Synthesis of 1′-[14C]-stavudine® (d4T)

Journal of Labelled Compounds and Radiopharmaceuticals

Volumn 38, Issue 7, 1996, Pages 613-623

  Discordia, Robert P ^a  

^a BRISTOL MYERS SQUIBB COMPANY   (United States)

Author keywords

AIDS; D4T; HIV; Nucleosides; Stavudine

Indexed keywords

AIDS; D4T; HIV; METHANESULFONATES; METHANOLYSIS; NUCLEOSIDE; QUANTITATIVE YIELDS; STAVUDINE; STAVUDINE®; SYNTHESISED; ONE POT;

CHROMATOGRAPHY;

STAVUDINE;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ANTIVIRAL ACTIVITY; ARTICLE; CRYSTALLIZATION; DRUG SYNTHESIS; DRUG TRANSFORMATION; ESTERIFICATION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; NONHUMAN;

EID: 0029684294     PISSN: 03624803     EISSN: None     Source Type: Journal    
DOI: 10.1002/(SICI)1099-1344(199607)38:7<613::AID-JLCR873>3.0.CO;2-X     Document Type: Article

References (21)

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7. (a) Frank-Kamenetokaya, M. D.; Knizhnikova, G. V.; Myasoyedov, N. F. -J. Radioanal. Nucl. Chem. 121: 161 (1988);
8. (b) For a review of nucleoside chemistry see: Chemistry of Nucleosides and Nucleotides: Townsend, L. B., Ed. Plenum Press: New York, 1988.
9. Chen, B- C.; Quinlan, S. L.; Stark, D. R.; Reid, J. G.; Audia, V. A.; George, J.; Eisenreich, E.; Brundidge, S. P.; Racha, S.; Spector, R. H. -Tetrahedron Lett. 36: 7957-7960 (1995).
10. Sodium benzoate was milled using an electric coffee grinder until the compound was a fine powder. Without milling, the reaction is sluggish and requires additional equivalents of reagent.
11. 14C]-D-Ribose was purchased from Vitrax Co., 660 S. Jefferson St., Placentia, CA, 92670. Material was received as a solution in anhydrous methanol, 6.17 mCi/mL, 96.2% radiochemical purity.
12. TLC conditions: 20% ethyl acetate/hexanes; Rf's: product 050; bisbenzoyl derivative 0.35; monobenzoyl derivative 0.18; benzoic anhydride 0.65.
13. Rf's: starting material 0.50; product 0.38.
14. 1H NMR was identical to commercially available material.
15. TLC Conditions: 30% Ethyl acetate/hexanes; Rf's: 3 0.55; product 0.25.
16. TLC Conditions: 60% Ethyl acetate/hexanes; Rf's: 2′,3′,5′-tribenzoyl-5-MU 0.60; product 0.05.
17. 3OD): δ 1.81 (s, 3H); 1.83 (s, α-anomer); 3.72 (d, 1H + α-anomer); 3.81 (d, 1H + α-anomer); 4.0 (m, 1H + α-anomer); 4.18 (m, 2H + α-anomer); 5.80 (s, α-anomer); 5.85 (s, 1H); 7.55 (s, α-anomer), 7.82 (s, 1H).
18. 4OAc. Gradient schedule: 100%A for 5 min, linear gradient to 60% B over 5 min, hold at 60% B for 5 min, linear gradient to 100% B over 5 min, hold for 10 min, reverse linear gradient to 100% A over 2 min, equilibrate at 100% A for 10 min. Retention times: 6, 10.7 min.; 7, 7.7 min.; 8, 11.9 min.; 9, 18.3 min.; 10, 13.1 min.; benzoic acid, 2.9 min.
19. 3CN, isocratic. Column: Supelcosil LC-18-DB 25 cm × 4.6 mm, 254 nm, 10 μL injection. . Samples prepared using 10-15 μL of a reaction aliquot dissolved in 1.5-2.0 mL of mobile phase. Retention times: 10, 4.3-4.5 min.; 11, 1.15-1.20 min.; methylbenzoate, 8.10-8.20 min.
20. Crude Dowex resin was conditioned by washing with deionized water and vacuum filtering followed by further rinsing of the resin cake with dry methanol.
21. 6): δ 1.71 (s, 3-H), 3.60 (br. s, 2-H), 4.78 (br. s., 1-H), 5.00 (AB t., 1-H), 5.90 (m. 1-H), 6.40 (m. 1-H), 6.80 (s, 1-H), 11.3 (br. s., 1-H).