Sodium Carbonate → HCID 86681215, compound

HRID 1848242Notes

Reaction equation

HRID 1848242 reaction equation
Br[C:2]1[CH:28]=[C:27]([F:29])[C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[O:30]1[CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[Na+].[Na+].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>[O:30]1[CH2:31][CH:32]=[C:33]([C:2]2[CH:28]=[C:27]([F:29])[C:5]3[N:6]([CH2:9][C:10]4[CH:26]=[CH:25][C:13]5[N:14]=[C:15]([NH:17][C@@H:18]6[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]6[OH:24])[S:16][C:12]=5[CH:11]=4)[CH:7]=[N:8][C:4]=3[CH:3]=2)[CH2:34][CH2:35]1

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 112180533,6-Dihydro-2H-pyran-4-boronic acid pinacol esterHCID 86681211HCID 86681211, compound

Product 1

HCID 86681215HCID 86681215, compoundYield 36.4%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

A stirred mixture of (1R,2R)-2-((6-((5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (150 mg, 0.316 mmol) from Example 203, 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (133 mg, 0.632 mmol), sodium carbonate (67 mg, 0.0632 mmol), 1,4-dioxane (2 mL), and water (0.5 mL) was purged with a stream of argon. To the mixture was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) DCM adduct (35 mg, 0.0474 mmol) and the mixture was heated in a sealed vessel at 100° C. for 3 h. The mixture was cooled to rt and purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5-(3,6-dihydro-2H-pyran-4-yl)-7-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (55 mg, 36%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.49-7.56 (m, 2H), 7.29 (d, J=8.1 Hz, 1H), 7.21 (d, J=13.0 Hz, 1H), 7.09 (m, 1H), 6.27 (br m, 1H), 5.51 (s, 2H), 4.72 (d, J=5.2 Hz, 1H), 4.21 (d, J=2.5 Hz, 2H), 4.06 (m, 1H), 3.81 (t, J=5.4 Hz, 2H), 3.61 (m, 1H), 3.51 (br m, 1H), 3.30 (br m, 1H), 2.00 (m, 1H), 1.88 (m, 1H), 1.55-1.67 (m, 2H), 1.11-1.32 (m, 4H); LCMS (ESI) m/z 479 (M+H)+.

Workup

  1. customwas purged with a stream of argon
  2. temperatureThe mixture was cooled to rt
  3. custompurified directly by reverse-phase preparative HPLC
  4. additiona mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase

Sources & evidence

ORD record
ord-756a64d45aa048b4a85a8e625ac54ffa
Source dataset
uspto-grants-2015_02
Patent number
US08952058B2

Reaction notes

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