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

HRID 1948477Notes

Reaction equation

HRID 1948477 reaction equation
[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](F)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH2:28]([O:30][C:31]([C@H:33]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][C@@H:40]([OH:51])[C:41]2[CH:46]=[CH:45][C:44](/[C:47](=[N:49]/O)/[NH2:48])=[CH:43][CH:42]=2)[CH2:34]1)=[O:32])[CH3:29].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(#N)C>[OH:51][C@@H:40]([C:41]1[CH:46]=[CH:45][C:44]([C:47]2[N:49]=[C:16]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]=3[C:12]([F:15])([F:14])[F:13])[O:17][N:48]=2)=[CH:43][CH:42]=1)[CH2:39][N:35]1[CH2:36][CH2:37][CH2:38][C@H:33]([C:31]([O:30][CH2:28][CH3:29])=[O:32])[CH2:34]1

Participants

7

Reactant 5

HCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 2724141Tetrabutylammonium FluorideHCID 58374067HCID 58374067, compoundHCID 58374160HCID 58374160, compound

Product 1

HCID 58374192(S)-ethyl 1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

3-Phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride, Int-I-G (214 mg, 0.78 mmol) was dissolved in acetonitrile (5.00 mL). DIEA (0.272 mL, 1.555 mmol) and (S)-ethyl-1-((S)-2-hydroxy-2-(4-((Z)-N′-hydroxycarbamimidoyl) phenyl)ethyl)-piperidine-3-carboxylate (261 mg, 0.778 mmol) were added. The reaction mixture was stirred for 2 hours, then 1M TBAF in THF (0.778 mL, 0.778 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and purified by HPLC in three batches. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were partitioned between EtOAc and saturated NaHCO3 with back extracting aqueous layer once. The organic layer was dried with MgSO4, filtered, and concentrated to give 155mg of (S)-ethyl 1-((S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.04 (2H, d, J=8.13 Hz), 7.55-7.60 (2H, m), 7.41-7.54 (5H, m), 4.81 (1H, ddd, J=8.35, 4.06, 3.84 Hz), 3.96-4.10 (2H, m), 2.82-3.08 (1H, m), 2.67-2.82 (1H, m, 2.36-2.61 (3H, m), 2.08-2.33 (2H, m), 1.73-1.87 (1H, m, J=8.54, 8.54, 4.45, 4.17 Hz), 1.32-1.70 (3H, m), 1.09-1.19 (3H, m). MS (m+1)=557. HPLC Peak RT=3.36 minutes. Purity=99%.

Workup

  1. stirringThe reaction mixture was stirred overnight at room temperature
  2. filtrationThe reaction mixture was filtered
  3. custompurified by HPLC in three batches
  4. custom25 minute
  5. customIsolated fractions with correct mass were partitioned between EtOAc and saturated NaHCO3 with back extracting aqueous layer once
  6. dry with materialThe organic layer was dried with MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-2a519b81a04145c58536443f68265e74
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

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