Morpholine → HCID 86681246, compound

HRID 1848272Notes

Reaction equation

HRID 1848272 reaction equation
I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:27]=[CH:26][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([OH:24])[C@H:19]5[OH:25])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[O:33]1[CH2:34][CH2:35][N:30]([C:2]2[CH:29]=[CH:28][C:5]3[N:6]([CH2:9][C:10]4[CH:27]=[CH:26][C:13]5[N:14]=[C:15]([NH:17][C@@H:18]6[CH2:23][CH2:22][CH2:21][C@@H:20]([OH:24])[C@H:19]6[OH:25])[S:16][C:12]=5[CH:11]=4)[CH:7]=[N:8][C:4]=3[CH:3]=2)[CH2:31][CH2:32]1

Participants

7

Reactant 4

HCID 8083MorpholineHCID 11430Potassium CarbonateHCID 145742L-ProlineHCID 86681242HCID 86681242, compound

Product 1

HCID 86681246HCID 86681246, compoundYield 1%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
110 °C

Procedure

A suspension of (1R,2S,3R)-3-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol (262 mg, 0.5 mmol) from Step 5 of Example 232, morpholine (264 μL, 3.0 mmol), L-proline (23 mg, 0.2 mmol), and K2CO3 (209 mg, 1.5 mmol) in DMSO (2.0 mL) was purged with argon for 5 min. Copper (I) iodide (19 mg, 0.02 mmol) was added, and the mixture was purged for an additional 5 min, then heated in a sealed tube at 110° C. for 2 h. The mixture was cooled to rt and filtered through Celite, and the filtrate was 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, followed by silica gel flash chromatography eluting with 5% MeOH in CH2Cl2 to afford (1R,2S,3R)-3-((6-((5-morpholino-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol (2 mg, 1%) as a white powder. 1H NMR (500 MHz, MeOH-d4) δ 8.19 (s, 1H), 7.50 (s, 1H), 7.31-7.39 (m, 2H), 7.16-7.23 (m, 2H), 7.05 (dd, J=2.0, 8.9 Hz, 1H), 5.44 (s, 2H), 3.95-4.06 (m, 2H), 3.80-3.88 (m, 4H), 3.50 (dd, J=2.6, 9.2 Hz, 1H), 3.06-3.14 (m, 4H), 2.09 (m, 1H), 1.77-1.86 (m, 2H), 1.48-1.53 (m, 2H), 1.33 (m, 1H); LCMS (ESI) m/z 480 (M+H)+.

Workup

  1. customwas purged with argon for 5 min
  2. customthe mixture was purged for an additional 5 min
  3. temperatureThe mixture was cooled to rt
  4. filtrationfiltered through Celite
  5. customthe filtrate was purified by reverse-phase preparative HPLC
  6. 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
  7. washeluting with 5% MeOH in CH2Cl2

Sources & evidence

ORD record
ord-b6047b5ba77c4487a17ff4a41c9a551e
Source dataset
uspto-grants-2015_02
Patent number
US08952058B2

Reaction notes

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