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Cesium carbonate → 4-amino-6-[[(1S)-1-(1-cyclopropyl-6-fluoro-7-phenyl-benzimidazol-2-yl)ethyl]amino]pyrimidine-5-carbonitrile

HRID 243489
Notes
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Reaction equation

HRID 243489 reaction equation
[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21](Br)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 66827Phenylboronic AcidHCID 681578024-amino-6-[(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile

Product 1

HCID 681571584-amino-6-[[(1S)-1-(1-cyclopropyl-6-fluoro-7-phenyl-benzimidazol-2-yl)ethyl]amino]pyrimidine-5-carbonitrileYield 15.1%

Reagents, catalysts & solvents 3

HCID 178418397
HCID 178418397, compound
Catalyst
HCID 962WaterSolvent
HCID 312751,4-DioxaneSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of 4-amino-6-[(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (68 mg, 0.16 mmol), phenylboronic acid (26 mg, 0.21 mmol), tetrakis(triphenylphosphine)palladium (19 mg, 10 mol %) and caesium carbonate (106 mg, 0.33 mol) in dioxane (3 mL) and H2O (1.5 mL) was purged with argon gas then heated at 140° C., for 30 min, by microwave irradiation. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM) followed by recrystallisation from EtOAc/cyclohexane to afford 415 as a white solid (10 mg, 15%). LCMS (Method K): RT 4.08 min [M+H]+ 414.08. 1H NMR (CDCl3 400 MHz): δ 8.17 (1H, s), 7.65 (1H, dd, J=8.89, 4.63 Hz), 7.43-7.42 (5H, m), 7.09 (1H, dd, J=10.20, 8.76 Hz), 6.35 (1H, d, J=7.83 Hz), 5.96 (1H, m), 5.32 (2H, s), 2.89-2.83 (1H, m), 1.69 (3H, d, J=6.74 Hz), 0.79 (1H, m), 0.61 (1H, m), 0.47 (1H, m), 0.23 (1H, m)

Workup

  1. customwas purged with argon gas
  2. temperatureAfter cooling to RT
  3. additionthe reaction mixture was diluted with MeOH
  4. washThe cartridge was washed with MeOH
  5. concentrationconcentrated in vacuo
  6. customthe resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM)
  7. customfollowed by recrystallisation from EtOAc/cyclohexane

Sources & evidence

ORD record
ord-57fbcf0176a44f968a4cd27aeff611fa
Source dataset
uspto-grants-2014_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08653089B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes