3-azetidinecarboxylic Acid → HCID 67170150, compound

HRID 1506423Notes

Reaction equation

HRID 1506423 reaction equation
[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[S:13][C:14]4[C:24]5[C:19](=[CH:20][C:21]([CH:25]=O)=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:15]=4[N:16]=3)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:31]1[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]1.C([BH3-])#N.[Na+]>ClCCCl.CO.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[S:13][C:14]4[C:24]5[C:19](=[CH:20][C:21]([CH2:25][N:31]6[CH2:34][CH:33]([C:35]([OH:37])=[O:36])[CH2:32]6)=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:15]=4[N:16]=3)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

7

Reactant 3

HCID 931923-azetidinecarboxylic AcidHCID 5003444Sodium cyanoborohydrideHCID 86669902HCID 86669902, compound

Product 1

HCID 67170150HCID 67170150, compoundYield 44.8%

Reagents, catalysts & solvents 3

HCID 11026Titanium isopropoxideCatalystHCID 111,2-DichloroethaneSolventHCID 887MethanolSolvent

Procedure

To a stirring solution of 2-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[2,1-d]thiazole-7-carbaldehyde (0.106 g, 0.249 mmol) in 1,2-dichloroethane (2.0 ml) at room temperature, was added azetidine-3-carboxylic acid (0.075 g, 0.746 mmol). The resulting pale suspension was stirred for 15 min after which tetraisopropyl titanate (0.222 ml, 0.746 mmol) was added dropwise. The reaction mixture turned light orange. Stirring was continued for 4 h after which sodium cyanoborohydride (0.023 g, 0.373 mmol) was added in one portion. After 90 min, the reaction mixture was diluted with MeOH and filtered through Celite. The filter cake was washed with MeOH (2×), and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (24 g Redisep® cartridge, eluting with 5%-MeOH in dichloromethane followed by 10% (10%-Ammonia-MeOH in dichloromethane) to yield 57 mg of the desired 1-((2-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl)methyl)azetidine-3-carboxylic acid as an off white solid. The product had an LC ret. time=1.927 min. (condition: Start % B=0; Final % B=100; Gradient Time=2 min; Flow Rate=5 ml/min; Wavelength=254; Solvent Pair=MeOH/H2O/TFA; Solvent A=0.1% TFA in MeOH: H2O (10:90); Solvent B=0.1% TFA in; MeOH: H2O (10:90); Column 1=Waters Sunfire C18 5 um 4.6×30 mm); LC/MS M+1=512.08. 1H NMR (400 MHz, CD3OD) δ ppm 7.75 (2H, d, J=7.48 Hz), 7.59-7.68 (3H, m), 7.53 (1H, d, J=7.70 Hz), 7.43 (1H, s), 7.38 (1H, dd, J=7.92, 1.54 Hz), 4.34 (2H, s), 4.16-4.23 (4H, m), 3.42 (1H, quin, J=8.36 Hz), 3.12-3.23 (4H, m).

Workup

  1. additionwas added dropwise
  2. waitAfter 90 min
  3. filtrationfiltered through Celite
  4. washThe filter cake was washed with MeOH (2×)
  5. concentrationthe filtrate was concentrated in vacuo
  6. customThe crude product was purified by flash chromatography (24 g Redisep® cartridge
  7. washeluting with 5%-MeOH in dichloromethane

Sources & evidence

ORD record
ord-aa0228b0e2a9471abac53685286919ab
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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