Organic Chemistry of Drug Synthesis. Volume 7

sequence, 5-FU is first converted to the silylated derivative ( 109 ) by means
of trimethylsilyl chloride. Treatment of that with ethyl chloromethyl ether in
the presence of stannic chloride leads to ethoxymethylated intermediate 110
with loss of the silyl groups. This compound ( 110 ) is then acylated with the
bis acid chloride ( 111 ). In a convergent step, the pyridinol ( 113 )is
acylated with benzoyl chloride; reaction takes place at the sterically
more open hydroxyl to afford monobenzoate ( 114 ). This compound is
then allowed to react with the acid chloride ( 112 ) under more forcing
conditions. Acylation of the remaining hydroxyl then affords the
prodrug 115.^16

HN

N

F

O

O

O

CiOC COCl

N

N

F

O

O

O

CiOC

O

N

CN

HO OH

HN

NH

F

O

O

N

N

F

O

O

Si(CH 3 ) 3

(CH 3 ) 3 Si ClCH 2 OEt

C 6 H 5 COCl N

CN

O OH

N

N

F

O

O

O

O O

O

N

CN

O O

O

(^108109110)
111
112
113 114
115
An important stage in the process of cell division comprises the for-
mation of structures called microtubules that will pull apart the halves of
the dividing cell nucleus in the course of replication. Microtubules normally
dissolve after they have fulfilled their function. The very effective che-
motherapy drug paclitaxel in effect stabilizes microtubules and halts cell
division in mid-process. The structurally relatively simple compound
monasterol( 120 ) hinders formation of tubules at their very inception by
inhibiting a required enzyme. This compound is prepared in a single
step by multicomponent reaction of m-hydroxybenzaldehyde ( 117 ),
ethyl acetoacetate ( 118 ), and thiourea ( 119 ).^17 One way this transform
can be visualized is to assume that the acetoacetate enolate adds to the
aldehyde. The second step involves conjugate addition of one of the urea
nitrogen to the resulting enone; reaction of the other nitrogen with the
ketone group would then close the ring.
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