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 1621856Notes

Reaction equation

HRID 1621856 reaction equation
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

Participants

9

Reactant 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

Product 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-carboxylateYield 80.2%

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent2×HCID 312751,4-DioxaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
120 °C

Procedure

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)+.

Workup

  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

Sources & evidence

ORD record
ord-b37dc458a3be4e06b30aedefeeb79aa5
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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