Diethyl L-glutamate

It was found that the A-protected p-nitrophenyl ester of L-Arg spontaneously cyclized into 42 (R = NO2) (61JOC3347). A related compound 42 (R = H) was obtained as a by-product in the reaction between N,N-dicarbobenzoxy-L-Arg and diethyl L-glutamate (59JA2878). 

Treatment of p-acetoxybenzoic acid with thionyl chloride generated the acid chloride, which was used without purification to acylate diethyl L-glutamate. Deacetylation of the resulting triester (36) gave (37) [51] (Scheme 3.6). 

Condensation of 4,4-dithiobis(benzoic acid) (38) [52] with diethyl L-glutamate in the presence of DCC produced (39), from which (40) was readily obtained by reduction with sodium borohydride [53] (Scheme 3.7). 

In one case, methyl terephthalic acid, obtained in two steps from p-formyl-benzoic acid, was converted to the phenacyl bromide (340) in the usual manner. Alkylation of 2,5-diamino-4,6-dihydroxypyrimidine with (340) with subsequent cyclization produced the dihydrooxazine pteroate ester (341), which was hydrolyzed to (342) [173]. Coupling (342) with diethyl L-glutamate using isobutyl chloroformate [ 174] yielded the diester (343a) which was then saponified to the dihydrooxazine FA analogue without the C-9,N-10 bridge (343b). 

Replacement of the benzene ring with an -butyl segment has been disclosed Scheme 3.124) [73, 248], Thus, methylation of 5-(A,-tosylamino)valeric acid [250], followed by coupling with diethyl L-glutamate, detosylation, alkylation with (26) HBr and hydrolysis afforded (594). 

Rosowsky and Forsch [253] studied the effect of removing the AP amide carbonyl group Scheme 3.127). Condensation of diethyl L-glutamate with... 

Deaza-ll-oxahomoAMT (IV.62) was synthesized by Nair / a/. [Ill] by a modification of their synthesis of lO-deaza-lO-oxaAMT (IV.52). 1-Bromo-4-[4-(carbomethoxy)phenoxy]-2-butanone (IV.63) was converted successively to the azide (IV.64), the ketal (IV.65), and the acid (IV.66). Mixed anhydride coupling of (IV.66) and diethyl L-glutamate, followed by catalytic hydrogenation of the azido group, yielded the amine (IV.67), which, on addition to 2,4-diamino-6-chloro-5-nitropyrimidine and hydrolysis of the ketal group with acid, gave the key intermediate, (IV.68). Dithionite reduction led... 

In order to determine whether a bridge containing at least two atoms is necessary for antifolate activity, Nair et al. [139] prepared V-[4-(2,4-diamino-6-pteridinyl)methyl]benzoyl-L-glutamate ( 9-nor-lO-deaza-AMT (IV. 160)). 1-Bromo-3-(4-methoxycarbonylphenyl)-2-propanone was converted by a series of standard reactions to the azido ketal acid (IV. 161), which was condensed with diethyl L-glutamate by the mixed anhydride method to form the diester (IV. 162). Reduction of the azido group followed by reaction with 2,4-diamino-... 

For the preparation of the 2-amino-4(3i7)-oxo analogues of this series, the 2,4-diamino-9,10-dehydro derivative (IV.175) was converted to (IV.187) (88%, yield) by heating in 1 M NaOH under reflux for 3 h [140a]. Treatment of (IV.187) with acetic anhydride containing a catalytic amount of 4- NJ -dimethylamino)pyridine afforded the 2-acetamido-4-oxo mixed anhydride (IV. 188) (84%), which on careful alkaline hydrolysis was converted to the protected acid (IV. 189) (77%,). Coupling to diethyl L-glutamate in V-methyl-pyrrolidin-2-one in the presence of phenyl iV-phenylphosphoramidochloridate... 

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