Hydrochloric Acid → HCID 117737021, compound

HRID 1504456Notes

Reaction equation

HRID 1504456 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]3[C:25]4[C:20](=[CH:21][C:22]([S:26](OC5C(F)=C(F)C(F)=C(F)C=5F)(=[O:28])=[O:27])=[CH:23][CH:24]=4)[CH:19]=[C:18]([O:41][CH3:42])[C:17]3=[O:43])=[CH:10][C:9]=2[F:44])=[CH:4][C:3]=1[CH3:45].[O:46]1[CH:50]=[CH:49][C:48]([NH2:51])=[N:47]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]3[C:25]4[C:20](=[CH:21][C:22]([S:26]([NH:51][C:48]5[CH:49]=[CH:50][O:46][N:47]=5)(=[O:27])=[O:28])=[CH:23][CH:24]=4)[CH:19]=[C:18]([O:41][CH3:42])[C:17]3=[O:43])=[CH:10][C:9]=2[F:44])=[CH:4][C:3]=1[CH3:45]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 18102163-IsoxazolamineHCID 2733832Lithium HexamethyldisilazideHCID 117737175HCID 117737175, compound

Product 1

HCID 117737021HCID 117737021, compoundYield 97%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A flask was charged with perfluorophenyl 1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-3-methoxy-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.2262 g, 0.338 mmol) and isoxazol-3-amine (0.034 g, 0.405 mmol). A septum was attached and THF (3.4 ml) was added under N2 flow. The solution was cooled to 0° C. and LHMDS (0.709 ml, 0.709 mmol) was added to give a bright yellow solution. After 10 min, 5 mL of 1 N HCl was added and the mixture was partitioned between 1 N HCL (10 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (1×10 mL). The combined organic layers were dried (Na2SO4) and concentrated for purification by MPLC (Biotage Isolera). The crude residue was taken up in minimal DCM and absorbed onto a 5 g loading cartridge and passed through a Interchim 25 g spherical silical gel column using a gradient of 5% EtOH and 15% EtOAc in heptane to 25% EtOH in EtOAc with 10% DCM constant additive to afford 1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-3-methoxy-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.187 g, 0.328 mmol, 97% yield) as a colorless foam. The racemic product was subjected to chiral separation by SFC on a Chiralcel OJ column (45% MeOH/80% CO2) to give (M)-1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-3-methoxy-2-oxo-1,2-dihydroquinoline-6-sulfonamide as peak 1 and (P)-1-(4′-chloro-2-fluoro-5-methoxy-3′-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-3-methoxy-2-oxo-1,2-dihydroquinoline-6-sulfonamide as peak 2. Data for peak 1: 1H NMR (500 MHz, DMSO-d6) δ 11.59 (br.s, 1H), 8.66 (d, J=1.62 Hz, 1H), 8.20 (d, J=1.88 Hz, 1H), 7.60-7.70 (m, 2H), 7.40-7.58 (m, 4H), 7.25-7.38 (m, 1H), 6.74 (d, J=8.89 Hz, 1H), 6.38 (d, J=1.56 Hz, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 2.37 (s, 3H). m/z (ESI) 568.2 (M+H)+. Data for peak 2: 1H NMR (500 MHz, DMSO-d6) δ 11.56 (br. s, 1H), 8.65 (d, J=1.56 Hz, 1H), 8.19 (d, J=1.95 Hz, 1H), 7.60-7.71 (m, 2H), 7.40-7.57 (m, 4H), 7.32 (d, J=6.88 Hz, 1H), 6.73 (d, J=8.89 Hz, 1H), 6.37 (d, J=1.62 Hz, 1H), 3.83 (s, 3H), 3.66 (s, 3H), 237 (s, 3H). m/z (ESI) 568.2 (M+H)+.

Workup

  1. customto give a bright yellow solution
  2. customthe mixture was partitioned between 1 N HCL (10 mL) and EtOAc (20 mL)
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with EtOAc (1×10 mL)
  5. dry with materialThe combined organic layers were dried (Na2SO4)
  6. concentrationconcentrated for purification by MPLC (Biotage Isolera)
  7. customabsorbed onto a 5 g loading cartridge

Sources & evidence

ORD record
ord-74472d9f0ec849a2bf082d53ffc50eed
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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