Toluene → propan-2-yl 4-[4-[(3aS,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]-4-methyl-piperidine-1-carboxylate

HRID 1642474Notes

Reaction equation

HRID 1642474 reaction equation
[CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[NH:16]1

Participants

7

Reactant 5

HCID 1140TolueneHCID 7917Isopropyl chloroformateHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 57619802(3aS,7aS)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one

Product 1

HCID 25195463propan-2-yl 4-[4-[(3aS,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-1-yl]-1-piperidyl]-4-methyl-piperidine-1-carboxylateYield 48%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of (3aS,7aS)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 99 mg, 0.25 mmol) and diisopropylethylamine (129.3 mg, 1.0 mmol) in dry dichloromethane (5 mL) at 0° C. was added with a solution of 1.0 N isopropyl chloroformate in toluene (0.3 mL, 0.3 mmol) dropwise and stirred at room temperature for 3 h. Saturated NaHCO3 (5 mL) was added followed by dichloromethane (20 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to give the title compound (49 mg, 48%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.95 (s, 3H), 1.21 (d, J=6.25 Hz, 6H), 1.31-1.49 (m, 6H), 1.52-1.64 (m, 1H), 1.65-1.88 (m, 7H), 1.95 (d, J=7.42 Hz, 1H), 2.10-2.20 (m, 2H), 2.26 (d, J=7.81 Hz, 1H), 2.89-3.15 (m, 4H), 3.31-3.44 (m, 2H), 3.42-3.51 (m, 2H), 3.53-3.64 (m, 1H), 4.78-4.90 (m, 1H). MS (M+1): 407.2.

Workup

  1. customThe phases were separated
  2. extractionthe aqueous phase was extracted with dichloromethane (2×10 mL)
  3. washThe combined organic phases were washed with brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified with preparative LC/MS (high pH)

Sources & evidence

ORD record
ord-0439840602a6466a95dd187367a39642
Source dataset
uspto-grants-2012_02
Patent number
US08119661B2

Reaction notes

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