Potassium Carbonate → Trifluoroacetic acid

HRID 926624Notes

Reaction equation

[CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].[CH3:45][N:46]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:47]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:1]([C:8]1[C:9]([C:49]2[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=2)=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]

Participants

Conditions

Temperature: 70 °C

Procedure

A mixture of (3-benzyl-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (523 mg, 0.960 mmol, Example 109), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (262 mg, 1.26 mmol), PdCl2(dppf) (71 mg, 0.097 mmol), K2CO3 (266 mg, 1.92 mmol), 1,4-dioxane (20 mL), and water (5 mL) was sparged with N2 for about 12 minutes, and then heated at 70° C. for 18 hours. After cooling to room temperature, the mixture was filtered through a syringe filter. The filtrate was concentrated, and the residue was partitioned between DCM and water. The organic layer was dried (Na2SO4), filtered, concentrated, and purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a TFA salt. 1H NMR (400 MHz, MeOH-d4) δ 9.05 (s, 1H), 8.85 (s, 1H), 8.38 (d, J=2.02 Hz, 1H), 8.16 (d, J=8.59 Hz, 1H), 8.11 (d, J=8.08 Hz, 1H), 7.86-7.94 (m, 2H), 7.76-7.86 (m, 1H), 7.71 (s, 1H), 7.24-7.32 (m, 2H), 7.18-7.23 (m, 1H), 7.14 (s, 1H), 7.03 (d, J=7.07 Hz, 2H), 4.58 (s, 2H), 3.90 (s, 3H), 3.73 (s, 3H). This TFA salt was neutralized by partitioning between saturated NaHCO3 aqueous solution and DCM. The organic layer was dried (Na2SO4), filtered, concentrated, and purified by chiral HPLC (Chiralcel OD, 85% heptanes/15% ethanol) to give two enantiomers which were further purified on a silica gel column (0-8% MeOH in DCM) to give the two compounds as white solids. The first eluting enantiomer, Example 111b, 1H NMR (400 MHz, CDCl3) δ 8.82-8.86 (m, 1H), 8.27 (d, J=2.02 Hz, 1H), 8.04 (d, J=9.09 Hz, 1H), 7.94 (d, J=8.59 Hz, 1H), 7.70 (s, 1H), 7.63-7.69 (m, 3H), 7.27-7.32 (m, 3H), 7.19-7.24 (m, 1H), 7.05 (d, J=7.07 Hz, 2H), 6.36 (s, 1H), 4.51 (s, 2H), 3.89 (s, 3H), 3.37 (s, 3H); MS m/e 589.2 [M+H]+. The second enantiomer to elute off chiral column, Example 111c, 1H NMR (400 MHz, CHLOROFORM-d) δ 8.84 (d, J=2.02 Hz, 1H), 8.28 (d, J=2.02 Hz, 1H), 8.04 (d, J=8.59 Hz, 1H), 7.94 (dd, J=2.02, 8.08 Hz, 1H), 7.70 (s, 1H), 7.63-7.69 (m, 3H), 7.27-7.32 (m, 3H), 7.19-7.24 (m, 1H), 7.05 (d, J=7.07 Hz, 2H), 6.36 (br. s., 1H), 4.51 (s, 2H), 3.89 (s, 3H), 3.38 (s, 3H); MS m/e 589.2 [M+H]+.

Workup

customwas sparged with N2 for about 12 minutes
temperatureAfter cooling to room temperature
filtrationthe mixture was filtered through a syringe
filtrationfilter
concentrationThe filtrate was concentrated
customthe residue was partitioned between DCM and water
dry with materialThe organic layer was dried (Na2SO4)
filtrationfiltered
concentrationconcentrated
custompurified by reverse phase HPLC (water/acetonitrile/0.1% TFA)

Sources & evidence

ORD record: ord-20711d3104d7433fb30c03c7ddadf7ca
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09284308B2

Reaction notes

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