1,1-Dimethylethyl 4-(4-amino-2-fluorophenyl)-3,6-dihydro-1(2h)-pyridinecarboxylate → Tert-butyl 4-(4-amino-2-fluorophenyl)piperidine-1-carboxylate

HRID 1276435Notes

Reaction equation

HRID 1276435 reaction equation
[CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3]>CO.[Pd]>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]

Participants

4

Reactant 1

HCID 543049921,1-Dimethylethyl 4-(4-amino-2-fluorophenyl)-3,6-dihydro-1(2h)-pyridinecarboxylate

Product 1

HCID 53981770Tert-butyl 4-(4-amino-2-fluorophenyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

A mixture of 3,6-dihydro-4-[4-amino-2-fluorophenyl]-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 3, 11.44 g) and 10% palladium-on-carbon (4 g) in methanol (400 mL) in four Parr bottles is shaken on the Parr apparatus under a hydrogen atmosphere at 40 psi for two hours, the catalyst is removed by filtration through Celite, and the filtrate is concentrated under reduced pressure to give the 4-[4-amino-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester intermediate. A mixture of this intermediate (11.17 g) and sodium bicarbonate (6.57 g) in dry tetrahydrofuran (390 mL) is treated with benzyl chloroformate (5.86 mL), and the resulting mixture is stirred at ambient temperature for 15 hours and washed with water (200 mL). The aqueous phase is extracted with methylene chloride (150 mL), and the combined organic phase is washed with saline (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (70 - 230 mesh, 800 g), eluting with a gradient of ethyl acetate/hexane (15/85 - 25/75). Pooling and concentration of those fractions with an Rf =0.38 by TLC (ethyl acetate/hexane, 25/75) gives the title compound, mp 96-98° C.

Workup

  1. customthe catalyst is removed by filtration through Celite
  2. concentrationthe filtrate is concentrated under reduced pressure

Sources & evidence

ORD record
ord-811c4ba316f34b0db8211ff66190d1a3
Source dataset
uspto-grants-2000_12
Patent number
US06166056

Reaction notes

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