Hydrochloric Acid → HCID 178494312, compound

HRID 2095731Notes

Reaction equation

[Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18](B3OC(C)(C)C(C)(C)O3)[C:17]([O:29][CH3:30])=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Br[C:32]1[CH:33]=[C:34]2[C:40]([C@@H:41]([C:43]3[C:48]([O:49][CH:50]([F:52])[F:51])=[CH:47][CH:46]=[C:45]([F:53])[C:44]=3[Cl:54])[CH3:42])=[CH:39][N:38](C(OC(C)(C)C)=O)[C:35]2=[N:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl.N#N.Cl>O1CCOCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].O1CCOCC1.O>[Cl:54][C:44]1[C:45]([F:53])=[CH:46][CH:47]=[C:48]([O:49][CH:50]([F:51])[F:52])[C:43]=1[C@H:41]([C:40]1[C:34]2[C:35](=[N:36][CH:37]=[C:32]([C:18]3[C:17]([O:29][CH3:30])=[N:16][N:15]([C@H:12]4[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]4)[CH:19]=3)[CH:33]=2)[NH:38][CH:39]=1)[CH3:42]

Participants

Conditions

Temperature: 100 °C

Procedure

A solution of 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0305 g, 0.0698 mmol), tert-butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.0330 g, 0.0635 mmol), potassium carbonate (0.0263 g, 0.190 mmol), and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride.dichloromethane (5.18 mg, 0.00635 mmol) in previously degassed dioxane/H2O (5:1)(2.03 mL) was evacuated and charged with N2 (3×) and heated to 100° C. for 1 h. The reaction mixture was charged with an additional amount 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.00800 g, 0.0183 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride.dichloromethane (5.18 mg, 0.00634 mmol) and evacuated and charged with N2 gas (3×) and heated 100° C. for an additional 1 h. The reaction was charged with 4 M of HCl in 1,4-dioxane (0.500 mL) and heated to 50° C. for 45 min. The reaction mixture was partitioned between CHCl3 and sat. NaHCO3 and separated. The aqueous was re-extracted with CHCl3/MeOH (4×) and the combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo resulting in a crude brown oil. The crude material was further purified by chromatography on silica gel [ISCO Combiflash, 4 g gold cartridge, eluting with 100% DCM→8% MeOH in DCM] resulting in the title compound as an orange solid. 1H NMR (400 MHz, CD3OD): δ=1.40-1.53 (m, 2H), 1.79-1.92 (m, 5H), 2.02-2.15 (m, 4H), 3.60-3.70 (m, 1H), 3.89-4.01 (m, 4H), 5.09 (q, J=7.2 Hz, 1H), 7.11 (br. s., 1H), 7.17-7.24 (m, 1H), 7.32 (d, J=1.3 Hz, 1H), 7.74 (s, 1H), 7.80 (d, J=1.8 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H). MS (ES+): m/z 535.05 (75), 537.02 (25) [MH+], HPLC: tR=2.63 min (vvnonpolar—5 min, ZQ3).

Workup

temperatureheated 100° C. for an additional 1 h
temperatureheated to 50° C. for 45 min
customThe reaction mixture was partitioned between CHCl3 and sat. NaHCO3
customseparated
extractionThe aqueous was re-extracted with CHCl3/MeOH (4×)
dry with materialthe combined organic fractions were dried over Na2SO4
filtrationfiltered
concentrationconcentrated in vacuo
customresulting in a crude brown oil
customThe crude material was further purified by chromatography on silica gel [ISCO Combiflash, 4 g gold cartridge, eluting with 100% DCM→8% MeOH in DCM]

Sources & evidence

ORD record: ord-01960ef878a24abb8ada0a6655dec176
Source dataset: uspto-grants-2013_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08445510B2

Reaction notes

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