Acetic Acid → 1-((1R,2R)-2-(methyl((S)-1-(4-nitrophenyl)piperidin-3-yl)amino)cyclohexyl)-3-phenylurea

HRID 2370016Notes

Reaction equation

HRID 2370016 reaction equation
[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:25])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C=O.[C:35](O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl>[CH3:35][N:16]([C@H:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)[C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[NH:23][C:24]([NH:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:25]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 712268371-((1R,2R)-2-((S)-1-(4-Nitrophenyl)piperidin-3-ylamino)cyclohexyl)-3-phenylurea

Product 1

HCID 712356081-((1R,2R)-2-(methyl((S)-1-(4-nitrophenyl)piperidin-3-yl)amino)cyclohexyl)-3-phenylureaYield 55.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a round bottom flask was added 1-((1R,2R)-2-((S)-1-(4-nitrophenyl)piperidin-3-ylamino)cyclohexyl)-3-phenylurea (prepared as described in Example 1) (30 mg, 0.069 mmol), formaldehyde (0.079 mL, 1.028 mmol) (37% in water), acetic acid (0.2 mL), CH2Cl2 (1 mL) and NaSO4 (3 gms). The reaction was stirred at rt for 2 hrs. Then sodium cyanoborohydride (21.54 mg, 0.343 mmol) was added to the reaction and the reaction was stirred for an additional 1 hr. After this time, the reaction was quenched with water (2 ml). The reaction was partitioned between CH2Cl2 (15 ml) and saturated aqueous NaHCO3 (10 ml). The organic layer was washed with water (10 ml) and saturated aqueous NaCl (10 ml). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC (Method A). The desired fractions were concentrated to give the product, 1-((1R,2R)-2-(methyl((S)-1-(4-nitrophenyl)piperidin-3-yl)amino)cyclohexyl)-3-phenylurea (18 mg, 0.038 mmol, 55.2% yield) as a yellow solid. Anal. Calcd. for C25H33N5O3 m/z 451.5, found: 452.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 10.60 (br. s., 1H), 7.89 (d, J=8.80 Hz, 2H), 7.52 (br. s., 1H), 7.33 (d, J=8.25 Hz, 2H), 7.30-7.19 (m, 2H), 7.03 (t, J=7.15 Hz, 1H), 6.75 (d, J=8.80 Hz, 2H), 3.87-3.56 (m, 4H), 3.51-3.34 (m, 4H), 3.23-3.13 (m, 1H), 2.82 (br. s., 3H), 2.25-1.32 (m, 10H); 13C NMR (126 MHz, CDCl3) δ ppm 158.25, 154.02, 139.91, 138.67, 128.85, 125.71, 123.04, 118.88, 114.37, 68.41, 60.22, 50.63, 48.67, 48.25, 32.33, 31.60, 25.29, 25.13, 24.18, 23.74, 22.28.

Workup

  1. stirringthe reaction was stirred for an additional 1 hr
  2. customAfter this time, the reaction was quenched with water (2 ml)
  3. customThe reaction was partitioned between CH2Cl2 (15 ml) and saturated aqueous NaHCO3 (10 ml)
  4. washThe organic layer was washed with water (10 ml) and saturated aqueous NaCl (10 ml)
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by RP prep-HPLC (Method A)
  9. concentrationThe desired fractions were concentrated

Sources & evidence

ORD record
ord-46dd3613ded64a27afa3946b3037583f
Source dataset
uspto-grants-2014_04
Patent number
US08710049B2

Reaction notes

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