Sulfuric Acid → 4-Aminomethyl-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester

HRID 2180185

Reaction equation

HRID 2180185 reaction equation
OS(O)(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16]([C:26]#[N:27])([C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][C:16]([CH2:26][NH2:27])([C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]

Participants

4

Reactant 2

HCID 1118Sulfuric AcidHCID 207794754-Cyano-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 207794744-Aminomethyl-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl esterYield 26%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of LiAH4 (8.5 mL of a 1.0M solution in THF, 8.5 mmol, 3.5 eq.) was cooled to 0° C. and concentrated H2SO4 (0.43 mL, 7.6 mmol, 3.2 eq) was added in a drop-wise fashion. The resulting white slurry was stirred at room temperature for 0.5 h then heated to 30° C. for 0.5 h. The reaction was cooled to room temperature and a solution of 4-cyano-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1 g, 2.43 mmol) in THF (3 mL) was added over 0.25 h. The mixture was heated to 55° C. and monitored by TLC. After 5 h the reaction was cooled to room temperature and quenched by careful addition of H2O (0.323 mL), 1 N NaOH (0.646 mL) and H2O (0.97 mL). This mixture was diluted with CH2Cl2 (25 mL) and stirred vigorously for 1 h and then filtered through a pad of celite®. The salts were washed with CH2Cl2 (5×25 mL) and the combined washings were concentrated by rotary evaporation to give the crude product as a yellow solid (0.597 g) which was purified by flash column chromatography by eluting with 1% MeOH/CH2Cl2 (+1% TEA) to give 4-aminomethyl-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.26 g, 26%). 1H NMR (CDCl3): δ 7.81 (d, 2H), 7.17 (d, 2H), 3.82 (m, 2H), 3.145 (m, 2H), 2.86 (s, 2H), 2.24 (m, 2H), 1.80 (m, 2H), 1.65 (br.m, 2H), 1.56 (s, 9H).

Workup

  1. temperaturethen heated to 30° C. for 0.5 h
  2. temperatureThe reaction was cooled to room temperature
  3. temperatureThe mixture was heated to 55° C.
  4. temperatureAfter 5 h the reaction was cooled to room temperature
  5. customquenched by careful addition of H2O (0.323 mL), 1 N NaOH (0.646 mL) and H2O (0.97 mL)
  6. additionThis mixture was diluted with CH2Cl2 (25 mL)
  7. stirringstirred vigorously for 1 h
  8. filtrationfiltered through a pad of celite®
  9. washThe salts were washed with CH2Cl2 (5×25 mL)
  10. concentrationthe combined washings were concentrated by rotary evaporation
  11. customto give the crude product as a yellow solid (0.597 g) which
  12. customwas purified by flash column chromatography
  13. washby eluting with 1% MeOH/CH2Cl2 (+1% TEA)

Sources & evidence

ORD record
ord-dbce0f9cfa65459c884e4ec73c030549
Source dataset
uspto-grants-2005_05
Patent number
US06887889B2

Linked notes

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