Isopropyl iodide → HCID 68289197, compound

HRID 541446Notes

Reaction equation

HRID 541446 reaction equation
FC(F)(F)C(O)=O.[NH:8]1[C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[C:18]1[C:19]([CH3:41])=[CH:20][C:21]([CH3:40])=[C:22]([CH:39]=1)[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].I[CH:43]([CH3:45])[CH3:44].CCN(C(C)C)C(C)C>CN(C)C=O.C(OCC)(=O)C>[CH:43]([N:15]1[CH2:14][CH2:13][C:12]2[N:8]=[C:9]([C:18]3[C:19]([CH3:41])=[CH:20][C:21]([CH3:40])=[C:22]([CH:39]=3)[C:23]([N:25]3[CH2:26][CH2:27][CH:28]([C:31]4[CH:32]=[CH:33][C:34]([C:35]#[N:36])=[CH:37][CH:38]=4)[CH2:29][CH2:30]3)=[O:24])[NH:10][C:11]=2[CH2:17][CH2:16]1)([CH3:45])[CH3:44]

Participants

6

Reactant 3

HCID 6362Isopropyl iodideHCID 81531DiisopropylethylamineHCID 68288579HCID 68288579, compound

Product 1

HCID 68289197HCID 68289197, compoundYield 21.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 4-(1-(5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile trifluoroacetate (429.5, 80.0 mg, 0.140 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) were added 2-iodopropane (270 mg, 1.59 mmol, 9.00 equiv) and DIEA (205 mg, 1.59 mmol, 9.00 equiv). The resulting solution was stirred overnight at 80° C. in an oil bath. After cooling to ambient temperature, the mixture was diluted with 50 mL of ethyl acetate, washed with 3×20 mL of brine, dried (Na2SO4), and concentrated. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10) as eluent. The product (50 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (38.0% CH3CN up to 51.0% in 8 min, up to 100.0% in 2 min, down to 38.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 15.0 mg (21%) of the title compound as a white solid. m/z (ES+) 496 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.69 (d, J=8.0 Hz, 2H), 7.49 (m, 2H), 7.33-7.23 (m, 2H), 4.86 (m, 1H), 3.65 (m, 1H), 3.30 (m, 1H), 3.15 (m, 1H), 2.99 (m, 6H), 2.80 (m, 4H), 2.45 (s, 3H), 2.40 and 2.29 (2 singlets, amide rotamers, 3H), 2.10 (m, 1H), 1.70 (m, 3H), 1.15 (d, J=6.8 Hz, 6H).

Workup

  1. temperatureAfter cooling to ambient temperature
  2. washwashed with 3×20 mL of brine
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated
  5. customThe residue was purified
  6. customThe product (50 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU))
  7. waitmobile phase, water with 0.03% NH3H2O and CH3CN (38.0% CH3CN up to 51.0% in 8 min
  8. waitup to 100.0% in 2 min
  9. waitdown to 38.0% in 1 min)
  10. additionThe fractions containing pure compound

Sources & evidence

ORD record
ord-8d346a1a172441e98c1555bcdf05efe5
Source dataset
uspto-grants-2014_10
Patent number
US08871790B2

Reaction notes

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