Ethyl Acetate → HCID 59512674, compound

HRID 1158319Notes

Reaction equation

HRID 1158319 reaction equation
[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC[O:13][C:14]([CH3:16])=[O:15].[CH:17]1([C:22](=[O:35])[CH2:23][CH2:24][C:25]2[CH:30]=[C:29]([CH2:31][CH3:32])[N:28]=[C:27]([CH2:33][CH3:34])[CH:26]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>CC(OC)(C)C>[CH:17]1([C:22]([OH:35])([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]([CH2:33][CH3:34])[N:28]=[C:29]([CH2:31][CH3:32])[CH:30]=2)[CH2:16][C:14]([OH:13])=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18]1

Participants

5

Reactant 3

HCID 8857Ethyl Acetate2×HCID 2733832Lithium HexamethyldisilazideHCID 59512675HCID 59512675, compound

Product 1

HCID 59512674HCID 59512674, compound

Reagents, catalysts & solvents 1

HCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
-34 °C

Procedure

A clean 2-L, 3-neck flask was charged with LiHMDS (1.0 M in THF, 355 mL, 0.355 mol) and purged with nitrogen. The flask was cooled to −34° C. An addition funnel was then charged with EtOAc (35 mL, 0.3583 mol) and this reagent was slowly added to the reaction vessel at such a rate that the low temperature of the vessel could be maintained. After complete EtOAc addition another addition funnel was charged with the 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one solution (crude MTBE soln from prior reaction, theor. 73.47 g, 0.2832 mol) and rinsed over with THF (anhydrous, 5 mL). The 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one solution was slowly added to the reaction flask at such a rate that the low internal temperature could be maintained. Five minutes after complete addition, a reaction aliquot was removed and analyzed by HPLC, showing less than 1% 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one. Ten minutes after complete ketone addition, the bath was switched to 0° C. Once the internal temperature had warmed to −10° C., 1M NaOH (510 mL) was added. After complete NaOH soln addition, the reaction was heated to 50° C. After 21 hours the reaction solution was cooled below 30° C. and an aliquot of both layers was removed and analyzed for completion. The mixture was added to a separatory funnel with MTBE (350 mL) and the phases were mixed well and separated. An aliquot of the organic phase was analyzed by HPLC, verifying no significant product, and this layer was discarded. The aqueous phase was added to a flask with CH2Cl2 (350 mL). Concentrated aqueous HCl (about 100 mL) was slowly added to the aqueous phase until the pH=5. The mixture was added back to a separatory funnel and mixed well. The phases were separated and the aqueous layer was extracted a second time with CH2Cl2 (150 mL). The organic layers were combined and charged to a clean flask set up for distillation. The solution was distilled down to 370 mL then displaced with THF by addition of solvent portions followed by continued distillation down to 370 mL after each addition. When the distillation head temp. held steady at 65° C. for 30 min an aliquot was removed and analyzed by 1H NMR, showing a 12.5:1 ratio of THF:CH2Cl2. The solution of 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid in THF was used directly in the next step.

Workup

  1. custompurged with nitrogen
  2. additionthis reagent was slowly added to the reaction vessel at such a rate that the low temperature of the vessel
  3. temperaturecould be maintained
  4. customreaction, theor
  5. wash73.47 g, 0.2832 mol) and rinsed over with THF (anhydrous, 5 mL)
  6. additionThe 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one solution was slowly added to the reaction flask at such a rate that the low internal temperature
  7. temperaturecould be maintained
  8. additionFive minutes after complete addition
  9. customa reaction aliquot was removed
  10. additionTen minutes after complete ketone addition
  11. customwas switched to 0° C
  12. temperatureOnce the internal temperature had warmed to −10° C.
  13. addition1M NaOH (510 mL) was added
  14. additionAfter complete NaOH soln addition
  15. temperaturethe reaction was heated to 50° C
  16. temperatureAfter 21 hours the reaction solution was cooled below 30° C.
  17. customan aliquot of both layers was removed
  18. additionThe mixture was added to a separatory funnel with MTBE (350 mL)
  19. additionthe phases were mixed well
  20. customseparated
  21. additionThe aqueous phase was added to a flask with CH2Cl2 (350 mL)
  22. additionConcentrated aqueous HCl (about 100 mL) was slowly added to the aqueous phase until the pH=5
  23. additionThe mixture was added back to a separatory funnel
  24. additionmixed well
  25. customThe phases were separated
  26. extractionthe aqueous layer was extracted a second time with CH2Cl2 (150 mL)
  27. additioncharged to a clean flask
  28. distillationset up for distillation
  29. distillationThe solution was distilled down to 370 mL
  30. additionthen displaced with THF by addition of solvent portions
  31. distillationfollowed by continued distillation down to 370 mL
  32. additionafter each addition
  33. customan aliquot was removed

Sources & evidence

ORD record
ord-c36fa50a982c4a659d19b1ea7b72db75
Source dataset
uspto-grants-2010_10
Patent number
US07807838B2

Reaction notes

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