Acetic Acid → 6-[1-(3-Ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic acid

HRID 913138Notes

Reaction equation

HRID 913138 reaction equation
Cl.Cl.C[O:4][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(C(C)C)C(C)C)C.[CH2:37]([O:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][C:47]=1[OH:48])[CH:43]=O)[CH3:38].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)C>[CH2:37]([O:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][C:47]=1[OH:48])[CH2:43][N:20]1[CH2:19][CH2:18][CH:17]([NH:16][C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]([C:5]([OH:4])=[O:23])=[CH:7][N:8]=2)[CH2:22][CH2:21]1)[CH3:38]

Participants

8

Reactant 6

HCID 176Acetic AcidHCID 8467EthylvanillinHCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 5003444Sodium cyanoborohydrideHCID 426042136-(Piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride2×

Product 1

HCID 674010866-[1-(3-Ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic acidYield 7%

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 3-ethoxy-4-hydroxy-benzaldehyde (30.0 mg, 0.18 mmol, 1.2 equiv; commercially available) 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. A solution of 10 M NaOH (0.5 mL) was added and the reaction mixture heated by microwave irradiation to 100° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 4.3 mg (7%) of the title compound. MS (ISP): 440.3 [M+H]+.

Workup

  1. additionwas added
  2. stirringthe mixture stirred at 55° C. over night
  3. temperaturethe reaction mixture heated by microwave irradiation to 100° C. for 15 min
  4. customRemoval of the solvent
  5. customunder reduced pressure and purification by preparative HPLC on reversed phase
  6. washeluting with a gradient of acetonitrile/water

Sources & evidence

ORD record
ord-2d3c95bde85649909680c85a7700a8aa
Source dataset
uspto-grants-2011_09
Patent number
US08026255B2

Reaction notes

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