alpha-Bromo-o-fluorotoluene → 1-(tert-Butoxycarbonyl)-4-(2-fluorobenzyl)piperidine-4-carboxylic acid

HRID 730198Notes

Reaction equation

HRID 730198 reaction equation
C([N-]C(C)C)(C)C.[Li+].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>O1CCCC1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[F:25])([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]

Participants

5

Reactant 3

HCID 67968alpha-Bromo-o-fluorotolueneHCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 2724682Lithium diisopropylamide

Product 1

HCID 236005311-(tert-Butoxycarbonyl)-4-(2-fluorobenzyl)piperidine-4-carboxylic acidYield 22%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Lithium diisopropylamide (10.9 mmol, 2M tetrahydrofuran) was added to a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.00 g, 4.36 mmol) in tetrahydrofuran (25 mL) at 0° C. After 1.5 h 2-fluorobenzyl bromide (0.788 mL, 6.54 mmol) was added, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with the addition of water (10 mL) followed by 1M hydrochloric acid (10 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), the organic layers collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.330 g, (22 %) of 4-(2-fluoro-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. 1H-NMR (CD3Cl3, 300 MHz) δ 7.11-7.00 (m, 5H), 4.00 (br., 2H), 2.92 (s, 2H), 2.90 (br., 2H), 2.05 (br., 2H), 1.46 (br., 2H), 1.44 (s, 9H).

Workup

  1. customThe reaction was quenched with the addition of water (10 mL)
  2. extractionThe aqueous layer was extracted with ethyl acetate (3×50 mL)
  3. customthe organic layers collected
  4. concentrationconcentrated under reduced pressure and crude product
  5. custompurified by column chromatography

Sources & evidence

ORD record
ord-f08888305c91470f8eac81c836f8dbe6
Source dataset
uspto-grants-2009_09
Patent number
US07582654B2

Reaction notes

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