Sodium Hydroxide → HCID 131729858, compound

HRID 1876738Notes

Reaction equation

HRID 1876738 reaction equation
Cl.Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][C@H:13]([CH3:16])[C@H:12]([NH:17][CH3:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]1([CH3:46])[CH:24]=[CH:23][C:22]([C:25]([C@@:27]([C:43]([OH:45])=[O:44])([OH:42])[C@@:28]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)=[O:34])([OH:32])[C:29]([OH:31])=[O:30])=[O:26])=[CH:21][CH:20]=1.[OH-].[Na+]>CO>[C:19]1([CH3:46])[CH:24]=[CH:23][C:22]([C:25]([C@@:27]([C:43]([OH:45])=[O:44])([OH:42])[C@@:28]([C:33]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[O:34])([OH:32])[C:29]([OH:31])=[O:30])=[O:26])=[CH:21][CH:20]=1.[CH2:3]([N:10]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@@H:12]([NH:17][CH3:18])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1

Participants

5

Reactant 3

HCID 14798Sodium HydroxideHCID 29414711Di-para-toluoyl-L-tartaric acidHCID 54758995(3S,4S)-1-Benzyl-N,4-dimethylpiperidin-3-amine--hydrogen chloride (1/2)

Product 1

HCID 131729858HCID 131729858, compoundYield 70.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
75 °C

Procedure

To a clean, dry, nitrogen-purged 250 ml flask were charged racemic cis-(1-benzyl-4-methyl-piperidine-3-yl)-methylamine bis hydrochloride (20.0 g, 68.7 mmol), di-p-toluoyl-L-tartaric acid (L-DPTT) (15.9 g, 41.2 mmol) and methanol (100 ml). A solution of sodium hydroxide (5.5 g, 137.3 mmol in water (100 ml)) was added to the reaction at a rate to maintain the temperature below 30° C. The reaction was heated to between 70-80° C. and held at this temperature for at least 60 minutes. The reaction was cooled to 5-15° C. over at least 4 hours and held at this temperature for at least 12 hours. The solids were filtered and washed with a 1:1 mixture of MeOH:water (60 ml). The wet-cake was returned to the 250 ml flask and methanol (100 ml) and water (100 ml) were charged. The reaction was heated to between 70-80° C. and held at this temperature for at least 120 minutes. The reaction was cooled to 5-15° C. over at least 4 hours and held at this temperature for at least 12 hours. The solids were filtered and washed with a 1:1 mixture of MeOH:water (60 ml). The wet-cake was sampled for purity (99.4% ee) to ensure an additional repulp was not necessary. After drying under vacuum at 40-50° C. for at least 24 hours with a slight nitrogen bleed, the title compound (11.9 g, 28.9 mmol) was isolated in 42.1% yield (98.6% enantiomeric excess, 0.63% trans isomer by GC (Cyclosil B column 30 m×I.D. 0.25 mm; Inlet Temp 250; 2.0 ml/min flow rate; 15 min run; 160 C isothermal method.

Workup

  1. customTo a clean, dry
  2. customnitrogen-purged 250 ml flask
  3. temperatureto maintain the temperature below 30° C
  4. waitheld at this temperature for at least 60 minutes
  5. temperatureThe reaction was cooled to 5-15° C. over at least 4 hours
  6. waitheld at this temperature for at least 12 hours
  7. filtrationThe solids were filtered
  8. washwashed with a 1:1 mixture of MeOH
  9. additionwere charged
  10. temperatureThe reaction was heated to between 70-80° C.
  11. waitheld at this temperature for at least 120 minutes
  12. temperatureThe reaction was cooled to 5-15° C. over at least 4 hours
  13. waitheld at this temperature for at least 12 hours
  14. filtrationThe solids were filtered
  15. washwashed with a 1:1 mixture of MeOH
  16. aliquotThe wet-cake was sampled for purity (99.4% ee)
  17. customAfter drying under vacuum at 40-50° C. for at least 24 hours with a slight nitrogen

Sources & evidence

ORD record
ord-874db52d80584bcabd6a0bd8fa7a08f8
Source dataset
uspto-grants-2012_11
Patent number
US08309716B2

Reaction notes

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