Acetic Acid → Tert-butyl 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylate

HRID 1506330Notes

Reaction equation

HRID 1506330 reaction equation
[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=O)=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:31]1[CH2:34][CH:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO.ClCCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH2:29][N:31]3[CH2:32][CH:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34]3)=[CH:23][CH:22]=5)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

9

Reactant 5

HCID 176Acetic Acid2×HCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 21828700tert-Butyl azetidine-3-carboxylateHCID 866698763-(3-Phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde

Product 1

HCID 67169968Tert-butyl 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylateYield 79%

Reagents, catalysts & solvents 3

HCID 11026Titanium isopropoxideCatalystHCID 111,2-DichloroethaneSolventHCID 887MethanolSolvent

Procedure

To a stirred solution of 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (7B, 2.1 g, 5.12 mmol), tert-butyl azetidine-3-carboxylate, AcOH (1.668 g, 7.68 mmol), and acetic acid (0.586 mL, 10.24 mmol) in anhydrous MeOH (10 mL) and anhydrous 1,2-dichloroethane (30 mL) was added titanium(IV) isopropoxide (3.05 mL, 10.24 mmol) dropwise at room temperature under nitrogen. The solution was stirred at room temperature for 1 hr before sodium triacetoxyborohydride (4.34 g, 20.47 mmol) was added in 10 portions over 3.5 hr. The mixture was stirred at room temperature for 2 hr. Saturated sodium bicarbonate (70 mL) was added slowly to make the mixture basic. After celite was added, the mixture was stirred at room temperature for 30 min and then filtered through a pad of celite. The aqueous filtrate was separated and extracted with dichloromethane (3×20 mL). The combined organic solutions were dried (sodium sulfate) and concentrated. Flash chromatography purification (120 g silica gel column, 25→70% ethyl acetate in hexanes) afforded tert-butyl 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylate (2.24 g, 4.06 mmol, 79% yield) as a yellow solid. The compound had an HPLC retention time=3.40 min (condition C); LC/MS M+1=552.1.

Workup

  1. additionwas added in 10 portions over 3.5 hr
  2. additionAfter celite was added
  3. stirringthe mixture was stirred at room temperature for 30 min
  4. filtrationfiltered through a pad of celite
  5. customThe aqueous filtrate was separated
  6. extractionextracted with dichloromethane (3×20 mL)
  7. dry with materialThe combined organic solutions were dried (sodium sulfate)
  8. concentrationconcentrated
  9. customFlash chromatography purification (120 g silica gel column, 25→70% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-79673e62fae44ec3b19224b73f551580
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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