Oxygen → (3R,4R)-1-(tert-Butoxycarbonyl)-4-(4-fluorophenyl)piperidine-3-carboxylic acid

HRID 253077Notes

Reaction equation

HRID 253077 reaction equation
O=O.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:12]([C:23]([OH:25])=[O:24])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[H][H]>COC(C)(C)C.CO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C@@H:12]([C:23]([OH:25])=[O:24])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]

Participants

7

Reactant 4

HCID 977OxygenHCID 8471TriethylamineHCID 533752574-(4-Fluoro-phenyl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl esterHCID 178418361HCID 178418361, compound

Product 1

HCID 58985839(3R,4R)-1-(tert-Butoxycarbonyl)-4-(4-fluorophenyl)piperidine-3-carboxylic acidYield 89%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 15413tert-Butyl methyl etherSolvent

Procedure

In a glove box (O2 content ≦2 ppm) a 35 ml autoclave equipped with a 15 ml glass insert and a magnetic stirring bar was charged with 4-(4-fluoro-phenyl)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid-1-tert-butyl ester (0.300 g, 0.934 mmol), [Ru(OAc)2((S)-3,5-Xyl-4-MeO)-MeOBIPHEP] (9.67 mg, 0.00936 mmol), triethylamine (15 mg, 0.16 mmol, 0.16 eq.) and 5 ml of methanol. The asymmetric hydrogenation was run for 42 h at 80° C. under 40 bar of hydrogen. After cooling to room temperature the pressure was released from the autoclave, the methanol solution was diluted with 50 ml of tert-butyl methyl ether and extracted with two 50-ml portions of a 1 M aqueous sodium hydroxide solution. The aqueous layer was poured on ice, acidified with ice-cold 2 M aqueous hydrochloric acid solution to pH 1 and extracted with two 100-ml portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give (+)-(3R,4R)-4-(4-fluoro-phenyl)-piperidine-1,3-dicarboxylic acid-1-tert-butyl ester in 89% yield (0.27 g) and with 96.6% ee.

Workup

  1. extractionextracted with two 50-ml portions of a 1 M aqueous sodium hydroxide solution
  2. additionThe aqueous layer was poured on ice
  3. extractionextracted with two 100-ml portions of ethyl acetate
  4. dry with materialThe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-e7f0c33efea142d1932d9cda389b3707
Source dataset
uspto-grants-2011_01
Patent number
US07872022B2

Reaction notes

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