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