A Career in Pharmaceuticals:Drug Hunting in The Lipitor Era          Gregg M Kamilar
14C   RadiosynthesisCustom Synthesis of Radiolabeled Compounds          ViTrax – Placentia, CA                2011-2012
Labeled ROMP Monomer         High SA Polymer Substrate
High % Isotopic Incorporation via “Click Labeling”
Addressing Unexpected Isomeric EffectsTetrahedron. 2004, 60, 11415-11420
Boranophosphate Nucleotide        Monomers   Building Blocks for RNAi Oligomer Synthesis          Pfizer, Inc – Cambridge,...
Boranophosphates Delivered               Adenosine (N-BZ)           3.15 g               Cytidine (N-BZ)            3.56 g...
Optimizing Boranophosphorylation                                                                                     Parti...
Protected ThymidineNucleosides, Nucleotides and Nucleic Acids, 20:12, 1927 - 1939
Protected GuanosineJ. Org. Chem. 2004, 69, 5261-5268
Boranophosphorylating Reagent – Literature Method•3 steps/3 purifications•Isolation of phosphitetriester was problematic  ...
Boranophosphorylating Reagent – Modified method•2 steps/2 purifications•No isolation of phosphite triester•Scaled successf...
Literature Synthesis of MNTP Condensing Reagent                              Key                          IntermediateTetr...
Alternate Synthesis of The Key Intermediate     Aldrich    D15,780-5$4.48 - 7.89 / gram J. Am. Chem. Soc. 1967, 89, 6276–6...
Completed Synthesis of MNTP     Aldrich    D15,780-5$4.48 - 7.89 / gramJ. Am. Chem. Soc. 1967, 89, 6276–6282Tetrahedron 20...
2’-Cyclopropyl Nucleotide A Building Block for RNAi Oligomer Synthesis         Pfizer, Inc – Cambridge, MA                ...
Route to 2’-Cyclopropyl U and CCAN. J. CHEM. VOL. 71, 1993, p 413J. Org. Chem., Vol. 62, No. 5, 1997
Scaled Synthesis of Starting KetoneCan. J. Chem. Vol 44 , 1966, p. 836
Mitsunobu Protection of Uridine O4J. Org. Chem., Vol. 62, No. 5, 1997
Scaled Cycloaddition                                                        Modified from                                 ...
Conversion to CyclopropaneCan. J. Chem. Vol 44 , 1966, p. 836
Undesired Glycosidic CleavageCan. J. Chem., 1993, 71, 413 Heterocycles, 2003, 59, 207
Substrate Effects in DeprotectionHeterocycles, 2003, 59, 207                                       OEt                    ...
New Protection Strategy for Uridine1) Benzoyl group can be left on until final oligo deprotection2) Can be removed under m...
Synthesis and SAR of A Bacterial     Translation Inhibitor        Pharmacia, Inc – Kalamazoo, MI                   1999-2003
A Three Ring PharmacophoreRing substitutionIsosteric carboxylicacid     replacementsLinkers                            ...
Synthetic Route                                                          R6                                         R6    ...
Direct o/p Chlorosulfonation    CO2H(Me)                    CO2H(Me)G              HSO3Cl       G               65o-120 oC...
m/o Chlorosulfonation via Diazotization           CO2Me                    HCl         CO2Me            CuCl . 2H2O       ...
Convergent Synthesis of Cyanoanthranilic Acids                                             COOH                           ...
Synthesis of a Versatile Intermediate                                                 OEt                                 ...
Parallel Routes Afford Diversity                                                    t-BuO                       METHOD A  ...
Synthesis of A NovelBacterial Gyrase Inhibitor    Pharmacia, Inc – Kalamazoo, MI               2004-2005
Mechanism of Alkylidene Cyclization                   O                                           O              HN       ...
Classical Morpholine Synthesis 2,6-Dimethylmorpholine is the only commercial 2,6-disubstituted morpholine. Beilstein sea...
Racemic Non-Symmetrical Analogs           H        O             H       O                       H       O           N    ...
Finishing the Asymmetric Synthesis                                                                               F       O...
Regioselectivity via Non-Symmetrical Morpholines                                                             O            ...
A Regioselective Synthesis                                                                                                ...
[1,5] Hydride Shift Mechanism           O                                              O                                  ...
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Career Research Summary

  1. 1. A Career in Pharmaceuticals:Drug Hunting in The Lipitor Era Gregg M Kamilar
  2. 2. 14C RadiosynthesisCustom Synthesis of Radiolabeled Compounds ViTrax – Placentia, CA 2011-2012
  3. 3. Labeled ROMP Monomer High SA Polymer Substrate
  4. 4. High % Isotopic Incorporation via “Click Labeling”
  5. 5. Addressing Unexpected Isomeric EffectsTetrahedron. 2004, 60, 11415-11420
  6. 6. Boranophosphate Nucleotide Monomers Building Blocks for RNAi Oligomer Synthesis Pfizer, Inc – Cambridge, MA 2008-2009
  7. 7. Boranophosphates Delivered Adenosine (N-BZ) 3.15 g Cytidine (N-BZ) 3.56 g Thymidine (N-BZ) 3.32 g Guanosine (N-PAC)(O-DPC) 3.21 g
  8. 8. Optimizing Boranophosphorylation Partial purification preserves overall yield Short reaction times reduces side-Working in 1 gram batches improves products reproducibility and yield Efficient purification at this step allows for use of less pure substrate increasing throughput
  9. 9. Protected ThymidineNucleosides, Nucleotides and Nucleic Acids, 20:12, 1927 - 1939
  10. 10. Protected GuanosineJ. Org. Chem. 2004, 69, 5261-5268
  11. 11. Boranophosphorylating Reagent – Literature Method•3 steps/3 purifications•Isolation of phosphitetriester was problematic J. Am. Chem. Soc., 98, 7327 (1976)
  12. 12. Boranophosphorylating Reagent – Modified method•2 steps/2 purifications•No isolation of phosphite triester•Scaled successfully to >25 g•Final salt is highly stable oil @ RT J. Am. Chem. Soc., 98, 7327 (1976)
  13. 13. Literature Synthesis of MNTP Condensing Reagent Key IntermediateTetrahedron 62 (2006) 3667–3673
  14. 14. Alternate Synthesis of The Key Intermediate Aldrich D15,780-5$4.48 - 7.89 / gram J. Am. Chem. Soc. 1967, 89, 6276–6282
  15. 15. Completed Synthesis of MNTP Aldrich D15,780-5$4.48 - 7.89 / gramJ. Am. Chem. Soc. 1967, 89, 6276–6282Tetrahedron 2006, 62, 3667-3673
  16. 16. 2’-Cyclopropyl Nucleotide A Building Block for RNAi Oligomer Synthesis Pfizer, Inc – Cambridge, MA 2009
  17. 17. Route to 2’-Cyclopropyl U and CCAN. J. CHEM. VOL. 71, 1993, p 413J. Org. Chem., Vol. 62, No. 5, 1997
  18. 18. Scaled Synthesis of Starting KetoneCan. J. Chem. Vol 44 , 1966, p. 836
  19. 19. Mitsunobu Protection of Uridine O4J. Org. Chem., Vol. 62, No. 5, 1997
  20. 20. Scaled Cycloaddition Modified from Org. Syn. 1935, 16, 3 Can. J. Chem. Vol 44 , 1966, p. 836 NH O HH3C N N N+ N O- O
  21. 21. Conversion to CyclopropaneCan. J. Chem. Vol 44 , 1966, p. 836
  22. 22. Undesired Glycosidic CleavageCan. J. Chem., 1993, 71, 413 Heterocycles, 2003, 59, 207
  23. 23. Substrate Effects in DeprotectionHeterocycles, 2003, 59, 207 OEt O 10 : 1 N HN OBz MeOH : 1 M HCl OBz O N O N TBDMSO HO O OBz O OBz RT TBDMSO OMe 83% OH OMe OEt OEt N 10 : 1 N OEt N O MeOH : 1 M HCl HO N O O N Si O HO + O O O N O RT 90 ºC OH H Si O OH
  24. 24. New Protection Strategy for Uridine1) Benzoyl group can be left on until final oligo deprotection2) Can be removed under mild conditions prior to phosphitylation3) Installation is a high yielding reactionJ. Am. Chem. Soc. 1992, 114, 4008-4010 J. Med. Chem., 1991, 34, 999-1002
  25. 25. Synthesis and SAR of A Bacterial Translation Inhibitor Pharmacia, Inc – Kalamazoo, MI 1999-2003
  26. 26. A Three Ring PharmacophoreRing substitutionIsosteric carboxylicacid replacementsLinkers HO O Ring substitution H Other Sulfonamides Br A N Linkers B O O S O Ring substitution N C Cl Meta is better Heterocycles
  27. 27. Synthetic Route R6 R6 R6 R5 COOH R5 CO2Cl Cl NR5 COOH H (COCl)2 R4 R2 R4 R2 CH2Cl2 O S O CH2Cl2 O S OR4 R2 Py N N SO2Cl Cl Cl O CH2Cl2 HO O O Py O O LiOH H R6 R5 H R6 R5 Br N Br NH2Br N Dioxane R4 R4 40 oC O O O O R2 S R2 S O O N Cl N Cl
  28. 28. Direct o/p Chlorosulfonation CO2H(Me) CO2H(Me)G HSO3Cl G 65o-120 oC SO2Cl CO2H(Me) CO2H(Me) HSO3Cl 65o-120 oC SO2Cl G G
  29. 29. m/o Chlorosulfonation via Diazotization CO2Me HCl CO2Me CuCl . 2H2O CO2Me AcOH SO2(g) + NaNO2 - H2O Cl AcOH + G NH2 -10 oC G N N 5 oC G SO2Cl CO2Me HCl CO2Me CuCl . 2H2O CO2Me G AcOH G SO2(g) G + NaNO2 - H2O Cl AcOH + NH2 -10 oC N 5 oC SO2Cl NOrganic Syntheses, Vol 60, p.121, (1981)
  30. 30. Convergent Synthesis of Cyanoanthranilic Acids COOH COOH Cl HOH H 1) (COCl)2 / DMF N SO2Cl O ON NaCNBH3 N O S O CH2Cl2 S H O AcOH MeOH N C N Cl Cl N Et3N 2) LiOH Dioxane O Cl PHA-xxx523 SAUR MIC 0.125 g/mL 2 g/mL in 5% serumBr COOMe N C COOMe + CuCN NMP Ratio = 16 Reflux NH2 NH2
  31. 31. Synthesis of a Versatile Intermediate OEt OH Cl OEt further DMF O O O O ClSO3H N heating N (COCl)2 N N O O O O 80 °C CH2Cl2 O O O S S S Cl Cl O Cl O O PHA-xxx228External CRO HO O PO H PG O R2 N N O O R2 NH2 H R2 N N O O 1) HNRR", base CH2Cl2 O 2) Deprotect acid O S O Py N O S R O R" ~ 15 gram scale Cl
  32. 32. Parallel Routes Afford Diversity t-BuO METHOD A O t-BuO O N C NH N O NH2 1. HNRR" X HO O 2. TFA O O N C N O O S N C NH N O O O CH2Cl2, reflux Cl S O Cl O X = OH N C BnO 1. HNRR" O S(COCl)2 O O 2. H2, Pd/CDMF NH2 N X = Cl N C NH RCH2Cl2 N O R" BnO O METHOD B O O S O Cl
  33. 33. Synthesis of A NovelBacterial Gyrase Inhibitor Pharmacia, Inc – Kalamazoo, MI 2004-2005
  34. 34. Mechanism of Alkylidene Cyclization O O HN NH HN NH - O O O O [1,5] Hydride Shift O2N O2N H + N N O O O H O HN NH N O - NH O O O2N O2N H H O H N + N O OVerboom, W.; Reinhoudt, D. N.;Visser, R.; Harkema, S. J. Org.Chem. 1984, 49, 269-276.
  35. 35. Classical Morpholine Synthesis 2,6-Dimethylmorpholine is the only commercial 2,6-disubstituted morpholine. Beilstein search reveals only 2 other 2,6-disubstituted morpholines. Symmetrical cis morpholines are meso. Non-symmetrical morpholines have regioselectivity problems in final step.Intermediates Made by Classical Morpholine Synthesis- O O OH OH H2SO4 H N N R R 150 ºC N H Bn  Cis and trans isomers difficult to separate. J. Het.Chem. 1977, 14, 899-904  Asymmetric synthesis is highly unlikely.  Morpholines are volatile.
  36. 36. Racemic Non-Symmetrical Analogs H O H O H O N N N O O OO2N NH O2N NH O2N NH H H H O O O N N N O O O CF3 H O H O H O N N N O O OO2N NH O2N NH O2N NH H H H O O O N CF3 N N O O O
  37. 37. Finishing the Asymmetric Synthesis F O O H O Cl O O N OUnpublished N O Cl NO2 H 1) CH2Cl2, RT N Hunigs HCl K2CO3 2) MeOH, reflux CH3CN NO2 reflux (2S,6S)-(-) (2S,6S)-(-) O H O HN NH N O O2N NH O O H O N CH3OH reflux O (2S,4S,4aS)-(-)-
  38. 38. Regioselectivity via Non-Symmetrical Morpholines O H O HN NH N - O O O O2N NH Favored? O2N H H O H N Me O Me + N O HN NH O CF3 - O O CF3 [1,5] hydrideO2N shift H + Me N O O H O HN NH N CF3 O - NH O O O2N O2N H H O H N CF3 + CF3 N O O Me Me
  39. 39. A Regioselective Synthesis O NH2 HO Br O O OH N CH3CN H TEA + + Br F3C F3C RT N Cl CH2Cl2 F3C 0o C Racemic Commercial F O H F3C O Cl O F3C ONaH/THF LAH/THF F3C O O Cl NO2 N O N HCl 60o N0o - RT H K2CO3 CH3CN reflux O O O NH NH F3C O O O O2N NH NH HN NH O2N H H N O O O O O N CF3 N H O O MeOH CF3 reflux NO2 88 : 12
  40. 40. [1,5] Hydride Shift Mechanism O O O HN NH H Ha H O H NH H N N O O H Ha O O O O2N NH O2N NH O2NO2N Ha [1-5] shift Hb O O NH Hb CH3 CH3 Me N N O Hb CH3 N O irreversible N O O CH3 CH3 O CH3 1 10a 11 Me bond rotation O O HN HN O NH O NH O HbO2N O2N O2N H HbO N O N Me N Ha H CH3 Ha H CH3 O O O CH3 9 Me 10b CH3 12 PNU-286607

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