solid phase synthesis presentation by komal
TRANSCRIPT
A SEMINAR ON SOLID PHASE SYNTHESIS
Presented BY:
Komal Rajgire
(M.PHARM : SEM 2nd )
M.V.P. Samaj’s college of Pharmacy, Nashik-2
Guided by : Dr. A. P. PingleAsso. Professor
DEPARTMENT OF PHRMACEUTICAL CHEMISTRY
CONTENTS
INTRODUCTION PLANING OF SOLID PHASE SYNTHESIS EXAMPLE OF SOLID PHASE SYNTHESIS ADVANTAGES DISADVANTAGES APPLICATION
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
Linker – (substrate)
ReagntLinker-(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
PLANNING OF SOLID PHASE SYNTHESIS
The Resin (solid support) The Linkers The protective group Reaction monitoring purification
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.
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 resins1. Benzylic halids – a) Merrifide resin. b) Trityl chloride resin.2. Benzylic amines – a) Rink amide resinb) Amino Ethyle polystyrene3. Benzylic alcohls – a) Wang resin4. Aromatic aldehyde – a) Backbone amide linkerb) Bal resin
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.
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.
2 Benzylic Amine Type resinAttachment - Carboxylic acid , alcohol , Phenol.
Cleavage – Mild acidic condition.
Application - Peptide synthesis( Aryle & Alkyle carboxamide)
3 Benzylic alcohol Type ResinAttachment - Carboxylic acid.
Cleavage – Acidic condition.
Application - Peptide synthesis.
4 Aromatic Aldehyde Type ResinAttachment – Primary Amine.
Cleavage – Mild acidic condition.
Application - Peptide synthesis.
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.
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.
TYPES OF LINKERS1 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
2) Base / Nucleophil-Laibale linkers:The commonly used Fmoc peptide coupling protocols
required Fmoc deprotection under basic conditions during synthesis.
R-COORSPS 20% DMF
2hr,RT
FIG : Base/ Nucleophilic Laibale Linker
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-RdcR-COOHSPS MeOH, 24 hr,RT
350nm
Fig : photo labile SP Linker
4 Safety- catch linkers:It is totally stable during the synthetic procedure & labile after a process known as activationIt 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.
SPSR_COOH Nucleophile
Slphonamide Based SCL
Fig: Safety catch (SC) Linker
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
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.
ACTUAL PROCESS IN SPS
1st Step: In this the stating molecule to an inert solid.
Typically inert polymers or resin are used.
These are commercially available.
2nd Step: Here, Solid are deep into solution containing subsequent reagent next they can be removed from the dip and placed into a ash solution.
3rd 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.
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.
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.
APPLICATION
Combinatorial synthesis f solid phase Peptide synthesis In DNA synthesis In various reactions
Clainsan rearrangement Beckmann rearrangement Organic synthesis
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
Thank you