Preparation of 2',3'-didehydro-3'-deoxythymidine from 5-methyluridine
AssigneeBristol-Myers Squibb Company
InventorsBang-Chi Chen, Derron Ray Stark, Stephen Richard Baker, Sandra L. Quinlan
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Abstract
An economical process, amenable to large-scale production, is disclosed for the preparation of 2',3'-didehydro-3'-deoxythymidine (d4T) from 5-methyluridine. The process employs a novel, 5'-,acyl-2'.alpha.-halo-3'.alpha.-alkanesulfonylthymidine intermediate as well as a highly efficient and practical deprotection, isolation and purification procedure for the d4T product.
Claims13
A process for producing 2',3'-didehydro-3'-deoxythymidine (d4T) comprising the steps of:
- (a) reacting 5-methyluridine (X) with mesyl chloride in the ##STR6## presence of an organic base with a pk.sub.a value between about 5.5 and 8.0 to mesylate the 2',3' and 5' hydroxy groups, followed by treatment with hydroxide to provide the 2,2'-anhydro compound (VIII);
- ##STR7## (b) displacing the 5'-mesyl group with benzoate anion followed by hydrobromination to give the 5'-benzoyl-2'-bromo compound (VI);
- ##STR8## (c) reducing the compound of Formula VI in the presence of zinc to provide the 5'-benzoate ester of d4T (III);
- ##STR9## (d) treating (III) with butylamine followed by N-methylpyrrolidinone and butyl acetate to give the d4T.NMPO solvate (II);
- ##STR10## and (e) generation of d4T product (I) by desolvating the d4T.NMPO solvate (II) in alcoholic medium.
A process for purification of crude d4T comprising 1) the formation and isolation of an N-methylpyrrolidinone solvate of d4T (II) from a process reaction mixture and 2) the generation of purified d4T by desolvation of the solvate (II) by heating in an alcoholic medium.
An intermediate of Formula V, useful in nucleoside derivative synthesis, ##STR11## wherein R.sup.5 is hydrogen or a hydroxyl-protecting group;
- R.sup.3 is C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.6-30 aryl, or C.sub.6-30 aryloxy;
- and X is chloro, bromo, or iodo.
A process for producing d4T by
- (a) treating a compound of Formula V, wherein R.sup.3 is selected from C.sub.1-6 alkyl and C.sub.6-30 aryl, and R.sup.5 is selected from C.sub.1-6 alkylcarbonyl and C.sub.6-30 arylcarbonyl and X is bromo, ##STR12## with zinc metal to give compound (III) wherein R is C.sub.1-6 alkyl or C.sub.6-30 aryl;
- ##STR13## (b) treating compound (III) with a primary or secondary alkylamine followed by N-methylpyrrolidinone to give the d4T.NMPO solvate (II);
- and
- (c) generating d4T product by desolvating the d4T.NMPO solvate (II) in alcoholic medium.
A process for preparing a compound of Formula III, wherein R is C.sub.1-6 alkyl or C.sub.6-30 aryl;
- ##STR14## comprising the zinc reduction of a compound of Formula V ##STR15## wherein R.sup.3 is C.sub.1-6 alkyl or C.sub.6-30 aryl, R.sup.5 is C.sub.1-6 alkylcarbonyl or C.sub.6-30 arylcarbonyl, and X is chloro, bromo or iodo.
Dependencies are inferred from the claim text.