Fludarabine phosphate

Fludarabine (phosphate) is an analogue of adenosine and deoxyadenosine, which is able to compete with dATP for incorporation into DNA and inhibit DNA synthesis.

Solid

Fludarabine phosphate is a purine arabinonucleoside monophosphate having 2-fluoroadenine as the nucleobase. A prodrug, it is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. Once incorporated into DNA, 2-fluoro-ara-ATP functions as a DNA chain terminator. It is used for the treatment of adult 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 regimenas. It has a role as an antimetabolite, an antineoplastic agent, an immunosuppressive agent, an antiviral agent, a prodrug and a DNA synthesis inhibitor. It is an organofluorine compound, a nucleoside analogue and a purine arabinonucleoside monophosphate. It derives from a 2-fluoroadenine.|Fludarabine Phosphate is the phosphate salt of a fluorinated nucleotide antimetabolite analog of the antiviral agent vidarabine (ara-A) with antineoplastic activity. 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 may inhibit DNA polymerase alpha, ribonucleotide reductase and DNA primase, thereby interrupting DNA synthesis and inhibiting tumor cell growth.

Fludarabine (19. 5g ; 0.0683 moles) and (EtO) 3PO (79.1 ml; 0.465 moles) are introduced into a reactor cooled to-15/-20°C. POC13 (15.3 ml; 0.164 moles) is added dropwise over a period of approximately 1 hour while maintaining the internal temperature at - 10/-15°C. Agitation is maintained at-10/-15°C for 48 hours; the reaction is regarded as complete when the amount of fludarabine, in the HPLC area, is less than 2percent. Cold toluene (780 ml; 40 volumes) is then added over a period of approximately 1.5 hours and agitation is maintained, still at - 10/-15°C, for 1-2 hours. Filtration is carried out and the filter cake is washed with toluene (20 ml). The moist solid (approximately 35 g) is suspended in H20 (40 ml) and the pH is adjusted to 11 with 32percent NaOH (approximately 20 ml). The solution is percolated into a beaker containing Dowex resin [the resin must first be activated and washed as follows: washing is effected with demineralized water until the washing liquors are colourless; acidification with 5percent HCl (approximately 200 ml) is carried out and washing is effected to a neutral pH with demineralized water]. The whole is agitated for approximately 15 minutes and filtered over a septum. The resin is resuspended in H20 (500 ml). Agitation is carried out for 15 minutes followed by filtering over a septum. This operation is repeated until no more fludarabine phosphate is present in the filtrate. The fractions containing product are reduced in volume by evaporation under vacuum (at a maximum temperature of 30-35°C) until the desired product starts to precipitate, this product finally being filtered and dried under vacuum at 60°C to constant weight. 10. lg (40percent yield) of a white solid having a purity greater than 97.5percent are obtained. It is possible to recrystallize this solid as follows: it is suspended in 10 volumes of water and the whole is heated at 70°C for 1 hour; the whole is filtered hot, washing the filter cake with acetone. A white solid having a purity greater than 99percent is obtained.Fludarabine (10g), triethyl phosphate (90mL), phosphorus oxychloride (6mL) were placed under stirring -5~-10°C low temperature circulating pump, while maintaining the internal temperature -5 ~ -1 ° C; stirring reaction at -5 ~ -1 ° C for 15 hours; when the amount of fludarabine in the HPLC detection area, less than 2percent is considered The reaction was completed, then pure water (50 mL) was added to the obtained mixture under stirring, and washed with dichloromethane. The obtained aqueous phase was adjusted to pH=3 with 50percent NaOH solution, concentrated under reduced pressure at 35-40 ° C, and recrystallized. Filtration, the filter cake was washed with a small amount of ethanol and water to obtain a white solid. The white solid was dried under vacuum at 45-50 ° C for 10-12 hours to obtain a crude product of fludarabine phosphate having a purity of 99.2percent and a yield of 73.3percent.The crude fludarabine phosphate obtained by the above preparation method is added to 100 mL of pure water at room temperature, stirred uniformly, and 50percent NaOH solution is slowly added dropwise until completely dissolved, and the filtrate is added dropwise to a dilute hydrochloric acid solution at room temperature with a white solid. Precipitate, After suction filtration, the filter cake was washed with a small amount of ethanol and water to obtain a white solid. The white solid was vacuum-dried at 45-50 ° C for 10-12 hours to obtain fludarabine phosphate. The purity was 99.9percent, and the yield was 96.5. percent.To a 500 mL flask was added 20 g of fludarabine followed by 200 mL of triethyl phosphate, and the flask was placed at a low temperature of -6 ° CReaction bath, 20min after slowly dropping phosphorus oxychloride 20mL (side drop while stirring), the reaction 12 hours (TCL tracking). Reaction reachedTo the request after the flask quickly add 80mL water and 200mL dichloroethane, standing for 30 minutes after the extraction of water and organic phase, the waterAdjust the pH value to 2-3. Recrystallization white floc with a Buchner funnel filter, vacuum dry weighing a white powder20.71 g, yield 81.02percent, HPLC mass fraction 99.95percent,

anticonvulsant

Molecular Weight:365.21
XLogP3:-3.1
Hydrogen Bond Donor Count:5
Hydrogen Bond Acceptor Count:12
Rotatable Bond Count:4
Exact Mass:365.05366293
Monoisotopic Mass:365.05366293
Topological Polar Surface Area:186
Heavy Atom Count:24
Complexity:514
Defined Atom Stereocenter Count:4
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes