Tetrahydrofuran → HCID 117736948, compound

HRID 1504505Notes

Reaction equation

HRID 1504505 reaction equation
C1COCC1.[F:6][C:7]1[CH:8]=[C:9]([C:13]2[N:18]=[CH:17][C:16]([N:19]3[C:28]4[C:23](=[CH:24][C:25]([S:29](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:31])=[O:30])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]3=[O:44])=[C:15]([O:45][CH3:46])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[NH2:47][C:48]1[CH:52]=[CH:51][O:50][N:49]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(Cl)Cl.CCOC(C)=O.CCO>[F:6][C:7]1[CH:8]=[C:9]([C:13]2[N:18]=[CH:17][C:16]([N:19]3[C:28]4[C:23](=[CH:24][C:25]([S:29]([NH:47][C:48]5[CH:52]=[CH:51][O:50][N:49]=5)(=[O:30])=[O:31])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]3=[O:44])=[C:15]([O:45][CH3:46])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1

Participants

7

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 18102163-IsoxazolamineHCID 2733832Lithium HexamethyldisilazideHCID 117737266HCID 117737266, compound

Product 1

HCID 117736948HCID 117736948, compoundYield 66.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 21584252Ethanol ethylacetateSolvent

Conditions

Temperature
0 °C

Procedure

A THF (2.4 mL) solution of perfluorophenyl 1-(6-(3-fluorophenyl)-4-methoxypyridin-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (140 mg, 0.236 mmol) and 3-aminoisoxazole (19.20 μl, 0.260 mmol) in a 40-mL vial was cooled to 0° C. and subsequently treated with lithium bis(trimethylsilyl)amide, 1.0M solution in THF (496 μl, 0.496 mmol). After stirring the yellow solution at 0° C. for 20 min, the reaction was quenched at 0° C. with 1 N HCl and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yellow residue. Column chromatography (25 g Snap Ultra column, 0-80% [3:1 EtOAc/EtOH]/hept gradient with 10% DCM) afforded racemic 1-(6-(3-fluorophenyl)-4-methoxy-3-pyridinyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide (76.6 mg, 0.156 mmol, 65.8% yield) as an amorphous white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.92 (s, 3 H) 6.46 (d, J=5.48 Hz, 1 H) 6.84 (d, J=9.64 Hz, 1 H) 6.92 (d, J=9.02 Hz, 1 H) 7.36 (d, J=8.22 Hz, 1 H) 7.61 (dd, J=7.98, 1.76 Hz, 1 H) 7.86 (dd, J=8.91, 2.28 Hz, 1 H) 7.92 (s, 1 H) 8.05-8.15 (m, 2 H) 8.27 (d, J=14.13 Hz, 1 H) 8.40 (d, J=2.18 Hz, 1 H) 8.50 (s, 1 H) 8.74 (d, J=1.76 Hz, 1 H) 11.67 (s, 1H). m/z (ESI) 493.0 (M+H)+. A portion of the racemic product was separated via Chiralpak AS-H (30% MeOH/70% CO2) to afford (P)-1-(6-(3-fluorophenyl)-4-methoxy-3-pyridinyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide (27 mg) and (M)-1-(6-(3-fluorophenyl)-4-methoxy-3-pyridinyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide (28 mg) as white amorphous solids. Data for peak 1: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.92 (s, 3 H) 6.40 (d, J=1.45 Hz, 1 H) 6.82 (d, J=9.64 Hz, 1 H) 6.88 (d, J=9.02 Hz, 1 H) 7.36 (t, J=8.03 Hz, 1 H) 7.57-7.65 (m, 1 H) 7.84 (dd, J=8.97, 2.13 Hz, 1H) 7.92 (s, 1 H) 8.07 (dd, J=10.42, 2.02 Hz, 1 H) 8.11 (d, J=8.09 Hz, 1 H) 8.25 (d, J=9.74 Hz, 1 H) 8.36 (d, J=1.76 Hz, 1 H) 8.50 (s, 1 H) 8.65 (s, 1 H) 11.50-11.82 (m, 1 H). m/z (ESI) 493.2 (M+H)+. Data for peak 2: 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.92 (s, 3 H) 6.38 (d, J=1.35 Hz, 1 H) 6.81 (d, J=9.64 Hz, 1 H) 6.86 (d, J=8.81 Hz, 1 H) 7.35 (t, J=8.20 Hz, 1 H) 7.61 (dd, J=7.93, 1.81 Hz, 1 H) 7.83 (dd, J=8.97, 2.02 Hz, 1 H) 7.92 (s, 1 H) 8.07 (dd, J=10.42, 2.02 Hz, 1 H) 8.11 (d, J=7.98 Hz, 1 H) 8.24 (d, J=9.64 Hz, 1 H) 8.34 (d, J=1.97 Hz, 1 H) 8.49 (s, 1 H) 8.61 (s, 1 H) 11.50-11.79 (m, 1 H). m/z (ESI) 493.2 (M+H)+.

Workup

  1. customthe reaction was quenched at 0° C. with 1 N HCl
  2. extractionextracted thrice with EtOAc
  3. washwashed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo to a yellow residue

Sources & evidence

ORD record
ord-dcd81429f27b4e79970f3781fab9fa4d
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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