the side chain starts with the condensation of dimethylglyoxylate ( 63 )
with guanidine to afford the pyrimidol ( 64 ). The hydroxyl group is
then replaced by a leaving group, in this case chlorine, by reaction
with phosphorus oxychloride. The product from this reaction ( 65 )is
then alkylated with N-carbethoxy piperazine to afford 66. Treatment
of 66 with acid removes the protecting group to afford piperazine 67 ,
an intermediate suitable for alkylation. Preparation of the indole
portion of the molecule begins with the two-step conversion (diazotiza-
tion then reduction) of the aniline ( 68 ) to the corresponding hydrazine
( 69 ). Heating this intermediate withv-chlorovaleraldehyde, itself pre-
pared in two steps from tetrahydropyran in the presence of acid,
leads directly to the indole ( 70 ), which has in place the requisite
side-chain link. Subsequent alkylation of the piperazine ( 67 ) with 70
leads to the serotonin antagonist 71.^10
SO 2 NHCH 3
NH 2- NaNO 2
2. SnCl 2
SO 2 NHCH 3NHNH 2SO 2 NHCH 3NHO=HC Cl ClOCH 3
O +NH
H 2 N NH 2N
HO N
OCH 3 OCH 3POCl (^3) Cl N N
OCH 3
C 2 H 5 O 2 CN
C 2 H 5 O 2 CNHN N
N N
OCH 3
NH
N
N N
OCH 3
H+
SO 2 NHCH 3
NH
N
N
N N
OCH 3
63 64 65 66
68 69 70 67
71
The highly substituted indole, ecopladib ( 82 ), which shares many
structural elements with the phospholipase inhibitor varespladib ( 37 ),
shows similar biological activity. Alkylation of hydroxy benzoate ( 72 )
with the dimethyl acetal from bromoacetaldehyde ( 73 ) affords the ether
( 74 ). Acid-catalyzed reaction of this intermediate with 2-methyl-5-
chloroindole ( 75 ) in the presence of triethylsilane leads in effect to conden-
sation of the acetal with the activated 3 position on the indole ring to afford
76. The nature of the reduction of the aldehyde carbon is not immediately
apparent. Alkylation of the anion on nitrogen from reaction of the indole
with sodium hydride and bromodiphenylmethane then adds the third
- COMPOUNDS WITH ONE HETEROATOM 147