IMPROVED SYNTHESIS OF SOME o-BSTERS OF N-PKOTECTED L-GLUTAMIC ACID

Quinazoline antifolates inhibiting thymidylate synthase: synthesis of four oligo(L-.gamma.-glutamyl) conjugates of N10-propargyl-5,8-dideazafolic acid and their enzyme inhibition

“…In planning our work we took note of the phenomenon of y ^a transpeptidation of glutamic acid derivatives, first observed in 195312 and subsequently confirmed.13 '16 This rearrangement is promoted by alkali, the use of which in the synthesis of compounds of this type received a cautionary note from Battersby and Robinson.17 21 22 23 24 25 26 27 28 29 30 31 32 33 butyl carboxyl protecting group as a device to prevent transpeptidation was first advocated by Schwyzer in 1961.18 Other workers went on to prove that transpeptidation does not occur when trifluoroacetic (TEA) is used to remove this group. 19 In a further study of TEA in this role, it was observed, parenthetically, that alkaline treatment of a trimethyl 7-diglutamate gave "eine Spur (hóchstens 2%)" of -glutamylglutamic acid.20 Toward (18) Schwyzer, R.; Dietrich, H. Helu.…”

“…The structure and purity of all compounds containing the propargyl group were established by elemental microanalysis (Tables II and III) and by NMR spectroscopy (Table IV). The final products 30-33 were additionally characterized by analytical HPLC and were found to be 97-98% pure (30)(31)(32) and 94% pure (33) (Table III). They were tested for their tight-binding inhibition of human WI-L2 thymidylate synthase.…”

“…The latter phenomenon has been amply demonstrated for thymidylate synthase.6 Biochemical and pharmacological studies7'9 of the polyglutamate derivatives of CB3717extent of formation, transport characteristics, and role in the antitumor activity of the drug-led to a need for pure reference samples. The synthesis of four conjugates (30)(31)(32)(33) of CB3717 and their inhibition of human TS is described herein. While our work was in progress, the preparation of these conjugates, by a different synthetic 4…”

Quinazoline Antifolate Thymidylate Synthase Inhibitors: γ-Linked l-d, d-d, and d-l Dipeptide Analogues of 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic Acid (ICI 198583),

“…They were synthesized by a route identical with that described above for the synthesis of the l - d analogues 32−44 , except that α- tert -butyl N -(benzyloxycarbonyl)- d -glutamate (Z- d -Glu-OBu t , 60 ) was used in place of Z- l -Glu-OBu t ( 4 ) (Scheme 5). α- tert -Butyl N -(benzyloxycarbonyl)- d -glutamate ( 60 ) was synthesized by a route similar to that employed for the synthesis of its l -enantiomer (Scheme 5). d -Glutamic acid was converted to its corresponding γ-methyl ester hydrochloride 57 by treatment with SOCl 2 /MeOH …”

“…d -Glutamic acid was converted to its corresponding γ-methyl ester hydrochloride 57 by treatment with SOCl 2 /MeOH and the α-carboxyl of 58 masked as its tert -butyl ester by treatment with Bu t OH/POCl 3 /pyridine . In the last step, the γ-methyl ester was hydrolyzed under alkaline conditions to afford 60 in 33% overall yield …”