Isolation, Synthesis, and Characterization of Impurities and Degradants from the Clofarabine Process

Anderson, B.; Bauta, William E.; Cantrell, William R.; Engles, Tracy; Lovett, Dennis P.

doi:10.1021/op800182x

Cited by 13 publications

(9 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Without going into details, it should be noted that a common drawback of both approaches is the indispensable introduction and subsequent removal of protective groups, which is associated with chromatographic purification in almost every step, a lack of selectivity of chemical reactions, and the problems associated with the poor regio-and stereoselectivity of chemical reactions (see, e.g. [12] and the papers cited therein).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 2,6‐Dihalogenated Purine Nucleosides by Thermostable Nucleoside Phosphorylases

et al. 2015

View full text Add to dashboard Cite

The enzymatic transglycosylation of 2,6-dichloropurine (26DCP) and 6-chloro-2-fluoropurine (6C2FP) with uridine, thymidine and 1-(b-d-arabinofuranosyl)-uracil as the pentofuranose donors and recombinant thermostable nucleoside phosphorylases from G. thermoglucosidasius or T. thermophilus as biocatalysts was studied. Selection of 26DCP and 6C2FP as substrates is determined by their higher solubility in aqueous buffer solutions compared to most natural and modified purines and, furthermore, synthesized nucleosides are valuable precursors for the preparation of a large number of biologically important nucleosides. The substrate activity of 26DCP and 6C2FP in the synthesis of their ribo-and 2'-deoxyA C H T U N G T R E N N U N G ribo-nucleosides was closely similar to that of related 2-amino-(DAP), 2-chloro-and 2-fluoroadenines; the efficiency of the synthesis of b-d-arabinofuranosides of 26DCP and 6C2FP was lower vs. that of DAP under similar reaction conditions. For a convenient and easier recovery of the biocatalysts, the thermostable enzymes were immobilized on MagReSyn epoxide beads and the biocatalyst showed high catalytic efficiency in a number of reactions. As an example, 6-chloro-2-fluoro-(b-d-ribofuranosyl)-purine (9), a precursor of various antiviral and antitumour drugs, was synthesized by the immobilized enzymes at 60 8C under high substrate concentrations (uriA C H T U N G T R E N N U N G dine:purine ratio of 2:1, mol). The synthesis was successfully scaled-up [uridine (2.5 mmol), base (1.25 mmol); reaction mixture 50 mL] to afford 9 in 60% yield. The reaction reveals the great practical potential of this enzymatic method for the efficient production of modified purine nucleosides of pharmaceutical interest.

show abstract

Section: Introductionmentioning

confidence: 99%

Synthesis of 2,6‐Dihalogenated Purine Nucleosides by Thermostable Nucleoside Phosphorylases

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Despite the detailed analysis and optimization of the clofarabine process [12–13] and the bulk production of the protected nucleoside glycon 9 by chemists at Eli Lilly and Co. [18] this chemical synthesis is connected with the use of great volumes of organic solvents and gives rise to the formation of the undesired α-anomer necessitating the chromatographic purification of the desired β-anomer, and finally affords clofarabine in a low yield.…”

Section: Introductionmentioning

confidence: 99%

The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases

Fateev

Antonov

Konstantinova

et al. 2014

Beilstein J. Org. Chem.

View full text Add to dashboard Cite

SummaryTwo approaches to the synthesis of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (1, clofarabine) were studied. The first approach consists in the chemical synthesis of 2-deoxy-2-fluoro-α-D-arabinofuranose-1-phosphate (12a, 2FAra-1P) via three step conversion of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranose (9) into the phosphate 12a without isolation of intermediary products. Condensation of 12a with 2-chloroadenine catalyzed by the recombinant E. coli purine nucleoside phosphorylase (PNP) resulted in the formation of clofarabine in 67% yield. The reaction was also studied with a number of purine bases (2-aminoadenine and hypoxanthine), their analogues (5-aza-7-deazaguanine and 8-aza-7-deazahypoxanthine) and thymine. The results were compared with those of a similar reaction with α-D-arabinofuranose-1-phosphate (13a, Ara-1P). Differences of the reactivity of various substrates were analyzed by ab initio calculations in terms of the electronic structure (natural purines vs analogues) and stereochemical features (2FAra-1P vs Ara-1P) of the studied compounds to determine the substrate recognition by E. coli nucleoside phosphorylases. The second approach starts with the cascade one-pot enzymatic transformation of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a, followed by its condensation with 2-chloroadenine thereby affording clofarabine in ca. 48% yield in 24 h. The following recombinant E. coli enzymes catalyze the sequential conversion of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a: ribokinase (2-deoxy-2-fluoro-D-arabinofuranose-5-phosphate), phosphopentomutase (PPN; no 1,6-diphosphates of D-hexoses as co-factors required) (12a), and finally PNP. The substrate activities of D-arabinose, D-ribose and D-xylose in the similar cascade syntheses of the relevant 2-chloroadenine nucleosides were studied and compared with the activities of 2-deoxy-2-fluoro-D-arabinose. As expected, D-ribose exhibited the best substrate activity [90% yield of 2-chloroadenosine (8) in 30 min], D-arabinose reached an equilibrium at a concentration of ca. 1:1 of a starting base and the formed 2-chloro-9-(β-D-arabinofuranosyl)adenine (6) in 45 min, the formation of 2-chloro-9-(β-D-xylofuranosyl)adenine (7) proceeded very slowly attaining ca. 8% yield in 48 h.

show abstract

“…该路线一共 6 步反应, 总收率仅为 6%. 2004 年, ILEX 公司 (San Antonio, TX, USA) 对上述方法进行了改进 [7,8] (图 2, 路线 b). 他们采用单一 α-构型的 1-溴-2-脱氧-2-β-氟-3,5-二-O-苯甲酰基-D-阿拉伯糖和 2,6-二氯嘌呤缩合, 提高了反应的立体选择性(β/α＝21/1), 经氨解和脱保护基之后可得氯法拉滨.…”

unclassified

A New Method for the Synthesis of Clofarabine

Ran¹,

Guo²,

Qin³

et al. 2014

Chin. J. Org. Chem.

View full text Add to dashboard Cite

Clofarabine is the active ingredient in the anti-pediatric leukemia drug, which was approved by U.S. Food and Drug Administration in 2004. However, the previous reported methods have long steps, low yield and difficult separation of α/β anomers, which restrict the wide use of the drug. In this manuscript, the cheap and commercial available 2-chloroadenosine was chose as the starting material to synthesize the clofarabine. By using acetic acid and hydrazine, the selective deprotection of acetyl group in 2'-position was accomplished. Subsequently, the fluorination step was realized by diethylaminosulfurtrifluoride (DAST). The clofarabine was synthesized with 4 steps in 49% total yield as a pure β-anomer. Meanwhile, the strong steric hindrance of 2-substitution was favorable for the 2'-deacetylation. Notably, the clofarobine could be synthesized at a gram scale using this method, which showed the good future of industrial application.

show abstract

Isolation, Synthesis, and Characterization of Impurities and Degradants from the Clofarabine Process

Cited by 13 publications

References 7 publications

Synthesis of 2,6‐Dihalogenated Purine Nucleosides by Thermostable Nucleoside Phosphorylases

Synthesis of 2,6‐Dihalogenated Purine Nucleosides by Thermostable Nucleoside Phosphorylases

The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases

A New Method for the Synthesis of Clofarabine

Contact Info

Product

Resources

About