- A new process for antineoplastic agent clofarabine
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Clofarabine is a promising DNA polymerase inhibitor currently in clinical trials for a variety of liquid and solid tumor indications. The efforts for development of a new manufacturing process for clofarabine are presented. This new process allows for the reliable and efficient production of drug substance in high anomeric excess and high overall purity, without using chromatography. The high anomeric selectivity is achieved by reacting 2-chloroadenine with 1-bromo-2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-ribofuranose (4) and potassium tert-butoxide in a mixture of three solvents. Following crystallization, anomeric ratios exceeding 50 (β/α) are achieved. Deprotection and additional crystallization afford a clofarabine drug substance containing less than 0.1% of the α-anomer.
- Bauta, William E.,Schulmeier, Brian E.,Burke, Brian,Puente, Jose F.,Cantrell Jr., William R.,Lovett, Dennis,Goebel, James,Anderson, Bruce,Ionescu, Dumitru,Guo, Ruichao
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Read Online
- Green synthesizing technology of clofarabine
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The invention relates to a green synthesizing technology of clofarabine which comprises the following steps: (the structural formula is shown in the description), dissolving a compound which is shownin formula II into an organic solvent, adding 40% of hydrobromic acid and tetrabutylammonium fluoride in an ice bath, performing stirring reaction for 3 hours, adding triethylamine trihydrofluoride and continuing the stirring reaction for 2 to 3 hours to obtain a compound which is shown in formula I; (2) dissolving a compound which is shown in formula III into acetonitrile, adding potassium tert-butoxide, calcium hydride and tert-butyl alcohol, heating to 60 DEG C, reacting for 1 hour, adding the compound which is shown in the formula I, keeping at 60 DEG C and continuing reacting for 10 hoursto obtain a compound which is shown in formula IV; (3) removing Bz in the compound which is shown in the formula IV under an alkaline condition to obtain a compound which is shown in a formula V, namely the clofarabine.
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Paragraph 0004; 0028-0032
(2019/02/25)
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- A green synthetic clofarabine pharmaceutical intermediates (by machine translation)
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The invention relates to a green synthetic clofarabine medical intermediates, in particular comprises the following steps: The formula II compound is dissolved in the organic solvent, under ice bath by adding 40% of the hydrobromic, tetrabutyl ammonium fluoride, stirring for 3 hours, adding triethylamine three [...], continuing to stir 2 - 3 hours, [...] I compound. (by machine translation)
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Paragraph 0021; 0022; 0023
(2019/02/25)
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- METHOD FOR THE SYNTHESIS OF CLOFARABINE
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The present invention relates to a method for the high yield production of the anticancer nucleoside clofarabine, the method comprising the preparation of 2-chloroadenosine by enzymatic transglycosylation between 2-chloroadenine and nucleosides, benzoylation, isomerization, sulfonate ester formation, fluorination, and deprotection.
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- Method for synthesizing clofarabine
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The invention discloses a method for synthesizing clofarabine; the method comprises the following synthetic routes described in the specification, wherein in the formula III and the formula IV, R1 and R2 are the same or different acyl groups. The method comprises the following steps: 1) ammoniation: dissolving a compound represented by the formula III in an organic solvent, introducing ammonia gas, and carrying out a closed reaction, to obtain a compound represented by the formula IV after the reaction is completed, wherein the organic solvent is any combination of one or two or more of acetonitrile, ethyl acetate, dichloromethane and tetrahydrofuran, the concentration of ammonia gas dissolved in the organic solvent is 0.1-20 wt%, the closed reaction is carried out for 10-40 hours, and the reaction temperature is 0-100 DEG C; and 2) protecting group removal: dissolving the compound represented by the formula IV and prepared in the step 1) in alcohol, adding an alcohol solution of sodium alkoxide, carrying out a reaction, then adjusting the pH value to 6-7, cooling and crystallizing, and thus obtaining a clofarabine crude product.
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Paragraph 0040; 0067; 0068
(2017/08/27)
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- Stereoselective synthesis of 2′-modified nucleosides by using ortho-alkynyl benzoate as a gold(i)-catalyzed removable neighboring participation group
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In the present paper, we report a novel strategy for highly efficient stereoselective synthesis of 2′-modified nucleosides by using ortho-alkynyl benzoate as neighboring participation group. Subsequently, ortho-alkynyl benzoate can be removed smoothly in the presence of 5 mol% Ph3PAuCl-AgOTf in dichloromethane with H2O (1 eq.) and ethanol (6 eq.) to afford 2′-OH nucleosides in high yields and selectivity.
- Ding, Haixin,Li, Chuang,Zhou, Yirong,Hong, Sanguo,Zhang, Ning,Xiao, Qiang
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p. 1814 - 1817
(2017/01/21)
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- BIOCATALYTIC PRODUCTION OF NUCLEOSIDE ANALOGUES AS ACTIVE PHARMACEUTICAL INGREDIENTS
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A biocatalytic process for producing active pharmaceutical ingredients (APIs) or intermediates thereof, wherein those APIs or their intermediates are nucleoside analogues (NAs) of formula I and wherein said NAs are active as pharmaceutically relevant antivirals and anticancer medicaments, intermediates or prodrugs thereof.
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Paragraph 0226
(2016/04/09)
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- Preparation methods for clofarabine intermediate and clofarabine
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The invention provides preparation methods for a clofarabine intermediate and clofarabine. The preparation method for the clofarabine intermediate, provided by the invention, comprises the steps of firstly mixing tertiary butanol, acetonitrile and calcium hydride; secondly mixing a to-be-reacted liquid obtained after stirring at the room temperature until no bubbles are generated, and 2-chloroadenine and reacting for 2-4 hours; and finally reacting with a 1-bromo-3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-Arabic ribofuranose solution to obtain clofarabine. Therefore, the time of reaction with the 1-bromo-3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-Arabic ribofuranose solution is greatly shortened; and the method is simple in post-treatment and relatively high in yield.
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Paragraph 0049- 0058
(2016/10/27)
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- The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: The electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases
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Two 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.
- Fateev, Ilja V.,Antonov, Konstantin V.,Konstantinova, Irina D.,Muravyova, Tatyana I.,Seela, Frank,Esipov, Roman S.,Miroshnikov, Anatoly I.,Mikhailopulo, Igor A.
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p. 1657 - 1669
(2014/10/15)
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- Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-Beta-D-arabinofuranosyl)-adenine
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A process for making clofarabine comprising: fluorinating a compound of formula VII wherein each R4 is independently a hydroxy protecting group, OR6 is a leaving group, with a fluorinating agent in the presence of guanidine carbonate to give a compound of formula VIII: wherein R4 is as defined above; and deprotecting the compound of formula VIII to give the clofarabine.
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Page/Page column 18-19
(2012/01/15)
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- Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-adenine
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A process for making clofarabine comprising: fluorinating a compound of formula VII wherein each R4 is independently a hydroxy protecting group, OR6 is a leaving group, with a fluorinating agent in the presence of guanidine carbonate to give a compound of formula VIII: wherein R4 is as defined above; and deprotecting the compound of formula VIII to give the clofarabine.
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Page/Page column 22
(2012/08/29)
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- HALOGENATED 2-DEOXY-LACTONES, 2'-DEOXY--NUCLEOSIDES, AND DERIVATIVES THEREOF
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Disclosed are halogenated 2-deoxy-lactone, 2'-deoxy-nucleosides, and derivatives thereof, for example, a compound of formula (I). Also disclosed are a composition comprising a pharmaceutically acceptable carrier and at least one compound or salt of the invention, and a method of treating a disorder is selected from the group consisting of an abnormal cellular proliferation, a viral infection, and an autoimmune disorder.
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- Efficient syntheses of clofarabine and gemcitabine from 2-deoxyribonolactone
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The development of a new methodology to achieve electrophilic fluorination of triisopropylsilyl-protected 2-deoxyribonolactone has been employed to synthesize clofarabine and gemcitabine with improved synthetic efficiency versus prior synthetic methods. These studies highlight the versatility of this new methodology to obtain medically relevant 2′-fluoronucleosides.
- Cen, Yana,Sauve, Anthony A.
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experimental part
p. 113 - 122
(2011/08/05)
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- Isolation, synthesis, and characterization of impurities and degradants from the clofarabine process
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The identification of clofarabine process impurities and their subsequent isolation, synthesis, and characterization is described. Two isomeric process impurities resulting from N6-attachment of a fluoroarabinose to clofarabine were found. Clofarabine's base degradation products, which were different from the process impurities, were also synthesized and characterized. These compounds resulted from modifications to the sugar moiety, the purine ring, or both. A mechanistic rationale for the formation of the various process impurities and degradation products is provided.
- Anderson, Bruce G.,Bauta, William E.,Cantrell Jr., William R.,Engles, Tracy,Lovett, Dennis P.
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p. 1229 - 1237
(2013/01/03)
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- Process for the preparation of 9-beta-anomeric nucleoside analogs
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A process for substantially enhancing the regio and stereoselective synthesis of 9-β-anomeric nucleoside analogs is described. The introduction of the sugar moiety onto a 6-substituted purine base was preformed so that only the 9-β-D- or L-purine nucleoside analogs were obtained. This regio and stereoselective introduction of the sugar moiety allows the synthesis of nucleoside analogs and in particular 2′-deoxy, 3′-deoxy, 2′-deoxy-2′-β-fluoro and 2′,3′-dideoxy-2′-β-fluoro purine nucleoside analogs in high yield without virtually any formation of the 7-positional isomers. The compounds are drugs or intermediates to drugs.
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- Method for synthesizing 2-chloro-9-(2-fluoro-beta-d-arabinofuranosyl)-9h-purin-6-amine
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2-Chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-9-amine is synthesized by reacting a 2-chloro-6-substituted purine with a protected and activated 2-deoxy-2-fluoro-D-arabinofuranose; and reacting with a base such as ammonia to provide 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purin-6-amine. When the purine reactant is substituted in the 6 position with a halogen, a reaction step with an alkoxide is carried out prior to the reaction with ammonia.
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- Oligonucleotides containing 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-adenine and -guanine: Synthesis, hybridization and antisense properties
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Synthesis of 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-adenine (7, ara-A2′F) and -guanine (12, ara-G2′F) was accomplished via the condensation of 2,6-dichloropurine (1) with 2-deoxy-2-fluoro-1,3,5-tri-O-benzoyl-α-D-arabinofuranose (2) as a key chemical step. Condensation of silylated N6-benzoyladenine (6) with 2 gave, after deblocking and chromatographic separation, ara-A2′F (7) (14%), it's α-anomer 8 (14%) and N7-α-isomer 9 (25%). The PSEUROT analysis of N9-β-D-arabinosides 7 and 12 manifested slight preference for the S rotamer (64%) for the former, and an equal population of the N and S rotamers for the latter. The arabinosides 7 and 12 were used for the preparation of the respective phosphoamidite building blocks 13 and 14 for automated oligonucleotide synthesis. Four 15-mer oligonucleotides (ONs) complementary to the initiation codon region of firefly luciferase mRNA were prepared: unmodified 2′-deoxy-ON (AS 1) and containing (i) ara-A2′F instead of the only A (AS2), (ii) ara-G2′F vs. 3-G from the 5′-terminus (AS3), and (iii) both arabinosides at the same positions (AS4). All these ONs display practically the same (i) affinity to both complementary DNA and RNA, and (ii) ability to inhibit a luciferase gene expression in a cell-free transcription-translation system.
- Tennilae, Tuula,Azhayeva, Elena,Vepsaelaeinen, Jouko,Laatikainen, Reino,Azhayev, Alex,Mikhailopulo, Igor A.
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p. 1861 - 1884
(2007/10/03)
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- 2'-fluoro-2-haloarabinoadinosines and their pharmaceutical compositions
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The present invention is directed to certain 2'-fluoro, 2-substituted purine nucleosides which are toxic to cancerous cell lines.
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- Synthesis and Biologic Activity of 2'-Fluoro-2-halo Derivatives of 9-β-D-Arabinofuranosyladenine
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The synthesis of 2-halo-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenines (4b and 4d) by coupling the 2,6-dihalopurine with 3-acetyl-5-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (2) followed by replacement of the 6-halogen with concomitant removal of the acyl blocking groups is described. 2-Fluoroadenine derivative 4g had to be prepared by the diazotization-fluorination of 2-aminoadenine nucleoside 4e.All three nucleosides provided good increases in life span of mice inoculated with P388 leukemia.The best results were obtained when the compounds were administered q3h*8 on days 1, 5, and 9 after implantation of the leukemia cells.The 2',3'-dideoxynucleoside 5b, prepared by deacetylation of 4f and deoxygenation of the resultant 4h followed by removal of the benzoyl group of 5a, was slightly active against HIV in cell culture.
- Montgomery, John A.,Shortnacy-Fowler, Anita T.,Clayton, Sarah D.,Riordan, James M.,Secrist, John A.
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p. 397 - 401
(2007/10/02)
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- 2-fluoro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) adenine nucleosides
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There are disclosed nucleosides having Formula I: STR1 wherein R is H or acyl. These compounds have anticancer activity.
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