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Eln 485554 Seminar V 1b

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David Quincy
David Quincy

The document describes improvements made to the synthesis of ELN 485554, a key intermediate for JNK inhibitors. The initial bromination step required excess bromine and produced side products. The reaction was optimized by using trifluoroacetic acid as the solvent and less bromine. Further improvements to isolation and purification included sublimation. Two regioisomeric products were observed from the Dimroth rearrangement. Overall, the described process optimizations enhanced the yield and purity of ELN 485554.

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In-Process Observations Resulting in an Improved Synthesis of ELN 485554 David A. Quincy Scientist Process Chemistry
ELN 485554 is a Key Intermediate in the Synthesis of Inhibitors of JNK Br N N ELN 485554 N S N ? JNK-1, -2, and -3 (c-Jun N-terminal Kinase, -1,-2, and -3) are a family phosphorylating of enzymes involved in cell signaling pathways, such as pathways for triggering cell death (apoptosis). ? JNK-3 is localized in the brain. ? Inhibitors of JNK-3 have been sought as possible treatments for neurological diseases, such as Alzheimer¡¯s disease.
The Original Med. Chem. Route Br Br Br 30 eq. Br2 S S AcOH (3x vol. of Br2) S 2.1 eq Zn O S formic acid O O CN ? 8 eq. NaOAc AcOH N N NH N NH NH ? 100oC, 2.5 - 6 hrs r.t. 16 hrs. H2N pyrimidone Poor solubility Poor solubility POCl3 ? ELN 485554 Br H Br Br Br N CH(OEt)3 S H2N S S H EtOH, S N N ?, 100o N NH N2H4 Cl N MeOH, 60oC N 2 H2N N N 40 min. N ? 1 hr. N N HN N chloro-pyrimidine poor solubility Sham, Hing L.; Konradi, Andrei W.; Hom, Roy K.; Probst, Gary D.; Bowers, Simeon; Truong, Anh; Neitz, Jeffrey R.; Sealy, Jennifer; Toth, Gergely; ¡°Inhibitors of Jun N- terminal Kinase,¡± PCT Int. Appl., (2010), WO 2010091310 A1, page 132.
The Preparation of Selectively Brominated Thiophenes is Important Br F Br F Br F S N S N 2.0 eq. Br2 S N Conditions N N Not Reported N N Acetic Acid (or Propionic N N Me Me Me Cl Cl Acid), Cl 1.9 eq. NaOAc (or KOAc) 70oC, 2 hrs., 83% yield 0.17 eq. n-BuLi, -70oC, THF, 1 hr., then H2O Patented by Dow Br Hegde, Vidyadhar B.; Schuster, Albert J.; ¡°Process F S N for the Preparation of Brominated Thiophenes,¡± PCT N N Int. Appl., (2000), WO 2000/24733. Me Cl
Examination of the initial Elan Bromination Conditions Br Br Br 30 eq. Br2 S S AcOH (3x vol. of Br2) S 2.1 eq Zn O O O 8 eq. NaOAc AcOH N N NH N NH NH ? 110oC, 2.5-6 hrs r.t. 16 hrs. pyrimidone ? Bromination is performed at a temperature much higher than prescribed by the Dow workers. ? Utilizes and requires a highly excessive amount of bromine. ? Observation ¨C Even though a reflux condenser was on the reaction flask, some Br2 was seen escaping the system. ? Innovation ¨C I proposed to perform the reaction in a closed pressure reactor behind a blast shield.
Round 1 Improvements to the Bromination Step Br Br 18 eq. Br2 S AcOH (3x vol. of Br2) S O O 8 eq. NaOAc N NH N NH ? 115oC, 2.5-6 hrs Sealed Pressure Reactor ? With the use of a pressure reaction vessel, the amount of bromine required was reduced. But 18 equivalents were still required for the reaction to complete. ? Observation - During concentration of the crude reaction on the rotary evaporator and attempted high vac. drying, a colorless liquid that crystallized at room temp. was discovered. It was identified as bromo-acetic acid. ? Innovation ¨C Use Trifluoro-acetic acid as the solvent.
Round 2 Improvements to the Bromination Step Br Br 4 eq. Br2 S TFA (7 x vol. of Br2) S O O 1.15 eq. K3PO4 N NH N NH ? 115oC, 4 hrs Sealed Pressure Reactor ? Result ¨C The bromination was complete in 4 hours with only 4 equivalents of Br2! Does this constitute a patentable process improvement? ? Observation ¨C The product has poor solubility characteristics. The majority of the product can be isolated by pouring the reaction mixture into ice water. Na2SO3 and NaHCO3 rinses should be performed.
Observations Leading to Improved Isolation & Purification of ELN 577104 Br Br Br Br S S S ~6 eq. Zn0 O POCl3 Cl O AcOH N NH ? 110oC N N N NH ? 65oC 6-10 hrs. ELN 577104 Poor solubility Poor solubility poor solubility ? After most of the POCl3 was removed under reduced pressure, the remaining reaction mixture was poured onto damp ice, to obtain a solid product. ? Observation ¨C While drying crude ELN 577104 in a vacuum oven under house vacuum at 55oC, the glass window was seen to cloud up with a fine white powder¡­.that led to the realization that the product sublimes. ? Result ¨C Purified by sublimation at 140-160oC.
Delivery of the Intermediate & a Bonus Br Br Br Br S S H S S EtOH, CH(OEt)3 Cl N NH N N N2H4 2 o ?, 100 N N N ? 1 hr. N N N N N N N 40 min. ELN 485554 ELN 577193 ? Two isomeric products were observed. Pure samples of each were analyzed and it was determined that ELN 577193 was the faster eluting, higher Rf, and more soluble product. ? Contrary to some suggestions, prolonged heating did not seem to convert ELN 577193 to ELN 485554. ? The observation of the two regio-isomeric products is known in the literature as the Dimroth Rearrangement.
Both Tricyclic Products Deprotect to the Same Amine Br Br Br H S S N S N + N H2N N N H2N N N N N N N MeOH, 60oC HN ELN 485554 ELN 577193
Major Contributions ? Modified bromination conditions to dramatically reduce reaction time and the amount of bromine required. ? Improved the isolation of the dibromo intermediate. ? Discovered that ELN 577104 could be easily isolated as a solid by pouring the reaction mixture into ice. ? Discovered that ELN 577104 sublimed and thereby improved the purification. ? Observed that ELN 485554 and the Dimroth Rearrangement product ELN 577193 gave the same desired product upon deprotection.
Acknowledgements: ? Elan Pharmaceuticals ? Michael Dappen, Lee Latimer, Gary Probst, Simeon Bowers, Anh Truong, and Roy Hom

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Eln 485554 Seminar V 1b

  • 1. In-Process Observations Resulting in an Improved Synthesis of ELN 485554 David A. Quincy Scientist Process Chemistry
  • 2. ELN 485554 is a Key Intermediate in the Synthesis of Inhibitors of JNK Br N N ELN 485554 N S N ? JNK-1, -2, and -3 (c-Jun N-terminal Kinase, -1,-2, and -3) are a family phosphorylating of enzymes involved in cell signaling pathways, such as pathways for triggering cell death (apoptosis). ? JNK-3 is localized in the brain. ? Inhibitors of JNK-3 have been sought as possible treatments for neurological diseases, such as Alzheimer¡¯s disease.
  • 3. The Original Med. Chem. Route Br Br Br 30 eq. Br2 S S AcOH (3x vol. of Br2) S 2.1 eq Zn O S formic acid O O CN ? 8 eq. NaOAc AcOH N N NH N NH NH ? 100oC, 2.5 - 6 hrs r.t. 16 hrs. H2N pyrimidone Poor solubility Poor solubility POCl3 ? ELN 485554 Br H Br Br Br N CH(OEt)3 S H2N S S H EtOH, S N N ?, 100o N NH N2H4 Cl N MeOH, 60oC N 2 H2N N N 40 min. N ? 1 hr. N N HN N chloro-pyrimidine poor solubility Sham, Hing L.; Konradi, Andrei W.; Hom, Roy K.; Probst, Gary D.; Bowers, Simeon; Truong, Anh; Neitz, Jeffrey R.; Sealy, Jennifer; Toth, Gergely; ¡°Inhibitors of Jun N- terminal Kinase,¡± PCT Int. Appl., (2010), WO 2010091310 A1, page 132.
  • 4. The Preparation of Selectively Brominated Thiophenes is Important Br F Br F Br F S N S N 2.0 eq. Br2 S N Conditions N N Not Reported N N Acetic Acid (or Propionic N N Me Me Me Cl Cl Acid), Cl 1.9 eq. NaOAc (or KOAc) 70oC, 2 hrs., 83% yield 0.17 eq. n-BuLi, -70oC, THF, 1 hr., then H2O Patented by Dow Br Hegde, Vidyadhar B.; Schuster, Albert J.; ¡°Process F S N for the Preparation of Brominated Thiophenes,¡± PCT N N Int. Appl., (2000), WO 2000/24733. Me Cl
  • 5. Examination of the initial Elan Bromination Conditions Br Br Br 30 eq. Br2 S S AcOH (3x vol. of Br2) S 2.1 eq Zn O O O 8 eq. NaOAc AcOH N N NH N NH NH ? 110oC, 2.5-6 hrs r.t. 16 hrs. pyrimidone ? Bromination is performed at a temperature much higher than prescribed by the Dow workers. ? Utilizes and requires a highly excessive amount of bromine. ? Observation ¨C Even though a reflux condenser was on the reaction flask, some Br2 was seen escaping the system. ? Innovation ¨C I proposed to perform the reaction in a closed pressure reactor behind a blast shield.
  • 6. Round 1 Improvements to the Bromination Step Br Br 18 eq. Br2 S AcOH (3x vol. of Br2) S O O 8 eq. NaOAc N NH N NH ? 115oC, 2.5-6 hrs Sealed Pressure Reactor ? With the use of a pressure reaction vessel, the amount of bromine required was reduced. But 18 equivalents were still required for the reaction to complete. ? Observation - During concentration of the crude reaction on the rotary evaporator and attempted high vac. drying, a colorless liquid that crystallized at room temp. was discovered. It was identified as bromo-acetic acid. ? Innovation ¨C Use Trifluoro-acetic acid as the solvent.
  • 7. Round 2 Improvements to the Bromination Step Br Br 4 eq. Br2 S TFA (7 x vol. of Br2) S O O 1.15 eq. K3PO4 N NH N NH ? 115oC, 4 hrs Sealed Pressure Reactor ? Result ¨C The bromination was complete in 4 hours with only 4 equivalents of Br2! Does this constitute a patentable process improvement? ? Observation ¨C The product has poor solubility characteristics. The majority of the product can be isolated by pouring the reaction mixture into ice water. Na2SO3 and NaHCO3 rinses should be performed.
  • 8. Observations Leading to Improved Isolation & Purification of ELN 577104 Br Br Br Br S S S ~6 eq. Zn0 O POCl3 Cl O AcOH N NH ? 110oC N N N NH ? 65oC 6-10 hrs. ELN 577104 Poor solubility Poor solubility poor solubility ? After most of the POCl3 was removed under reduced pressure, the remaining reaction mixture was poured onto damp ice, to obtain a solid product. ? Observation ¨C While drying crude ELN 577104 in a vacuum oven under house vacuum at 55oC, the glass window was seen to cloud up with a fine white powder¡­.that led to the realization that the product sublimes. ? Result ¨C Purified by sublimation at 140-160oC.
  • 9. Delivery of the Intermediate & a Bonus Br Br Br Br S S H S S EtOH, CH(OEt)3 Cl N NH N N N2H4 2 o ?, 100 N N N ? 1 hr. N N N N N N N 40 min. ELN 485554 ELN 577193 ? Two isomeric products were observed. Pure samples of each were analyzed and it was determined that ELN 577193 was the faster eluting, higher Rf, and more soluble product. ? Contrary to some suggestions, prolonged heating did not seem to convert ELN 577193 to ELN 485554. ? The observation of the two regio-isomeric products is known in the literature as the Dimroth Rearrangement.
  • 10. Both Tricyclic Products Deprotect to the Same Amine Br Br Br H S S N S N + N H2N N N H2N N N N N N N MeOH, 60oC HN ELN 485554 ELN 577193
  • 11. Major Contributions ? Modified bromination conditions to dramatically reduce reaction time and the amount of bromine required. ? Improved the isolation of the dibromo intermediate. ? Discovered that ELN 577104 could be easily isolated as a solid by pouring the reaction mixture into ice. ? Discovered that ELN 577104 sublimed and thereby improved the purification. ? Observed that ELN 485554 and the Dimroth Rearrangement product ELN 577193 gave the same desired product upon deprotection.
  • 12. Acknowledgements: ? Elan Pharmaceuticals ? Michael Dappen, Lee Latimer, Gary Probst, Simeon Bowers, Anh Truong, and Roy Hom