Acetonitrile → HCID 67178098, compound

HRID 1698038Notes

Reaction equation

HRID 1698038 reaction equation
[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:16]3[CH2:17][CH2:18][N:19]4[C@H:23]([C:24]=3[N:25]=2)[CH2:22][CH2:21][C:20]4=[O:26])=[CH:9][CH:8]=1)=[O:5])[CH3:2].ClC1N=C(N2CCOCC2)C2CCN3C(C=2N=1)CCC3=O.B(O)O.C([O-])(=O)C.[K+].C(#N)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:16]3[CH2:17][CH2:18][N:19]4[C@@H:23]([C:24]=3[N:25]=2)[CH2:22][CH2:21][C:20]4=[O:26])=[CH:11][CH:12]=1)=[O:5])[CH3:2]

Participants

8

Reactant 5

HCID 6342AcetonitrileHCID 61668Boronic AcidHCID 517044Potassium AcetateHCID 67178353HCID 67178353, compoundHCID 86640115HCID 86640115, compound

Product 1

HCID 67178098HCID 67178098, compound

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×

Conditions

Temperature
90 °C

Procedure

and (S)-1-ethyl-3-(4-(4-morpholino-8-oxo-5,6,8,9,10,10a-hexahydropyrimido[5,4-g]indolizin-2-yl)phenyl)urea (xl2): 2-Chloro-4-morpholino-5,6,10,10a-tetrahydropyrimido[5,4-g]indolizin-8(9H)-one (0.232 g, 0.000751 mol), [4-Ethylureido)phenyl]boronic acid, pinacol ester (0.284 g, 0.000979 mol), Tetrakis(triphenylphosphine)palladium(0) (0.0541 g, 0.0000468 mol) Sodium carbonate (0.122 g, 0.00115 mol) and Potassium acetate (0.118 g, 0.00120 mol) were combined, nitrogen purged three times, added dry Acetonitrile (6.00 mL, 0.115 mol) followed by deoxygenated Water (3.80 mL, 0.211 mol), heated at 90° C. and stirred overnight. The reaction mixture was diluted with water, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, chromatographed through silica gel (12 g, 0-50% EtOAc in heptane followed by 5% MeOH in dichloromethane), purified by HPLC, and the enantiomers were separated out by SFC. Enantiomer 1 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.20 (d, J=8.7, 2H), 7.49 (d, J=8.8, 2H), 6.15 (t, J=5.5, 1H), 4.68 (t, J=8.2, 1H), 4.11 (dd, J=12.4, 5.0, 1H), 3.78 (dd, J=8.9, 6.2, 2H), 3.71-3.62 (m, 2H), 3.61-3.50 (m, 2H), 3.31 (m, 2H), 3.18-3.05 (m, 2H), 2.91 (t, J=10.2, 1H), 2.84-2.71 (m, 1H), 2.70-2.59 (m, 1H), 2.57-2.43 (m, 2H), 2.35-2.22 (m, 1H), 1.93-1.80 (m, 1H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+437.2 (M+H)+; Enantiomer 2 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.20 (d, J=8.7, 2H), 7.49 (d, J=8.7, 2H), 6.15 (t, J=5.4, 1H), 4.68 (t, J=8.0, 1H), 4.11 (dd, J=12.6, 5.3, 1H), 3.78 (dd, J=8.8, 6.3, 2H), 3.73-3.61 (m, 2H), 3.56 (dd, J=11.9, 5.3, 2H), 3.31 (m, 2H), 3.18-3.06 (m, 2H), 2.91 (t, J=12.3, 1H), 2.83-2.71 (m, 1H), 2.70-2.59 (m, 1H), 2.59-2.42 (m, 2H), 2.37-2.21 (m, 1H), 1.94-1.79 (m, 1H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+437.2 (M+H)+.

Workup

  1. customnitrogen purged three times
  2. extractionextracted three times with 10% MeOH in dichloromethane
  3. dry with materialdried over Magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customchromatographed through silica gel (12 g, 0-50% EtOAc in heptane followed by 5% MeOH in dichloromethane)
  7. custompurified by HPLC
  8. customthe enantiomers were separated out by SFC

Sources & evidence

ORD record
ord-6660ccf8e0a34222a9eff69ea595d781
Source dataset
uspto-grants-2012_04
Patent number
US08163763B2

Reaction notes

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