1,4-Dioxane → HCID 69067836, compound

HRID 1822031Notes

Reaction equation

HRID 1822031 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=2)[C@H:10]([CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[Cl:29][C:30]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([NH:21][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:30]=3[Cl:29])[CH:18]=[CH:19][CH:20]=2)[CH:10]([CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 312751,4-DioxaneHCID 27365462-Chloro-4-fluorobenzoyl chlorideHCID 57893732HCID 57893732, compound

Product 1

HCID 69067836HCID 69067836, compound

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Combine racemic 3-(1-benzyl-cis-3-methyl-piperidin-4-yloxy)-phenylamine (preparation 41, 0.80 g, 2.7 mmol), 1,4-dioxane (20 mL), and 2-chloro-4-fluoro-benzoyl chloride (0.625 g, 3.24 mmol), stir and heat at reflux. After 2 hr., cool to ambient temperature. Dilute with methanol and load the resulting solution on 210 g SCX columns. Wash each with methanol (2×50 mL). Elute product from each column with 2M ammonia/methanol (2×50 mL). Combine and concentrate the eluents. Purify residue by silica gel flash chromatography eluting with 5% (2M NH3/methanol)/methylene dichloride to obtain the title compound as a racemic mixture (1.07 g, 87.7%). Resolve using a Chiralpak AD™ 4.6×250 mm column eluting at 1.0 mL/min. with 10% absolute ethanol/90% Heptane with 0.2% DMEA to obtain of the title compound (0.524 g, 49.0%). Mass spectrum (electrospray): m/z=453.2 (M+1); 1H NMR (CDCl3): 7.85 (bs, 1H), 7.8 (dd, 1H), 7.45 (s, 1H), 7.3 (m, 7H), 7.1 (m, 1H), 7.0 (m, 1H), 6.75 (dd, 1H), 4.4 (m, 1H), 3.5 (m, 2H), 2.5 (m, 2H), 2.4 (m, 2H), 2.1 (m, 2H), 1.8 (m, 1H), 1.0 (d, 3H).

Workup

  1. temperatureheat
  2. temperatureat reflux
  3. washWash each with methanol (2×50 mL)
  4. concentrationCombine and concentrate the eluents
  5. washPurify residue by silica gel flash chromatography eluting with 5% (2M NH3/methanol)/methylene dichloride

Sources & evidence

ORD record
ord-5c1a6b7d6ec74e83a9896e16069af1c4
Source dataset
uspto-grants-2009_10
Patent number
US07608629B2

Reaction notes

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