Diisopropylethylamine → (3S)-ethyl 1-(2-hydroxy-2-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate

HRID 1948500Notes

Reaction equation

HRID 1948500 reaction equation
[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10](F)=[O:11])[C:6]=1[C:13]([F:16])([F:15])[F:14])[CH:2]([CH3:4])[CH3:3].[OH:17][CH:18]([C:31]1[CH:36]=[CH:35][C:34](/[C:37](=[N:39]/O)/[NH2:38])=[CH:33][CH:32]=1)[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21]1.CCN(C(C)C)C(C)C>C(#N)C.ClCCl>[OH:17][CH:18]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:39]=[C:10]([C:7]3[C:6]([C:13]([F:16])([F:15])[F:14])=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[O:9][N:8]=3)[O:11][N:38]=2)=[CH:33][CH:32]=1)[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21]1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 86656389(3S)-ethyl 1-(2-hydroxy-2-(4-(N'-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylateHCID 866563945-Isobutyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride

Product 1

HCID 68260588(3S)-ethyl 1-(2-hydroxy-2-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylateYield 54.5%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 5-isobutyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride; Int-V-D (0.045 g, 0.188 mmol), (3S)-ethyl 1-(2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (0.063 g, 0.188 mmol), and DIEA (0.043 mL, 0.245 mmol) in acetonitrile (1 mL) was stirred at room temperature for 4 days. The reaction was complete by HPLC. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated. The crude reaction mixture was purified by flash silica gel chromatography using a 20% mixture of ethyl acetate in hexane to give (3S)-ethyl 1-(2-hydroxy-2-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate (0.055 g, 0.103 mmol, 54.5% yield) as a clear, colorless oil. The product was >99% pure by HPLC with a ret. time=2.87 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=537.2.

Workup

  1. washwashed with a saturated aqueous solution of sodium bicarbonate
  2. dry with materialdried over anhydrous sodium sulfate
  3. concentrationconcentrated
  4. customThe crude reaction mixture
  5. customwas purified by flash silica gel chromatography

Sources & evidence

ORD record
ord-86cc0afde8ec426083a023ebba1001c5
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

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