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

HRID 527427

Reaktionsgleichung

Reaktionsgleichung von HRID 527427
[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]

Komponenten

8

Edukt 4

HCID 13387N-methyl-2-pyrrolidoneHCID 81531DiisopropylethylamineHCID 70143433HCID 70143433, VerbindungHCID 86732006tert-butyl (3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate

Produkt 1

HCID 78318938HCID 78318938, VerbindungAusbeute 60,7 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 679Dimethyl SulfoxideLösungsmittelHCID 6386tert-ButanolLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

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).

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-26cbc6ff744543df95f5661a80fa8caf
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09346801B2

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