3-Bromopyridine → Synthesis of 3-((6-chloro-2-cyclopropyl-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid sodium salt

HRID 522794Notes

Reaction equation

HRID 522794 reaction equation
Br[C:2]1[N:3]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:4]2[C:9]([C:10]=1[S:11][C:12]1[C:13]([F:23])=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=[C:6]([Cl:24])[C:5]=2[F:25].BrC1C=N[CH:36]=[CH:37][CH:38]=1.N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[Cl:24][C:6]1[C:5]([F:25])=[C:4]2[C:9]([C:10]([S:11][C:12]3[C:13]([F:23])=[C:14]([CH:20]=[CH:21][CH:22]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([CH:37]3[CH2:38][CH2:36]3)[N:3]2[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][CH:7]=1

Participants

7

Reactant 4

HCID 122863-BromopyridineHCID 438061,2-Diaminocyclohexane, trans-HCID 62657Potassium Phosphate, TribasicHCID 118094271Synthesis of 34(2-bromo-6-chloro-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid

Product 1

HCID 118104212Synthesis of 3-((6-chloro-2-cyclopropyl-7-fluoro-1-(pyridin-3-yl)-1H-indol-3-yl)thio)-2-fluorobenzoic acid sodium saltYield 8.6%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
140 °C

Procedure

To a stirred solution of compound 2 (100 mg, 0.24 mmol) in toluene (5 mL) were added 3-bromopyridine (59.3 mg, 0.36 mmol), trans-1,2-diaminocyclohexane (11.2 mg, 0.098 mmol), K3PO4 (130 mg, 0.65 mmol), CuI (4.6 mg, 0.024 mmol) at RT under argon in a sealed tube. The solution was purged with argon; heated to 140° C. and stirred for 40 h. The mixture was cooled to RT, added n-hexane (6 mL), stirred for 5 minutes and then filtered. The filtrate was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water and brine solution, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the crude. This was purified (silica gel; 5-10% EtOAc/hexanes) to afford compound 3 (10 mg, 8.4%) as a pale brown solid. 1H NMR (400 MHz, CDCl3): 8.77 (br s, 2H), 7.81 (d, J=8.0 Hz, 1H), 7.68-7.62 (m, 1H), 7.53-7.50 (m, 1H), 7.25-7.23 (m, 1H), 7.17-7.11 (m, 1H), 6.96 (t, J=7.6 Hz, 1H), 6.82 (dt, J=8.4, 1.6 Hz, 1H), 4.40 (q, 2H), 1.65-1.60 (m, 1H), 1.41 (t, J=7.2 Hz, 3H), 0.91-0.82 (m, 4H); LC-MS (ESI): m/z 485.5 (M+H+).

Workup

  1. customThe solution was purged with argon
  2. temperatureThe mixture was cooled to RT
  3. additionadded n-hexane (6 mL)
  4. stirringstirred for 5 minutes
  5. filtrationfiltered
  6. additionThe filtrate was diluted with water (20 mL)
  7. extractionextracted with EtOAc (2×50 mL)
  8. washThe combined organic extracts were washed with water and brine solution
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customto obtain the crude
  13. customThis was purified (silica gel; 5-10% EtOAc/hexanes)

Sources & evidence

ORD record
ord-b08035dc2c5746f983f18c57939cca99
Source dataset
uspto-grants-2016_05
Patent number
US09334261B2

Reaction notes

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