Ethanol → HCID 46240139, compound

HRID 1971147Notes

Reaction equation

HRID 1971147 reaction equation
CCO.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:23]#[N:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:13](F)[CH:12]=1.O>C(COC)OC>[Cl:10][C:11]1[CH:16]=[C:15]2[NH:24][CH2:23][C:17]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:14]2=[CH:13][CH:12]=1

Participants

6

Reactant 4

HCID 702EthanolHCID 962WaterHCID 21226445Aluminium lithium hydrideHCID 66937918HCID 66937918, compound

Product 1

HCID 46240139HCID 46240139, compoundYield 96%

Reagents, catalysts & solvents 1

HCID 80711,2-DimethoxyethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

HCl (4.0 N in dioxane, 10 mL, 40 mmol, 7.1 equiv) was added to a solution of 1,1-dimethylethyl 4-(4-chloro-2-fluorophenyl)-4-cyano-1-piperidinecarboxylate (1.9 g, 5.6 mmol, 1 equiv) in 1,4-dioxane (25 mL) at 23° C. The resulting solution was warmed to 45° C. and stirred for 1 hour (white precipitation formed). The suspension was concentrated to afford 4-(4-chloro-2-fluorophenyl)-4-piperidinecarbonitrile as a pale-yellow solid. EtOH (1.6 mL, 38.1 mmol, 6.8 equiv) was slowly added to a suspension of lithium aluminium hydride (LAH) (1.15 g, 30.3 mmol, 5.4 equiv) in glyme (16 mL) at 0° C. The resulting suspension was heated to reflux and stirred for 5 min. A suspension of the newly prepared 4-(4-chloro-2-fluorophenyl)-4-piperidinecarbonitrile in glyme (10 mL) was added in portions. The resulting brown suspension was refluxed for 1 h, then cooled to 0° C. Water (8 mL) was added slowly at 0° C. and the resulting suspension was warmed to room temperature and stirred for 30 min. The suspension was filtered through Celite pad and the solid was rinsed with CH2Cl2 (200 mL). The filtrate was dried over anhydrous potassium carbonate. The dried solution was concentrated. The residue was purified by reverse phase C18 column to afford 6-chloro-1,2-dihydrospiro[indole-3,4′-piperidine] as a white powder (1.2 g, 5.4 mmol, 96%). MS (ES) m/e 223 [M+H]+.

Workup

  1. temperatureThe resulting suspension was heated
  2. temperatureto reflux
  3. additionwas added in portions
  4. temperatureThe resulting brown suspension was refluxed for 1 h
  5. temperaturethe resulting suspension was warmed to room temperature
  6. stirringstirred for 30 min
  7. filtrationThe suspension was filtered through Celite pad
  8. washthe solid was rinsed with CH2Cl2 (200 mL)
  9. dry with materialThe filtrate was dried over anhydrous potassium carbonate
  10. concentrationThe dried solution was concentrated
  11. customThe residue was purified by reverse phase C18 column

Sources & evidence

ORD record
ord-e10cec08c96d4065bacc5620d27a6517
Source dataset
uspto-grants-2013_04
Patent number
US08431590B2

Reaction notes

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