Organic Chemistry

1224 CHAPTER 30 The Organic Chemistry of Drugs

R^3

R^3

NH 2

NH CH C

O

Pr F

Pr

R^2

R^1

O O

1. piperidine, DMF
   
   
   1. base
   
   
   2. 
      
   
   
   
   


2. 5% acetic acid, DMF

R^2

R^1

O

NH

N

H

R^3

R^2

R^1

O

O

H

N

N

R^4

R^4

X

R^3

R^2

R^1

N

N

R^4

R^3

R^2

R^1

N O

N H+

H 2 O

resin

Figure 30.2

Combinatorial organic synthesis of benzodiazepines.

The 2-aminobenzophenone is attached to a solid support in a manner that allows it

to be readily removed by acid hydrolysis (Figure 30.2). The amino acid—N-protected

and activated by being converted into an acyl fluoride—is then added. After the amide

is formed, the protecting group is removed and the seven-membered ring is created as

a result of imine formation. A base is added to remove the amide hydrogen, forming a

nucleophile that reacts with the added alkylating agent. The final product is then re-

moved from the solid support.

In order to synthesize a library of these compounds, the solid support containing the

2-aminobenzophenone can be divided into several portions, and a different amino acid

can then be added to each portion. Each ring-closed product can also be divided into

several portions, and a different alkylating agent can be added to each portion. In this

way, many different benzodiazepines can be prepared. Note that while a combinatorial

synthesis does not have to have one of the reactants anchored to a solid support, such a

support improves yields because none of the product is lost during the purification step.

Tutorial:

Combinatorial synthesis

R^1 R^3

N

N

O

R^4

R^4 X

a 2-aminobenzophenone

an amino acid

an alkylating

agent

R^2

R^1

NH 2

O

R^2

R^3

−O

H 3 N+

O

a benzodiazepine

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