Isobutyryl chloride → (S)-1-(3-((2-(2-(1-hydroxyethyl)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)azetidin-1-yl)-2-methylpropan-1-one

HRID 1946196Notes

Reaction equation

HRID 1946196 reaction equation
[NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:33])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[C@@H:30]([OH:32])[CH3:31])[N:9]=3)[CH2:2]1.CCN(C(C)C)C(C)C.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>C1COCC1>[OH:32][C@H:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:4][N:1]([C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])[CH2:2]4)[N:7]3[CH3:33])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]

Participants

5

Reactant 3

HCID 62325Isobutyryl chlorideHCID 81531DiisopropylethylamineHCID 59605413(S)-1-[1-(8-Azetidin-3-ylmethyl-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-1H-benzoimidazol-2-yl]ethanol

Product 1

HCID 59606183(S)-1-(3-((2-(2-(1-hydroxyethyl)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)azetidin-1-yl)-2-methylpropan-1-oneYield 27%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (S)-1-[1-(8-azetidin-3-ylmethyl-9-methyl-6-morpholin-4-yl-9H-purin-2-yl)-1H-benzoimidazol-2-yl]ethanol (70 mg, 0.16 mmol) in THF (2 mL) was added DIPEA (30 μL, 0.17 mmol) and isobutyryl chloride (17 μL, 0.16 mmol) and the resulting mixture stirred at r.t. for 1 h. The reaction mixture was partitioned between DCM and sat. aq. NaHCO3, the organic phase dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-30%) then (Si—PCC, MeOH:DCM, 0-8%) affording 859 (22 mg, 27%). LCMS (method I): RT 3.46 min, [M+H]+ 519.3. 1H NMR (DMSO, 400 MHz): δ 7.95-7.95 (1 H, m), 7.70-7.69 (1 H, m), 7.30-7.26 (2 H, m), 5.59-5.57 (1 H, m), 5.39 (1 H, d, J=6.33 Hz), 4.39-4.10 (4 H, brd s), 4.34 (1 H, t, J=8.25 Hz), 4.02 (1 H, t, J=8.79 Hz), 3.95 (1 H, dd, J=8.47, 5.27 Hz), 3.80-3.75 (4 H, m), 3.72 (3 H, s), 3.67-3.65 (1 H, m), 3.27-3.21 (3 H, m), 2.48-2.39 (1 H, m), 1.60 (3 H, d, J=6.48 Hz), 0.98 (3 H, d, J=1.76 Hz), 0.96 (3 H, d, J=1.78 Hz)

Workup

  1. customThe reaction mixture was partitioned between DCM and sat. aq. NaHCO3
  2. customthe organic phase dried (phase separator)
  3. concentrationconcentrated in vacuo
  4. customThe resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-30%)

Sources & evidence

ORD record
ord-0ba4e4349b414f1ebce71ad3e74a7c41
Source dataset
uspto-grants-2013_03
Patent number
US08394796B2

Reaction notes

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