75607-67-9

Basic information

• Product Name: Fludarabine phosphate
• Synonyms: 9-beta-d-arabinofuranosyl-2-fluoroadenine5’-monophosphate;fludarabinemonophosphate;9-bata-d-arabinofuranosyl-2-fluoroadenine phosphate;9-BETA-D-ARABINOFURANOSYL-2-FLUOROADENINE-5'-DIHYDROGEN PHOSPHATE;FLUDARUBINE PHOSPHATE;FLUDARABINE PHOSPHATE;FludarabinePhosphateFdaInspected;FludarabinePhosphateUsp28
• CAS NO: 75607-67-9
• Molecular Formula: C₁₀H₁₃FN₅O₇P
• Molecular Weight: 365.2116842
• EINECS: 2017-001-1
• Product Categories: Active Pharmaceutical Ingredients;Antineoplastics;Antineoplastic;API;Anti-cancer&immunity;Inhibitors
• Mol File: 75607-67-9.mol
• Article Data: 9

Chemical Properties

• Melting Point: 203°C(dec.)(lit.)
• Boiling Point: 864.2 °C at 760 mmHg
• Flash Point: 476.4 °C
• Appearance: white/Powder
• Density: 2.39 g/cm³
• Vapor Pressure: 7.38E-32mmHg at 25°C
• Refractive Index: 1.878
• Storage Temp.: -20°C
• Solubility: DMSO: soluble1mg/mL
• PKA: 1.86±0.10(Predicted)
• Water Solubility: Soluble in DMSO or water at 5mg/ml
• Stability: Hygroscopic
• Merck: 14,4126
• CAS DataBase Reference: Fludarabine phosphate(CAS DataBase Reference)
• NIST Chemistry Reference: Fludarabine phosphate(75607-67-9)
• EPA Substance Registry System: Fludarabine phosphate(75607-67-9)

Safety Data

• WGK Germany: 3
• RTECS: UO7440900
• Hazardous Substances Data: 75607-67-9(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
Fludarabine phosphate is used as an antineoplastic agent for the treatment of chronic lymphatic leukemia and low-grade lymphoma. It is effective in patients who are refractory to other treatments and helps in managing the disease by targeting rapidly dividing cancer cells.
Used in Anticonvulsant Therapy:
Although not its primary use, fludarabine phosphate has been studied for its potential application as an anticonvulsant. This suggests that it may have uses beyond oncology, possibly in the management of certain seizure disorders.
In terms of pharmacokinetics, once in circulation, fludarabine phosphate is immediately dephosphorylated to the nucleoside fludarabine, with about 30-40% of it being excreted into the urine. Additionally, fludarabine is metabolized into a hypoxanthine metabolite, which is also excreted through urine.

Originator

Southern Research Institute (U.S.A.)

Pharmacology

Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted. Phase I studies in humans have demonstrated that fludarabine phosphate is rapidly converted to the active metabolite, 2-fluoro-ara-A, within minutes after intravenous infusion. Consequently, clinical pharmacology studies have focused on 2-fluoro-ara-A pharmacokinetics. After the five daily doses of 25 mg 2-fluoro-ara-AMP/m2 to cancer patients infused over 30 minutes, 2-fluoro-ara-A concentrations show a moderate accumulation. During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough levels increased by a factor of about 2. The terminal half-life of 2-fluoro-ara-A was estimated as approximately 20 hours. In vitro, plasma protein binding of fludarabine ranged between 19% and 29%.

Clinical Use

Fludarabine phosphate (Fludara ? ), is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-β-D-arabinofuranosyladenine(ara-A), which differs only by the presence of a fluorine atom at position 2 of the purine moiety and a phosphate group at position 5 of the arabinose moiety (Plunkett et al., 1993). These structural modifications result in increased aqueous solubility and resistance to enzymatic degradation by adenosine deaminases compared to vidarabine (Brockman et al., 1977; Plunkett et al., 1990). Fludarabine phosphate is indicated for the treatment of patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating agent containing regimen (Boogaerts et al., 2001; Rossi et al., 2004).

Drug interactions

Potentially hazardous interactions with other drugs Antipsychotics: avoid concomitant use with clozapine, increased risk of agranulocytosis. Cytotoxics: increased pulmonary toxicity with pentostatin (unacceptably high incidence of fatalities); increases intracellular concentration of cytarabine.

Metabolism

Intravenous fludarabine phosphate is rapidly dephosphorylated to fludarabine which is taken up by lymphocytes and rephosphorylated via the enzyme deoxycytidine kinase to the active triphosphate nucleotide. Clearance of fludarabine from the plasma is triphasic; elimination is mostly via renal excretion: 40-60% of an intravenous dose is excreted in the urine. The pharmacokinetics of fludarabine show considerable inter-individual variation

InChI:InChI=1/C10H13FN5O7P/c11-10-14-7(12)4-8(15-10)16(2-13-4)9-6(18)5(17)3(23-9)1-22-24(19,20)21/h2-3,5-6,9,17-18H,1H2,(H2,12,14,15)(H2,19,20,21)/t3-,5-,6+,9-/m1/s1

Upstream product

• 512-56-1 trimethyl phosphite 
• 146-78-1 Fludarabine 
• 78-40-0 triethyl phosphate 
• 7440-44-0 pyrographite 

Downstream Products

• 146-78-1 Fludarabine 

Relevant articles and documents

Synthesis method of fludarabine phosphate

The invention provides a synthesis method of fludarabine phosphate, and the synthesis route is as follows: with vidarabine as a starting raw material, fludarabine is obtained through upper protection,nitrification, fluorination denitration and deprotection, so that the fludarabine is prepared by adopting a brand-new synthesis route; meanwhile, by improving the process of phosphorylation and refining of fludarabine, the reaction time is shortened, the generation of by-products is reduced, and the product quality is improved. The method has the following advantages: 1, the initial raw materialis beta-configuration, isomer separation is avoided, and the yield is improved; raw materials are easy to obtain, the route is simple, and the price is low; 3, salification and column-passing purification and separation are avoided, so that the method is suitable for industrialization.

A 9 - β - D - arabinofuranosyl -2 - fluoro adenine -5 ' - phosphate ester preparation method (by machine translation)

The invention discloses a preparation method for 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate. The method employs 9-beta-D-arabinofuranosyl-2-fluoroadenine as an initial raw material, enables the raw material to be reacted with a mixture of triethyl phosphate and phosphorus oxychloride and employs water for post-processing, thereby solving the problems in other synthetic methods that reaction temperature is sever, reaction time is long and post-processing operation is complex. Also, the invention discloses a simple practicable refining method, and helps to effectively improve the purity of 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate.

Fludarabine phosphate preparation method

The invention discloses a fludarabine phosphate preparation method. The method comprises the specific steps that fludarabine and triethyl phosphate are added into a reaction container, the reaction container is placed into a subzero 6 DEG C low-temperature reaction bath, phosphorus oxychloride is added on the stirring condition, water and dichloromethane are added into the reaction container after the reaction is performed for 12 h, standing is performed, then, extraction is performed to obtain a water phase and an organic phase, the pH value of the water phase is adjusted to 2-3, recrystallization is performed to obtain white focculus, and filtering and vacuum drying are performed to obtain a target product of fludarabine phosphate with the purity being 99.95%. The method has the advantages that reaction conditions are mild, operation is easy, the product is easy to separate and purify, the yield is high, the product is environmentally friendly, high in purity, small in organic solvent residual quantity and capable of meeting the medicinal standard, and the method is suitable for industrial production.

Immobilized Drosophila melanogaster deoxyribonucleoside kinase (DmdNK) as a high performing biocatalyst for the synthesis of purine arabinonucleotides

Fruit fly (Drosophila melanogaster) deoxyribonucleoside kinase (DmdNK; EC: 2.7.1.145) was characterized for its substrate specificity towards natural and non-natural nucleosides, confirming its potential in the enzymatic synthesis of modified nucleotides. DmdNK was adsorbed on a solid ion exchange support (bearing primary amino groups) achieving an expressed activity >98%. Upon cross-linking with aldehyde dextran, expressed activity was 30-40%. Both biocatalysts (adsorbed or cross-linked) were stable at pH 10 and room temperature for 24 h (about 70% of retained activity). The cross-linked DmdNK preparation was used for the preparative synthesis of arabinosyladenine monophosphate (araA-MP) and fludarabine monophosphate (FaraAMP). Upon optimization of the reaction conditions (50 mM ammonium acetate, substrate/ATP ratio= 1:1.25, 2 mM MgCl2, 378C, pH 8) immobilized DmdNK afforded the title nucleotides with high conversion (>90%), whereas with the soluble enzyme lower conversions were achieved (78-87%). Arabinosyladenine monophosphate was isolated in 95% yield and high purity (96.5%).

PROCESS FOR THE PREPARATION OF FLUDARABINE PHOSPHATE

A description is given of a process for the preparation of 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate starting from 9-beta-D-arabinofuranosyl-2-fluoroadenine by reaction with a mixture composed of triethyl phosphate and phosphorus oxychloride and in accordance with a work-up which provides for the use of toluene.

Process for the production of fludarabine-phosphate lithium, sodium, potassium, calcium and magnesium salts and purification process for the production of fludarabine-phosphate and fludarabine-phosphate with a purity of at least 99.5%

A reduced temperature crystallization process for the obtaining fludarabine phosphate at a purity of at least 99.5%.

Hydrogenation of 2-fluoro-9-(2,3,5-tri-o-benzyl-beta-D-arabinofuranosyl)adenine

A process for the preparation of 2-fluoro-9-beta-D-arabinofuranosyl purine (VII) by a reaction of palladium chloride and hydrochloric acid with 2-fluoro-9-(2,3,5-tribenzyl-beta-D-arabinofuranosyl)adenine (VI) at elevated pressures in a solvent for (VI) is described. The reaction is rapid, economical and efficient.

Process for the preparation of 2-amino-9-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl) adenine and novel intermediates

A process for the preparation of 2,6-diamino-9-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)purine (V) by reacting 2,6-di(alkoxyacetamido)purine (II) with 2,3,5-tri-O-benzyl-1-chloro-alpha-D-arabinofuranose (III) to produce 2,6-di(alkoxyacetamido)-9-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)purine (IV) and then deprotecting the 2,6-positions to produce the 2,6-diamine (V) is described. The process provides purine (V) in high yield. Purine (V) is an intermediate in the preparation of 9-beta-D-arabinofuranosyl-2-fluoroadenine which is a cytotoxic agent.

Prodrug derivatives of 9β-D-arabinofuranosyl-2-fluoroadenine

The 5'-formate and the 5'-phosphate derivatives of 9-β-D-arabinofuranosyl-2-fluoroadenine have been prepared as prodrug forms of the anti-cancer agent 9-β-D-arabinofuranosyl-2-fluoroadenine, known as F-ara-A. These derivatives are quite water soluble whereas F-ara-A itself is sparingly soluble in water or in any organic solvents. Delivery of these prodrug forms to mice with L1210 leukemia results in the formation of higher levels of the triphosphate of F-ara-A, the active form of the drug, in the target L1210 leukemia cells. These prodrug forms are much more active chemotherapeutically than 9-β-D-arabinofuranosyladenine, known as ara-A, and equivalent in activity to the combination of ara-A and 2'-deoxycoformycin, known as 2'-dCF, an effective in vivo inhibitor of adenosine deaminase, a ubiquitous enzyme that destroys ara-A in vivo.