Organic Chemistry of Drug Synthesis. Volume 7

N

N

CH 3

1

N

N

CH 3

2

I

Cl

PdPh 3 PCl

CuI

iPr3Si

N

N

Cl CH^3

iPr 3 Si

3

N

N

Cl CH^3

iPr 3 Si

ZnAcOH

4

N

N

Cl CH^3

5

Bu 4 N+ F-

As noted several times in Chapter 5, a five-membered ring containing
one or more heteroatoms comprises the central element in a great majority
of COX-2 inhibitor NSAIDs. Interestingly, that moiety can be replaced by a
six-membered pyridine ring. One of the two adjacent rings that characterize
these agents in this case include a nitrogen atom. One of the routes to this
agent starts with the nicotinic ester ( 6 ). The ester group is then reduced by
means of DIBAL-H; back oxidation with manganese dioxide affords alde-
hyde 7. Reaction with aniline and diphenylphosphate gives adduct 8 in a
reaction that parallels formation of a cyanohydrin. Treatment of intermedi-
ate 8 with strong base generates an ylide on the carbon bearing nitrogen.
Condensation of 8 with benzaldehyde 9 leads to enamine 10 which now
contains two of the requisite rings. Hydrolysis of 10 leads to the

C 6 H 5 NH 2

(C 6 H 5 O) 2 PH

N

8

CH 3

(C 6 H 5 O)P

NHC 6 H 5

SO 2 CH 3

O=HC

N

CH 3

C 6 H 5 HN

SO 2 CH 3

N

CH 3

H 3 CO 2 C N

CH 3

O=HC

6

1. DIBAL-H


2. MnO 2

(^79)
H 3 O=
N
CH 3
O
SO 2 CH 3
(^1110)
ClCH 2 CO 2 H
N(CH 3 ) 2
+N(CH 3 ) 2
Cl

1. DMF


2. NaOH3. HPF

(^613)
N
CH 3
SO 2 CH 3
15
N
Cl
N
CH 3
SO 2 CH 3
Me 2 N
Cl
O
NH 4 OH
14
12
tBuOK
tBuOK
116 SIX-MEMBERED HETEROCYCLES