Acetic Acid → tert-Butyl (3R)-3-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]-phenyl}amino)pyrimidin-4-yl]oxy}pyrrolidine-1-carboxylate

HRID 1028128Notes

Reaction equation

HRID 1028128 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:23]1[N:28]=[C:27]([O:29][C@@H:30]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]2)[CH:26]=[CH:25][N:24]=1.CC(O)=O>O1CCOCC1.C(=O)(O)[O-].[Na+]>[CH3:8][C:6]1[CH:7]=[C:2]([NH:1][C:23]2[N:28]=[C:27]([O:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)[CH:26]=[CH:25][N:24]=2)[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=1

Participants

6

Reactant 3

HCID 176Acetic Acid3×HCID 60137519(R)-tert-Butyl 3-((2-chloropyrimidin-4-yl)oxy)pyrrolidine-1-carboxylateHCID 67236328HCID 67236328, compound2×

Product 1

HCID 86674326tert-Butyl (3R)-3-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]-phenyl}amino)pyrimidin-4-yl]oxy}pyrrolidine-1-carboxylateYield 26%

Reagents, catalysts & solvents 2

HCID 312751,4-DioxaneSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
120 °C

Procedure

To a stirred solution of the 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 165 mg, 0.55 mmol) and tert-butyl (3R)-3-[(2-chloropyrimidin-4-yl)oxy]pyrrolidine-1-carboxylate (164 mg, 0.55 mmol) in dioxane (2.7 ml) was added AcOH (66 μl, 1.15 mmol). The mixture was heated to 120° C. for 5 h, treated with additional portion of AcOH (66 μl, 1.15 mmol), and left to stir overnight. Additional AcOH (66 μl, 1.15 mmol) was then added and the resultant mixture was left to stir overnight. The mixture was then cooled to room temperature, diluted with saturated sodium bicarbonate solution, and extracted with ethyl acetate (×3). The combined organics were washed with brine, dried over sodium sulfate, concentrated, and purified by Combiflash. (ethyl acetate/hexanes) to afford 80 mg (0.14 mmol, 26% yield) of tert-butyl (3R)-3-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}pyrrolidine-1-carboxylate.

Workup

  1. waitleft
  2. stirringto stir overnight
  3. temperatureThe mixture was then cooled to room temperature
  4. extractionextracted with ethyl acetate (×3)
  5. washThe combined organics were washed with brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated
  8. custompurified by Combiflash

Sources & evidence

ORD record
ord-8a1fca8547614f15b73376b7e56589f3
Source dataset
uspto-grants-2014_05
Patent number
US08735417B2

Reaction notes

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