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

HRID 2095727Notes

Reaction equation

HRID 2095727 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.[CH3:32][C:33]1[N:37]([CH:38]2[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]2)[N:36]=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1.[F-].[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:34]3[CH:35]=[N:36][N:37]([CH:38]4[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]4)[C:33]=3[CH3:32])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 962Water2×HCID 522689Potassium FluorideHCID 59392638Tert-butyl 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylateHCID 67003931tert-Butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

Product 1

HCID 546735943-{(1S)-1-[2-Chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-5-[5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
30 °C

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 (60.0 mg, 0.115 mmol), tert-butyl 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (58.73 mg, 0.1501 mmol), Pd(PPh3)4 (6.670 mg, 0.005772 mmol), potassium fluoride (20.12 mg, 0.3463 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated in a microwave reactor at 100° C. for 30 min. 12 M of HCl in H2O (0.19 mL, 2.3 mmol) was added, and the solution was heated to 30° C. overnight. The organic solvent was removed in vacuo, and the material was extracted with DCM and sat. NaHCO3. The organic layer was concentrated in vacuo and purified via column chromatography, eluting with 3-8% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as white solid. 1H NMR (400 MHz, CD3OD): δ=1.84 (d, J=7.3 Hz, 3H), 1.87-1.96 (m, 2H), 2.00-2.12 (m, 2H), 2.23 (s, 3H), 2.72-2.82 (m, 2H), 3.15-3.23 (m, 2H), 4.31 (tt, J=11.6, 3.9 Hz, 1H), 5.11 (q, J=7.3 Hz, 1H), 6.43 (br. s., 1H), 7.12 (dd, J=9.0, 4.7 Hz, 1H), 7.18 (t, J=8.7 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.39 (d, J=1.3 Hz, 1H), 7.48 (s, 1H), 8.13 (d, J=2.0 Hz, 1H). MS (ES+): m/z=504.15/506.16 (100/50) [MH+]. HPLC: tR=1.15 min (polar—3 min, UPLC-ACQUITY).

Workup

  1. customThe organic solvent was removed in vacuo
  2. extractionthe material was extracted with DCM and sat. NaHCO3
  3. concentrationThe organic layer was concentrated in vacuo
  4. custompurified via column chromatography
  5. washeluting with 3-8% (7N NH3 in MeOH)/DCM
  6. additionThe fractions containing the pure product
  7. concentrationwere concentrated in vacuo

Sources & evidence

ORD record
ord-3c6e7de7a93e47c69d63dccb523f8945
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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