A Practical Synthesis of Multitargeted Antifolate LY231514

Abstract

A concise and scalable synthesis of LY231514 (1), a new pyrrolo[2,3-d]pyrimidine-based antitumor agent, is presented. Reaction of 2-bromo-4-arylbutanal 9 with 2,4-diamino-6-hydroxypyrimidine (10) regioselectively provided pyrrolo[2,3-d]pyrimidine 11, representing the core structure of the drug, in good yield. Assimilation of the glutamic acid residue by conventional means completed the synthesis. Development of the optimized synthetic route emphasized avoiding isolation of the relatively unstable aldehyde and bromoaldehyde intermediates.

Synthesis and Physicochemical Characterization of the Impurities of Pemetrexed Disodium, an Anticancer Drug

“…Convergent synthesis of pemetrexed disodium heptahydrate from key synthetic intermediates (Scheme 1) is well documented and involves firstly the preparation of the p -toluenesulfonic acid salt ( 5a ) [10]. The acid 2 is activated for coupling by reaction with 2-chloro-4,6-dimethoxytriazine (CDMT) in presence of N -methylmorpholine (NMM) to form an active ester 3 and then reacted with diethyl L -glutamate 4 .…”

An Efficient Synthesis of Pemetrexed Disodium

“…After filtration, the solvent was evaporated under reduced pressure to afford the compound 2 (10.70 g, 91.2% yield) as yellow oil (lit. [7] light yellow oil) with a purity of 96.0%. …”

“…Pemetrexed disodium ( Figure 1) was first synthesized by Taylor and his co-workers at Princeton University [6], and then, a number of synthetic methods have been reported for the preparation of pemetrexed during recent years [7][8][9][10][11][12]. Among them, the most applicable synthetic method [8] was shown in Scheme 1.…”

Synthetic Approaches to the 2004 New Drugs

“…[46][47][48][49][50][51][52][53][54][55][56]. A practical and scalable synthetic route [56] is depicted in Scheme 9. Palladium (0) coupling of methyl 4-bromobenzoate (57) with 3-butyn-1-ol (58) gave crystalline 59, which was then reduced over palladium on carbon in DCM to give alcohol 60.…”