55-98-1

Basic information

• Product Name: Busulfan
• Synonyms: BUSULFAN;busulfex;busulphan;1,4-dimethanesulfonoxybutane;1，4-Bis(methyl sulfonoxy)butane;1,4-BUTANEDIOL DIMETHANESULFONATE;1，4-Butanediol dimethyl sulfonate;tetramethylene bis(methanesulfonate)
• CAS NO: 55-98-1
• Molecular Formula: C₆H₁₄O₆S₂
• Molecular Weight: 246.3
• EINECS: 200-250-2
• Product Categories: Antitumors for Research and Experimental Use;Biochemistry;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;MYLERAN
• Mol File: 55-98-1.mol
• Article Data: 17

Chemical Properties

• Melting Point: 114-117 °C(lit.)
• Boiling Point: 359.3°C (rough estimate)
• Flash Point: 9℃
• Appearance: Pale Brown/Crystalline Powder
• Density: 1.305 (estimate)
• Refractive Index: 1.5630 (estimate)
• 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).
• Water Solubility: Decomposes
• Stability: Moisture Sensitive
• Merck: 14,1505
• BRN: 1791786
• CAS DataBase Reference: Busulfan(CAS DataBase Reference)
• NIST Chemistry Reference: Busulfan(55-98-1)
• EPA Substance Registry System: Busulfan(55-98-1)

Safety Data

• Hazard Codes: T+,T,F
• 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
• Hazardous Substances Data: 55-98-1(Hazardous Substances Data)

Usage

Description

Chemically, 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 Properties

White Crystalline Solid

Originator

Myleran,Burroughs- Wellcome,US,1954

Uses

Different sources of media describe the Uses of 55-98-1 differently. You can refer to the following data:
1. Antineoplastic alkylating agent, the palliative treatment of chronic myeloid leukemia, and insect sterilant.
2. Busulfan USP (Myleran) is used to treat Chronic granulocytic leukemia; other myeloproliferative disorders.

Indications

Busulfan (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 urine. 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.

Definition

ChEBI: 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 Process

3.6 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 name

Myleran (GlaxoSmithKline).

Therapeutic Function

Antineoplastic

General Description

Different sources of media describe the General Description of 55-98-1 differently. You can refer to the following data:
1. White crystals or powder.
2. As 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.
3. Busulfan 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 Reactions

Busulfan is an alkylating agent which hydrolyzes in water. .

Reactivity Profile

Busulfan is an alkylating agent which hydrolyzes in water. . Strong reducers may yield hydrogen sulfide.

Hazard

Extremely toxic, carcinogen, clastogenic, teratogenic, immunosuppressive, delayed bone marrow aplasia, cataracts, pigmentation, pulmonary thrombosis, cardiotoxic effects, thrombocytopenia.

Fire Hazard

Flash point data for Busulfan are not available. Busulfan is probably combustible.

Clinical Use

Busulfan is used in the treatment of chronic myelogenous leukemia and can be administered either orally or by IV infusion.

Side effects

Serious bone marrow hypoplasia and myelosuppression are possible with this agent, and recovery from busulfaninduced pancytopenia can take up to 2 years.

Safety Profile

Confirmed 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.

Synthesis

Busulfan, 1,4-butandioldimethansulfonate (30.2.3.1), is made by reacting butandiol with methanesulfonyl chloride.

Veterinary Drugs and Treatments

Busulfan may be useful in the adjunctive therapy of chronic granulocytic leukemias or polycythemia vera in small animals. Not commonly used in veterinary medicine.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration increased by metronidazole. Antipsychotics: avoid with clozapine, increased risk of agranulocytosis. Antifungals: metabolism inhibited by itraconazole, monitor for signs of busulfan toxicity.

Carcinogenicity

1,4-Butanediol dimethanesulfonate is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.

Metabolism

Busulfan is extensively metabolised in the liver, mainly by conjugation with glutathione, either spontaneously or mediated by the enzyme glutathione-S-transferase. About 12 inactive metabolites have been identified, which are excreted in the urine. About 1% of busulfan is excreted unchanged. Elimination in the faeces is considered to be negligible.

references

[1]. probin v, wang y, zhou d. busulfan-induced senescence is dependent on ros production upstream of the mapk pathway. free radic biol med, 2007, 42(12): 1858-1865. [2]. probin v, wang y, bai a, et al. busulfan selectively induces cellular senescence but not apoptosis in wi38 fibroblasts via a p53-independent but extracellular signal-regulated kinase-p38 mitogen-activated protein kinase-dependent mechanism. j pharmacol exp ther, 2006, 319(2): 551-560.[3]. choi yj, ok dw, kwon dn, et al. murine male germ cell apoptosis induced by busulfan treatment correlates with loss of c-kit-expression in a fas/fasl- and p53-independent manner. febs lett, 2004, 575(1-3): 41-51.

InChI:InChI=1/C6H14O6S2/c1-13(7,8)11-5-3-4-6-12-14(2,9)10/h3-6H2,1-2H3

Synthetic route

Butane-1,4-diol (110-63-4) + methanesulfonamide (3144-09-0) → busulfan (55-98-1)

Conditions	Yield
With triethylamine at 5 - 40℃; for 4h; Temperature;	91%

Butane-1,4-diol (110-63-4) + methanesulfonyl chloride (124-63-0) → busulfan (55-98-1)

Conditions	Yield
With triethylamine In dichloromethane at 10 - 20℃; for 24h;	86%
With triethylamine In dichloromethane at 0 - 20℃; for 4h;	73.52%
With pyridine at 25℃; for 2h;	55%

tetrahydrofuran (109-99-9) + methanesulfonyl bromide (41138-92-5) → 1,4-dibromo-butane (110-52-1) + 4,4'-dibromo-di-n-butyl ether (7239-41-0) + busulfan (55-98-1) + 1-bromo-4-methanesulfonyloxy-butane (40671-33-8)

Conditions	Yield
zinc(II) chloride at 75℃; for 5h;

1-bromo-4-methanesulfonyloxy-butane (40671-33-8) + silver methanesulfonate (2386-52-9) → busulfan (55-98-1)

Conditions	Yield
In acetonitrile for 5h; Heating;

Butane-1,4-diol (110-63-4) + Methanesulfonic anhydride (7143-01-3) → busulfan (55-98-1)

bistrimethyl(1,4-butanedioxy)silane (18001-91-7) + methanesulfonyl chloride (124-63-0) → busulfan (55-98-1)

Conditions	Yield
With tin(IV) chloride at 80 - 100℃;

4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran (96042-30-7) + methanesulfonyl chloride (124-63-0) → busulfan (55-98-1)

Conditions	Yield
With triethylamine In water; ethyl acetate

busulfan (55-98-1) + 1,10-N,N'-bis-[cyclomaltoheptaosyl-6A-deoxy-6A-ureido]-4,7,13,16-tetraoxa-1,10-diazacyclooctadecane (1182838-48-7) → C6H14O6S2*C98H164N4O74 (1182838-51-2)

Conditions	Yield
In water; dimethyl sulfoxide at 20℃; for 18h; Inert atmosphere;	100%

busulfan (55-98-1) + 1,10-N,N'-bis-(β-D-ureidocellobiosyl)-4,7,13,16-tetraoxa-1,10-diazacyclooctadecane (1182838-47-6) → C6H14O6S2*C38H68N4O26 (1182838-49-8)

Conditions	Yield
In water; dimethyl sulfoxide at 20℃; for 18h; Inert atmosphere;	100%

busulfan (55-98-1) + 2-(benzhydrylideneamino)-1-(10,10-dimethyl-3,3-dioxo-3λ6-thia-4-aza-tricyclo[5.2.1.01.5]dec-4-yl)ethanone (138566-17-3) → C16H26N2O3S

Conditions	Yield
Stage #1: 2-(benzhydrylideneamino)-1-(10,10-dimethyl-3,3-dioxo-3λ6-thia-4-aza-tricyclo[5.2.1.01.5]dec-4-yl)ethanone With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.333333h; Inert atmosphere; Stage #2: busulfan In tetrahydrofuran at -78℃; for 3.16667h;	83%

busulfan (55-98-1) + potassium thioacetate (10387-40-3) → 1,4-bis-acetylsulfanyl-butane (6633-90-5)

Conditions	Yield
In acetone for 70h; Ambient temperature;	82%

busulfan (55-98-1) + 4-methoxy-aniline (104-94-9) → N-(4-methoxyphenyl)pyrrolidine (54660-04-7)

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	81.3%

busulfan (55-98-1) + C116H146O24 + 3-phenyl-3H-diazirine (42270-91-7) → C120H152O24*C7H6N2

Conditions	Yield
With caesium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide at 20℃; for 84h;	80.6%

busulfan (55-98-1) + C116H130(2)H16O24 + 3-phenyl-3H-diazirine (42270-91-7) → C120H136(2)H16O24*C7H6N2

Conditions	Yield
With caesium carbonate In N,N,N,N,N,N-hexamethylphosphoric triamide at 20℃; for 84h;	80%

busulfan (55-98-1) + aniline (62-53-3) → N-phenylpyrrolidine (4096-21-3)

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	78.6%

ethanol (64-17-5) + busulfan (55-98-1) + carbon monoxide (201230-82-2) → diethyl adipate (141-28-6)

Conditions	Yield
With sodium iodide; dicobalt octacarbonyl In various solvent(s) at 100℃; under 38000 Torr; for 24h;	78%

busulfan (55-98-1) + C18H27N3O5 (193282-97-2) → C23H37N3O8S (1610616-07-3)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 7h;	77%

busulfan (55-98-1) + benzo[1,3]dioxolo-5-ylamine (14268-66-7) → 1-(3,4-methylenedioxyphenyl)pyrrolidine

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	76.3%

busulfan (55-98-1) + p-toluidine (106-49-0) → 1-p-tolylpyrrolidine (54104-82-4)

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	75.1%

busulfan (55-98-1) + 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (582-52-5) → Methanesulfonic acid 4-[(3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-6-yloxy]-butyl ester + 1,4-bis<3-O-(1,2:5,6-di-O-isopropylidene-α-D-glucofuranos-3-yl)>butane (167535-48-0)

Conditions	Yield
With potassium hydroxide In dimethyl sulfoxide; toluene at 50℃; for 8h;	A 3.2% B 75%

busulfan (55-98-1) + 4-chloro-aniline (106-47-8) → 1-(4-chlorophenyl)pyrrolidine (4280-30-2)

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	72.4%

busulfan (55-98-1) + 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (4064-06-6) → Methanesulfonic acid 4-((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyl-tetrahydro-bis[1,3]dioxolo[4,5-b;4',5'-d]pyran-5-ylmethoxy)-butyl ester + 1,4-bis<6-O-(1,2:3,4-di-O-isopropylidene-α-D-galactopyranos-6-yl)>butane (167535-76-4)

Conditions	Yield
With potassium hydroxide In dimethyl sulfoxide; toluene at 50℃; for 8h;	A 3.2 g B 72%

busulfan (55-98-1) + 3-chloro-aniline (108-42-9) → N-(3-chlorophenyl)tetrahydropyrrole

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	70.2%

busulfan (55-98-1) + 4-Aminoacetophenone (99-92-3) → N-(4-acetylphenyl)pyrrolidine (21557-09-5)

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	65.5%

busulfan (55-98-1) + 2-Chloroaniline (95-51-2) → N-(2-chlorophenyl)tetrahydropyrrole (105516-46-9)

Conditions	Yield
With potassium carbonate In water at 100℃; for 1h; Microwave irradiation;	64.7%

Upstream product

• 40671-33-8 1-bromo-4-methanesulfonyloxy-butane 
• 2386-52-9 silver methanesulfonate 
• 18001-91-7 bistrimethyl(1,4-butanedioxy)silane 
• 124-63-0 methanesulfonyl chloride 
• 110-63-4 Butane-1,4-diol 
• 3144-09-0 methanesulfonamide 
• 96042-30-7 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran 
• 7143-01-3 Methanesulfonic anhydride 
• 109-99-9 tetrahydrofuran 
• 41138-92-5 methanesulfonyl bromide 

Downstream Products

• 15394-33-9 methyl 4-(methylsulfanyl)butyl sulfide 
• 72144-83-3 1,4-di(cyclohexylphenylphosphino)butane 
• 161264-20-6 8,9,10,11,39,40,41,42-octahydro-1,18,26,28,53,55,63,74-octaphenethyl-34,47-(epoxybutanoxy)-20,24:57,61-dimethano-2,52:3,51:16,30;17,29-tetrametheno-1H,18H,26H,28H,53H,55H-bis[1,3]benzodioxocino[9,8-d:9',8'-d']bis[1,3]benzodioxocino... 
• 1610616-08-4 C₂₃H₃₇N₃O₈S 
• 1610616-07-3 C₂₃H₃₇N₃O₈S 
• 129414-26-2 4-pyrrolidin-1-yl-benzoic acid methyl ester 
• 105516-46-9 N-(2-chlorophenyl)tetrahydropyrrole 
• 88154-24-9 N-(3-chlorophenyl)tetrahydropyrrole 
• 4096-21-3 N-phenylpyrrolidine 
• 10220-22-1 1-(4-nitro-phenyl)-pyrrolidine 
• 54660-04-7 N-(4-methoxyphenyl)pyrrolidine 
• 21557-09-5 N-(4-acetylphenyl)pyrrolidine 
• 4280-30-2 1-(4-chlorophenyl)pyrrolidine 
• 54104-82-4 1-p-tolylpyrrolidine 

Relevant articles and documents

Busulfan drug intermediate 1,4 bis-methyl sulfonate butyl diester synthetic method

A busulfan drug intermediate 1,4-bis-methyl sulfonate butyl diester synthetic method comprises the following steps: 0.15mol of 1,4-butanediol and 150-170ml of triethylamine are added into a reaction vessel, solution temperature is reduced to 3-5 DEG C, stirring speed is controlled at 130-160rpm, 0.36-0.38mol of methanesulfonic acid amine is slowly dropwise added, after the completion of the dropwise addition, the solution temperature is raised to 35-40 DEG C, the solution is stirred for 3-4h, solution temperature is reduced to 15-20 DEG C, a solid is precipitated, and the solid is filtered, washed with a saline solution, dehydrated with a dehydrating agent, and recrystallized in cyclohexane to obtain a white solid of 1,4-bis-methyl sulfonate butyl diester; and the saline solution in the step is any one of sodium nitrate and potassium sulphate.

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