Oxime Formation Step Optimization


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Oxime Intermediate Step Optimization via Lean Six Sigma Process

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Oxime Formation Step Optimization

  1. 1. Optimization of Oxime Formation Process Louis Matty 4 December 2011
  2. 2. Oxime Formation The oxime formation is the second chemical transformation in a 5 step process designed to produce the pharmacologically active PPAR Agonist described in the publication: An Efficient Synthesis of a Duel PPAR  /γ Agonist and the Formation of a Sterically Congested  -Aryloxyisobutyric Acid via a Bargellini Reaction , Raymond J. Cvetovich, et al. , JOC 2005 , 70 (21), 8560. O H F 3 C N O H O H O H F 3 C O O H H 2 N O H
  3. 3. Overall Process Scheme – PPAR Agonist
  4. 4. Objectives of Development <ul><li>Reaction </li></ul><ul><ul><li>Determine any source of variability </li></ul></ul><ul><ul><li>Decrease hydroxylamine charge </li></ul></ul><ul><ul><li>Decrease salt/solids load in reaction mixture </li></ul></ul><ul><ul><li>Optimize performance, shorten time, increase yield </li></ul></ul><ul><li>Workup </li></ul><ul><ul><li>Optimize workup for robust operation </li></ul></ul><ul><ul><li>Reduce impurities to eliminate down stream column purification </li></ul></ul><ul><ul><li>Investigate through process capability </li></ul></ul>
  5. 5. Oxime Step Formation Issues <ul><li>Initial conditions : 4 eq H 2 NOH-HCl/EtOH, 24 hr, 60°C </li></ul><ul><li>High solids load, difficult to stir </li></ul><ul><li>Conversion of 96%, step yield of 86% </li></ul><ul><li>Final desired intermediate is the E-isomer </li></ul><ul><li>Workup : labor intensive 8 step, ill-defined </li></ul><ul><li>Required impurity reduction via down stream column chromatography </li></ul>
  6. 6. Proposed Reaction Screens <ul><li>Use Hydroxylamine HCl salt or Free base </li></ul><ul><li>Base additive </li></ul><ul><li>Solvent choice </li></ul><ul><li>Temperature </li></ul><ul><li>Concentration </li></ul><ul><li>Addition mode – hydroxylamine </li></ul>
  7. 7. Trends of Reaction Screens <ul><li>Reaction time variability source acidic carryover from previous acylation step </li></ul><ul><li>Hydroxylamine free base eliminated solids content </li></ul><ul><li>Base additive enabled reduction of hydroxylamine 4 eq- 2 eq </li></ul><ul><li>Choice of base additive n-butylamine >>tri-butylamine. NH 3 OH poor. </li></ul><ul><li>Solvent choice indicated that MeOH > EtOH > IPa </li></ul><ul><li>Reaction temperature – best at stated 60C </li></ul><ul><li>Reaction concentration – no effect </li></ul><ul><li>Mode of addition – no effect </li></ul>
  8. 8. Source Reaction Time Variability <ul><li>Acidic carry over from acylation step of dipropylresorcinal (DPR) 5 </li></ul><ul><li>Recommended additional base washes to post acylation </li></ul>
  9. 9. Proposed Workup Evalution <ul><li>Evaluate workup “as is” </li></ul><ul><li>Define steps of workup to determine performance </li></ul><ul><li>Screen changes - determine trend (better/worse) </li></ul><ul><li>Determine conditions of impurity formation, NaOH extraction </li></ul>
  10. 10. Workup Definition <ul><li>Initial HCl quench, wash to remove excess H 2 NOH </li></ul><ul><li>Removal of DPR via NaOH/toluene extraction </li></ul><ul><li>Subsequent pH adjustment, iPAc extraction, brine washes </li></ul><ul><li>Hold batch solution for next step </li></ul>
  11. 11. Test Modified Process -Serendipity Strikes <ul><li>Performance exceeded Basis Reaction </li></ul><ul><ul><li>Reaction <18 hr, high conversion </li></ul></ul><ul><li>Oxime product crystallized upon cooldown </li></ul><ul><ul><li>White dense crystal, mono salt of n-BA </li></ul></ul><ul><ul><li>Correct E-isomer </li></ul></ul><ul><ul><li>Simple water addition to increase recovery of high purity intermediate </li></ul></ul><ul><ul><li>LCWP >98 LCAP > 99 </li></ul></ul>
  12. 12. Final Process <ul><li>NH 2 OH, 2 eq </li></ul><ul><li>N-butylamine, 2 eq </li></ul><ul><li>Solvent change to methanol </li></ul><ul><li>Faster, consistent reaction time < 18 hours, 60°C </li></ul><ul><li>Improved step yield 88% to 93% </li></ul><ul><li>Clean solids via simple crystallization as salt via H 2 O </li></ul><ul><li>Total elimination of extractive workup </li></ul><ul><li>Elimination of silica gel treatment for next step. </li></ul><ul><li>Simple quantitative salt break recovery prep for next step </li></ul>
  13. 13. Conclusion <ul><li>Step optimization is affected by previous step </li></ul><ul><li>Break down of process activity enables definition of process issues </li></ul><ul><li>Use of Lean Six Sigma screens effective means to determine directional trends </li></ul>