Diisopropylethylamine → [3-cyclopropyl-5-fluoro-2-[(1S)-1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl]benzimidazol-4-yl]-morpholino-methanone

HRID 243474Notes

Reaction equation

HRID 243474 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].Cl[C:26]1[C:27]2[N:34]=[CH:33][S:32][C:28]=2[N:29]=[CH:30][N:31]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[CH:22]1([N:5]2[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]=[C:4]2[C@@H:2]([NH:1][C:26]2[C:27]3[N:34]=[CH:33][S:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH3:3])[CH2:23][CH2:24]1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 2630077-Chlorothiazolo[5,4-D]pyrimidineHCID 68158081[2-((S)-1-Aminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazol-4-yl]-morpholin-4-yl-methanone

Product 1

HCID 68157960[3-cyclopropyl-5-fluoro-2-[(1S)-1-(thiazolo[5,4-d]pyrimidin-7-ylamino)ethyl]benzimidazol-4-yl]-morpholino-methanoneYield 71.3%

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 (108 mg, 0.33 mmol), 7-chloro-thiazolo[5,4-d]pyrimidine (61 mg, 0.36 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 DCM) to afford 400 as a pale yellow solid (110 mg, 39%). LCMS (Method K): RT 3.16 min [M+H]+ 468.02. 1H NMR (CDCl3, 400 MHz): δ 8.82 (0.7H, s), 8.77 (0.3H, s), 8.54 (0.3H, s), 8.52 (0.7H, s), 7.73-7.65 (1H, m), 7.17 (0.7H, d, J=8.02 Hz), 7.05-6.95 (1H, m), 6.67 (0.3H, d, J=8.45 Hz), 6.31-6.23 (0.3H, m), 6.14-6.04 (0.7H, m), 4.23-4.14 (1H, m), 3.93-3.72 (4H, m), 3.68-3.51 (2H, m), 3.47-3.33 (2H, m), 1.84 (1H, d, J=6.77 Hz), 1.75 (2H, d, J=6.76 Hz), 1.54-1.46 (0.7H, m), 1.41-1.29 (1H, m), 1.20-1.10 (0.3H, m), 1.03-0.93 (1H, m), 0.86-0.71 (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 DCM)

Sources & evidence

ORD record
ord-dab50b98a1b74efea640ce224f51f8e3
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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