Improved Methodology for the Preparation of Chiral Amines

Chapter 4
Drugs and Reductive Amination
4.1 Reductive Amination in the Synthesis of Drugs and Natural Products:
Different natural products and pharmaceutical drugs contain amino group as an important
part of their structure. Of course some drugs are still sold as racemic compounds but the latest
trend over the past three decades is to design, develop and market new drug entities as a
single isomeric form. Amino group can be introduced in the drug entity through different
strategies one of these strategies is reductive amination. Older reports describing the
synthesis of natural products and pharmaceutical drugs utilizing reductive amination did not
involve any source of chirality resulting in the synthesis of racemic product. Recent
literatures focused on utilizing the asymmetric versions of reductive amination for the
synthesis of enantiopure compounds. I will try to give a brief overview on the potential
applications of this powerful methodology in the synthesis of natural products and
pharmaceutical drugs. We will try also to show the relevance of our developed strategy for
the efficient synthesis of these entities.
4.1.1. Synthesis of Delavirdine:
This compound is a member of nonnucleoside HIV-1 reverse transcriptase inhibitors. [1] This
class of compounds was discovered by Upjohn scientists from a computer-directed
dissimilarity analysis of the Pharmacia & Upjohn chemical library to select compounds for
screening against HIV-1 reverse transcriptase. Synthesis of this compound starts with the
addition of piperazine (20) to chloropyridine (21). The nitro group is reduced to the amino
group and the resultant amine undergoes reductive amination with acetone to provide
pyridylpiperazine (23). Coupling of (23) with 6-nitroindole-2-carboxylic acid (24) is
accomplished using either 1-ethyl-3-(dimethylamino) propylcarbodiimide (EDC) or 1,10-
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