Organic Chemistry of Drug Synthesis. Volume 7

( 39 ). Condensation of the product from that reaction with ethyl cyano-
acetate in the presence of acid affords the enamine ( 40 ) from displace-
ment of dimethylamine. Heating this product in Dowtherm closes the
ring via the ester group to form the cyano quinoline ( 41 ). The next
step invokes one of the standard schemes in heterocyclic chemistry
used to transform a hydroxyl to a better leaving group. Treatment of
the enol ( 41 ) with phosphorus oxychloride thus affords the chlorinated
derivative ( 42 ). Reaction of 42 with the halogenated aniline ( 43 ) leads
to displacement of chlorine by the basic nitrogen and formation of 43.
Treatment of that intermediate with iron powder in acetic acid serves to
reduce the nitro group that was put in place early in the sequence to the
amine ( 44 ). Acylation of that newly introduced amine with 4-N,N-
dimethylaminobut-2-enol chloride gives the irreversible kinase inhibitor
pelitinib ( 45 ).^8

C 2 H 5 O NH 2

37

CH 3 O

H 3 CO

N

C 2 H 5 O N N

38

C 2 H 5 O N N

39

O 2 N

CN

CO 2 C 2 H 5

C 2 H 5 O NH

40

O 2 N NC CO 2 C 2 H 5

Heat

C 2 H 5 O

O 2 N

OH

CN

41

POCl 3

C 2 H 5 O

O 2 N

Cl

CN

42

F

Cl

H 2 N

F

Cl

C 2 H 5 O

R 2 N

HN

CN

F

Cl

C 2 H 5 O

HN HN CN

45

1. 
   
   
   
   2. Fe
   
   
   
   

43 ; R = O

44 ; R = H

O

(CH 3 ) 2 N COCl (CH 3 ) 2 N

Neurokinins comprise a group of peptides involved in nerve trans-
mission. Specific members of this class of mediators control such
diverse functions as visceral regulation, and CNS function. The non-
peptide neurokinin antagonisttalnetant( 51 ), for example, is currently
being evaluated for its effect on irritable bowel syndrome, urinary

168 SIX-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING