Morpholine → HCID 178463572, compound

HRID 243375Notes

Reaction equation

HRID 243375 reaction equation
[F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([C@@H:15]([NH:17][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCC[O:28]3)[CH3:16])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[C:3]=1[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[NH4+:6].[OH-:28].[F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([CH:15]([NH:17][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[CH3:16])[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:4]=2[C:3]=1[C:35]([N:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1)=[O:36]

Participants

8

Reactant 4

HCID 8083MorpholineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 681574615-Fluoro-3-phenyl-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid

Product 2

HCID 14923Ammonium HydroxideHCID 178463572HCID 178463572, compoundYield 141.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 5-fluoro-3-phenyl-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid (100 mg, 0.2 mmol), HATU (91 mg, 0.24 mmol), morpholine (26 μL, 0.3 mmol) and DIPEA (69 μL, 0.4 mmol) in DCM (2 mL) was stirred at RT for 1 h. The crude mixture was diluted with water and extracted with DCM. The aqueous phase was further extracted with DCM and the combined organic fractions were dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in MeOH (2 mL) and 4N HCl in dioxane (0.25 mL) and the mixture was stirred at RT for 30 min. The volatiles were removed under reduced pressure and the resulting residue purified by HPLC (Waters C18 XBridge, on a 20 min gradient 10-90%, 0.1% NH4OH in acetonitrile/water) to afford 203 (69 mg, 71%). LCMS (Method K): RT 2.64 and 2.67 min [M+H]+ 487.1. 1H NMR (DMSO-d6+TFA-D, 400 MHz, 80° C.): δ 8.52 (1H, br s), 8.46 (1H, d, J=6.25 Hz), 7.83-7.75 (1H, m), 7.57-7.43 (5H, m), 7.32-7.15 (2H, m), 5.66 (1H, br s), 3.50-3.24 (5H, m), 3.15-3.05 (1H, m), 3.04-2.95 (1H, m), 2.70-2.58 (1H, m), 1.74-1.65 (3H, m)

Workup

  1. extractionextracted with DCM
  2. extractionThe aqueous phase was further extracted with DCM
  3. dry with materialthe combined organic fractions were dried (MgSO4)
  4. concentrationconcentrated in vacuo
  5. dissolutionThe resulting residue was dissolved in MeOH (2 mL)
  6. stirring4N HCl in dioxane (0.25 mL) and the mixture was stirred at RT for 30 min
  7. customThe volatiles were removed under reduced pressure
  8. customthe resulting residue purified by HPLC (Waters C18 XBridge

Sources & evidence

ORD record
ord-5f0244e304cd4478a54f5c3b1dadd80f
Source dataset
uspto-grants-2014_02
Patent number
US08653089B2

Reaction notes

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