4-Aminopyrimidine → 1-(3'-chloro-5'-fluoro-4-methoxy-[1,1'-biphenyl]-3-yl)-2-oxo-N-(pyrimidin-4-yl)-1,2-dihydroquinoline-6-sulfonamide

HRID 1504510Notes

Reaction equation

HRID 1504510 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]3[C:33]4[C:28](=[CH:29][C:30]([S:34](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:36])=[O:35])=[CH:31][CH:32]=4)[CH:27]=[CH:26][C:25]3=[O:49])[CH:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CS(C)=O.O1CCCC1.CCOC(C)=O.Cl>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]3[C:33]4[C:28](=[CH:29][C:30]([S:34]([NH:1][C:2]5[CH:7]=[CH:6][N:5]=[CH:4][N:3]=5)(=[O:35])=[O:36])=[CH:31][CH:32]=4)[CH:27]=[CH:26][C:25]3=[O:49])[CH:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1

Participants

8

Reactant 3

HCID 689584-AminopyrimidineHCID 2733832Lithium HexamethyldisilazideHCID 117737031Perfluorophenyl 1-(3'-chloro-5'-fluoro-4-methoxy-[1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate

Product 1

HCID 1177371531-(3'-chloro-5'-fluoro-4-methoxy-[1,1'-biphenyl]-3-yl)-2-oxo-N-(pyrimidin-4-yl)-1,2-dihydroquinoline-6-sulfonamideYield 49%

Reagents, catalysts & solvents 4

HCID 313Hydrochloric AcidSolventHCID 679Dimethyl SulfoxideSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

4-Aminopyrimidine (0.099 g, 1.038 mmol) was dissolved in dimethyl sulfoxide (1.997 ml), and perfluorophenyl 1-(3′-chloro-5′-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.500 g, 0.799 mmol) in tetrahydrofuran (5.99 ml) was added as a solution. The reaction was cooled to 0° C. and LHMDS, 1.0M in THF (1.837 ml, 1.837 mmol) was added drop wise. The reaction mixture was diluted with EtOAc and 1N HCl (aq). The layers were separated, and the aqueous was washed (xl) with EtOAc. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified via MPLC, eluting with 0-100% ethyl acetate in heptane (with a 10% DCM additive), to yield 1-(3′-chloro-5′-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)-2-oxo-N-(pyrimidin-4-yl)-1,2-dihydroquinoline-6-sulfonamide (0.210 g, 0.391 mmol, 49.0% yield) as a white solid. m/z (ESI) 537.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H) 6.75 (d, J=8.91 Hz, 1 H) 6.80 (d, J=9.64 Hz, 1 H) 7.00 (br. s., 1 H) 7.34-7.42 (m, 2 H) 7.59-7.64 (m, 1 H) 7.68 (t, J=1.61 Hz, 1 H) 7.86 (d, J=2.49 Hz, 1 H) 7.89 (dd, J=8.97, 2.02 Hz, 1 H) 8.02 (dd, J=8.76, 2.44 Hz, 1 H) 8.24 (d, J=9.54 Hz, 1 H) 8.27-8.34 (m, 1 H) 8.43 (s, 1 H) 8.60 (s, 1 H). 1-(3′-chloro-5′-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)-2-oxo-N-(pyrimidin-4-yl)-1,2-dihydroquinoline-6-sulfonamide was separated by chiral SFC on a Chiralpak AD with 30% isopropanol to give (P)-1-(3′-chloro-5′-fluoro-4-methoxy-3-biphenylyl)-2-oxo-N-4-pyrimidinyl-1,2-dihydro-6-quinolinesulfonamide as peak 1 and (M)-1-(3′-chloro-5′-fluoro-4-methoxy-3-biphenylyl)-2-oxo-N-4-pyrimidinyl-1,2-dihydro-6-quinolinesulfonamide as peak 2. Data for peak 1: m/z (ESI) 537.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H) 6.75 (d, J=8.81 Hz, 6.79 (d, J=9.64 Hz, 1 H) 6.98 (br. s., 1 H) 7.34-7.41 (m, 2 H) 7.62 (dt, J=7.63 Hz, 1 H) 7.68 (t, J=1.61 Hz, 1 H) 7.86 (d, J=2.38 Hz, 1 H) 7.87-7.91 (m, 1 H) 8.02 (dd, J=8.76, 2.44 Hz, 1 H) 8.23 (d, J=9.54 Hz, 1 H) 8.26-8.31 (m, 1 H) 8.40-8.44 (m, 1 H) 8.59 (s, 1 H). Data for peak 2: m/z (ESI) 537.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3H) 6.75 (d, J=9.02 Hz, 1 H) 6.79 (d, J=9.64 Hz, 1 H) 7.00 (br. s., 1 H) 7.35-7.41 (m, 2 H) 7.61 (dt, J=6.43 Hz, 1 H) 7.68 (t, J=1.55 Hz, 1 H) 7.86 (d, J=2.49 Hz, 1 H) 7.87-7.91 (m, 1H) 8.02 (dd, J=8.71, 2.49 Hz, 1 H) 8.24 (d, J=9.64 Hz, 1 H) 8.29 (br. s., 1 H) 8.41-8.44 (m, 1H) 8.59 (s, 1 H). The sulfonamide —NH was not observed in the NMR spectra of the three compounds.

Workup

  1. customThe layers were separated
  2. washthe aqueous was washed (xl) with EtOAc
  3. dry with materialThe combined organics were dried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude material was purified via MPLC
  7. washeluting with 0-100% ethyl acetate in heptane (with a 10% DCM additive),

Sources & evidence

ORD record
ord-35aee9a7026e4ffd9828567df08eda2c
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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