Overview Existing Chemistry to 2380 by wulinqing


									 Commercial Scale Counter Current Chromatographic
     Separation of a Pharmaceutical Intermediate:
Achieving purity when conventional chemical approaches

        Eastern Analytical Symposium
                & Exposition
             November 16, 1999

         T.G. Archibald, G.G. McParland, M. Chalker,
     B. Kelson, A.A. Malik, T. E. Clement, H. Palandoken,
                A tale of two epoxides

                   BocNH                               O
                                   O           H

   We were making one epoxide and throwing the other
    away in the waste stream.
   One day someone came along and wanted the other
    epoxide diastereomer.
   Oh Boy, we said. We can sell our waste for lots of
Very Clean Commercial Process Currently in
 Operation at Multi-metric Ton/month Scale

                    Et3N                                     CH2N 2
                                                O       O
  BocNH    COOH                BocNH                         R        BocNH          N2
                                            O       O                            O

          HCl                       [H]                               Base

            BocNH                         BocNH                  Cl      BocNH
                               Cl                                                         O

          We Need both S,S- and R,S- Diastereomers
Ideally, you control the reduction chemistry
       to get the desired diastereomer.

                  H                        H

        BocNH         COOH        BocNH    CCH2Cl


                      H                                             H
                             Cl                     BocNH                       Cl
         BocNH                                                              H
                           OH                               HO

          BocNH                                                         O
                            O                               H
                  S,S-                                   R,S-
        So We Tried Hundreds of Reagents
            and Reaction Conditions:
           Some Selected Reductions of CMK to CMA
                   Reagent(s)                Solvent(s)   Temp     Time     R,S:S,S
                   Li(OtBu)3AlH              Et2O         0C       3Hrs     8:1
                   (+)-Dip Chloride(1.4eq)   THF          5C-RT    12Hrs    5:1
                   K-Selectride              THF          Reflux   2 Hrs    2:1
                   R-Alpine Borane(Conc.)    THF          Reflux   9Dys     1:1
                   L-Selectride              THF          R.T.     1 Hr     0.9:1
Most conditions    NaBH4/CeCl3(anh.)         THF          RT       2 Hrs    0.8:1
give mixtures      NaCNBH3                   THF          RT       36Hrs    0.7:1
                   (+)-2-Butanol/NaBH4       THF          RT       1 Hr     0.6:1
of R,S-            NaBH4/(-)-2-Butanol       THF          RT       30Min    0.6:1
and S,S-           NaBH4/L-Tartaric Acid     THF          5C       1 Hr     0.6:1
                   NaBH4/D-Tartaric Acid     THF          RT       30Min    0.5:1
in high isolated   BH3-t-butylamine          THF          R.T.     1 Hr     0.5:1
 yield.            LAH                       THF          25 C     1 Hr     0.5:1
                   THF*BH3                   EtOH/THF     R.T.     2 Hrs    0.2:1
                   Al(iOPr)3                 IPA          50C      3 Days   0.05:1
        With the reduction well understood:

   It should now be easy to get R,S- or S,S- at any “almost
    purity” you liked from 95:5 to 10:80.
   But, Typical demand is for >99.8% de
   So, it becomes just a purification problem.
However - Real Life is Often Not So Clean

     S,S- is highly crystalline and easily purified
         Typical purity is 99.8% with <0.1% R,S-
     R,S- is lower melting and more soluble
         Forms a 94:6 eutectic with S,S-
         Can not be purified to 99% by crystallization either at
          chloromethyl alcohol or epoxide stage.
    So - How to Make Pure R,S-
     by Most Efficient Route?

   We looked at alternative
    chemical routes
        Inversion
        Epoxidation
Alternate Routes Gave High-purity R,S- but at
                 High Cost.

                                                 Inversion route 90% yield 99% de

           H               H                 H                   H
                                                   Br                     BocN H
                  BocN H   CCH2Br   BocN H                                                   O
  BocN H   COOH                                  OH     BocN H                       H
                           O                                                  R,S-

                                                  Olefin Route 65% yield 98% de
We Began to Look at Industrial Scale Counter
     Current (SMB) Chromatography
             as an Alternative.

   Is it real?
        Does the technology really exist and will it work
   Can we win?
        If we use the technology, will it make the desired product with
         the desired quality.
   Is it worth it?
        Can we use the technology cost effectively against other
                    Counter Current Separation

                               Feed Racemate

Weaker Retained Enantiomer                                      Stronger Retained Enantiomer
        (Raffinate)                                                       (Extract)

                                                                              Wind (Mobile Phase)

                                Conveyor Belt
                              (Stationary Phase)

                                                   M. Negawa, F. Shoji, Journal of Chromatography 1992, 590, 113
                     t0                              t0 + T / 2
ELUENT                    EXTRACT   ELUENT                         EXTRACT

            Liquid                              Liquid

RAFFINATE                   FEED    RAFFINATE                        FEED
                     t0 + 1 T                            t0 + 1 T + T / 2
            ELUENT                                   ELUENT

                                        EXTRACT                                EXTRACT

RAFFINATE                                RAFFINATE

               Liquid                                   Liquid

                                 FEED                                 FEED
                         Machine Operation

Diastereomer A
Diastereomer B

                                                           Racemate Feed

The diastereomers move at different rates on the stationary phase. By moving
the location of feed and removal lines by solenoids, a continuous separation of
enantiomers takes place.
Analytical scale HPLC Separation of
         R,S- and S,S-CMA
Normal Phase Separation on Silica Gel
       Operational Conditions
Modeled from Analytical Chromatogram

  Feed, Raffinate and Extract
In Operation on Reverse Phase
                Selected Separation Conditions

CSP                       k’1          Solubility %   productivity g/day/kg
                                                       of phase.
Chiralpak® AD   CMA       0.9    2.6    1.0            100
Zorbax C-18     CMA       0.91   1.43   0.05           22
Zorbax C-18     Epoxide   0.46   1.6    2.6            130
Silica Gel      Epoxide   0.85   1.3    25             400
Chiralpak® AD   Epoxide   0.9    2.1    25             100

   Various solvents and column media can be used
   Separations scale from analytical data
   Preparation of multi-kilograms within short period of time
    is possible.
                               Facilitization Plan

   Lab SMB for training, customer demonstrations, and process

        1-15 kg quantities.

        In operation.

   Semi-works (“8-200”) unit capable of three to five metric tons per year
        Phase III product support

        Early commercial quantities

        In Operation

   Commercial scale (“6-800”) unit to support a commercial product
    launch ( 40-75 metric tons per year)
        Operational July 2000
       Selected Milestones in Counter-Current
           Chromatography Development

1960’s       UOP - Industrial separation of xylenes
1985         Prochrom and Separex started
1987         FDA approves first drug purified by batch prep HPLC
1992         Daicel Patents for Chiral Separations
1993         First implementation of short column/non-rotary valve equipment by NOVASEP
1994         First “real” operating machine with multi-ton capacity (8 x 200 at NOVASEP)
             First commercial batches (600 g) of CSP by Daicel
1997         First 6 x 450 plant begins operation.
1999         Large scale plant constructed at Aerojet for commercial production

                                       “Apologies to any historians present”
Licosep Lab Unit
Aerojet Lab in Sacramento CA
Control Screen for Lab Unit
Licosep 6-450
SMB Facility is Under Construction

                    April 30, 1999
         Commercial Separations Suite

   Modular Building Design
       2 Large-scale SMB units on one side
       Reactor suite, solvent recycle and solids isolation on
   Class 100,000 Building
   All operations are conducted under cGMP
   Goal is to combine chemical steps with
    chromatographic purification.
       Chemical manufacture
       Derivatization and purification
       Racematization
                      Is it worth it?

   Cost of separations vary with chromatographic
   Single enantiomer separations are cost competitive at
    throughputs rates of 1 kg/day/kg of phase.
   Multiple component mixtures can be separated.
   High containment of materials and very high recoveries
    are possible.
                          In Summary

   Continuous separations are producing R,S-epoxide
       Purity of 99.8 % de and 96% recovery are obtained.
       “waste” from S,S- process can be mined for R,S- by this method.
       Chromatography gives separations at a lower cost than inversion
       The separation technology coupled with reduction control gives
        flexibility in product mix to meet commercial demand.

   Roger-Marc Nicoud, NOVASEP
   Tom Lewis, Chiral Technologies
   Rob Miotke, Aerojet Fine Chemicals

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