Busulfan Chemical Properties
- Melting point:114-117 °C(lit.)
- Boiling point:359.3°C (rough estimate)
- Density 1.305 (estimate)
- refractive index 1.5630 (estimate)
- Flash point:9℃
- storage temp. Hygroscopic, Refrigerator, Under Inert Atmosphere
- solubility Very slightly soluble in water, freely soluble in acetone and in acetonitrile, very slightly soluble in ethanol (96 per cent).
- form Crystalline Powder
- color Pale Brown
- Water Solubility Decomposes
- Merck 14,1505
- BRN 1791786
- Stability:Moisture Sensitive
- CAS DataBase Reference55-98-1(CAS DataBase Reference)
- IARC1 (Vol. 4, Sup 7, 100A) 2012
- EPA Substance Registry SystemBusulfan (55-98-1)
- Hazard Codes T+,T,F
- Risk Statements 45-26/27/28-63-46-36/37/38-23/24/25-39/23/24/25-11
- Safety Statements 53-36/37/39-45-28A-36/37-16-7
- RIDADR UN 2811 6.1/PG 1
- WGK Germany 3
- RTECS EK1750000
- HazardClass 6.1(b)
- PackingGroup III
- HS Code 29053990
- Hazardous Substances Data55-98-1(Hazardous Substances Data)
- ToxicityLD50 i.v. in rats: 1.8 mg/kg (Scherf)
Busulfan Usage And Synthesis
- DescriptionChemically, busulfan is classified as an alkyl sulfonate. One or both of the methylsulfonate ester moieties can be displaced by the nucleophilic N7 of guanine, leading to monoalkylated and cross-linked DNA. The extent of alkyl sulfonate–mediated DNA interstrand cross-linking has been shown to vary with the length of the alkyl chain between sulfonate esters, with the tetramethylene-containing busulfan showing less interstrand cross-linking capability than hexamethylene, methylene, or octamethylene analogues. Intrastrand cross-linking also occurs, preferentially at 5′-GA-3′ but also at 5′-GG-3′ sequences. Alkylation of Cys sulfhydryl groups is yet another mechanism of cytotoxicity.
- Chemical PropertiesWhite Crystalline Solid
- OriginatorMyleran,Burroughs- Wellcome,US,1954
- UsesAlkylating agent with antileukemic activity. Antineoplastic
- UsesAntineoplastic alkylating agent, the palliative treatment of chronic myeloid leukemia, and insect sterilant.
- UsesBusulfan USP (Myleran) is used to treat Chronic granulocytic leukemia; other myeloproliferative disorders.
- IndicationsBusulfan (Myleran) is a bifunctional methanesulfonic
ester that forms intrastrand cross-linkages with DNA.
The drug is well absorbed after oral administration and
has a plasma half-life of less than 5 minutes. Metabolites
and degradation products are excreted primarily in the
Busulfan is used in the palliative treatment of chronic granulocytic leukemia. Daily oral therapy results in decreased peripheral white blood cells and improved symptoms in almost all patients during the chronic phase of the disease. Excessive uric acid production from rapid tumor cell lysis should be prevented by coadministration of allopurinol.
At usual therapeutic dosages, busulfan is selectively toxic to granulocyte precursors rather than lymphocytes. Thrombocytopenia and anemia and less commonly, nausea, alopecia, mucositis, and sterility also may occur. Unusual side effects of busulfan include gynecomastia, a general increase in skin pigmentation, and interstitial pulmonary fibrosis.
- DefinitionChEBI: A methanesulfonate ester that is butane-1,4-diol in which the hydrogens of the hydroxy groups are replaced by methanesulfonyl groups. An alkylating antineoplastic agent, it is used for the treatment of chronic myeloid leukemia (although it has been largely replaced by newer drugs). It is also used as an insect sterilant.
- Manufacturing Process3.6 grams of redistilled 1,4-butanediol were dissolved in 10 ml of pyridine and
the solution was cooled in ice and water. 9.6 grams of redistilled methanesulfonyl-
chloride were added dropwise at such a rate that the temperature did
not rise above 20°C. The solution was then allowed to stand at room
temperature to; 30 minutes, during which time the temperature rose to 60°C.
A thick precipitate of pyridine hydrochloride was formed.
The mass was cooled in ice water and was treated with 30 ml of ice cold water. On agitation, a white crystalline precipitate was formed. This was filtered off and washed well with ice cold water and allowed to drain on the pump. It weighed 7.8 grams and had a melting point of 100°C. 3.5 grams of the material were recrystallized from acetone and ether to give small white needles, having a melting point of 106°-107°C, unchanged by further recrystallization.
- brand nameMyleran (GlaxoSmithKline).
- Therapeutic FunctionAntineoplastic
- General DescriptionWhite crystals or powder.
- General DescriptionAs an alternative to utilizing aziridines as electrophilic species,it was found that simply utilizing a carbon chain terminated atboth ends by leaving groups gave compounds capable of actingas cross-linking agents.Busulfan utilizestwo sulfonate functionalities as leaving groups separated by afour-carbon chain that reacts with DNA to primarily form intrastrandcross-link at 5'-GA-3' sequences.The sulfonatesare also subject to displacement by the sulfhydryl functionsfound in cysteine and glutathione, and metabolic products areformed as a result of nucleophilic attack by these groups togenerate sulfonium species along with methane sulfonicacid.This is followed by conversion to tetrahydrothiophene,and further oxidation products are subsequently produced togive the sulfoxide and sulfone. The cyclic sulfone known assulfolane may be further oxidized to give 3-hydroxysulfolane.
- General DescriptionBusulfan is available as 2-mg tablets for oral administrationand 10-mL vials for IV administration in the treatment ofchronic myelogenous leukemia (CML) and in high-dosetherapy for refractory leukemia with bone marrow transplant.The agent is well absorbed when given orally, well distributedinto tissues, and crosses the blood-brain barrier.Metabolism occurs in the liver to give mainly methane sulfonic acid by the action of glutathione-S-transferase. Other identified metabolites in humanshave included tetrahydrothiophene-1-oxide, sulfalene,primarily in the urine, and the terminal elimination half-lifeis 2.5 hours. Adverse effects include dose-limiting myelosuppression;nausea and vomiting that occur commonly butare generally mild; and pulmonary symptoms including interstitialpulmonary fibrosis, which is referred to as “busulfanlung,” occurs belatedly (1–10 years posttreatment) andalthough rare, it is severe. Other adverse effects includemucositis, skin rash, impotence, amenorrhea, infertility, hepatoxicity,insomnia, anxiety, and an increased risk of secondarymalignancies. At normal doses, the agent is welltolerated except for the myelosuppression that occurs. Thishas allowed for high-dose therapy with the agent when accompaniedby bone marrow transplant to counter the myelosuppressiveeffects.
- Air & Water ReactionsBusulfan is an alkylating agent which hydrolyzes in water. .
- Reactivity ProfileBusulfan is an alkylating agent which hydrolyzes in water. . Strong reducers may yield hydrogen sulfide.
- HazardExtremely toxic, carcinogen, clastogenic, teratogenic, immunosuppressive, delayed bone marrow aplasia, cataracts, pigmentation, pulmonary thrombosis, cardiotoxic effects, thrombocytopenia.
- Fire HazardFlash point data for Busulfan are not available. Busulfan is probably combustible.
- Clinical UseBusulfan is used in the treatment of chronic myelogenous leukemia and can be administered either orally or by IV infusion.
- Side effectsSerious bone marrow hypoplasia and myelosuppression are possible with this agent, and recovery from busulfaninduced pancytopenia can take up to 2 years.
- Safety ProfileConfirmed carcinogen producing leukemia, kidney, and uterine tumors. Experimental neoplastigenic and tumorigenic data. Poison by ingestion, subcutaneous, intraperitoneal, intravenous, and possibly other routes. Ingestion by pregnant women can cause cancer of the reproductive system of the fetus includtng the uterus. Human teratogenic effects by ingestion and possibly other routes include developmental abnormaltties of the eye, ear, craniofacial area including the nose and tongue, gastrointestinal system, endocrine system, urogenital system, and other unspecified areas. Other human reproductive effects by ingestion and possibly other routes include: impotence, changes in the uterus, cervix, and vagina, and menstrual-cycle dtsorders. Experimental reproductive effects. Human systemic effects by ingestion: general arteriolar or venous ddation of the eye, changes in structure or function of salivary glands. When heated to decomposition it emits toxic fumes of SOx. See also SULFONATES.
- Chemical SynthesisBusulfan, 1,4-butandioldimethansulfonate (18.104.22.168), is made by reacting
butandiol with methanesulfonyl chloride.
- Veterinary Drugs and TreatmentsBusulfan may be useful in the adjunctive therapy of chronic granulocytic leukemias or polycythemia vera in small animals. Not commonly used in veterinary medicine.
- Carcinogenicity1,4-Butanediol dimethanesulfonate is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.
Busulfan Preparation Products And Raw materials
- (+)-1,4-DI-O-MESYL-2,3-O-ISOPROPYLIDENETHREITOL L-Dihydroxy-Busulfan (R)-1,2,4-BUTANETRIOL TRIMESYLATE 1,2,4-TRIS(METHANESULFONYLOXY)BUTANE Busulfan-D8(tetramethylene),Busulfan-d8,BUSULFAN-D8 (TETRAMETHYLENE-D8) SALOR-INT L163503-1EA AURORA KA-611 AKOS BBS-00002040 dimethylmyleran (R)-1,4-DITOSYLOXY-2-BUTANOL AURORA KA-659 (S)-1,2,4-BUTANETRIOL TRIMESYLATE AKOS 90005 (S)-1,2,4-TRITOSYL BUTANETRIOL Busulfan methanesulfonate 2,3-Butanediol 1,4-Butanediol
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