Potassium Phosphate, Tribasic → ethyl 3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate

HRID 2171299Notes

Reaction equation

HRID 2171299 reaction equation
Br[C:2]1[N:3]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=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].[CH:33]1(B(O)O)[CH2:35][CH2:34]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[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:33]3[CH2:35][CH2:34]3)[N:3]2[C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=2)=[CH:8][CH:7]=1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 2760897Cyclopropylboronic acidHCID 118094246ethyl 3-((2-bromo-6-chloro-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate

Product 1

HCID 118094209ethyl 3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoate

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of compound 11 (150 mg, 0.27 mmol) in toluene (10 mL) under inert atmosphere was purged with argon at RT for 10 min. To this, cyclopropylboronic acid (48 mg, 0.55 mmol), tricyclohexyl phosphine (16 mg, 0.05 mmol), Pd(OAc)2 (6 mg, 0.02 mmol) and potassium phosphate (202 mg, 0.01 mmol) were added at RT under argon. The resultant solution was purged again with argon at RT for 5 min. The reaction mixture was then heated to reflux temperature and stirred for 3 h. The reaction was monitored by TLC & LC-MS; after completion of the reaction, the reaction was cooled to RT, diluted with EtOAc (20 mL) and filtered. The filtrate was washed with water (2×10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified (silica gel chromatography; 6% EtOAc/Hexanes) to afford 7 as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.66-7.7.60 (m, 3H), 7.18 (d, J=8.4 Hz, 1H), 7.08 (dd, J=8.4, 6.5 Hz, 1H), 6.93 (t, J=8.4 Hz, 1H), 6.79-6.75 (m, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.26 (q, J=7.6 Hz, 2H), 1.74-1.68 (m, 1H), 1.56 (t, J=7.2 Hz, 3H), 1.41 (t, J=7.6 Hz, 3H), 1.08-1.04 (m, 2H), 0.89-0.84 (m, 2H); LC-MS (ESI): 92.9%; m/z 502.5 (M+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.85 min; 5 mM NH4OAc: ACN; 0.8 mL/min); HPLC: 93.1%; (column: Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 3.44 min; ACN: 0.025% TFA (aq); 0.5 mL/min.

Workup

  1. customThe resultant solution was purged again with argon at RT for 5 min
  2. temperatureThe reaction mixture was then heated
  3. temperatureto reflux temperature
  4. customafter completion of the reaction
  5. filtrationfiltered
  6. washThe filtrate was washed with water (2×10 mL) and brine (10 mL)
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customto obtain the crude
  11. customThis was purified (silica gel chromatography; 6% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-f17b303a159742ddb1100035fd867ffa
Source dataset
uspto-grants-2015_06
Patent number
US09051320B1

Reaction notes

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