Water → Crenolanib

HRID 351308Notes

Reaction equation

HRID 351308 reaction equation
C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[C:21]([N:24]2[C:28]4[CH:29]=[CH:30][C:31]([O:33][CH2:34][C:35]5([CH3:39])[CH2:38][O:37][CH2:36]5)=[CH:32][C:27]=4[N:26]=[CH:25]2)[CH:20]=[CH:19]3)[CH2:10][CH2:9]1)(C)(C)C.CC(C)([O-])C.[Na+].O>CC1CCCO1>[CH3:39][C:35]1([CH2:34][O:33][C:31]2[CH:30]=[CH:29][C:28]3[N:24]([C:21]4[CH:20]=[CH:19][C:18]5[C:23](=[C:14]([N:11]6[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]6)[CH:15]=[CH:16][CH:17]=5)[N:22]=4)[CH:25]=[N:26][C:27]=3[CH:32]=2)[CH2:38][O:37][CH2:36]1

Participants

5

Reactant 3

HCID 962WaterHCID 11692406HCID 11692406, compoundHCID 23676156Sodium t-butoxide

Product 1

HCID 10366136CrenolanibYield 86%

Reagents, catalysts & solvents 1

HCID 73012-MethyltetrahydrofuranSolvent

Procedure

The compound, (1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-yl)-carbamic acid tert-butyl ester (2 g, 3.68 mmol, 1 equivalent), sodium t-butoxide (1.77 g, 18.4 mmol, 5 equivalents), 2-methyltetrahydrofuran (30 mL, 15 volumes), and water (66 mL, 1 equivalent) were added to a 100 mL round bottom flask. The mixture was heated to reflux and held at reflux for 24–30 hours. At reaction completion, the mixture was cooled to 20–30° C. The reaction was quenched into a 20% citric acid solution (10 volumes) and stirred at 20–30° C. for 30–60 minutes. The citrate salt precipitated out of solution during this time. A 50% sodium hydroxide solution (˜1 weight equivalent) was charged to basify the reaction mixture (pH 10–12). The layers were separated at 30–40° C. The aqueous layer was washed with ethyl acetate (10 volumes) and then the combined organics were concentrated to low volume. Ethyl acetate (14 mL, 7 volumes) was charged and the slurry was allowed to granulate for 10–20 hours. The solids were filtered and 1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine (1.4 g, 86% yield) was isolated.

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux
  3. temperatureat reflux for 24–30 hours
  4. customAt reaction completion
  5. temperaturethe mixture was cooled to 20–30° C
  6. customThe reaction was quenched into a 20% citric acid solution (10 volumes)
  7. customThe citrate salt precipitated out of solution during this time
  8. additionA 50% sodium hydroxide solution (˜1 weight equivalent) was charged
  9. customThe layers were separated at 30–40° C
  10. washThe aqueous layer was washed with ethyl acetate (10 volumes)
  11. concentrationthe combined organics were concentrated to low volume
  12. additionEthyl acetate (14 mL, 7 volumes) was charged
  13. waitto granulate for 10–20 hours
  14. filtrationThe solids were filtered

Sources & evidence

ORD record
ord-aa7bae0d45fb46a0bde169681f7aa7d6
Source dataset
uspto-grants-2007_02
Patent number
US07183414B2

Reaction notes

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