Methanol → Trifluoroacetic acid

HRID 1506540Notes

Reaction equation

HRID 1506540 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]3[O:21][N:20]=[C:19]4[C:22]5[C:27]([CH2:28][CH2:29][C:18]=34)=[CH:26][C:25]([CH:30]=O)=[CH:24][CH:23]=5)[CH:10]=[N:9]2)=[N:6][CH:7]=1.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1.C1CCN2C(=NCCC2)CC1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:52])C.[Na+].[CH3:64][OH:65]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:14])[F:15])=[C:11]([C:17]3[O:21][N:20]=[C:19]4[C:22]5[C:27]([CH2:28][CH2:29][C:18]=34)=[CH:26][C:25]([CH2:30][N:32]3[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]3)=[CH:24][CH:23]=5)[CH:10]=[N:9]2)=[N:6][CH:7]=1.[C:64]([OH:52])([C:13]([F:16])([F:15])[F:14])=[O:65]

Participants

8

Reactant 5

HCID 887MethanolHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 931923-azetidinecarboxylic AcidHCID 5049666Sodium triacetoxyborohydride2×HCID 866699373-(1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde

Product 2

HCID 6422Trifluoroacetic acidYield 84%HCID 671696561-((3-(1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred mixture of 3-(1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 122C, 40 mg, 0.093 mmol), dichloromethane (4 mL) and MeOH (1 mL) was added azetidine-3-carboxylic acid (28.3 mg, 0.280 mmol) at room temperature followed by DBU (0.028 mL, 0.187 mmol). The reaction mixture was stirred at room temperature for 5 min. before sodium triacetoxyborohydride (59.4 mg, 0.280 mmol) was added in one lot. The mixture was stirred at room temperature overnight. More sodium triacetoxyborohydride (30 mg) was added and the mixture was stirred at room temperature for 4 hr. The mixture was concentrated and dissolved in 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 1-((3-(1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid, TFA (51 mg, 0.079 mmol, 84% yield) as a white solid. The compound had an HPLC retention time=2.77 min. (condition C); LC/MS M+1=513.9; 1H NMR (400 MHz, MeOD) δ ppm 8.49 (1H, s), 8.18 (1H, s), 8.02 (1H, d, J=7.7 Hz), 7.89-7.93 (2H, m), 7.52 (1H, s), 7.49 (1H, d, J=7.7 Hz), 4.46 (2H, s), 4.31-4.42 (4H, m), 3.70 (1H, quin, J=8.3 Hz), 3.09 (2H, t, J=6.9 Hz), 2.93 (2H, t, J=7.0 Hz).

Workup

  1. additionwas added in one lot
  2. stirringthe mixture was stirred at room temperature for 4 hr
  3. concentrationThe mixture was concentrated
  4. dissolutiondissolved in methanol
  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-438c8f088604473c8d750fe276baac7a
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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