Organic Chemistry of Drug Synthesis. Volume 7

the amide carbonyl is converted to a thioamide with phosphorus pentoxide
64. Reaction of this last intermediate with hydrazine gives the cyclic amino-
amidine ( 65 ) putting in place the nitrogen atoms of the future triazole ring.
Condensation of that product with ethylorthoacetate leads to formation of
the last fused heterocyclic ring. Ester–amide interchange of this last
product with morpholine completes the synthesis ofapafant( 67 ).^8
The adventitious discovery of the utility ofa-adrenergic blockers for
treating benign prostatic hypetrophy led to the introduction of several of
these agent. The majority of these compounds, for example, alfuzocin
(Chapter 8), consist of modified quinazolines. A structurally quite distant
heterocyclic compound has been found to have much the same activity at
adrenergic receptors in experimental system. This activity extends to
a-adrenergic receptors located in the prostate. One arm of the convergent
synthesis starts with the condensation of the anion from dimethylresorcinol
with DMF. Hydrolysis of the initial product then yields the aldehyde.
Reaction with aluminum chloride leads to scission of one of the methyl
ethers to give the phenol ( 68 ). Heating 68 with acetic anhydride probably
leads initially to formation of the acetylated phenol. The presence of base
then causes the phenol to cyclize to coumarin ( 69 ). Condensation of 69
with the azomethine ylide from 70 leads to 3þ2 cycloadditon to the cou-
marin double bond. The presence of the chiral auxiliarya-phenethylamine
leads to the formation of the addition product as an essentially single enan-
tiomer ( 71 ). Reduction of the coumarin carbonyl with lithium borohydride
gives the ring-opened hydroxy phenol ( 72 ). A mixture of mesylates (phenol
and hydroxymethyl) is obtained on treating 72 with methanesulfonyl chlor-
ide. In the next step, treatment with strong base leads to internal displace-
ment of the mesylate closing the ring to afford the corresponding
benzopyran ( 73 ). Hydrogenation then cleaves the phenethyl group to afford

OH

OCH 3

68

CH=O

O

OCH 3

Ac O

2 O

69

N

C 6 H 5

OCH 3

H 3 C

N Me 3 Si

C 6 H 5

OCH 3

H 3 C

Me 3 Si –

O

OCH 3

O

N

H 3 C

C 6 H 5

71

LiBH 4

OH

OCH 3

OH

N

H 3 C

C 6 H 5

72

1. CH 3 SO 2 Cl
   2.tBuOK

O

OCH 3 N

H 3 C

C 6 H 5

73

H 2

O

OCH 3 NH

74

70

1. COMPOUNDS WITH THREE FUSED RINGS 225