Methanol → Trifluoroacetic acid

HRID 1506405Notes

Reaction equation

HRID 1506405 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)[OH:16].[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[CH:37]=[N:38][N:39]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:40]=3[C:41]([F:44])([F:43])[F:42])=[C:31]1[CH2:30][CH2:29]2)[CH2:22]O.[CH3:55][OH:56]>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[CH:37]=[N:38][N:39]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:40]=3[C:41]([F:44])([F:43])[F:42])=[C:31]1[CH2:30][CH2:29]2)=[O:1].[C:55]([OH:16])([C:41]([F:44])([F:43])[F:42])=[O:56]

Participants

7

Reactant 4

HCID 887MethanolHCID 1004Phosphoric AcidHCID 14812Phosphorus oxide (P4O10)HCID 671710162-amino-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butan-1-ol

Product 2

HCID 6422Trifluoroacetic acidYield 60.3%HCID 671707982-amino-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butyl dihydrogen phosphate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of phosphorus pentoxide (300 mg, 1.057 mmol) and 85% phosphoric acid (0.3 mL, 0.021 mmol) was stirred at 100° C. under nitrogen for 1 hr before 2-amino-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butan-1-ol (Example 50, 10 mg, 0.021 mmol) was added. The clear solution was stirred at the same temperature for 2 hr before ice (˜2 gram) was added. The reaction mixture was stirred at room temperature for 3 hour and dissolved in a minimum amount of methanol and 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-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butyl dihydrogen phosphate, 0.4 TFA (8 mg, 0.012 mmol, 60.3% yield) as a white solid. The compound had an HPLC retention time=3.16 min (condition C); LC/MS M+1=563.4; 1H NMR (400 MHz, MeOD+CDCl3) δ ppm 8.07 (1H, s), 7.86 (1H, d, J=7.7 Hz), 7.52-7.63 (5H, m), 7.24-7.33 (2H, m), 3.98 (1H, dd, J=11.5, 5.5 Hz), 3.89 (1H, dd, J=11.5, 5.5 Hz), 3.04 (2H, t, J=6.9 Hz), 2.90 (2H, t, J=6.9 Hz), 2.65-2.85 (2H, m), 2.08 (1H, td, J=13.1, 4.7 Hz), 1.94 (1H, td, J=13.1, 4.7 Hz), 1.41 (3H, s).

Workup

  1. additionwas added
  2. additionwas added
  3. customPurification
  4. 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-a13bff5747d340459ee41dd3535fcc8e
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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