Hydrochloric Acid → 3-[4-(3-{(1S)-1-[2-Chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl]cyclobutanone

HRID 2095708Notes

Reaction equation

HRID 2095708 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH:20]([F:22])[F:21])=[CH:17][CH:16]=[C:15]([F:23])[C:14]=3[Cl:24])[CH3:12])=[CH:9][N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.[CH2:32]1[C:35]2(OCC[O:36]2)[CH2:34][CH:33]1[N:40]1[C:44]([CH3:45])=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1.C([O-])([O-])=O.[K+].[K+].O.Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:24][C:14]1[C:15]([F:23])=[CH:16][CH:17]=[C:18]([O:19][CH:20]([F:21])[F:22])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:43]3[CH:42]=[N:41][N:40]([CH:33]4[CH2:34][C:35](=[O:36])[CH2:32]4)[C:44]=3[CH3:45])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 962Water2×HCID 11430Potassium CarbonateHCID 67003931tert-Butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylateHCID 670044581-(5,8-dioxaspiro[3.4]oct-2-yl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Product 1

HCID 546739103-[4-(3-{(1S)-1-[2-Chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl]cyclobutanone

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Procedure

A mixture of tert-butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (41.1 mg, 0.0791 mmol), 1-(5,8-dioxaspiro[3.4]oct-2-yl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (38.0 mg, 0.119 mmol), Pd(PPh3)4 (4.57 mg, 0.00396 mmol), K2CO3 (32.8 mg, 0.237 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated to 95° C. for 1 h. The solution was allowed to cool to rt, and 2 M of HCl in H2O (2 mL, 4 mmol) was added. The mixture was heated at 45° C. overnight. The organic solvent was removed in vacuo, and the material was extracted with DCM and sat. NaHCO3. The organic layer was loaded onto silica gel for column chromatography, eluting with 1-3% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=489.09/491.09 (100/50) [MH+]. HPLC: tR=4.04 min (polar—5 min, ZQ3).

Workup

  1. temperatureThe mixture was heated at 45° C. overnight
  2. customThe organic solvent was removed in vacuo
  3. extractionthe material was extracted with DCM and sat. NaHCO3
  4. washeluting with 1-3% MeOH/DCM
  5. additionThe fractions containing the pure product
  6. concentrationwere concentrated in vacuo

Sources & evidence

ORD record
ord-90a6d6d558ab4b9a88244efc7397190d
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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