Reaktion #1604540

Reaktionsgleichung

dichloromethane

(R)-benzyl 3-(3-chloro-2-fluoro-N-(1-(4-oxo-3-(phenylamino)-3,4-dihydropyrido[3,2-d]pyrimidin-2-yl)but-3-ynyl)benzamido)propylcarbamate

iodotrimethylsilane

NaHCO3

→

(R)-N-(3-aminopropyl)-3-chloro-2-fluoro-N-(1-(4-oxo-3-(phenylamino)-3,4 dihydropyrido[3,2-d]pyrimidin-2-yl)but-3-ynyl)benzamide

Ausbeute 50.4%

Lösungsmittel

acetonitrile

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigeat 0° C
2. 2
   Sonstigeto quench
3. 3
   Sonstigethe reaction
4. 4
   Waschenwashed with water (30 ml), brine (30 ml)
5. 5
   Trocknendried over Na2SO4
6. 6
   Einengenconcentrated to dryness under reduced pressure
7. 7
   SonstigeThe crude product was purified by preparative HPLC
8. 8
   workup.DISSOLUTIONThe resulted product (TFA salt) was dissolved in dichloromethane (100 ml)
9. 9
   Waschenwashed
10. 10
    TrocknenNaCl solution (20 ml), dried over Na2SO4
11. 11
    Einengenconcentrated to dryness under reduced pressure
12. 12
    workup.ADDITIONTo a solution of the residue in EtOAc (2 ml) was added HCl
13. 13
    workup.STIRRINGThe mixture was stirred at room temperature for 30 minutes
14. 14
    Einengenconcentrated

Vorschrift

To a solution of (R)-benzyl 3-(3-chloro-2-fluoro-N-(1-(4-oxo-3-(phenylamino)-3,4-dihydropyrido[3,2-d]pyrimidin-2-yl)but-3-ynyl)benzamido)propylcarbamate (100 mg, 0.153 mmol) in acetonitrile (2 ml) was slowly added iodotrimethylsilane (83 μl, 0.613 mmol) at 0° C. After stirring for 10 minutes, 0.5 ml of sat.NaHCO3 solution was added to quench the reaction. 100 ml of dichloromethane was added to the reaction mixture, then washed with water (30 ml), brine (30 ml), dried over Na2SO4 and concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC. The resulted product (TFA salt) was dissolved in dichloromethane (100 ml) and washed with sat.NaHCO3 solution (20 ml), sat.NaCl solution (20 ml), dried over Na2SO4 and concentrated to dryness under reduced pressure. To a solution of the residue in EtOAc (2 ml) was added HCl:EtOAc (3.0 M, 1.0 ml). The mixture was stirred at room temperature for 30 minutes and concentrated to afford (R)-N-(3-aminopropyl)-3-chloro-2-fluoro-N-(1-(4-oxo-3-(phenylamino)-3,4 dihydropyrido[3,2-d]pyrimidin-2-yl)but-3-ynyl)benzamide (40 mg, 44%, 2HCl) as a pale yellow solid, M.p. 198-200° C. LCMS: m/e 519 [M+H]. 1H NMR (CD3OD): δ 8.93 (s. 1H), 8.59 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.52 (s, 1H), 7.27 (d, J=6.4 Hz, 2H), 7.10 (s, 2H), 7.00 (m, 1H), 6.85 (s, 1H), 6.53 (s, 1H), 6.38 (s, 1H), 5.51 (s, 1H), 5.26 (s, 1H), 3.73-3.59 (m, 2H), 2.65-2.29 (m, 2H), 2.01-1.59 (m, 2H), 1.19 (m, 4H).

Quelle