Hydrochloric Acid → (S)-1-ethyl-3-(4-(8-(3-hydroxyazetidin-3-yl)-9-methyl-6-(3-methylmorpholino)-9H-purin-2-yl)phenyl)urea

HRID 2063378Notes

Reaction equation

HRID 2063378 reaction equation
[CH2:1]([NH:3][C:4](=[O:41])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:20]=[C:19]3[C:15]([N:16]=[C:17]([C:22]4([OH:33])[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]4)[N:18]3[CH3:21])=[C:14]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]3[CH3:40])[N:13]=2)=[CH:8][CH:7]=1)[CH3:2].Cl.O1CCOCC1.FC(F)(F)C(O)=O>ClCCl.CO>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:20]=[C:19]3[C:15]([N:16]=[C:17]([C:22]4([OH:33])[CH2:23][NH:24][CH2:25]4)[N:18]3[CH3:21])=[C:14]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]3[CH3:40])[N:13]=2)=[CH:8][CH:7]=1)=[O:41])[CH3:2]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 312751,4-DioxaneHCID 58222521(S)-tert-butyl 3-(2-(4-(3-ethylureido)phenyl)-9-methyl-6-(3-methyl-morpholino)-9H-purin-8-yl)-3-hydroxyazetidine-1-carboxylate

Product 1

HCID 52915452(S)-1-ethyl-3-(4-(8-(3-hydroxyazetidin-3-yl)-9-methyl-6-(3-methylmorpholino)-9H-purin-2-yl)phenyl)ureaYield 21%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

To (S)-tert-butyl 3-(2-(4-(3-ethylureido)phenyl)-9-methyl-6-(3-methyl-morpholino)-9H-purin-8-yl)-3-hydroxyazetidine-1-carboxylate (45.2 mg, 0.08 mmol) in anhydrous dichloromethane (3.0 mL) and anhydrous methanol (3.0 mL) at 0° C. was added 4M hydrogen chloride in 1,4-dioxane (0.20 mL, 0.80 mmol, 10.0 eq.). The reaction mixture was stirred at RT under N2 for 16 h. Trifluoroacetic acid (0.20 mL) was added and the reaction mixture was stirred at 40° C. under N2 for 24 h. The reaction was then cooled to RT. The reaction mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by reverse phase HPLC to give the title compound as a white solid (7.8 mg, 21%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.70 (s, 1H), 8.27 (d, J=8.8 Hz, 2H), 7.95 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 6.44 (s, 1H), 6.22 (t, J=5.5 Hz, 1H), 5.48 (broad s, 1H), 5.15 (broad s, 1H), 4.14 (d, J=8.2 Hz, 1H), 4.08 (d, J=8.3 Hz, 1H), 4.01 (d, J=8.3 Hz, 1H), 3.84 to 3.67 (m, 7H), 3.61 to 3.52 (m, 1H), 3.50 to 3.39 (m, 1H), 3.17 to 3.07 (m, 2H), 1.34 (d, J=6.7 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); LC-MS m/z (method C)=467.2 [M+H]+, RT=3.21 min.

Workup

  1. stirringthe reaction mixture was stirred at 40° C. under N2 for 24 h
  2. temperatureThe reaction was then cooled to RT
  3. concentrationThe reaction mixture was concentrated in vacuo
  4. additionthe residue was diluted with ethyl acetate
  5. washThe organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude was purified by reverse phase HPLC

Sources & evidence

ORD record
ord-5136ca497e3648088361e8546395e14d
Source dataset
uspto-grants-2012_10
Patent number
US08288381B2

Reaction notes

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