Potassium Acetate → ethyl 3-((6-chloro-2-cyclopropyl-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate

HRID 522757Notes

Reaction equation

HRID 522757 reaction equation
Br[C:2]1[N:3]([C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][CH3:31])[CH:28]=2)[C:4]2[C:9]([C:10]=1[S:11][C:12]1[CH:13]=[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:23])[CH:5]=2.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.CC([O-])=O.[K+]>COCCOC.O.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]>[Cl:23][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([S:11][C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([CH:32]3[CH2:34][CH2:33]3)[N:3]2[C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][CH3:31])[CH:28]=2)=[CH:8][CH:7]=1

Participants

7

Reactant 3

HCID 517044Potassium AcetateHCID 2760897Cyclopropylboronic acidHCID 118094237ethyl 3-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate

Product 1

HCID 118094300ethyl 3-((6-chloro-2-cyclopropyl-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoateYield 47.1%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

To a stirred solution of ethyl 3-((2-bromo-6-chloro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)benzoate 1 (Example 2, Step 3; 100 mg, 0.19 mmol) in DME (20 mL) under inert atmosphere were added cyclopropyl boronic acid (16.6 mg, 0.19 mmol), KOAc (56.8 mg, 0.58 mmol) at RT and degassed for 15 min. To this, was added Pd(dppf)Cl2 (28.3 mg, 0.038 mmol), heated to 85° C. and stirred for 7 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified by silica gel column chromatography using 8-10% EtOAc/Hexanes to afford 43 mg of compound 2 with 51% purity. The impure material was further purified by preparative HPLC to afford pure compound 2 (25 mg, 27%) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.83 (s, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.69 (s, 1H), 7.65 (s, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.26-7.22 (m, 2H), 7.14-7.08 (m, 2H), 4.34 (q, J=7.5 Hz, 2H), 4.21 (t, J=7.0 Hz, 2H), 2.03-1.98 (m, 2H), 1.76-1.75 (m, 1H), 1.05-1.01 (m, 2H), 1.36 (t, J=7.5 Hz, 3H), 1.00 (t, J=7.0 Hz, 3H), 0.87-0.84 (m, 2H); LC-MS (ESI): 89.7%; m/z 480.5 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.83 min; 5 mM NH4OAc: ACN; 0.8 mL/min).

Workup

  1. customdegassed for 15 min
  2. customafter completion of the reaction
  3. extractionextracted with CH2Cl2 (3×20 mL)
  4. dry with materialThe combined organic extracts were dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customto obtain the crude
  8. customThe crude was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-1d4be27fa02049e288cfee53fa212f63
Source dataset
uspto-grants-2016_05
Patent number
US09334261B2

Reaction notes

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