N-methyl-2-pyrrolidone → HCID 78318938, compound

HRID 527427Notes

Reaction equation

HRID 527427 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:12][N:11]([C:13](=[O:15])[CH3:14])[CH2:10]2)=[CH:4][C:3]=1[O:16][CH3:17].CS[C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])OC(C)(C)C)[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1.[CH3:45][CH2:46]N(C(C)C)C(C)C.CN1C(=O)CCC1>O1CCOCC1.CC(O)(C)C.CS(C)=O>[C:13]([N:11]1[CH2:12][CH:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:20]3[N:21]=[CH:22][C:23]4[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]5[CH:32]=[C:33]([NH:37][C:38](=[O:44])[CH:45]=[CH2:46])[CH:34]=[CH:35][CH:36]=5)[C:24]=4[N:25]=3)=[C:3]([O:16][CH3:17])[CH:4]=2)[CH2:10]1)(=[O:15])[CH3:14]

Participants

8

Reactant 4

HCID 13387N-methyl-2-pyrrolidoneHCID 81531DiisopropylethylamineHCID 701434331-(3-((4-Amino-3-methoxyphenyl)amino)azetidin-1-yl)ethanoneHCID 86732006tert-butyl (3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate

Product 1

HCID 78318938HCID 78318938, compoundYield 60.7%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
85 °C

Procedure

To a suspension of 1-(3-((4-amino-3-methoxyphenyl)amino)azetidin-1-yl)ethanone (14a, prepared according to the procedures described in WO 2012064706 A1 (April, 2012), Avila Therapeutics, Inc.) (120 mg, 0.51 mmol) and N-(3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (51) (150 mg, 0.42 mmol) in 1 mL of dioxane and 1 mL of tBuOH at RT was added DIEA (0.22 mL, 1.27 mmol). The mixture was heated in an oil bath at 85° C. for 1 h. NMP (0.5 mL) was added to the reaction mixture and heating was continued 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 90% pure. This 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 MeOH, passed through a Silicycle (5 G) carbonate cartridge, rinsed with MeOH (20 mL). The fractions were collected and concentrated to give N-(3-(2-((4-((1-acetylazetidin-3-yl)amino)-2-methoxyphenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (14) (135 mg, 0.257 mmol, 60.7% yield) as a yellow crystalline solid. m/z (ESI, +ve ion) 526.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.42 (1H, br.), 8.74 (1H, s), 8.15 (1H, s), 7.91 (2H, d, J=9.4 Hz), 7.61 (1H, br.), 7.51 (1H, t, J=8.0 Hz), 7.18 (1H, br.), 7.02 (1H, d, J=8.0 Hz), 6.36-6.56 (2H, m), 6.23-6.36 (1H, m), 6.15 (2H, 5.71-5.87 (1H, m), 4.44 (1H, m), 4.18 (1H, 4.10 (1H, 3.75 (1H, m), 3.73 (3H, s), 3.58 (1H, m), 3.03 (1H, m), 1.80 (3H, s).

Workup

  1. customprepared
  2. temperatureheating
  3. concentrationIt was concentrated under reduced pressure
  4. 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)
  5. customto give a material that
  6. custompurified on a reverse phase HPLC
  7. customDesired fractions were collected
  8. dissolutionthe powdery residue was dissolved in MeOH
  9. washrinsed with MeOH (20 mL)
  10. customThe fractions were collected
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-26cbc6ff744543df95f5661a80fa8caf
Source dataset
uspto-grants-2016_05
Patent number
US09346801B2

Reaction notes

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