p-Toluenesulfonic acid monohydrate → HCID 67007910, compound

HRID 1672423Notes

Reaction equation

HRID 1672423 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C@H:17](O)[CH2:18][C@@H:19]([OH:21])[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([O:21][C@@H:19]([CH3:20])[CH2:18][C@H:17]([CH3:16])[O:14]2)[C@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 5609651-Benzyl-3-methyl-4-piperidoneHCID 69502002,4-Pentanediol, (+)-

Product 1

HCID 67007910HCID 67007910, compound

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Procedure

To a solution of 1-benzyl-3-methylpiperidin-4-one (Acros, 62.09 g, 305.4 mmol) and (2S,4S)-pentane-2,4-diol (TCI-US, 34.06 g, 327.0 mmol) in benzene (800 mL) was added p-toluenesulfonic acid mono hydrate (69.72 g, 404.9 mmol). The flask was fitted with a Dean-Stark trap and heated to reflux. The reaction mixture was cooled after 16 hours of reflux, concentrated to a total volume of about 500 mL and transferred to an Erlenmeyer flask with ethyl acetate. A sodium bicarbonate solution (500 mL) added with stirring and the mixture was further neutralized with solid Na2CO3 (35 g). The layers were partitioned, the organic phase washed with sodium bicarbonate, dried (Na2SO4) and concentrated to yield approximately 95 g of crude material. The residue was purified in 15 g batches by silica gel chromatography (Analogix SF-65-600 g; 35 micron silica; elution with 10% ethyl acetate-hexane) at 50 mL/min to provide 42.33 g of the first eluting isomer, (2S,4S,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane. 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.19 (m, 5H), 4.07-3.86 (m, 2H), 3.40 (ABq, 2H, JAB=13.5 Hz, δνAB=23.3 Hz), 2.41-2.20 (m, 4H), 1.90-1.76 (m, 2H), 1.59-1.47 (m, 3H), 1.12 (d, 3H, J=6.4 Hz), 1.11 (d, 3H, J=6.4 Hz), 0.90 (d, 3H, J=7.1 Hz); MS (DCI/NH3) m/e 290 (M+H)+.

Workup

  1. customThe flask was fitted with a Dean-Stark trap
  2. temperatureheated to reflux
  3. temperatureThe reaction mixture was cooled after 16 hours
  4. temperatureof reflux
  5. concentrationconcentrated to a total volume of about 500 mL
  6. additionA sodium bicarbonate solution (500 mL) added
  7. customThe layers were partitioned
  8. washthe organic phase washed with sodium bicarbonate
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated
  11. customto yield approximately 95 g of crude material
  12. customThe residue was purified in 15 g batches by silica gel chromatography (Analogix SF-65-600 g; 35 micron silica; elution with 10% ethyl acetate-hexane) at 50 mL/min

Sources & evidence

ORD record
ord-f0e29f0c86ad4222a68c6f92b5c9edb0
Source dataset
uspto-grants-2011_08
Patent number
US07998982B2

Reaction notes

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