Organic Chemistry of Drug Synthesis. Volume 7

O

68

NH 2 OH N

69

OH

BuLi

Ac 2 O N

70

O

O CH 3

O

N

HO CH^3

O

N

CH 3

O

N

CH 3

1. ClSO 3 H
   2. NH 3

71

73 72

H 2 NO 2 S

1. Ac 2 O
   O 2. NaOH

N

CH 3

74

OS 2

H 3 C N

O

• Na+

The immune system is believed to play a role in rheumatoid arthritis, in
contrast to the far more common osteoarthritis, which is related to aging. An
agent that has immunosuppressive action has proven useful for treating
rheumatoid arthritis. This compoundlenflunomide( 77 ), can be prepared
in a single step by acylation ofp-trifluoromethylaniline ( 76 ) with the com-
mercially available isoxazole ( 75 ).^12 The isoxazole ring, it was later found,
is readily cleavedin vivoto give the cyano ketone,teriflunomide( 78 ).
Lenfluomides is consequently considered to be a prodrug for the latter.
This agent can be prepared by condensation of the sodium salt from cyanoa-
cetone ( 79 ) withp-trifluoromethylphenyl isocyanate ( 80 ),^13 itself readily
accessible from the aniline ( 76 ). Teriflunomide, is used in the clinic as a
potential drug for relieving some of the effects of multiple scelerosis.

O

N

H 3 C

O

Cl

+

H 2 N

CF 3 O

N

H 3 C

O H

N

HN

CF 3

O CN

H 3 C

HO

O CN CF 3

+

CF 3

O C N

75 76 77

79 80 78

Metabolism

2. COMPOUNDS WITH TWO HETEROATOMS 93