Morpholine → HCID 71548896, compound

HRID 1848080Notes

Reaction equation

HRID 1848080 reaction equation
I[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.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[O:32]1[CH2:33][CH2:34][N:29]([C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([CH2:11][C:12]4[CH:28]=[CH:27][C:15]5[N:16]=[C:17]([NH:19][C@@H:20]6[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]6[OH:26])[S:18][C:14]=5[CH:13]=4)[C:5]3=[N:6][CH:7]=2)[CH2:30][CH2:31]1

Participants

7

Reactant 4

HCID 8083MorpholineHCID 11430Potassium CarbonateHCID 145742L-ProlineHCID 86681061HCID 86681061, compound

Product 1

HCID 71548896HCID 71548896, compoundYield 11%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
100 °C

Procedure

To a stirred solution of (1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol from Step 2 of Example 96 (150 mg, 0.30 mmol) in DMSO (3 mL) were added morpholine (156 μL, 1.78 mmol), CuI (23 mg, 0.12 mmol), L-proline (14 mg, 0.12 mmol), and K2CO3 (123 mg, 0.89 mmol). The resulting mixture was flushed with argon, the reaction vessel was sealed and the mixture was heated at 100° C. for 2 h, then at 110° C. for 2 h. LCMS analysis showed that the reaction complete. The reaction mixture was cooled to rt, filtered through a Celite plug, and the filtrate was purified by preparative HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((6-morpholino-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (15 mg, 11%) as a tan powder. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.63 (br s, 2H), 7.24-7.34 (m, 1H), 7.14-7.22 (m, 1H), 5.42 (s, 2H), 3.70-3.83 (m, 4H), 3.48-3.55 (m, 2H), 3.07-3.15 (m, 4H), 2.03 (d, J=10.2 Hz, 1H), 1.87 (d, J=9.6 Hz, 1H), 1.61 (br s, 2H), 1.22 (d, J=7.3 Hz, 4H). LCMS (ESI) m/z 465 (M+H)+.

Workup

  1. customThe resulting mixture was flushed with argon
  2. customthe reaction vessel was sealed
  3. temperatureThe reaction mixture was cooled to rt
  4. filtrationfiltered through a Celite plug
  5. customthe filtrate was purified by preparative HPLC
  6. additiona mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase

Sources & evidence

ORD record
ord-ea5013972bd0441f84e3d23b82e0d028
Source dataset
uspto-grants-2015_02
Patent number
US08952058B2

Reaction notes

Loading…