Acetic Acid → HCID 86719534, compound

HRID 2208846Notes

Reaction equation

HRID 2208846 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH:27](=O)[CH3:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([N:8]([CH2:27][CH3:28])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 177Acetaldehyde2×HCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydride2×HCID 70873837HCID 70873837, compound

Product 1

HCID 86719534HCID 86719534, compoundYield 98%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 962WaterSolvent

Procedure

To a solution of tert-butyl 4-{[5-chloro-3-(methoxycarbonyl)-2-methylphenyl]amino}piperidine-1-carboxylate (125 mg, 0.33 mmol) in 1,2-dichloroethane (1.6 ml) at room temperature under nitrogen was added acetaldehyde (37 μl, 0.65 mmol) followed by acetic acid (0.11 ml, 1.96 mmol). This solution was stirred for 5 minutes before adding sodium triacetoxyborohydride (0.21 g, 0.98 mmol) at room temperature. The reaction was monitored by LCMS and after 4.5 h a further acetaldehyde (73 μl, 1.31 mmol) and sodium triacetoxyborohydride (0.28 g, 1.31 mmol) were added to the reaction mixture. The mixture was stirred for a further 18 hours after which deionized water (10 ml) was added and the mixture was neutralised with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 8:2 Heptane:EtOAc) to give 131 mg (98%) of the title compound as a thick colourless oil. LC-MS 98%, m/z=433.5/435.1 (M+Na), 1H NMR (500 MHz, Chloroform-d) δ ppm 7.57 (1H, d, J=2.21 Hz), 7.22 (1H, d, J=2.05 Hz), 3.97-4.14 (2H, m), 3.90 (3H, s), 3.04 (2H, q, J=6.99 Hz), 2.81-2.91 (1H, m), 2.70 (2H, br. t, J=11.50, 11.50 Hz), 2.45 (3H, s), 1.69-1.80 (2H, m), 1.47-1.56 (2H, m), 1.46 (9H, s), 0.87 (3H, t, J=7.09 Hz).

Workup

  1. waitThe reaction was monitored by LCMS and after 4.5 h
  2. additionwas added
  3. customThe phases were separated
  4. extractionthe aqueous layer was extracted with EtOAc (2×10 ml)
  5. dry with materialThe combined organic extracts were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 8:2 Heptane:EtOAc)

Sources & evidence

ORD record
ord-7e1b5b716a834c46a004fe732df60b2e
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

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