Tetrabutylammonium Hydroxide → ((3S)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid

HRID 1948475Notes

Reaction equation

HRID 1948475 reaction equation
Cl.[O:2]1[CH2:7][CH2:6]OCC1.[OH-:8].C([N+:13]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18]CCC)CCCC)CCC.Br[CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]=[C:39]([C:41]3[C:45]([CH2:46][CH2:47][CH3:48])=[C:44]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[O:43][N:42]=3)[O:38][N:37]=2)=[CH:32][CH:31]=1)[OH:29]>>[OH:29][CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:40]=[C:39]([C:41]3[C:45]([CH2:46][CH2:47][CH3:48])=[C:44]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[O:43][N:42]=3)[O:38][N:37]=2)=[CH:32][CH:31]=1)[CH2:27][N:13]1[CH2:18][CH2:25][CH2:24][C@@H:23]([CH2:6][C:7]([OH:2])=[O:8])[CH2:22]1

Participants

4

Reactant 3

HCID 2723671Tetrabutylammonium HydroxideHCID 204431481,4-Dioxane hydrochlorideHCID 583740872-Bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol

Product 1

HCID 50925335((3S)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid

Conditions

Temperature
80 °C

Procedure

To (S)-tert-butyl 2-(piperidin-3-yl)acetate, HCl (31.1 mg, 0.132 mmol) was added 4M HCl/dioxane (3 mL) and the reaction mixture was stirred for 30 minutes. Next, the reaction mixture was concentrated in vacuo and dried. This crude material was dissolved in DMSO (2 mL) and tetrabutylammonium hydroxide (0.198 mL, 0.198 mmol) was added. The reaction mixture was stirred for 30 minutes, followed by the addition of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol). The reaction mixture was heated at 80° C. for 2 hours, and then filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 20 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 5 mg of ((3S)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.12 (2H, m, J=8.35 Hz), 7.69-7.75 (2H, m), 7.60 (2H, m, J=8.13 Hz), 7.43-7.55 (3H, m), 5.16 (1H, dd, J=9.34, 4.50 Hz), 3.71-3.89 (1H, m), 3.52-3.68 (3H, m), 3.23-3.28 (1H, m), 2.96 (2H, dd, J=8.90, 6.92 Hz), 2.84-2.92 (1H, m), 2.17-2.38 (3H, m), 1.76-1.93 (3H, m), 1.62-1.73 (2H, m), 1.21 (1H, dd, J=12.30, 4.17 Hz), 0.95 (3H, t, J=7.25 Hz). MS (m+1)=517. HPLC Peak RT=3.37 minutes. (Analytical Method A). Purity=94%.

Workup

  1. concentrationNext, the reaction mixture was concentrated in vacuo
  2. customdried
  3. dissolutionThis crude material was dissolved in DMSO (2 mL)
  4. stirringThe reaction mixture was stirred for 30 minutes
  5. filtrationfiltered
  6. custompurified by HPLC
  7. custom25 minute
  8. customIsolated fractions with correct mass were freeze-dried overnight

Sources & evidence

ORD record
ord-8817554441604a298a2bd1a108387769
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

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