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SiliaBond® Sulfonic Acids – Versatile and Useful Products for Purification Needs Geneviève Gingras, Annie Michaud, Delphine Desplantier-Giscard, Michel Morin and François Béland* SiliCycle® Inc., www.silicycle.com 1200 Ave Saint-Jean-Baptiste 1200, Saint-Jean-Baptiste, suite 114, 114 Quebec City, City Quebec, Quebec Canada, Canada G2E 5E8 *[email protected] “Catch and Release” Purification of Amines using SiliaBond® SCX & SCX-2 Amine Free Basing using SiliaBond® SCX & SCX-2 Supported sulfonic acids are a class of strong acids (pKa <<1) widely used in different fields of synthetic organic chemistry. Amine purification and elimination of basic impurities are easily and efficiently accomplished by a “Catch and Release” purification with the SiliaBond® SCX and SCX-2. Using the “Catch and Release” method, SiliaBond® Sulfonic Acids quickly deprotonate amine with very high yields. Their applications are widely known and their various forms are used in a large number of settings: from the drug discovery laboratories to the manufacturing processes. “Catch and Release” Purification of Amines using SiliaBond® Products in MeOH SiliCycle® SiliaBond® Sulfonic Acids SiliCycle® has developed the two following SiliaBond® Sulfonic Acids: Amine pKa O O S S OH O SiliaBond® SCX-2 [PN: R51230B] We are presenting different applications using SiliaBond® Sulfonic Acids to demonstrate the effectiveness and versatility of these silicabased products in bulk and SPE cartridge medias such as: 9 “Catch and Release” purification of amine (or removal of basic impurities) 9 Amine free basing 9 Boc groups deprotection Silica × 300 Polymer Silica, in toluene, 110°C,4 h 15kV 500μm × 30 Polystyrene, in toluene, 110°C, 1h Principle of “Catch and Release” Purification in SPE 1) Column conditioning 2) Apply sample 3) Interference elution Catch (%) Release (%)b Release (%)b 4) Amine released with ammonia /methanol 98 100 100 100 Aniline 4.62 100 95 100 90 4-Methoxyaniline 5.29 100 100 100 92 2-Aminothiazole 5.39 100 100 100 Morpholine 8.36 100 100 100 87 Benzylmethylamine 9.58 100 100 100 92 Cyclohexylamine 10.64 100 95 100 79 Tributylamine 10.75 100 100 100 91 Quinuclidine 11.00 100 94 100 65 Amine collected a . OH N TFA Amine salts Ephedrine • SiliaBond® SCX SiliaBond® SCX-2 Yieldb (%) Yieldb (%) 92.8 93.4 98.7 95.3 97.9 95.4 HCl TFA AcOH a: “Catch and Release” procedure using SiliaBond® SCX and SCX-2 SPE Cartridges (4eq. in MeOH), b: Yields were determined by GC-FID Boc- Groups Deprotection using SiliaBond® SCX The tert-butoxycarbonyl (Boc-) is widely used as an amino protecting group in organic synthesis and can be easily removed by our SiliaBond® SCX with high yield and purity (Exp #3). Exp #1: Room temperature Reaction time: 1h Note: Deprotection not completed 4-Nitroanilinec 0.98 97 100 100 100 Aniline 4.62 100 96 100 88 4-Methoxyaniline 5.29 100 100 100 92 2-Aminothiazole 5.39 100 100 100 88 Morpholine 8.36 100 89 100 83 Benzylmethylamine 9.58 100 97 100 84 Cyclohexylamine 10.64 96 96 100 74 Tributylamine 10.75 100 98 100 92 Conclusion Quinuclidine 11.00 100 98 100 77 SiliaBond® Sulfonic Acids (SCX & SCX-2) are two versatile, easy to use, and very efficient products for purification needs. Both can be used in many applications such as: Solvent Effect on the “Catch and Release” Purification of 2-Aminothiazolea Eluted non-basic impurities SiliaBond® SCX or SiliaBond® SCX-2 HCl AcOH 87 a: 10 min stirring for both Catch and Release steps, b: Release % is calculated in function of the Catch % proportion, c: in CH2Cl2 Amine “Caught” OH Amine Free Basing using SiliaBond® productsa 0.98 SiliaBond® SCX-2 (or SiliaBond® Propylsulfonic Acid) No static charge Solvent independent High thermal and mechanical stability 10kV 50μm Catch (%) 4-Nitroanilinec Characteristics of SiliaBond® products No swelling Suitable for µ-wave use Bulk media (4 eq.)a SiliaBond® SCX (or SiliaBond® Tosic Acid) OH O SiliaBond® SCX [PN: R60530B] SPE Cartridge (2 eq.) N Acetone CH2Cl2 MeOH THF Catch (%) ≥ 98 ≥ 98 100 100 Release (%) 100 100 100 100 Using SiliaBond® SCX SPE Cartridge (2.0 eq.) (N.B.: SiliaBond® SCX-2 can also be used for the Boc- group deprotection). Exp #2: Room temperature Reaction time: 17h Note: Deprotection not completed Exp #3: using µ-wave irradiation Reaction time: 5 x 1min Yield: 99% (isolated product) 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 PPM 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4 Using SiliaBond® SCX (3.0 eq.) “Catch and Release” purification of amine Removal of basic impurities from an unpurified sample Amine free basing Boc- group deprotection Acknowledgements The authors Th th th k Annie thank A i Cummings, C i Sté h Stéphane P ll ti and Pelletier d Catherine C th i Tessier for their analytical support.