Hydrochloric Acid → (S)-6-(3-cyano-1-cyclobutyl-6 (difluoromethoxy)-5-fluoro-4-methyl-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide

HRID 1028028

Reaction equation

HRID 1028028 reaction equation
[CH3:1][Zn]Cl.Br[C:5]1[C:13]([F:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[CH:11]=[C:10]2[C:6]=1[C:7]([C:39]#[N:40])=[C:8]([C:23]1[N:28]=[CH:27][C:26]([S:29]([NH:32][C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[N:9]2[CH:19]1[CH2:22][CH2:21][CH2:20]1.Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[C:39]([C:7]1[C:6]2[C:10](=[CH:11][C:12]([O:15][CH:16]([F:18])[F:17])=[C:13]([F:14])[C:5]=2[CH3:1])[N:9]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:8]=1[C:23]1[N:28]=[CH:27][C:26]([S:29]([NH:32][C@@H:33]([CH3:38])[C:34]([F:36])([F:35])[F:37])(=[O:30])=[O:31])=[CH:25][CH:24]=1)#[N:40]

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 86668143(S)-6-(4-bromo-3-cyano-1-cyclobutyl-6 (difluoromethoxy)-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamideHCID 178477798HCID 178477798, compound

Product 1

HCID 86668144(S)-6-(3-cyano-1-cyclobutyl-6 (difluoromethoxy)-5-fluoro-4-methyl-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamideYield 65%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

A solution of MeZnCl (2 M in THF, 370 μL, 0.74 mmol) was added to a mixture of (S)-6-(4-bromo-3-cyano-1-cyclobutyl-6 (difluoromethoxy)-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (200 mg, 0.33 mmol), Pd(dppf)Cl2 (25 mg, 0.034 mmol), and THF (1.2 mL). This was heated at 40° C. for 25 hours. The reaction mixture was then poured onto aq. HCl. This was extracted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (20% ethyl acetate in hexanes), followed by washing with hexanes/ether (1:1) yielded (S)-6-(3-cyano-1-cyclobutyl-6 (difluoromethoxy)-5-fluoro-4-methyl-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (117 mg, 65%) as a white solid. Melting point: 182-186° C.; MS m/z 547.0 M+H+; 1H NMR (CDCl3, 500 MHz): δ 9.22 (d, 1H, J=2 Hz), 8.35 (dd, 2H, J=8.5 Hz, 2 Hz), 8.02 (d, 1H, 8.5 Hz), 7.40 (d, 1H, J=6.5 Hz), 6.62 (t, 1H, J=75 Hz), 5.26 (pentet, 1H, J=8.5 Hz), 4.95 (d, 1H, J=9.5 Hz), 4.16 (m, 1H), 2.75 (d, 3H, J=2.0 Hz), 2.47 (m, 2H), 2.38 (m, 2H), 1.87 (m, 2H), 1.47 (d, 3H, J=7 Hz).

Workup

  1. extractionThis was extracted with ethyl acetate
  2. washthe organic layer was washed with brine
  3. dry with materialThe organic layer was dried over MgSO4
  4. filtrationfiltered
  5. concentrationthe filtrate was concentrated under vacuum
  6. customPurification by silica gel chromatography (20% ethyl acetate in hexanes)
  7. washby washing with hexanes/ether (1:1)

Sources & evidence

ORD record
ord-b41038e2d2044fe6830b6231bdb421c2
Source dataset
uspto-grants-2014_05
Patent number
US08735414B2

Linked notes

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