Tetrabutylammonium Hydroxide → 2-((3R)-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 1948476Notes

Reaction equation

HRID 1948476 reaction equation
[NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH2:2]1.Cl.O1CCOCC1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:41][CH:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[N:54]=[C:53]([C:55]3[C:59]([CH2:60][CH2:61][CH3:62])=[C:58]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[O:57][N:56]=3)[O:52][N:51]=2)=[CH:46][CH:45]=1)[OH:43]>>[OH:43][CH:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[N:54]=[C:53]([C:55]3[C:59]([CH2:60][CH2:61][CH3:62])=[C:58]([C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=4)[O:57][N:56]=3)[O:52][N:51]=2)=[CH:46][CH:45]=1)[CH2:41][N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1

Participants

5

Reactant 4

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)ethanolHCID 58423403HCID 58423403, compound

Product 1

HCID 509253362-((3R)-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

(R)-tert-Butyl 2-(piperidin-3-yl)acetate (66 mg, 0.331 mmol) was treated with 4N HCl/dioxane for 30 minutes. The reaction mixture was concentrated in vacuo and dried. The solid material was dissolved in DMSO (2 mL) and tetrabutylammonium hydroxide (0.352 mL, 0.352 mmol) was added. After stirring 15 minutes, 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (40 mg, 0.088 mmol) was added. 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 9 mg of 2-((3R)-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 8.11 (2H, m), 7.68-7.75 (2H, m), 7.59 (2H, m, J=8.35 Hz), 7.43-7.55 (3H, m), 5.16 (1H, dd, J=9.01, 4.61 Hz), 3.71-3.89 (1H, m), 3.50-3.67 (2H, m), 3.24 (1H, d, J=2.42 Hz), 2.96 (2H, dd, J=8.90, 6.92 Hz), 2.83-2.93 (1H, m), 2.72 (1H, td, J=11.86, 5.27 Hz), 2.16-2.39 (3H, m), 1.77-2.00 (3H, m), 1.59-1.75 (2H, m, J=7.61, 7.61, 7.61, 7.61, 7.36 Hz), 1.13-1.32 (1H, m), 0.95 (3H, t, J=7.25 Hz). MS (m+1)=517. HPLC Peak RT=3.32 minutes (Analytical Method A). Purity=95%.

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. customdried
  3. dissolutionThe solid material was dissolved in DMSO (2 mL)
  4. additionwas added
  5. filtrationfiltered
  6. custompurified by HPLC
  7. custom25 minute
  8. customIsolated fractions with correct mass were freeze-dried overnight

Sources & evidence

ORD record
ord-6c43cce39d2e41b39879224edc1bc468
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

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