Water → HCID 67171201, compound

HRID 1506507Notes

Reaction equation

HRID 1506507 reaction equation
[O:1]=[P:2]12[O:13]P3(OP(OP(O3)([O:9]1)=O)(=O)[O:3]2)=O.P(=O)(O)(O)O.[NH2:20][C:21]([CH3:54])([CH2:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:51](=[CH:52][CH:53]=1)[C:32]1=[N:33][O:34][C:35]([C:36]3[C:40]([C:41]([F:44])([F:43])[F:42])=[C:39]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[O:38][N:37]=3)=[C:31]1[CH2:30][CH2:29]2)[CH2:22]O.O>CO.ClCCl>[P:2]([OH:13])([OH:9])([O:3][CH2:54][C:21]([NH2:20])([CH3:22])[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:51](=[CH:52][CH:53]=1)[C:32]1=[N:33][O:34][C:35]([C:36]3[C:40]([C:41]([F:44])([F:43])[F:42])=[C:39]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[O:38][N:37]=3)=[C:31]1[CH2:30][CH2:29]2)=[O:1]

Participants

7

Reactant 4

HCID 962WaterHCID 1004Phosphoric AcidHCID 14812Phosphorus oxide (P4O10)HCID 67171863HCID 67171863, compound

Product 1

HCID 67171201HCID 67171201, compoundYield 52%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of phosphorus pentoxide (150 mg, 0.528 mmol) and 85% phosphoric acid (0.15 mL, 0.017 mmol) was stirred at 100° C. under nitrogen for 1 hr before 2-amino-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butan-1-ol (Isomer 1 of Example 93, 8 mg, 0.017 mmol) was added. The clear solution was stirred at the same temperature for 3 hr before being cooled. Water (0.4 mL) was added while the mixture was cooled with ice. The mixture was stirred at room temperature for 30 min. The mixture was dissolved in methanol and a little dichloromethane. Purification using reverse phase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization gave 2-amino-2-methyl-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butyl dihydrogen phosphate (5 mg, 8.6 μmol, 52% yield) as a white solid. The compound had an HPLC retention time=3.55 min. (condition C); LC/MS M+1=564.6. 1H NMR (400 MHz, MeOD) δ ppm 7.88 (1H, d, J=7.9 Hz), 7.76 (2H, d, J=7.3 Hz), 7.57-7.69 (3H, m), 7.31 (1H, s), 7.28 (1H, d, J=7.9 Hz), 3.82-3.99 (2H, m), 3.04-3.10 (4H, m), 2.67-2.83 (2H, m), 1.89-2.10 (2H, m), 1.40 (3H, s).

Workup

  1. additionwas added
  2. temperaturebefore being cooled
  3. temperaturewas cooled with ice
  4. stirringThe mixture was stirred at room temperature for 30 min
  5. customPurification
  6. concentrationphase HPLC (Phenomenex Luna AXIA 5 u c18 30×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA), concentration and lyophilization

Sources & evidence

ORD record
ord-80c547ed7d2744b991d0014b0967db8e
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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