Reaction equation
Br[C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.[NH4+].[Cl-].C[N:14](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[Cl:49][C:50]1[C:55]([F:56])=[CH:54][CH:53]=[C:52]([O:57][CH3:58])[C:51]=1[C@H:59]([C:61]1[C:69]2[C:64](=[N:65][CH:66]=[C:67](B3OC(C)(C)C(C)(C)O3)[CH:68]=2)[NH:63][CH:62]=1)[CH3:60].C([O-])([O-])=O.[K+].[K+].O>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:49][C:50]1[C:55]([F:56])=[CH:54][CH:53]=[C:52]([O:57][CH3:58])[C:51]=1[C@H:59]([C:61]1[C:69]2[C:64](=[N:65][CH:66]=[C:67]([C:2]3[C:3]([C:8]([NH2:14])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=3)[CH:68]=2)[NH:63][CH:62]=1)[CH3:60]Participants
Reactant 8
HCID 962Water
HCID 6228Dimethylformamide
HCID 11430Potassium Carbonate
HCID 25517Ammonium Chloride
HCID 81531Diisopropylethylamine
HCID 5360134-bromo-1-methyl-1H-pyrazole-3-carboxylic acid
HCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
HCID 670040713-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridineProduct 1
Reagents, catalysts & solvents 2
Procedure
A mixture of 4-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (20.0 mg, 0.0976 mmol), NH4Cl (52.2 mg, 0.976 mmol), TBTU (62.6 mg, 0.195 mmol), DIPEA (0.0340 mL, 0.195 mmol) and DMF (2 mL, 20 mmol) was stirred at rt for 10 min. The material was extracted with EtOAc, and washed with sat. NaHCO3 (3×) to remove carboxylic acid starting material. The organic layer was concentrated in vacuo. 3-[(S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (15.0 mg, 0.0348 mmol), (1,1′bis-(diphenylphosphino)-ferrocene) palladium dichloride (3.57 mg, 0.00488 mmol), K2CO3 (20.2 mg, 0.146 mmol) and 4:1 dioxane:H2O (1 mL, 10 mmol) were added, and the mixture was heated to 95° C. for 30 min. 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=1.80 (d, J=7.1 Hz, 3H), 3.70 (br. s., 3H), 3.96 (s, 3H), 5.14 (q, J=7.2 Hz, 1H), 6.88 (dd, J=9.2, 4.2 Hz, 1H), 7.05 (t, J=8.8 Hz, 1H), 7.30 (d, J=1.0 Hz, 1H), 7.66 (s, 1H), 7.72 (s, 1H), 8.22 (br. s., 1H). MS (ES+): m/z=428.11/430.12 (100/50) [MH+]. HPLC: tR=1.33 min (polar—3 min, UPLC-ACQUITY).
Workup
- extractionThe material was extracted with EtOAc
- washwashed with sat. NaHCO3 (3×)
- customto remove carboxylic acid starting material
- concentrationThe organic layer was concentrated in vacuo
- temperaturethe mixture was heated to 95° C. for 30 min
- customThe solution was used directly for HPLC purification
- additionthe fractions containing the pure product
- concentrationwere concentrated in vacuo
Sources & evidence
- ORD record
- ord-85d36c3e3cfc421bb4558f6ee94264c4
- Source dataset
- uspto-grants-2013_05
- Patent number
- US08445510B2
Linked notes
Loading…