Diisopropylethylamine → N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxyphenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide

HRID 527423Notes

Reaction equation

HRID 527423 reaction equation
[F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1.CS([C:21]1[N:22]=[CH:23][C:24]2[CH:30]=[CH:29][C:28](=[O:31])[N:27]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=3)[C:25]=2[N:26]=1)=O.CCN(C(C)C)C(C)C>O1CCOCC1.CC(O)(C)C.CS(C)=O>[F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[CH:29][C:28](=[O:31])[N:27]([C:32]5[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=5)[C:25]=4[N:26]=3)=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1

Participants

7

Reactant 3

HCID 81531DiisopropylethylamineHCID 86709973HCID 86709973, compoundHCID 86732033N-(3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide

Product 1

HCID 78318875N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxyphenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamideYield 32%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 6386tert-ButanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

To a suspension of N1-(1-(2-fluoroethyl)azetidin-3-yl)-3-methoxybenzene-1,4-diamine (11c) (135 mg, 0.56 mmol) and N-(3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (11b) (230 ing, 0.65 mmol) in 1 mL of dioxane and 1 mL of tBuOH at RT was added DIEA (0.29 mL, 1.69 mmol). The mixture was heated in an oil bath at 85° C. for 3 h. It was concentrated under reduced pressure. The residue was purified on a silica gel column (5% MeOH in DCM followed by 2-6% of 2 M NH3 in MeOH in DCM) to give a material that was about 95% pure. The material was dissolved in 10 mL of DMSO and purified on a reverse phase HPLC, using a gradient of 10-90% of (0.1% TFA in CH3CN) in (0.1% TFA in water). Desired fractions were collected, lyophilized and the powdery residue was dissolved in 2 mL of MeOH, passed through a Silicycle (5 G) carbonate cartridge, rinsed with MeOH (20 mL). The fractions were collected and concentrated to give the title compound (95 mg, 31% yield) as a brown crystalline solid. m/z (ESI, +ve ion) 530.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.40 (1H, br.), 8.73 (1H, br.), 8.10 (1H, br.), 7.90 (1H, d, J=9.4 Hz), 7.83 (1H, br.), 7.64 (1H, s), 7.51 (1H, t, J=8.0 Hz), 7.15 (1H, br.), 7.02 (1H, d, J=8.6 Hz), 6.44 (2H, m), 6.29 (1H, m), 6.16 (1H, d, J=2.0 Hz), 5.86 (1H, br.), 5.78 (1H, m), 5.57 (1H, br.), 4.49 (1H, t, J=4.8 Hz), 4.37 (1H, t, J=4.9 Hz), 3.90 (1H, br.), 3.72 (3H, s), 3.70 (2H, m), 2.83 (2H, m), 2.74 (1H, 1, J=4.8 Hz), 2.67 (1H, t, J=4.8 Hz).

Workup

  1. concentrationIt was concentrated under reduced pressure
  2. customThe residue was purified on a silica gel column (5% MeOH in DCM followed by 2-6% of 2 M NH3 in MeOH in DCM)
  3. customto give a material that
  4. custompurified on a reverse phase HPLC
  5. customDesired fractions were collected
  6. dissolutionthe powdery residue was dissolved in 2 mL of MeOH
  7. washrinsed with MeOH (20 mL)
  8. customThe fractions were collected
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-435a21ce0fbc439a9e5078ea77957d5e
Source dataset
uspto-grants-2016_05
Patent number
US09346801B2

Reaction notes

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