N-bromobutanimide → Synthesis of 34(2-bromo-6-chloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid

HRID 522793Notes

Reaction equation

HRID 522793 reaction equation
[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]=3[F:38])=[C:7](C3CC3)[N:8]2[C:12]2[CH:13]=N[N:15]([CH2:17][CH2:18]CC(O)=O)[CH:16]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:46])C(=O)C1>C(Cl)Cl.O>[Br:46][C:7]1[N:8]([C:12]2[CH:16]=[N:15][CH:17]=[CH:18][CH:13]=2)[C:9]2[C:5]([C:6]=1[S:26][C:27]1[C:28]([F:38])=[C:29]([CH:30]=[CH:31][CH:32]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[F:11]

Participants

5

Reactant 2

HCID 67184N-bromobutanimideHCID 1181041884-(4-(6-chloro-2-cyclopropyl-3-((3-(ethoxycarbonyl)-2-fluorophenyl) thio)-7-fluoro-1H-indol-1-yl)-1H-pyrazol-1-yl)butanoic acid

Product 1

HCID 118094271Synthesis of 34(2-bromo-6-chloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic acidYield 51.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of indole 1 (Example 22, Step 2; 60 mg, 0.13 mmol) in CH2Cl2 (5 mL) under inert atmosphere was added NBS (60 mg, 0.33 mmol) at RT and stirred for 16 h. The mixture was diluted with water (10 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. This was purified (silica gel; 10% EtOAc/hexanes) to afford compound 2 (35 mg, 50%) as a pale brown solid. 1H NMR (500 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.81-8.80 (m, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.70-7.66 (m, 2H), 7.40-7.37 (m, 2H), 7.18 (t, J=8.0 Hz, 1H), 7.16-7.13 (m, 1H), 4.33 (q, 2H), 1.32 (t, J=7.5 Hz, 3H); MS: m/z 525.3 (M++2).

Workup

  1. extractionextracted with CH2Cl2 (2×25 mL)
  2. washThe combined organic extracts were washed with brine (10 mL)
  3. dry with materialdried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customto obtain the crude
  7. customThis was purified (silica gel; 10% EtOAc/hexanes)

Sources & evidence

ORD record
ord-b4ed957020c14ca99bbf332fc3787f9d
Source dataset
uspto-grants-2016_05
Patent number
US09334261B2

Reaction notes

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