Formaldehyde → 1-(4-cyanophenyl)-3-((2R,4R)-2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)urea

HRID 1971309Notes

Reaction equation

HRID 1971309 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][C:11]([C@H:13]1[CH2:18][C@H:17]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)=[O:21])[CH2:16][CH2:15][N:14]1[C:31](OC(C)(C)C)=O)=O.C=O.C([BH3-])#N.[Na+].C1COCC1>C(O)(=O)C.O.CO>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20]([NH:19][C@@H:17]2[CH2:16][CH2:15][N:14]([CH3:31])[C@@H:13]([C:11]3[NH:10][C:3]4[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=4[N:1]=3)[CH2:18]2)=[O:21])=[CH:28][CH:27]=1)#[N:30]

Participants

8

Reactant 4

HCID 712FormaldehydeHCID 8028TetrahydrofuranHCID 5003444Sodium cyanoborohydrideHCID 67266293(2R,4R)-tert-butyl 2-((2-amino-4,5-dimethylphenyl)carbamoyl)-4-(3-(4-cyanophenyl)ureido)piperidine-1-carboxylate

Product 1

HCID 575390051-(4-cyanophenyl)-3-((2R,4R)-2-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)ureaYield 86%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
65 °C

Procedure

(2R,4R)-tert-butyl 2-((2-amino-4,5-dimethylphenyl)carbamoyl)-4-(3-(4-cyanophenyl)ureido)piperidine-1-carboxylate (104 mg, 0.205 mmol) was dissolved in acetic acid (1 mL) and stirred at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove acetic acid. Then TFA (1 mL) was added to the residue. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove TFA and did next reaction without further purification. 37% formaldehyde solution (0.046 mL, 0.616 mmol) in water was added to a solution of the residue in methanol (2 mL) and the reaction mixture was stirred at room temperature for 1 hour, then 1M sodium cyanoborohydride in THF (0.62 mL, 0.62 mmol) was added carefully at 0° C. The reaction mixture was stirred at room temperature for 18 hours and then solvent was evaporated in vacuum. Saturated sodium bicarbonate solution (5 mL) and ethyl acetate (20 mL) were added and the mixture was stirred about 30 min. The organic layer was separated and dried over MgSO4, and concentrated. Product was purified by Companion (ReadySep 12 g, silica gel packed) with CH3OH/CH2Cl2 from 1-5% to give the title compound as an off-white solid 71 mg (73%). LC-MS: 403.3, 401.4 (t=1.8 min).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customto remove acetic acid
  3. additionThen TFA (1 mL) was added to the residue
  4. stirringThe resulting solution was stirred at room temperature for 2 hours
  5. concentrationThe reaction mixture was concentrated
  6. customto remove TFA
  7. customreaction
  8. customwithout further purification
  9. stirringthe reaction mixture was stirred at room temperature for 1 hour
  10. stirringThe reaction mixture was stirred at room temperature for 18 hours
  11. customsolvent was evaporated in vacuum
  12. additionSaturated sodium bicarbonate solution (5 mL) and ethyl acetate (20 mL) were added
  13. stirringthe mixture was stirred about 30 min
  14. customThe organic layer was separated
  15. dry with materialdried over MgSO4
  16. concentrationconcentrated
  17. customProduct was purified by Companion (ReadySep 12 g, silica gel packed) with CH3OH/CH2Cl2 from 1-5%

Sources & evidence

ORD record
ord-92e5c93764dd42a8846f9a1bfd919b1d
Source dataset
uspto-grants-2013_04
Patent number
US08431597B2

Reaction notes

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