Methanol → Trifluoroacetic acid

HRID 1506350Notes

Reaction equation

HRID 1506350 reaction equation
[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=O)=[CH:18][CH:17]=4)=[C:7]([C:26]([F:29])([F:28])[F:27])[CH:6]=1)([CH3:3])[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C([BH3-])#N.[Na+].[CH3:41][OH:42]>ClC(Cl)C.CC(O)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH2:24][N:30]2[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]2)=[CH:18][CH:17]=4)=[C:7]([C:26]([F:28])([F:29])[F:27])[CH:6]=1)([CH3:3])[CH3:2].[C:41]([OH:35])([C:26]([F:29])([F:28])[F:27])=[O:42]

Participants

8

Reactant 4

HCID 887MethanolHCID 931923-azetidinecarboxylic AcidHCID 5003444Sodium cyanoborohydrideHCID 866698813-(4-Isopropoxy-2-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde

Product 2

HCID 6422Trifluoroacetic acidYield 41%HCID 671695861-((3-(4-Isopropoxy-2-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 63651,1-DichloroethaneSolvent

Conditions

Temperature
80 °C

Procedure

To 3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 17C, 0.22 g, 0.548 mmol) in dichloroethane (2 mL) and methanol (2.000 mL) were sequentially added azetidine-3-carboxylic acid (0.066 g, 0.658 mmol) and 8 drops of AcOH at room temperature. The contents were heated at 80° C. for 75 minutes. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (0.041 g, 0.658 mmol) was added in one lot. The contents were stirred at room temperature for 30 minutes. The reaction mixture was concentrated, dissolved in acetonitrile (1.5 mL), and subjected to prep. HPLC (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). The desired fractions were concentrated and freeze dried to yield 1-((3-(4-isopropoxy-2-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, TFA (0.135 g, 0.225 mmol, 41.0% yield) as a tan solid. The compound had an HPLC retention time=3.01 min (condition C); LC/MS M+1=487.2; 1H NMR (500 MHz, MeOD) δ ppm 8.01 (1H, d, J=7.8 Hz), 7.55 (1H, d, J=8.6 Hz), 7.50 (1H, s), 7.48 (1H, dd, J=8.0, 1.7 Hz), 7.36 (1H, d, J=2.5 Hz), 7.31 (1H, dd, J=8.6, 2.5 Hz), 4.79 (1H, spt, J=6.1 Hz), 4.46 (2H, s), 4.32-4.41 (4H, m), 3.71 (1H, quin, J=8.3 Hz), 3.04 (2H, t, J=7.1 Hz), 2.77 (2H, t, J=7.2 Hz), 1.39 (6H, d, J=6.1 Hz).

Workup

  1. customat room temperature
  2. temperatureThe reaction mixture was cooled to room temperature
  3. concentrationThe reaction mixture was concentrated
  4. dissolutiondissolved in acetonitrile (1.5 mL)
  5. customHPLC (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA)
  6. concentrationThe desired fractions were concentrated
  7. customfreeze dried

Sources & evidence

ORD record
ord-3ad949ad030c4e019913d86b7c4f51db
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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