Chloroquine (3) and amodiaquine Synthesis

The key intermediate for synthesizing chloroquine, amodiquine and other 4- aminoquinoline drugs is 4,7dichloroquinoline (91), which can be prepared by reacting m-chloroaniline (83) with diethyl oxaloacetate (EtO-CO-CH2-CO-COOEt) or ethoxymethylene malonic ester [EtO-CH=C(COOE02] as shown in scheme I

The synthesis of various 4-aminoquinoline antimalarials may be achieved by nucleophilic reaction of 91 with desired amines.

Scheme 2 outlines the preparation of chloroquine (3) and amodiaquine (8) starting from 4,7-dichloroquinoline (91)

Reaction of 83 with methyl acrylate to get via 98 and 99 the adduct 100, which is converted into 7-chloro-1,2,3,4tetrahydroquinoline-4-one (103). Reaction of 103 with novaldiamine (92) under dehydrogenating conditions gives chloroquine in about 25% overall yield(Scheme 3).

Primaquine Synthesis Primaquine (35) Elderfield and coworkers synthesized primaquine starting from 8-amino-6-methoxyquinoline (104) by the reaction sequence outlined in Scheme 4.

The required 8-amino-6-methoxyquinoline can be obtained by Skraup's reaction on 4-methoxy-2nitroaniline (106) to get 107, which is reduced to yield 104