Methanol → Trifluoroacetic acid

HRID 1506498Notes

Reaction equation

HRID 1506498 reaction equation
[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=O)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:32]([CH2:34][C:35]([OH:37])=[O:36])[CH3:33].C([O-])(=[O:40])C.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].C([BH3-])#N.[Na+].[CH3:54][OH:55]>ClCCCl>[CH3:33][N:32]([CH2:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:14]1=[N:15][O:16][C:12]([C:9]3[C:8]([C:27]([F:28])([F:29])[F:30])=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:11][N:10]=3)=[C:13]1[CH2:24][CH2:23]2)[CH2:34][C:35]([OH:37])=[O:36].[C:54]([OH:40])([C:27]([F:30])([F:29])[F:28])=[O:55]

Participants

9

Reactant 6

HCID 887MethanolHCID 24436Sodium SulfateHCID 69483Glycine, N-methyl-, hydrochloride (1:1)HCID 517045Sodium AcetateHCID 5003444Sodium cyanoborohydrideHCID 866698753-(5-Phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde

Product 2

HCID 6422Trifluoroacetic acidYield 60.7%HCID 671715862-(Methyl((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)amino)acetic acid

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
60 °C

Procedure

A stirred mixture of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 88A, 28 mg, 0.068 mmol), sarcosine hydrochloride (42.8 mg, 0.341 mmol), sodium acetate (28.0 mg, 0.341 mmol), anhydrous sodium sulfate (1 g), anhydrous MeOH (1 mL), and anhydrous 1,2-dichloroethane (3 mL) was stirred at 60° C. under nitrogen for 1 hr. After the mixture was cooled to room temperature, sodium cyanoborohydride (8.58 mg, 0.136 mmol) was added. The reaction mixture was stirred at room temperature for 30 min and then filtered. The filtrate was concentrated. 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-(methyl((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)amino)acetic acid, TFA (25 mg, 0.041 mmol, 60.7% yield) as a white solid. The compound had an HPLC retention time=3.39 min. (condition C); LC/MS M+1=484.4. 1H NMR (400 MHz, MeOD) δ ppm 8.08 (1H, d, J=7.9 Hz), 7.77 (2H, d, J=7.3 Hz), 7.54-7.72 (5H, m), 4.45 (2H, s), 4.08 (2H, s), 3.07-3.19 (4H, m), 2.94 (3H, s).

Workup

  1. temperatureAfter the mixture was cooled to room temperature
  2. stirringThe reaction mixture was stirred at room temperature for 30 min
  3. filtrationfiltered
  4. concentrationThe filtrate was concentrated
  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-5574e99e1f2a432a900b493f45d60825
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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