Organic Chemistry of Drug Synthesis. Volume 7

applications of this compound. The synthesis of this compound begins
with addition of the Grignard reagent from substituted the bromobenzene
( 20 ) to the piperidone ( 19 ). The hydroxyl group is then acylated with ethyl
chloroformate. Heating the resulting ester ( 22 ) leads to formation of the
styrene ( 23 ). Treatment with base under equilibrium conditions leads to
migration of the negative charge to the quarternary carbon adjacent to
the aromatic ring. Addition of dimethyl sulfate thus leads to alkylation at
that position.^5 Reaction of 24 with sodium borohydride leads to reduction
of what is now an enamine, and thus formation of the saturated piperidine
( 25 ). The methyl group is then removed using chloroformate in the modern
version of the Von Braun reaction. Treatment of product 26 , with methyl
acrylate leads to Michael addition and formation of 27. The carbon adja-
cent to the ester is next converted to its enolate with lithium diisopropyl-
amine (LDA); addition of benzyl bromide leads to alkylation and
formation of 28. The ester ( 29 ) is then saponified. Condensation with
glycine ester followed by saponification yields 30.^6

O N

19

+

iPrO Br

20

CH 3 Mg

NCH 3

iPrO HO

C NCH^3

iPrO 2 H 5 OCO

ClCO 2 C 2 H 5

Heat

NCH 3

iPrO

21 22

BuLi

(CH 3 ) 2 SO 4

NCH 3

iPrO H 3 C

24

NCH 3 NaBH^4

iPrO H 3 C

25 23

1. ClCO 2 C 6 H 5


2. HBr

NH

HO H 3 C

26

CO 2 CH 3

N

N

O

CO 2 H

HN

H 3 C

H 3 C

HO

HO

CO 2 CH 3

27

N

N

HO

HO

28

NaOH

C 6 HLDA 5 CH 2 Br H

3 C

H 3 C

CO 2 CH 2

CO 2 H

29

Glycine

DCC

30

Multidrug resistance, where a tumor becomes immune to a broad range
of compounds without regard to their mechanism of action, comprises one

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