Acetic Acid → 6-[1-(4-Methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide

HRID 913134Notes

Reaction equation

HRID 913134 reaction equation
Cl.Cl.CO[C:5](=[O:23])[C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:8][CH:7]=1.C(O)(=O)C.C([N:30](C(C)C)C(C)C)C.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][C:40]=1[O:47][CH2:48][CH2:49][CH3:50].C([BH3-])#N.[Na+].[C-]#N.[K+].[NH4+].[OH-]>C(O)C>[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][N:20]2[CH2:21][CH2:22][CH:17]([NH:16][C:9]3[CH:10]=[C:11]([C:12]([F:14])([F:15])[F:13])[C:6]([C:5]([NH2:30])=[O:23])=[CH:7][N:8]=3)[CH2:18][CH2:19]2)=[CH:41][C:40]=1[O:47][CH2:48][CH2:49][CH3:50]

Participants

9

Reactant 7

HCID 176Acetic AcidHCID 9032Potassium CyanideHCID 14923Ammonium HydroxideHCID 81531DiisopropylethylamineHCID 5921094-Methoxy-3-propoxybenzaldehydeHCID 5003444Sodium cyanoborohydrideHCID 426042136-(Piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride2×

Product 1

HCID 426049596-[1-(4-Methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamideYield 38%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
55 °C

Procedure

To a solution of 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (56.42 mg, 0.15 mmol, 1.0 equiv; intermediate B7) in ethanol (2 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) was added 4-methoxy-3-propoxy-benzaldehyde (35.0 mg, 0.18 mmol, 1.2 equiv; intermediate E11) and the mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. The solvents were removed under reduced pressure and the residue taken up in DMAc (0.5 ml). Potassium cyanide (30.0 mg, 0.47 mmol, 3.1 equiv) and a conc. solution of NH4OH (1 mL) was added and the reaction mixture heated by microwave irradiation to 100° C. for 8 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 26.5 mg (38%) of the title compound. MS (ISP): 468.4 [M+H]+.

Workup

  1. additionwas added
  2. stirringthe mixture stirred at 55° C. over night
  3. customThe solvents were removed under reduced pressure
  4. temperaturethe reaction mixture heated by microwave irradiation to 100° C. for 8 h
  5. customRemoval of the solvent
  6. customunder reduced pressure and purification by preparative HPLC on reversed phase
  7. washeluting with a gradient of acetonitrile/water

Sources & evidence

ORD record
ord-ac0e635a93614702aa25e671cba7c91e
Source dataset
uspto-grants-2011_09
Patent number
US08026255B2

Reaction notes

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