Multi-component Microwave Assisted Reactions

Pharmaceutical Green Chemistry Application.

Asha

Reason to do this topic…..

Received (in Cambridge, UK) 29th February 2008, Accepted 9th April 2008

Multi-component reactions

Reaction between 3 or more components to form a desired product in one

step are called multi-component reaction.

or

Cascade of reactions involving two or more bond forming transformation

that take place under unchanged reaction conditions and in which the

subsequent reactions result from the functionality formed in the previous

step.

Multi-component reactions

Two types of multicomponent reactions:

• ‘True’ Multi-component mode-in which all the substances and reagents are

mixed together initially and subsequently processed.

• ‘One-pot’ Multi-step mode- when one or several of the reaction

components are added to the reaction at a later stage.

Advantages of Multi-component Reactions

• Multicomponent reactions (MCRs) eliminate the need for work –up or

purification between the different reaction steps making the reaction both

more eco-friendly and faster.

• MCRs make possible the speedy synthesis of molecular libraries that have a high degree of structural diversity in one step as many of these structures are accessible only after 5-10 steps.

• Combinations of different starting materials can produce a variety of products with facility, a process that is of great value in the search for new drugs.

• MCR can significantly unclog the bottleneck commonly arising in the HTS (High Throughput Screening) discovery process, that centers around the generation of the molecules.

Multi-component Reactions Assisted In

Microwave

• As multicomponent reactions offer convenient procedures for the

introduction of many points of structural diversity into heterocyclic

compounds prepared in a straightforward manner in a single synthetic step.

• Combining these features with the extremely fast reaction kinetics of

microwave-assisted organic synthesis provides new methods for the rapid

and efficient synthesis of heterocyclic libraries suitable for biological

evaluation and SAR studies.

New Developments…..

Discoveries in microwave-assisted multicomponent reactions, carried out using

modern microwave synthesizers, for the preparation of both simple and fused

heterocyclic targets.

Reaction components are premixed and irradiated statically.

Larhed, M.;, 35, 717Moberg, C.; Hallberg, A. Acc.

Chem. Res., 2002

Name Reactions

Time required

MW

~

Conventional

heating ~

Stecker 10 min at 150 C 2-4 hrs

Hantzsch 5 min 5hrs

Hantzsch 5min 5hrs

Bignellli 10min 9hrs

Mannich 3 min 5-hrs

Passerini 4-10 min 6-9 hrs

Buchrer-Bergs 15 min 4 hrs

Ugi 10 min at 150 C 12- 48 hrs at RT

Pauson -Khand 10 min 15 min.

Microwave Assisted continuous flow reactions.

The area of Microwave –Assisted continuous flow organic synthesis that

combines the sample handling advantages of flow with the rate enhancing

features of MAOS . The detail use of MACOS to prepare medicinally

relevant ,heterocyclic compounds is as follows…

The capillaries used for this process are generally 1200micrometer diameter, although they

can be of any size, and they are fed by integrated syringe pumps. One plug of reactant s spends

in the magnetron region of microwave under continuous flow conditions.Fast kinetics

observed is assumed due to adequate mixing which may be due to microwave’s heating that

helps to promote turbulent flow

.

Application in Pharmaceutical Industry.

MC-MAR synthesis has the potential to influence medicinal chemistry

efforts in at least three major phases of the drug discovery process:

generation of a discovery library;

hit-to-lead efforts;

and lead optimization.

Common theme throughout all these processes is speed.

Study done by Center for the Study of Drug Development at

Tufts University in 1995 states…..

• A Pharmaceutical Research and Development(R&D) facility discovering

and developing a new medicinal agent will evaluate approximately 5,000 to

10,000 compounds. (generation of discovery)

• Research is done for identifying , isolating or synthesizing each new

chemical entity that will be evaluated to its potential therapeutic

effectiveness.(hit –to-lead)

• Once lead compound is been identified some 1,000 related chemical

susbtances will be synthesized out of which 250 compounds may hold

therapeutic potential which is studied by laboratory assay systems.and

enter preclinical testing. However, of which only 5 will go to limited

human clinical testing.

• Susequently , only one , after 15.3 years of Research and Development,

will be introduced commercially as a new drug(PhRMA, 1997).

Biginelli three-component reaction for generation of

multifunctionlized dihydropyrimidine libraries

Big picture

• Considerable amount of waste can be reduce by performing MC-MAR to

create complex diversified heterocyclic molecule in one step efficiently

which would have taken 5-6 steps otherwise.

Issues-

• Optimization of MCRs becomes difficult if reaction is not controlled it

costs yield of the product by forming a byproduct.

• Scope is limited as only certain MCRs are known till now.

Thank you