Diisopropylethylamine → 4-amino-6-[[(1S)-1-[1-cyclopropyl-6-fluoro-7-(morpholine-4-carbonyl)benzimidazol-2-yl]ethyl]amino]pyrimidine-5-carbonitrile

HRID 243475Notes

Reaction equation

HRID 243475 reaction equation
[NH2:1][C@H:2]([C:4]1[N:5]([CH:22]2[CH2:24][CH2:23]2)[C:6]2[C:12]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:11]([F:21])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30](Cl)[N:29]=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30]([NH:1][C@H:2]([C:4]2[N:5]([CH:22]3[CH2:23][CH2:24]3)[C:6]3[C:12]([C:13]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[O:14])=[C:11]([F:21])[CH:10]=[CH:9][C:7]=3[N:8]=2)[CH3:3])[N:29]=[CH:28][N:27]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 122782624-Amino-6-chloropyrimidine-5-carbonitrileHCID 68158081[2-((S)-1-Aminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazol-4-yl]-morpholin-4-yl-methanone

Product 1

HCID 681584424-amino-6-[[(1S)-1-[1-cyclopropyl-6-fluoro-7-(morpholine-4-carbonyl)benzimidazol-2-yl]ethyl]amino]pyrimidine-5-carbonitrileYield 41.6%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of [2-((S)-1-aminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazol-4-yl]-morpholin-4-yl-methanone (106 mg, 0.32 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (54 mg, 0.35 mmol) and DIPEA (170 μL, 0.98 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 17 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto 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 0-10% MeOH in EtOAc) followed by trituration with EtOAc to afford 401 as a white solid (60 mg, 31%). LCMS (Method K): RT 2.81 min [M+H]+ 451.06. 1H NMR (CDCl3, 400 MHz): δ 8.18 (1H, s), 7.71-7.65 (1H, m), 7.05-6.97 (1H, m), 6.47-6.40 (0.7H, m), 6.15-6.05 (0.3H, m), 5.98-5.88 (1H, m), 5.38-5.31 (2H, m), 4.22-4.14 (1H, m), 3.93-3.72 (4H, m), 3.69-3.52 (2H, m), 3.44-3.33 (2H, m), 1.73 (1H, d, J=6.78 Hz), 1.65 (2H, d, J=6.76 Hz), 1.43-1.24 (2H, m), 1.11-0.93 (1H, m), 0.86-0.69 (1H, m)

Workup

  1. temperatureAfter cooling to RT
  2. washThe cartridge was washed with MeOH
  3. concentrationconcentrated in vacuo
  4. customthe resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc)

Sources & evidence

ORD record
ord-4fc6d21c178e4fcfb90a59216b706fd8
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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