355138-50-0

Basic information

• Product Name: 2-Chloro-9-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-9H-purin-6-aMine
• Synonyms: 2-Chloro-9-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-9H-purin-6-aMine;clofarabine-1
• CAS NO: 355138-50-0
• Molecular Formula: C₂₄H₁₉ClFN₅O₅
• Molecular Weight: 511.8895632
• Mol File: 355138-50-0.mol

Chemical Properties

• Appearance: /
• Storage Temp.: Refrigerator
• Solubility: Acetonitrile, Chloroform, Methanol
• CAS DataBase Reference: 2-Chloro-9-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-9H-purin-6-aMine(CAS DataBase Reference)
• NIST Chemistry Reference: 2-Chloro-9-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-9H-purin-6-aMine(355138-50-0)
• EPA Substance Registry System: 2-Chloro-9-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-9H-purin-6-aMine(355138-50-0)

Safety Data

• Hazardous Substances Data: 355138-50-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
2-Chloro-9-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-9H-purin-6-aMine is used as an intermediate in the synthesis of clofarabine, a second-generation purine nucleoside analog. Clofarabine is an antineoplastic agent that inhibits DNA synthesis and resists deamination by adenosine deaminase, making it a valuable tool in the fight against cancer.
2-Chloro-9-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-9H-purin-6-aMine's role in the synthesis of clofarabine is significant because it contributes to the development of a potent antimetabolite with potential applications in the treatment of various types of cancer. By serving as a key intermediate, 2-Chloro-9-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-9H-purin-6-aMine enables the creation of new therapeutic options for patients in need.

Upstream product

• 329187-80-6 ((2R,3R,4S,5R)-3-(benzoyloxy)-5-(2,6-dichloro-9H-purin-9-yl)-4-fluorotetrahydrofuran-2-yl)methyl benzoate 
• 97614-43-2 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranose 
• 75788-35-1 9-Trimethylsilyl-2,6-dichlorpurin 
• 5451-40-1 2,6 dichloropurine 
• 6974-32-9 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose 
• 1839-18-5 2-chloroadenine 
• 1353040-42-2 2-chloro-9-(3',5'-di-O-benzoyl-β-D-ribofuranosyl)adenine 
• 1055168-98-3 6-amino-2-chloro-9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-9H-purine 
• 1353040-43-3 2-chloro-9-(3',5'-di-O-benzoyl-2'-O-trifluoromethylsulfonyl-β-D-ribofuranosyl)adenine 
• 97614-44-3 2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-arabinofuranosyl bromide 
• 146-77-0 2-Chloroadenosine 
• 118-00-3 G 
• 58-96-8 uridine 
• 98855-71-1 ((2R,3R,4S)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydrofuran-2-yl)methyl benzoate 

Downstream Products

• 136834-22-5 (2R,3R,4S,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluorotetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite 
• 20187-82-0 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine 
• 123318-82-1 clofarabine 

Relevant articles and documents

A green synthetic clofarabine pharmaceutical intermediates (by machine translation)

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)

Green synthesizing technology of clofarabine

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.

Method for synthesizing clofarabine

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.

METHOD FOR THE SYNTHESIS OF CLOFARABINE

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.

Stereoselective synthesis of 2′-modified nucleosides by using ortho-alkynyl benzoate as a gold(i)-catalyzed removable neighboring participation group

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.

Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-adenine

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.

Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-Beta-D-arabinofuranosyl)-adenine

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.

Isolation, synthesis, and characterization of impurities and degradants from the clofarabine process

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.

A new process for antineoplastic agent clofarabine

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.

Oligonucleotides containing 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-adenine and -guanine: Synthesis, hybridization and antisense properties

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.