Tetrahydrofuran → HCID 50923122, compound

HRID 1948488Notes

Reaction equation

HRID 1948488 reaction equation
[OH:1][C:2]([C:16]1[CH:21]=[CH:20][C:19](/[C:22](=[N:24]/[OH:25])/[NH2:23])=[CH:18][CH:17]=1)([CH3:15])[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([C:10]([O:12]CC)=[O:11])[CH2:5]1.[C:26]1([C:32]2[C:36]([C:37]([F:40])([F:39])[F:38])=[C:35]([C:41](F)=O)[O:34][N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(#N)C>[OH:1][C:2]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:41]([C:35]3[O:34][N:33]=[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:36]=3[C:37]([F:40])([F:38])[F:39])[O:25][N:24]=2)=[CH:20][CH:21]=1)([CH3:15])[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([C:10]([OH:12])=[O:11])[CH2:5]1

Participants

7

Reactant 5

HCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 2724141Tetrabutylammonium FluorideHCID 58374065HCID 58374065, compoundHCID 58374067HCID 58374067, compound

Product 1

HCID 50923122HCID 50923122, compoundYield 10.7%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a mixture of (3S)-ethyl 1-(2-hydroxy-2-(4-((Z)-N′-hydroxycarbamimidoyl)phenyl)propyl)piperidine-3-carboxylate (72 mg, 0.206 mmol) and 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (53.4 mg, 0.206 mmol) in acetonitrile (5 mL) was added DIEA (0.072 mL, 0.412 mmol). After 2 hr, TBAF in THF (0.206 mL, 0.206 mmol) was added and the reaction was stirred overnight at RT. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass and concentrated in vacuo. The residue was treated with 6N HCl with MeCN as a co-solvent and heated at 50° C. for 4 days. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 12 mg of (35)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.10-8.19 (2H, m), 7.68-7.80 (2H, m), 7.59 (2H, d, J=6.59 Hz), 7.44-7.56 (3H, m), 3.59-3.81 (2H, m), 3.31-3.53 (2H, m), 3.01-3.19 (1H, m), 2.73-3.00 (2H, m), 1.73-2.12 (2H, m), 1.60 (3H, d, J=15.82 Hz), 0.68-1.45 (3H, m). HPLC Peak RT=3.35 minutes (Analytical Method A). Purity=90%.

Workup

  1. filtrationThe reaction mixture was filtered
  2. custompurified by HPLC
  3. custom25 minute
  4. concentrationIsolated fractions with correct mass and concentrated in vacuo
  5. additionThe residue was treated with 6N HCl with MeCN as a co-solvent
  6. temperatureheated at 50° C. for 4 days
  7. filtrationThe reaction mixture was filtered
  8. custompurified by HPLC
  9. custom25 minute
  10. customIsolated fractions with correct mass were freeze-dried overnight

Sources & evidence

ORD record
ord-9cbf126b3bd94b9eb2f6e9866b94fb95
Source dataset
uspto-grants-2013_03
Patent number
US08399451B2

Reaction notes

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