Process of preparing etoposide phosphate and etoposide
AssigneeBristol-Myers Squibb Company
InventorsLee J. Silverberg, Purushotham Vemishetti, John L. Dillon, Jr., John J. Usher
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Abstract
Etoposide phosphate is prepared by coupling dibenzyl 4'-demethyl-4-epipodophyllotoxin-4'-phosphate with 2,3-di-O-benzyl-4,6-O-ethylidene-.alpha.,.beta.-D-glucopyranose in a solvent and subsequently removing the protecting groups. The tetra-benzyl protected etoposide phosphate is recrystallized from methanol or directly crystallized from acetonitrile by adding methanol to yield substantially the pure C-1"-.beta. form. The benzyl protecting groups are simultaneously removed by hydrogenation to produce etoposide phosphate in high yields. In a further embodiment, etoposide phosphate is treated with a phosphatase enzyme to yield etoposide.
Claims12
A process for preparing a compound of Formula VI ##STR22## comprising phosphorylating a compound of Formula I ##STR23## with a phosphorylation agent to produce a protected 4'-demethyl-4-epipodophyllotoxin-4'-phosphate of Formula II ##STR24## where R.sub.3 is an arylmethyl phosphate protecting group, reacting said compound of Formula II with a protected sugar of Formula III in the presence of a Lewis acid ##STR25## to produce a compound of Formula IV, where R.sub.1 is an arylmethyl hydroxy protecting group;
- ##STR26## isolating the C-1"-.beta. form of Formula IV;
- removing the hydroxy and phosphate protecting groups to produce a compound of Formula V;
- ##STR27## treating said compound of Formula V with a phosphatase enzyme to produce the compound of Formula VI.
A glucopyranose compound having the Formula IIIb ##STR28## wherein R.sub.1 is arylmethyl and R.sub.2 is arylmethyl, or the two R.sub.2 together are C.sub.1-5 alkylidene.
Dependencies are inferred from the claim text.