800 ml of ethyl acetate washed with water (3×), saturated salt solution, dried sodium sulfate, filtered and concentrated to residue. The crude was purified by silica gel chromatography using 300 g column eluting from 0-55% ethyl acetate in heptane. The desired peak was concentrated to constant mass to give 6560 mg of the desired product as free base used as is, (86% yield). LCMS (m/z): 696.3 (MH+) weak, 1.25 min. Note: −112 fragment at 584.2 is major ion in LCMS as expected from loss of two t-butyl protecting groups. 1H NMR (<cd3od>) d: 7.79 (d, J=7.3 Hz, 2H), 7.64 (d, J=7.3 Hz, 2H), 7.58 (s, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.34-7.42 (m, 2H), 7.22-7.32 (m, 2H), 7.12 (d, J=9.1 Hz, 1H), 4.90 (t, J=6.0 Hz, 1H), 4.41-4.48 (m, 1H), 4.31-4.40 (m, 1H), 4.21 (t, J=6.6 Hz, 1H), 4.08 (t, J=6.3 Hz, 2H), 1.42 (s, 9H), 1.40 (s, 9H).

Aufarbeitung

  1. dissolutionto dissolve under argon for 2-3 minutes
  2. stirringstirred at room temperature for 2 hours
  3. washeluting with 1:1 ethyl acetate/heptane
  4. customThe crude reaction
  5. customwas placed in a water bath
  6. stirringthe mixture was stirred at room temperature for 30 minutes
  7. customThe crude reaction
  8. customwas placed in an ice bath
  9. customTo the crude reaction mixture
  10. washwashed with water (3×), saturated salt solution, dried sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated to residue
  13. customThe crude was purified by silica gel chromatography
  14. washeluting from 0-55% ethyl acetate in heptane
  15. concentrationThe desired peak was concentrated to constant mass

Quellen und Nachweise

ORD-Eintrag
ord-47e2d355113b4b93894b6fbed40bcd10
Quelldatensatz
uspto-grants-2016_01
Patentnummer
US09242996B2

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