Methanol → (3S)-tert-butyl 4-((1R)-1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate

HRID 1812264Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1812264
Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C@@H:31]([C:33]2[CH:34]=[C:35](B(O)O)[C:36]([F:39])=[N:37][CH:38]=2)[CH3:32])[C@@H:27]([CH3:43])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C([O-])(=O)C.[K+].CO>O1CCOCC1.ClCCl.O.[Cl-].[Na+].O>[F:39][C:36]1[N:37]=[CH:38][C:33]([C@H:31]([N:28]2[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[CH2:26][C@@H:27]2[CH3:43])[CH3:32])=[CH:34][C:35]=1[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1

Komponenten

9

Edukt 4

HCID 887MethanolHCID 517044Potassium AcetateHCID 595482686-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purineHCID 685129855-((R)-1-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid

Produkt 1

HCID 68511317(3S)-tert-butyl 4-((1R)-1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylateAusbeute 80,2 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 962WaterLösungsmittel2×HCID 6344DichloromethaneLösungsmittel2×HCID 312751,4-DioxaneLösungsmittelHCID 57417360Sodium chloride; waterLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

A glass microwave reaction vessel was charged with 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.200 g, 0.791 mmol) and 5-((R)-1-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (0.407 g, 1.108 mmol) in dioxane (3 mL). Then A-Phos (0.056 g, 0.079 mmol), potassium acetate (0.233 g, 2.374 mmol) and water (0.5 mL) was added into the reaction mixture. The reaction mixture was stirred and heated in a CEM Explorer Microwave at 120° C. for 10 min (120 watts, Powermax feature on). The mixture was diluted with dichloromethane (10 mL), water (10 mL) and brine solution (5 mL). The organic layer was collected by extracting with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude material as tan oil. The crude material was adsorbed onto silica gel and purified by chromatography through a silica-gel column (40 g) eluting with 100% ethyl acetate, then with 10% methanol in dichloromethane to give (3S)-tert-butyl 4-((1R)-1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.342 g, 0.634 mmol, 80% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 8.26-8.35 (m, 3H) 5.86 (dd, J=10.37, 2.35 Hz, 1H) 4.19 (d, J=11.74 Hz, 2H) 3.83 (d, J=2.54 Hz, 1H) 2.89 (s, 3H) 2.54 (d, J=2.93 Hz, 2H) 2.16 (s, 1H) 2.11 (s, 1H) 2.07 (d, J=17.80 Hz, 1H) 1.81 (d, J=11.54 Hz, 2H) 1.59-1.75 (m, 3H) 1.39-1.49 (m, 15H) 1.02 (d, J=5.67 Hz, 3H). m/z (ESI, +ve ion) 540.2 (M+H).

Aufarbeitung

  1. customA glass microwave reaction vessel
  2. customThe organic layer was collected
  3. extractionby extracting with dichloromethane (3×10 mL)
  4. dry with materialThe combined organic extracts were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto give the crude material as tan oil
  8. custompurified by chromatography through a silica-gel column (40 g)
  9. washeluting with 100% ethyl acetate

Quellen und Nachweise

ORD-Eintrag
ord-b2b4b5be6acb47f4a59b5010150b7b04
Quelldatensatz
uspto-grants-2013_01
Patentnummer
US08362241B2

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