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US 7,582,748 B2Granted
Methods of manufacture of 2′-deoxy-β-L-nucleosides
AssigneeMicrobiologica Quimica E Farmaceutical Ltd.
InventorJaime A. Rabi
Life of this patent
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Abstract
The present invention relates to the synthesis of 2′-deoxy-β-L-thymidine, 2′-deoxy-β-L-uridine and 2′-deoxy-β-L-cytidine, and their derivatives, such as the 3′-O-acyl or 3′,5′-O-diacyl prodrugs, including the 3′-O-L-aminoacyl and 3′,5′-O-L-diaminoacyl prodrugs, and particularly the 3′-O-L-valinyl and 3′,5′-O-L-divalinyl prodrugs.
Claims23
A process for the preparation of β-L-2′-deoxythymidine comprising the steps of:
- (a) reacting a L-2-deoxyribose with an alcohol to form a L-1-O-alkyl-2-deoxyribose;
- (b) protecting the remaining free hydroxyls of the L-1-O-alkyl-2-deoxyribose to form protected L-1-O-alkyl-2-deoxyribose;
- (c) reacting the protected L-1-O-alkyl-2-deoxyribose with an anhydrous acid halide to form a protected L-1-halo-2-deoxyribose, wherein the anhydrous acid halide is produced in situ by the reaction of an acyl halide with a sub-equivalent amount of a second alcohol;
- (d) coupling the protected L-1-halo-2-deoxyribose with silylated thymine in chloroform to form a protected β-L-2′-deoxythymidine and a protected α-L-2′-deoxythymidine, wherein the ratio of the silylated thymine to the protected L-1-halo-2-deoxyribose is at least 1:1 and wherein the ratio of the protected β-L-2′-deoxythymidine to the protected α-L-2′-deoxythymidine is greater than about 10:1;
- and then
- (e) deprotecting the protected β-L-2′-deoxythymidine to obtain a β-L-2′-deoxythymidine.
3 more elements
A process for the preparation of β-L-2′-deoxyuridine comprising the steps of:
- (a) reacting a L-2-deoxyribose with an alcohol to form a L-1-O-alkyl-2-deoxyribose;
- (b) protecting the remaining free hydroxyls of the L-1-O-alkyl-2-deoxyribose to form a protected L-1-O-alkyl-2-deoxyribose;
- (c) reacting the protected L-1-O-alkyl-2-deoxyribose with an anhydrous acid halide to form protected L-1-halo-2-deoxyribose, wherein the anhydrous acid halide is produced in situ by the reaction of an acyl halide with a sub-equivalent amount of a second alcohol;
- (d) coupling the protected L-1-halo-2-deoxyribose with silylated uracil in chloroform to form a protected β-L-2′-deoxyuridine and a protected α-L-2′- deoxyuridine, wherein the ratio of the silylated uracil to the protected L-1-halo-2-deoxyribose is at least 1:1 and wherein the ratio of the protected β-L-2′-deoxyuridine to the protected α-L-2′-deoxyuridine is greater than about 10:1;
- and then
- (e) deprotecting the protected β-L-2′-deoxyuridine to obtain a β-L-2′-deoxyuridine.
3 more elements
Dependencies are inferred from the claim text.