Hydrochloric Acid → HCID 178422168, compound

HRID 2095736Notes

Reaction equation

HRID 2095736 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH:40](I)([CH3:42])[CH3:41].[CH3:44][C:45]1[N:49]([C@H:50]2[CH2:55][CH2:54][C@H:53]([OH:56])[CH2:52][CH2:51]2)[N:48]=[CH:47][C:46]=1B1OC(C)(C)C(C)(C)O1.O.Cl>CCOC(C)=O.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:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([O:19][CH:40]([CH3:42])[CH3:41])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:46]3[CH:47]=[N:48][N:49]([C@H:50]4[CH2:55][CH2:54][C@H:53]([OH:56])[CH2:52][CH2:51]4)[C:45]=3[CH3:44])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]

Participants

11

Reactant 7

HCID 313Hydrochloric AcidHCID 962Water2×HCID 6228DimethylformamideHCID 6362Isopropyl iodideHCID 11430Potassium Carbonate2×HCID 67003938tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylateHCID 178421686HCID 178421686, compound

Product 1

HCID 178422168HCID 178422168, compound

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (13.0 mg, 0.0277 mmol) and K2CO3 (12.7 mg, 0.0919 mmol) in DMF (0.8 mL, 10 mmol) was added isopropyl iodide (16.06 mg, 0.09451 mmol), and the mixture was heated to 40° C. for 2 h. The reaction mixture was diluted with EtOAc and washed with water (3×). The organic layer was concentrated in vacuo, and trans-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanol (12.71 mg, 0.04151 mmol), Pd(PPh3)4 (1.599 mg, 0.001384 mmol), K2CO3 (3 eq) and 4:1 dioxane:H2O (1 mL, 10 mmol) were added. The mixture was heated in a microwave reactor at 95° C. for 20 min. 12 M of HCl in H2O (0.069 mL, 0.83 mmol) was added, and the solution was heated to 45° C. for 1 h. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=0.68 (br. s., 3H), 1.24 (d, J=5.8 Hz, 3H), 1.45-1.57 (m, 2H), 1.80 (d, J=7.1 Hz, 3H), 1.94-2.11 (m, 6H), 2.19 (s, 3H), 3.68 (tt, J=11.0, 4.2 Hz, 1H), 4.12-4.24 (m, 1H), 4.35-4.51 (m, 1H), 5.01-5.12 (m, 1H), 6.83 (dd, J=8.3, 3.8 Hz, 1H), 7.05 (t, J=8.8 Hz, 1H), 7.33 (dd, J=2.9, 1.6 Hz, 2H), 7.45 (s, 1H), 8.09 (d, J=2.0 Hz, 1H). MS (ES+): m/z=511.34/513.33 (100/50) [MH+]. HPLC: tR=1.33 min (polar—2 min, UPLC-ACQUITY).

Workup

  1. washwashed with water (3×)
  2. temperatureThe mixture was heated in a microwave reactor at 95° C. for 20 min
  3. temperaturethe solution was heated to 45° C. for 1 h
  4. customThe solution was used directly for HPLC purification
  5. additionthe fractions containing the pure product
  6. concentrationwere concentrated in vacuo

Sources & evidence

ORD record
ord-a4859c677cf0435aa46aa14d8d34a8da
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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