solid phase synthesis Presentation by komal

solid phase synthesis

1. A SEMINAR ON SOLID PHASE SYNTHESIS Presented BY: Komal Rajgire (M.PHARM : SEM 2 nd ) M.V.P. Samaj’s college of Pharmacy, Nashik-2 Guided by : Dr. A. P. Pingle Asso . Professor DEPARTMENT OF PHRMACEUTICAL CHEMISTRY

2. CONTENTS INTRODUCTION PLANING OF SOLID PHASE SYNTHESIS EXAMPLE OF SOLID PHASE SYNTHESIS ADVANTAGES DISADVANTAGES APPLICATION

3. INTRODUCTION “Solid phase synthesis is heterogeneous reaction in which a reagent is coupled to a solid support via chemical functionality present on solid support. A multistep synthesis on solid phase then transforms the bound intermediate into the target molecule but eventually cleaved from support. This technique is called as solid phase synthesis” Solid phase synthesis was invented by Bruce Merrifield in 1963

4. Linker – (substrate) Reagnt Linker-(product)+(Reagent) Filter Linker-(product) + (Reagent) (Substrate) (product) + (reagent) (product) (Reagent) purification Fig: SOLID PHASE SYNTHESIS Vs SOLTION PHASE SYNTHESIS Solid Phase Synthesis Solution Phase Synthesis

5. PLANNING OF SOLID PHASE SYNTHESIS The Resin (solid support) The Linkers The protective group Reaction monitoring purification

6. The Resin (solid support) Resin act as a solid support for a solid phase synthesis. The term solid support use to denote the matrix upon which chemical reaction is performed. Solid support must be inert. Its always swells extensively in solvent .

7. A) Hydrophobic polystyrene resins: Polystyrene resin beads under class Gelatinous solid support Cross linked with 1-2% divinylbenzene Particle size 90-200µm Used in large number of reaction sites They are cheap & commercially available with any functional groups Examples of resins 1. Benzylic halids – a) Merrifide resin. b) Trityl chloride resin. 2. Benzylic amines – a) Rink amide resin b) Amino Ethyle polystyrene 3. Benzylic alcohls – a) Wang resin 4. Aromatic aldehyde – a) Backbone amide linker b) Bal resin

8. B) Hybrite Hydrophilic Polystyrene Resin (HHPSR): A major drawback of hydrophilic PS resin is poor swelling in protic solvent. Thus support is prepared by grafting hydrophilic mono-functional or bi-functional polystyrene glycol (PEG). Examples ChemMatriex 1 It has chemical and thermal stability 2 Compatible with microwave 3 High degree of swelling in acetonitrile, DMF, TFA 4 Used for synthesis of difficult and long peptides.

9. 1 Hydrophobic polystyrene resins: 1.Benzylic Halide Type a) Merrifie Resin Attachment - Carboxylic acid, Alcohol, Phenol. Cleavage – Strong acidic condition Application - Peptide synthesis b) Trityle chloride Resin Attachment - Carboxylic acid, Alcohol, Amine. Cleavage – Mild acidic condition Application - Peptide synthesis, Alcohol & Amine synthsis .

10. 2 Benzylic Amine Type resin Attachment - Carboxylic acid , alcohol , Phenol. Cleavage – Mild acidic condition. Application - Peptide synthesis( Aryle & Alkyle carboxamide ) 3 Benzylic alcohol Type Resin Attachment - Carboxylic acid. Cleavage – Acidic condition. Application - Peptide synthesis. 4 Aromatic Aldehyde Type Resin Attachment – Primary Amine. Cleavage – Mild acidic condition. Application - Peptide synthesis.

11. The Linker Linker referred as a handle to attach the small molecule onto polymeric resin Linkers has many similarities to protecting group in solid phase synthesis.

12. Properties of linkers which may assist Solid phase synthesis are: Stable to the reaction conditions Cleaved selectively at the end of synthesis Re-useable Facilitate reactions monitoring Sequential / Partial release Easy to prepared It should be highly selective to one or most small number of specific cleavage reagents/ conditions.

13. TYPES OF LINKERS 1 Acid-Cleavable Anchors and Linker: SPS of peptides was developed using this type of linkers Fig: Acid labile, commercialy available SP Linker SPS 30°C RT

14. 2) Base / Nucleophil-Laibale linkers: The commonly used Fmoc peptide coupling protocols required Fmoc deprotection under basic conditions during synthesis. R-COOR SPS 20% DMF 2hr,RT FIG : Base/ Nucleophilic Laibale Linker

15. 3) Photo Labile Linkers The light is used to break the bond between the intermediate and the linker and releases pure compound from the SPS into solution without interference from side produced . HOOC- Rdc R-COOH SPS MeOH , 24 hr,RT 350nm Fig : photo labile SP Linker

16. 4 Safety- catch linkers: It is totally stable during the synthetic procedure & labile after a process known as activation It is very popular and allows the support and release of many different functionalities. Examples : sulfonamide based safety catch linkers, phenol based safety linkers, acid labile safety catch linkers, imidazole safety linkers. Act. SPS R_COOH Nucleophile Slphonamide Based SCL Fig: Safety catch (SC) Linker

17. Examples of linkers: Trialkylsillyl choliride (or triflate ) generated from ethanophenylsane . Attachment of alcohols ketones Function of linkers: 1) As a functional group 2) As a linker releases another functional group

18. Procteive group Due to amino acid excess used to ensure complete during each synthesis step, polymerization of amino acids is common in reactions where each amino acid is not protected. In order to prevent this polymerization , protecting group are used. Examples : 1) Fomac protective group [ fomac (9 H- fluoren -9-ylmethoxycarbonyl) it is currently widely useds group that removed the N- terminal of peptide in synthesis of a peptide from amino acid terminal.

19. ACTUAL PROCESS IN SPS 1 st Step: In this the stating molecule to an inert solid. Typically inert polymers or resin are used. These are commercially available. 2 nd Step: Here, Solid are deep into solution containing subsequent reagent next they can be removed from the dip and placed into a ash solution. 3 rd Step: After all reactions are don the product is still attached to the insoluble bead Product Can be washed in a reaction well excess solvent is washed out finally the product is cleaved from the bead and isolated. Washing: After each synthetic step and prior to cleavage the solid support must be exhaustically washed with large vol. of solvent. Purifications: purification is done by semi preprative HPLC utilizing.

20. ADVANTAGES Over all process is quick Purification of each product can be achieved in one step. Only purification technique is filtration. Purification in each step is possible. Synthetic intermediates don’t have to be isolated. Can be automated with Roberts. Use of solvent are minimized. Less health hazards and eco- friendly and hence follows the principle of GREEN CHEMISTRY.

21. DISADVANTAGES High chemical consume. Expensive. Low reaction rates. Special substances needed. It produces very few molecules at a time for testing. Solid phase synthesis without using any solvents.

22. APPLICATION Combinatorial synthesis f solid phase Peptide synthesis In DNA synthesis In various reactions Clainsan rearrangement Beckmann rearrangement Organic synthesis

23. References R.B. Merriffield , G. Barany, W.L. Cosand , M. Engelhard and S. Mojsov , pept . Am pept . Symp . 5 th edittion 1997, page no 48-55. Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library synthesis Ley et al. J. Chem . Soc., Perkin Trans 1 2000 , 3815-4195 Preparation of polymer-supported ligands and metal complexes for use in catalysis Leadbeater , Marco Chem. Rev. 2002 , 102 , 3217-3273

24. Thank you