Acetaldehyde → 1-Ethyl-5,5-difluoro-4-hydroxy-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester

HRID 1257568Notes

Reaction equation

HRID 1257568 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:15][C:16]2C=CC=CC=2)[CH2:9][C:10]([F:14])([F:13])[C:11]=1[OH:12])=[O:5])[CH3:2].C(=O)C>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([CH2:15][CH3:16])[CH2:9][C:10]([F:13])([F:14])[C:11]=1[OH:12])=[O:5])[CH3:2]

Participants

5

Reactant 2

HCID 177AcetaldehydeHCID 67343743Ethyl 1-benzyl-5,5-difluoro-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate

Product 1

HCID 673440141-Ethyl-5,5-difluoro-4-hydroxy-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 1-benzyl-5,5-difluoro-4-hydroxy-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester was (59.46 g, 0.2 mol, prepared according to EP2123651 A1) in ethyl acetate (600 ml) was degassed and charged with acetaldehyde (13.22 g, 0.3 mol) and 10% palladium on activated carbon (6 g). This mixture was allowed to stir for three hours under an atmosphere then filtered through Celite, washed with copious methanol and concentrated under vacuum to give 1-ethyl-5,5-difluoro-4-hydroxy-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester that was immediately taken up into a 3N solution of hydrochloric acid (470 ml) and heated to reflux for four hours. Upon completion, the reaction was cooled to room temperature and concentrated under vacuum to yield 43.5 g 1-ethyl-3,3-difluoro-4,4-dihydroxy-piperidinium as a pale yellow powder (100%) LCMS (Method F): RT=0.13 min, m+H=182.0 1H NMR (400 MHz, DMSO) δ 10.84 (s, 1H), 6.93 (s, 2H), 3.82 (s, 1H), 3.60-3.32 (m, 2H), 3.15 (d, J=41.5, 2H), 3.09 (s, 1H), 2.07 (dd, J=30.7, 17.4, 2H), 1.25 (t, J=7.2, 3H).

Workup

  1. customwas degassed
  2. filtrationthen filtered through Celite
  3. washwashed with copious methanol
  4. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-7b7141ff61b443a2ad4b533f1e815805
Source dataset
uspto-grants-2013_06
Patent number
US08461328B2

Reaction notes

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