Phenyl isocyanate → 1-((1R,2R)-2-(1-benzylpiperidin-3-ylamino)cyclohexyl)-3-phenylurea

HRID 2369967Notes

Reaction equation

HRID 2369967 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:23]=[O:24].CCN(CC)CC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[NH:21][C:23]([NH:22][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 7672Phenyl isocyanateHCID 8471TriethylamineHCID 71235672(1R,2R)-N1-(1-benzylpiperidin-3-yl)cyclohexane-1,2-diamine

Product 1

HCID 712356561-((1R,2R)-2-(1-benzylpiperidin-3-ylamino)cyclohexyl)-3-phenylureaYield 42.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a round bottom flask was added (1R,2R)—N1-(1-benzylpiperidin-3-yl)cyclohexane-1,2-diamine (3.23 g, 8.05 mmol), THF (30 mL), isocyanatobenzene (0.958 g, 8.05 mmol) and Et3N (5.61 mL, 40.2 mmol). The reaction was stirred at rt for 2 hrs. After this time, the reaction mixture was concentrated. The residue was diluted with EtOAc (100 ml). The resulting solution was washed with water (50 ml) and saturated aqueous NaCl (50 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with 5% MeOH/CH2Cl2 with NH3) to give the product, 1-((1R,2R)-2-(1-benzylpiperidin-3-ylamino)cyclohexyl)-3-phenylurea (1.4 g, 3.44 mmol, 42.8% yield), as a white solid. Anal. Calcd. for C25H32N4O m/z 407, found: 408.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.41-7.15 (m, 9H), 6.97 (q, J=7.15 Hz, 1H), 4.51-4.27 (m, 1H), 3.58-3.34 (m, 2H), 3.23-3.08 (m, 1H), 2.96-2.80 (m, 1H), 2.66 (br. s., 1H), 2.40 (br. s., 1H), 2.29-2.11 (m, 2H), 2.11-1.92 (m, 2H), 1.77-1.57 (m, 5H), 1.57-1.42 (m, 1H), 1.31 (d, J=3.85 Hz, 1H), 1.30-1.05 (m, 4H).

Workup

  1. concentrationAfter this time, the reaction mixture was concentrated
  2. additionThe residue was diluted with EtOAc (100 ml)
  3. washThe resulting solution was washed with water (50 ml) and saturated aqueous NaCl (50 ml)
  4. dry with materialThe organic layer was dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe resulting residue was purified
  8. washeluting with 5% MeOH/CH2Cl2 with NH3)

Sources & evidence

ORD record
ord-6e366f01c1504e85853cd20823a3f5ff
Source dataset
uspto-grants-2014_04
Patent number
US08710049B2

Reaction notes

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