Organic Chemistry

because it was not the quinazoline 3-oxide he had set out to synthesize. Two years

after the project was abandoned, a laboratory worker came across this compound

while cleaning up the lab, and Sternbach decided that he might as well submit it for

testing before it was thrown away. The compound was shown to have tranquilizing

properties and, when its structure was investigated, was found be a benzodiazepine

4-oxide. Methylamine, instead of displacing the chloro substituent to form a different

quinazoline 3-oxide, had added to the imine group of the six-membered ring, causing

the ring to open and reclose to a seven-membered ring. The compound was given the

trade name Librium®when it was put into clinical use in 1960.

Librium®was structurally modified in an attempt to find other tranquilizers. One

successful modification produced Valium®, a tranquilizer almost 10 times more potent

than Librium®. Currently, there are eight benzodiazepines in clinical use as tranquilizers

in the United States and some 15 others abroad. Xanax®is one of the most widely

prescribed medications; Rohypnol®is one of the so-called date-rape drugs.

Section 30.5 Serendipity in Drug Development 1213

N

a quinazoline

3-oxide

a benzodiazepine 4-oxide

chlordiazepoxide

Librium (1960)

CH 2 Cl

H

N

+

CH 2 Cl

NHCH 3

N

N

CH 2 Cl

NHCH 3

OH

N CH 2 NHCH 3

CH 3 NH 2

CH 3 NH 2

Cl

Cl Cl Cl

Cl

N

N

NHCH 3

O−

N+ O− N+ O−

N+ O−

an addition

reaction occurred

a substitution reaction

did not occur

O 2 N Cl

Cl

N

N

O

CH 3

N

N

F

F

O

CH 2 CH 2 NCH 2 CH 3

CH 2 CH 3

O 2 N

H

N

H

N

N

Cl

O

Cl N

Cl

OH

O

N

N

N

N

H 3 C

flunitrazepam

Rohypnol (1963)

Cl

N

N

O

CH 3

diazepam

Valium (1963)

flurazepam

Dalmane (1970)

clonazepam

Klonopin (1975)

lorazepam

Ativan (1977)

alprazolam

Xanax (1970)

Leo H. Sternbachwas born in

Austria in 1908. In 1918, after World

War I and the dissolution of the

Austro-Hungarian Empire,

Sternbach’s father moved to Krakow

in the re-created Poland and obtained

a concession to open a pharmacy. As

a pharmacist’s son, Sternbach was

accepted at the Jagiellonian

University School of Pharmacy,

where he received both a master’s

degree in pharmacy and a Ph.D. in

chemistry. With discrimination

against Jewish scientists growing in

Eastern Europe in 1937, Sternbach

moved to Switzerland to work with

Ru i ka (p. 000) at the ETH

(the Swiss Federal Institute of

Technology). In 1941, Hoffmann–

LaRoche brought Sternbach and

several other scientists out of Europe.

Sternbach became a research chemist

at LaRoche’s U.S. headquarters in

Nutley, New Jersey, where he later

became director of medicinal

chemistry.

zMcM

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