Organic Chemistry of Drug Synthesis. Volume 7

186

C 2 H 5 O 2 CNH 2 + CN C^2 H^5 O^2 C NH

187

NaH O NH

NC

188

NC

(tBuOC) 2 O O NCOtBu

NC

189

1. NaBH 4

HO NCOtBu

NC

190

1. LiAlH 4


2. (tBuOC) 2 O

HO NCOtBu

191

tBuOCNH

O NCOtBu SO 3 .Py

192

tBuOCNH

N NCOtBu

193

tBuOCNH

CH 3 ONH 2

CH 3 O

CH 3 CO 2 H N NH

194

H 2 N

CH 3 O N N

F

Cl

O CO

2 H

N N

F

O

CO 2 H

N

H 2 N

CH 3 O

195

196

The search for better tolerated folate antagonist antitumor agents
continues to produce yet more variants on methotrexate [see pemetrexed
( 46 ) for structure]. The analoguepralatrexate( 202 ) retains most of the
features of the prototype, but replaces the side-chain tertiary amine by a

N

N N

N

NH 2

H 2 N

CO 2 H

CO 2 H

CO 2 CH 3

H 3 CO 2 C

197

+

Br

KH

CO 2 CH 3

H 3 CO 2 C

198

Br

199

N

N N

N

NH 2

H 2 N

CO 2 CH 3

H 3 CO 2 C

200

NaOH

heat

N

N N

N

NH 2

H 2 N

CO 2 H

N

N N

N

NH 2

H 2 N

1. Diethylglutamate2. NaOH

201

202

2. COMPOUNDS WITH TWO FUSED SIX-MEMBERED RINGS 211