Application Of Macroporous Scavengers For Parallel Synthesis

1. Application Of Macroporous Scavengers For Parallel Synthesis Qunjie Wang, Joseph J. Kirkland, Timothy Langlois. Agilent Technologies Inc.; Lorin A. Thompson. DuPont Pharmaceuticals

2. 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 - cannot be pre-packed and stored in a cartridge or column format; 2) necessity of swelling - narrow range of compatible solvents. • New macroporous scavengers-CombiZorb have been developed based on ultra-pure, spherical silica and low swelling macro-porous polystyrene/DVB, to overcome these drawbacks.

3. 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-mercaptan, S-diphenylethylphosphine. • Based on low-swelling macroporous polystyrene/DVB: MP-isocyanate, MP-aldehyde, MP-mercaptan, MP-trisamine(NH, NH2), MP-piperidinomethyl, MP-sulfonyl hydrazide(-NHNH2), MP-sulfonyl chloride

4. 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

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

6. Performance Comparison

7. Performance comparison (cont’d)

8. Performance comparison (cont’d) Scavenging aldehyde/ketones by polymer-SO2NHNH2 (3 eq., 2h, RT). residue (%) MP-: Macroporous CombiZorb Scavengers Gel-: Gel polystyrene based Scavengers

9. Scavenging Test of S-triamine

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

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

12. 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

13. Flow-Through Method Reaction Block Filter Block prepacked with scavenger (Polyfiltronics) Vacuum Collection Block

14. Aqueous Cosolvent Sequestering % Acid Remaining

15. 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.

16. 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 weres 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.

17. Example 4

18. Stability of Silica-based Scavengers safety zone - Non-aqueous solution: 1< pH<14 , >24 h - 10% H2O: 1<pH<10, >5h - > 50% H2O: 1<pH<10, >2h

19. 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.

20. References For general application of scavengers