tert-Butyl isocyanate → HCID 58709959, compound

HRID 2375931Notes

Reaction equation

HRID 2375931 reaction equation
Cl.Cl.Cl.[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.C(N(CC)C(C)C)(C)C.[C:39]([N:43]=[C:44]=[O:45])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([NH:43][C:44]([N:27]1[CH2:26][CH:25]=[C:24]([C:22]2[NH:21][C:17]3[N:18]=[CH:19][N:20]=[C:15]([NH:14][C:10]4[CH:9]=[C:8]5[C:13](=[CH:12][CH:11]=4)[N:5]([CH3:4])[N:6]=[CH:7]5)[C:16]=3[CH:23]=2)[CH2:29][CH2:28]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]

Participants

5

Reactant 3

HCID 62412tert-Butyl isocyanate2×HCID 81531DiisopropylethylamineHCID 69275387HCID 69275387, compound

Product 1

HCID 58709959HCID 58709959, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
-20 °C

Procedure

To a suspension of (1-methyl-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (166.8 mg, 0.3631 mmol, 1 eq) in anhydrous DMF (17 mL), N,N-diisopropylethylamine (DiPEA) (260 μL, 4.1 eq) was added at rt. The solution was then cooled to −20° C., after which tert-butyl isocyanate (36.5 mg, 0.368 mmol, 1 eq in anhydrous DMF (2 mL) was added. The solution was stirred at rt for 1 h. The reaction was cooled to 0° C., after which additional tert-butyl isocyanate (11.4 mg, 0.115 mmol, 0.3 eq) in anhydrous DMF (1 mL) was added. The reaction was stirred again at rt for 4 h. The reaction was quenched with MeOH, concentrated in vacuo, and dried under vacuum pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH:DCM 1%→5%]. Fractions containing product were combined and concentrated in vacuo. The material was further purified by trituration in MeOH, yielding the title compound as an off-white solid. 1H NMR (400 MHz, DMSOd6): δ=1.28 (s, 9H), 2.44 (s, br, 2H), 3.52 (t, J=5.6 Hz, 2H), 3.99 (d, J=2.0 Hz, 2H), 4.03 (s, 3H), 5.77 (s, —NH), 6.40 (s, br, 1H), 6.75 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.69 (dd, J=8.8, 2.0 Hz, 1H), 8.01 (s, 1H), 8.26 (s, 1H), 8.39 (s, 1H), 9.32 (s, —NH), 11.89 (s, —NH). MS (ES+): m/z 445.07 (100) [MH+]. HPLC: tR=2.29 min (ZQ2000, polar—5 min).

Workup

  1. additionwas added at rt
  2. temperatureThe reaction was cooled to 0° C.
  3. stirringThe reaction was stirred again at rt for 4 h
  4. customThe reaction was quenched with MeOH
  5. concentrationconcentrated in vacuo
  6. customdried under vacuum pressure
  7. customdry loaded
  8. custompurified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH:DCM 1%→5%]
  9. additionFractions containing product
  10. concentrationconcentrated in vacuo
  11. customThe material was further purified by trituration in MeOH

Sources & evidence

ORD record
ord-ae38b2530de84aa1b2351cbe1545cd23
Source dataset
uspto-grants-2008_12
Patent number
US07465726B2

Reaction notes

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