Hydrochloric Acid → Hydrochloric Acid

HRID 2095704Notes

Reaction equation

HRID 2095704 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]([C@H:38]2[CH2:43][CH2:42][C@H:41]([OH:44])[CH2:40][CH2:39]2)[N:36]=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O.[ClH:61].CCOCC>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]([C@H:38]4[CH2:43][CH2:42][C@H:41]([OH:44])[CH2:40][CH2:39]4)[C:33]=3[CH3:32])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12].[ClH:61]

Participants

10

Reactant 6

HCID 313Hydrochloric Acid2×HCID 962Water2×HCID 3283Diethyl EtherHCID 11430Potassium CarbonateHCID 67003931tert-Butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylateHCID 178421686HCID 178421686, compound

Product 2

HCID 313Hydrochloric AcidHCID 178422172HCID 178422172, compound

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
45 °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 (70.0 mg, 0.135 mmol), trans-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanol (53.6 mg, 0.175 mmol), Pd(PPh3)4 (7.78 mg, 0.00673 mmol), K2CO3 (0.0558 g, 0.404 mmol) and 4:1 dioxane:H2O (5 mL, 50 mmol) was heated to 95° C. for 2 h. The solution was cooled to 45° C., and 12 M of HCl in H2O (0.2 mL, 2 mmol) was added, stirring for an additional 2 h. The solution was concentrated in vacuo and transferred to a separation funnel. The material was extracted with DCM and sat. NaHCO3. The organic layer was loaded onto silica gel for column chromatography, eluting with 2-4% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo, redissolved in MeOH, and 2.0 M of HCl in Et2O (1 mL, 2 mmol) was added at rt. The solution was stirred for 1 h, and concentrated in vacuo to afford the title compound as an HCl salt. 1H NMR (free base; 400 MHz, CD3OD): δ=1.45-1.57 (mc, 2H), 1.84 (d, J=7.0 Hz, 3H), 1.91-2.12 (m, 6H), 2.22 (s, 3H), 3.67 (tt, J=10.8, 4.4 Hz, 1H), 4.18 (tt, J=11.0, 4.4 Hz, 1H), 5.11 (q, J=7.2 Hz, 1H), 6.44 (brt, J=73.8 Hz, 1H), 7.13 (dd, J=8.8, 4.4 Hz, 1H), 7.19 (dd, J=8.8, 8.4 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.39 (d, J=1.2 Hz, 1H), 7.46 (s, 1H), 8.12 (d, J=2.0 Hz, 1H). 1H NMR(HCl salt; 400 MHz, CD3OD): δ=1.45-1.57 (mc, 2H), 1.89 (d, J=7.0 Hz, 3H), 1.91-2.12 (m, 6H), 2.23 (s, 3H), 3.67 (tt, J=11.2, 4.2 Hz, 1H), 4.24 (tt, J=11.0, 4.4 Hz, 1H), 5.20 (q, J=7.2 Hz, 1H), 6.71 (brt, J=73.6 Hz, 1H), 7.19 (dd, J=8.8, 4.4 Hz, 1H), 7.26 (dd, J=8.8, 8.0 Hz, 1H), 7.64 (s, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 8.38 (d, J=1.6 Hz, 1H). MS (ES+): m/z=519.16/521.18 (100/50) [MH+]. HPLC: tR=1.45 min (polar—3 min, UPLC-ACQUITY).

Workup

  1. concentrationThe solution was concentrated in vacuo
  2. customtransferred to a separation funnel
  3. extractionThe material was extracted with DCM and sat. NaHCO3
  4. washeluting with 2-4% (7N NH3 in MeOH)/DCM
  5. additionThe fractions containing the pure product
  6. concentrationwere concentrated in vacuo
  7. dissolutionredissolved in MeOH
  8. stirringThe solution was stirred for 1 h
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-7051b824b16c43978394c4c8800fb9cf
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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