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Application Of Non-swelling For Parallel

Application Of Non-swelling For Parallel Qunjie Wang, Joseph J. Kirkland, Timothy Langlois. Lorin A. Thompson. DuPont Pharmaceuticals. Porous Scavengers Synthesis Agilent Technologies Inc.

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Application Of Non-swelling For Parallel

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  1. Application Of Non-swelling For Parallel Qunjie Wang, Joseph J. Kirkland, Timothy Langlois. Lorin A. Thompson. DuPont Pharmaceuticals

  2. Porous Scavengers Synthesis Agilent Technologies Inc.

  3. Application Of Non-swelling Porous Scavengers For Parallel Synthesis Qunjie Wang, Joseph J. Kirkland, Timothy Langlois. Agilent Technologies Inc.; Lorin A. Thompson. DuPont Pharmaceuticals

  4. Introduction • Solid scavengers are increasingly used in parallel organic synthesis to remove excess reactants or by-products. However, most of scavengers are based on gel-type poly- styrene, which feature: 1) very high swelling in some solvents - allow only small amount of scavenger in a well, and cannot be pre-packed and stored in a cartridge or column format; 2) necessity of swelling - narrow range of compatible solvents. • In this research, new macroporous scavengers have been developed and investigated, based on ultra-pure, spherical silica and low swelling macroporous polystyrene/DVB.

  5. Volume Restraints • For Automated Synthesis Using 96 wells Block: • Blocks hold 2 mL volume: Reaction volume should be at most half of the volume of the well, scavenger only around 500 mL • Collection blocks hold 2.0 mL, but can only safely concentrate about 1.2 mL • So: Scavenge with at most 450 mL volume of scavenger in reaction wells or develop Flow-through method

  6. 96-Wells Blocks

  7. Macroporous scavengers • Based on ultra-pure, spherical silica: S-monoamine(NH2), S-triamine(NH, NH2), S-tertiaryamine, S-sulfonic acid, S-aldehyde, S-epoxide, S-mecaptan, S-diphenylethylphosphine. • Based on low-swelling macroporous polystyrene/DVB: MP-isocyanate, MP-aldehyde, MP-mecaptan, MP-trisamine(NH, NH2), MP-piperidinomethyl, MP-sulfonyl hydrazide(-NHNH2), MP-sulfonyl chloride

  8. Features and advantages (vs gel-polystyrene based scavengers) • Silica-based: Ultra pure silica - no interference with reactions. Spherical silica - easy to handle, good through-flow. No-swelling, high density - larger amount for available volume; possible incorporation into different format (membrane, column). Porous structure - solvent independent, good mass transfer of reactants. • Low-swelling Macroporous polystyrene/DVB-based: Low swelling (30% vs 500% for gel)- larger capacity per vol. easy to handle, possible in different format (membrane, column). Porous structure - broad solvent compatibility

  9. Types of Silica Standard Commercial Silica Gel HP Ultrapure Silica Gel

  10. CombiZorb (macropolymer-based)

  11. CombiZorb (silica-based) S: HP ultra pure silica

  12. Scavenging Test of S-monoamine

  13. Scavenging Test of S-triamine

  14. Scavenging Test of MP-NCO(2.5 equiv.)

  15. Scavenging Test of MP-CHO (3 equiv.)

  16. Example 1 • Rxn run in 2 mL of Ethyl Acetate, THF, or DMF. Added 200 mL of water, stirred 16 h at rt. • The solution is forced with a pipet bulb through a plug of 450 mL of scavenger in a 2.0 mL tube, and the scavenger is then rinsed with 1.0 mL of solvent. • The eluents are concentrated, redissolved in 4.0 mL of solvent and analyzed by HPLC

  17. Flow-Through Method Reaction Block Filter Block prepacked with scavenger (Polyfiltronics) Vaccuum Collection Block

  18. Aqueous Cosolvent Sequestering % Acid Remaining

  19. Example 2 - Benzylamine, chlorobenzoyl chloride and S-tertiaryamine were mixed with 2 mL CH2Cl2 at RT and shaken for 1 hour. - S-triamine plus 1 mL acetonitrile was added to the mixture and shaken for 1 h, the solid was filtered off and washed with CH2Cl2 (twice, 0.5 mL each). - Benzyl chlorobenzamide was obtained as a pure product upon solvent evaporation.

  20. Example 3 - Benzylamine and phenyl isocyanate was mixed with 1.5 mL dichloromethane and shaken for 1 hour at RT. - MP-isocyanate and 1 mL MeOH were added to the reaction mixture, shaken for two more hours; the solid was filtered off and washed with 1 mL MeOH. - Phenyl benzyl urethane was obtained as a pure product upon solvent evaporation.

  21. Example 4

  22. Summary • Two types of porous scavengers (ultra pure silica, low-swelling polystyrene) have been developed with a variety of functionality. • The preliminary studies demonstrate the major advantages of the new scavengers: - higher capacity for available volume; - broad solvent compatibility; - compatible with different application format.

  23. Stability of Silica-based scavengers

  24. References For general application of scavengers

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