Phosphate → Mavelertinib

HRID 928176Notes

Reaction equation

HRID 928176 reaction equation
F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[C:14]([O:19][CH3:20])=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1.[F:21][C@@H:22]1[CH2:26][NH:25][CH2:24][C@H:23]1[NH:27][C:28](=[O:35])[CH2:29][CH2:30]S(C)(=O)=O.C(N(CC)C(C)C)(C)C.CC(C)([O-])C.[K+].P([O-])([O-])([O-])=O>CS(C)=O.C1COCC1.O>[F:21][C@@H:22]1[CH2:26][N:25]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH3:11])=[C:4]([NH:12][C:13]3[C:14]([O:19][CH3:20])=[N:15][N:16]([CH3:18])[CH:17]=3)[N:3]=2)[CH2:24][C@H:23]1[NH:27][C:28](=[O:35])[CH:29]=[CH2:30]

Participants

9

Reactant 5

HCID 1061PhosphateHCID 81531DiisopropylethylamineHCID 23665647Potassium tert-butoxide2×HCID 1180735462-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amineHCID 118073579N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide

Product 1

HCID 91668194MavelertinibYield 75%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

To a stirred suspension of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (554 mg, 2.00 mmol, 1.00 eq) and N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (500 mg, 2.10 mmol, 1.05 eq) in DMSO (4.2 mL) was added N,N-diisopropylethylamine (0.83 mL, 5.00 mmol, 2.50 eq). The reaction mixture was then heated at 100° C. for 16 hr, cooled to ambient temperature, diluted with THF (4 mL), and treated with potassium tert-butoxide (4.00 mL, 1 M in THF, 2.00 eq). After 1 hr, an additional portion of potassium tert-butoxide (0.50 mL, 1 M in THF, 0.25 eq) was added to the reaction mixture. After a further 1 hr, the reaction mixture was poured into phosphate buffer (50 mL, pH=7) and water (50 mL), and extracted with ethyl acetate (5×40 mL). The combined organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. This crude product was then dissolved in ethyl acetate (40 mL) at 60° C. and then treated with heptanes (20 mL), at which point the solution became cloudy and was allowed to cool to ambient temperature and then to 0° C. After 16 hr at 0° C., the resulting solids were filtered and dried at ambient temperature to give the title compound (620.5 mg, 75% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=6.5 Hz, 1 H) 7.97 (s, 1 H) 7.82 (s, 1 H) 7.78 (s, 1 H) 6.23 (dd, J=10.0, 17.0 Hz, 1 H) 6.14 (dd, J=2.8, 17.0 Hz, 1 H) 5.62 (dd, J=2.8, 10.0 Hz, 1 H) 5.12 (d, J=51.0 Hz, 1 H) 4.46 (td, J=6.0, 11.9 Hz, 1 H) 3.88-3.6 (m, 4 H) 3.82 (s, 3 H) 3.71 (s, 3 H) 3.62 (s, 3 H). m/z (APCI+) for C18H23FN9O2 416.3 (M+H)+.

Workup

  1. temperaturecooled to ambient temperature
  2. waitAfter a further 1 hr
  3. extractionextracted with ethyl acetate (5×40 mL)
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated under reduced pressure
  6. dissolutionThis crude product was then dissolved in ethyl acetate (40 mL) at 60° C.
  7. additiontreated with heptanes (20 mL), at which point the solution
  8. temperatureto cool to ambient temperature
  9. customto 0° C
  10. waitAfter 16 hr at 0° C.
  11. filtrationthe resulting solids were filtered
  12. customdried at ambient temperature

Sources & evidence

ORD record
ord-ed240ee3a70c4755aec7fe30a3114134
Source dataset
uspto-grants-2016_03
Patent number
US09290496B2

Reaction notes

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