Dichloromethane → (1R,2R)-2-((6-((6-vinyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

HRID 1848081Notes

Reaction equation

HRID 1848081 reaction equation
Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH:29]([B-](F)(F)F)=[CH2:30].[K+].C(Cl)Cl>C(O)CC.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]>[CH:29]([C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1)=[CH2:30]

Participants

6

Reactant 3

HCID 6344DichloromethaneHCID 23679353Potassium vinyltrifluoroborateHCID 86681028(1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol

Product 1

HCID 71548899(1R,2R)-2-((6-((6-vinyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanolYield 23%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 10311-PropanolSolvent

Conditions

Temperature
100 °C

Procedure

To a stirred mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (200 mg, 0.44 mmol) from Example 29 in n-PrOH were added potassium vinyltrifluoroborate (117 mg, 0.88 mmol), PdCl2(dppf).DCM (18 mg, 0.022 mmol), and TEA (122 μL, 0.88 mmol). The resulting mixture was purged with argon for 5 min, the reaction vessel was sealed and the mixture was heated at 100° C. overnight. LCMS analysis showed that the reaction was complete. The reaction mixture was cooled to rt and purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-2-((6-((6-vinyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a tan powder (40 mg, 23%). 1H NMR (300 MHz, MeOH-d4) δ 8.50 (d, J=1.7 Hz, 1H), 8.43 (s, 1H), 8.15 (d, J=1.7 Hz, 1H), 7.63 (s, 1H), 7.32-7.41 (m, 1H), 7.25-7.32 (m, 1H), 6.91 (dd, J=10.9, 17.7 Hz, 1H), 5.91 (d, J=17.5 Hz, 1H), 5.53 (s, 2H), 5.35 (d, J=11.1 Hz, 1H), 3.50-3.66 (m, 1H), 3.37-3.49 (m, 1H), 2.14 (d, J=12.1 Hz, 1H), 2.01 (br s, 1H), 1.63-1.82 (m, 2H), 1.13-1.50 (m, 4H). LCMS (ESI) m/z 406 (M+H)+.

Workup

  1. customThe resulting mixture was purged with argon for 5 min
  2. customthe reaction vessel was sealed
  3. temperatureThe reaction mixture was cooled to rt
  4. custompurified by reverse-phase preparative HPLC
  5. additiona mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase

Sources & evidence

ORD record
ord-4e5274cb6385452a9674631abbdf3396
Source dataset
uspto-grants-2015_02
Patent number
US08952058B2

Reaction notes

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