Fludarabine

Details:

Melting point     265-268°C
alpha     D25 +17 ±2.5° (c = 0.1 in ethanol)
Boiling point     747.3±70.0 °C(Predicted)
density     2.17±0.1 g/cm3(Predicted)
storage temp.     2-8°C
solubility     DMF: 20 mg/mL, clear, faintly yellow
pka    13.05±0.70(Predicted)
form     Powder
color     White to Pale Yellow
Water Solubility     Soluble in DMF, DMSO, methanol or ethanol. Sparingly soluble in water
Merck     13,4152
BRN     1225932
CAS DataBase Reference    21679-14-1(CAS DataBase Reference)
Safety Information
Hazard Codes     Xn
Risk Statements     23/24/25-36/37/38-39/23/24/25-39-22
Safety Statements     26-36/37-45-36
WGK Germany     3
RTECS     AU6207000
F     10
HS Code     29349990
Hazardous Substances Data    21679-14-1(Hazardous Substances Data)
MSDS Information
Provider    Language
9-bata-D-Arabinofuranosyl-2-fluoroadenine    English
SigmaAldrich    English
Fludarabine Usage And Synthesis
Chemical Properties    White Solid
Originator    Fludarabine,Union Pharmaceutical
Uses    Used as an antineoplastic
Uses    A STAT-1 activation inhibitor and a DNA synthesis inhibitor.
Uses    phosphate as antineoplastic;inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase
Uses    Irreversible muscarinic agonist
Uses    DNA synthesis and methylation inhibitor;A cell permeable agent that interferes with DNA synthesis and repair; also inhibits RNA transcription
Indications    Fludarabine (Fludara) is a fluorinated purine analogue of the antiviral agent vidarabine.The active metabolite, 2-fluoro-ara-adenosine triphosphate, inhibits various enzymes involved in DNA synthesis, including DNA polymerase-α, ribonucleotide reductase, and DNA primase. Unlike most antimetabolites, it is toxic to nonproliferating as well as dividing cells, primarily lymphocytes and lymphoid cancer cells.
The drug is highly active in the treatment of chronic lymphocytic leukemia, with approximately 40% of patients achieving remissions after previous therapy with alkylating agents has failed. Activity is also seen in the low-grade lymphomas.
The major side effect is myelosuppression, which contributes to fevers and infections in as many as half of treated patients. Nausea and vomiting are mild. Occasional neurotoxicity has been noted at higher doses, with agitation, confusion, and visual disturbances.
Manufacturing Process    Guanosine (87 g, 0.31 mL, predried for two days under vacuum at 100°C over P2O5) was combined with acetic anhydride (180 mL, 1.9 mol), pyridine (90 mL, 1.11 mol) and DMF (245 mL) and heated in oil bath at 75°C. The reaction was monitored by TLC on silica gel plates eluted with mixture of ethyl acetate:DMF:1-butanol (6:3:1). After 2 hours, the guanosine was consumed and the 2',3',5'-tri-O-acetylguanosine was observed to be the major product. The mixture was concentrated under vacuum. The residue was suspended in ethyl ether:2-propanol (1:1) and the solid collected by filtration was recrystallized from absolute ethanol. The product was dried at 80°C under vacuum to obtain 106.9 g (84%) of 2',3',5'-tri-O-acetylguanosine as a fluffy white solid; M.P. 229-233°C.
Distilled phosphorous oxychloride (47.7 mL, 510 mmol) was added to a solution of dried 2',3',5'-tri-O-acetylguanosine (36.1 g, 88 mmol), benzyltriethylammonium chloride (40.2 g, 176 mmol), and N,Ndimethylaniline (11.2 mL, 88 mmol, distilled from CaH2 in anhydrous acetonitrile (200 mL, distilled from P2O5). The flask was fitted with a reflux condenser and placed in an oil bath preheated at 100°C. The mixture was heated to reflux, and heating was continued for 10 min. The mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (800 mL). The solution was stirred with ice for 15 min before the layers were separated. The aqueous layer was then washed with several portions of dichloromethane. The combined organic extracts were washed with water and then with portions of saturated sodium bicarbonate until neutral. Finally, it was dried over MgSO4, filtered, and concentrated under vacuum. The residue was recrystallized twice from 300 mL of 2-propanol to obtain the purified 2',3',5'-tri-O-acetyl-6-chloroguanosine; 32.2 g (85%); M.P. 146- 148°C.
A round bottom flask fitted with a mechanical stirrer and cold finger condenser was charged with potassium fluoride (140 g, 2.4 mole), 2',3',5'-tri- O-acetyl-6-chloroguanosine (70 g, 0. 16 mol) and anhydrous DMF (1.5 L). About 5-7 mL of trimethylamine was condensed into the flask. The suspensionwas stirred at ambient temperature for 24 hours and then the mixture was concentrated under vacuum. The residue was suspended in chloroform and filtered and the insoluble material was washed thoroughly with chloroform (1.5 L total). The filtrate was concentrated under vacuum and the residue was recrystallized from 2-propanol to obtain 61.7 g (92%) of the 6-fluoro-2',3',5'- tri-O-acetylguanosine, M.P. 143-144°C.
The protecting groups in 6-fluoro-2',3',5'-tri-O-acetylguanosine was then deleted (alcaline saponification by action lithium hydroxide or NH3) and the product was transformed into 9-beta-D-arabinofuranosyl-2-fluoro-adenine.
Therapeutic Function    Antineoplastic
General Description    The drug is available as the phosphate salt in a 50-mg vialfor IV use. Fludarabine is used to treat chronic lymphocyticleukemia and non-Hodgkin’s lymphoma. The mechanism ofaction involves the triphosphate metabolite and its inhibitionof DNA chain elongation. The 2-fluoro group on the adeninering renders fludarabine resistant to breakdown byadenosine deaminase. The drug is rapidly dephosphorylatedto 2-fluoro-ara-adenosine (F-ara-A) after administration. Fara-A is taken into the cell and subsequently re-phosphorylatedto yield the triphosphate (F-ara-ATP), the active drugspecies. Resistance can occur via decreased expression ofthe activating enzymes and decreased drug transport.Fludarabine is orally bioavailable and is distributed throughoutthe body reaching high levels in liver, kidney, andspleen. The drug is metabolized to F-ara-A, which enterscells via the nucleoside transport system and is rephosphorylatedby deoxycytidine kinase to fludarabine monophosphateand finally fludarabine triphosphate, the activespecies. About 25% of F-ara-A is excreted unchanged inurine. Drug interactions include an increased incidence offatal pulmonary toxicity when fludarabine is used in combinationwith pentostatin. Additionally, fludarabine may potentiate the effects of several other anticancer drugs includingcytarabine, cyclophosphamide, and cisplatin.Toxicities include myelosuppression, immunosuppression,fever, nausea, and vomiting.
Biological Activity    Purine analog that inhibits DNA synthesis. Exhibits antiproliferative activity (IC 50 = 1.54 μ M in RPMI cells) and triggers apoptosis through increasing Bax and decreasing Bid, XIAP and survivin expression. Displays anticancer activity against hematological malignancies in vivo .
Fludarabine Preparation Products And Raw materials
Raw materials    Acetic anhydride-->Fluoroboric acid-->Boron trichloride-->2,4,5,6-TETRAAMINOPYRIMIDINE-->2,6-Diaminopurine-->DIACETAMIDE-->Ammonia-->p-Hydroxyphenyl dimethylcarbamate-->Aniline-->Phosphorus oxychloride-->Potassium fluoride-->Guanosine-->N,N-Dimethylaniline