TỔNG HỢP PHA RẮN (SOLID PHASE SYNTHESIS) A classical synthesis example: Synthesis of 2-substituted benzimidazoles Workup procedure: When the reaction was accomplished (monitored by TLC), the solvent was evaporated under reduced pressure The crude product was subjected to chromatography on silica gel and eluted with petroleum ether or a mixture of petroleum ether and ethyl acetate to afford the corresponding benzimidazole Another example: Efficient Synthesis of Selectively Protected LDopa Derivatives from L-Tyrosine via Reimer-Tiemann and Dakin Reactions Workup procedure: The reaction was diluted with water and ethyl acetate, and the aqueous layer was acidified to pH with N HCl and back extracted with ethyl acetate The organic extracts were washed with brine, dried over MgSO4, and concentrated Flash column chromatography afforded the desired product as a brown oil TỔNG HỢP TRONG DUNG DỊCH A + B → C (chính) + D (phụ) + E (phụ) + … C + E → F (chính) + G (phụ)… Vấn đề giải quyết: - Hiệu suất tổng hợp, - Tinh chế sản phẩm, - Bảo vệ/Giải bảo vệ nhóm chức, - … TỔNG HỢP CỔ ĐIỂN Tổng hợp dung dịch: - Dùng dư tác nhân phản ứng - Cô lập tinh chế chất trung gian, sản phẩm phản ứng,… TỔNG HỢP PHA RẮN Là kỹ thuật tổng hợp theo chất cần tổng hợp tổng hợp chất mang rắn (polymeric resin) S S S S S S S S S S S S Benzodiazepine drugs (half-life values) Synthesis of benzodiazepines Rachedine Kaoua et al Molecules 2011, 16, 92-99 Cleavage Possibilities of Ester and Thioester Linkers • Cleavage Yielding Primary and Secondary Amides Ester resins cleavable by aminolysis Cleavage Possibilities of Ester and Thioester Linkers • Cleavage Yielding Alkyl-O- and S-Esters Methods for transesterification of ester linkers Cleavage Possibilities of Ester and Thioester Linkers • Cleavage Yielding Hydroxamates Synthesis of hydroxamates via ester linker Esters Type B Loading Carboxylic Acid on Solid Support: Amide-Type Linker Amide formation is one of the most important reactions on solid supports Cleavage Possibilities of Amide-Type Linker Polymer-Supported Reagents • Polymer-supported reagents are reactive species which are associated with a support material • They transform a substrate (or substrates) to a new chemical product (or products) and the excess or spent reagent may be removed by filtration Polymer-supported reagents and sequestering agents: Synthesis of Hydroxamic acid derivatives R' O H2 N pyridine O HCl R'' R'' S O Cl S O O CH2Cl2, 2-4 CH2Cl2, R' O NH2 O N H O 5-7 NEt2 Br R''' N CH2Cl2 CH2Cl2, N P N N NH2 R'' R' O H N S O N O R''' 26-34 OH R'' TFA, CH2Cl2 CBr4, O-benzylhydroxylamine NEt3, CH2Cl2, PPh2 CH2Cl2, R' O S O O N O NH2 Pd/C, H2, EtOAc/iPrOH or MeOH R''' 8-16 Polymer-Supported Catalysts • Supported catalysts are reactive species which are associated with a support material • They are used in sub-stoichiometric quantities to transform a substrate (or substrates) to a new chemical product (or products) and may be removed by filtration and recycled Polymer-Supported Catalysts Polymer-Supported Catalysts Polymer-Supported Catalysts Polymer-Supported Catalysts [...].. .Synthesis of benzodiazepines Sternbach et al J Org Chem 1962, 27, 3788 Lednicer et al Organic Chemistry of Drug Synthesis; Wiley-Interscience: New York, 1998 Lednicer et al The Organic Chemistry of Drug Synthesis; Wiley-Interscience: New York, 1977 Ellman’s solid- phase synthesis of 1,4-benzodiazepines Ưu điểm của Tổng hợp Pha rắn? Không... động hóa quá trình tổng hợp TỔNG HỢP PHA RẮN TỔNG HỢP PHA RẮN SOLID PHASE SYNTHESIS • The scale SPS is limited and restricted by the amount of the solid support and its loading capacity • The preparation of multi-milligram quantities can be cumbersome and expensive for large combinatorial libraries: for 50mg -10,000 compounds (MW=500), 3-step synthesis 95% yield/step, 1.166 kg resin (1 mmol/g loading)... reagent SOLID SUPPORT The level of functional groups or “loading,” expressed in mmol/g, can cover a wide range of values (from 0 to virtually 7 mmol/g) Generally, the loading and application of polystyrene resins can be grouped as follows: