Chlorambucil Chemical Properties

Melting point:

65-70 °C

Boiling point:

460.1±40.0 °C(Predicted)

Density 

1.2486 (rough estimate)

refractive index 

1.6070 (estimate)

storage temp. 

2-8°C

solubility 

Practically insoluble in water, freely soluble in acetone and in ethanol (96 per cent).

pka

pKa ～1.3(H2O) (Uncertain)

form 

Solid

color 

White to Light yellow

Water Solubility 

<0.01 g/100 mL at 22 ºC

λmax

588nm(DMSO aq.)(lit.)

Merck 

14,2073

BRN 

999011

BCS Class

3/1

Stability:

Stable, but may be light sensitive. Store cold. Incompatible with strong oxidizing agents.

InChIKey

JCKYGMPEJWAADB-UHFFFAOYSA-N

CAS DataBase Reference

305-03-3(CAS DataBase Reference)

NIST Chemistry Reference

Chlorambucil(305-03-3)

IARC

1 (Vol. 26, Sup 7, 100A) 2012

EPA Substance Registry System

Chlorambucil (305-03-3)

Safety Information

Hazard Codes 

T

Risk Statements 

45-25-36/37/38

Safety Statements 

53-26-45

RIDADR 

UN 2811 6.1/PG 3

WGK Germany 

3

RTECS 

ES7525000

HazardClass 

6.1(b)

PackingGroup 

III

HS Code 

29224999

Hazardous Substances Data

305-03-3(Hazardous Substances Data)

Toxicity

LD50 i.p. in rats: 58.2 mmole/kg (Ross)

MSDS

• Language:English Provider:Chloroambucil
• Language:English Provider:SigmaAldrich

Chlorambucil Usage And Synthesis

Description

Chlorambucil, approved by the Food and Drug Administration (FDA) in 1957, is an antineoplastic/alkylating agent with a broad spectrum of antitumor activity used to treat chronic lymphocytic leukemia (CLL), Hodgkin’s and non-Hodgkin’s lymphomas.

Chemical Properties

beige powder

Chemical Properties

Chlorambucil is a crystalline solid

Originator

Leukeran,BurroughsWellcome,US,1957

Uses

Chlorambucil is a alkylating agent that is used as an chemotherapy drug in the treatment of chronic lymphocytic leukemia. Chlorambucil is also used to treat non-Hodgkin's lymphoma (NHL) and Hodgkin's disease.

Uses

Chlorambucil-d8 is the isotope labelled analogue of Chlorambucil (C324050), an alkylating agent that is used in the treatment of chronic lymphocytic leukemia. Chlorambucil is also used to treat non-Ho dgkin's lymphoma (NHL) and Hodgkin's disease.

Uses

antineoplastic, alkylating agent

Uses

tranquilization aid

Definition

ChEBI: A monocarboxylic acid that is butanoic acid substituted at position 4 by a 4-[bis(2-chloroethyl)amino]phenyl group. A chemotherapy drug that can be used in combination with the antibody obinutuzumab for the treatment of chronic lymphocytic leukemia.

Indications

Chlorambucil (Leukeran) is an aromatic nitrogen mustard that is intermediate in chemical reactivity between mechlorethamine and melphalan. Its mechanisms of action and range of antitumor activity are similar to theirs. It is well absorbed orally, but detailed information concerning its metabolic fate in humans is lacking.
Chlorambucil is used primarily as daily palliative therapy for chronic lymphocytic leukemia, Waldenstr?om’s macroglobulinemia, myeloma, and other lymphomas.
Bone marrow toxicity is the major side effect of chlorambucil. Nausea is uncommon or mild, and hair loss does not occur. Chlorambucil shares the immunosuppressive, teratogenic, and carcinogenic properties of the nitrogen mustards.

Manufacturing Process

Acetanilide and maleic acid are condensed to give beta-(p-acetaminobenzoyl) acrilic acid which is hydrogenated to give methyl-gamma-(p-aminophenyl) butyrate. That is reacted with ethylene oxide and then with phosphorus oxychloride to give the methyl ester which is finally hydrolyzed to give chlorambucil.

brand name

Leukeran (GlaxoSmithKline.

Therapeutic Function

Antineoplastic

General Description

Chlorambucil is available as 2-mg tablets for oral administrationin the treatment of Hodgkin’s lymphoma, andchronic lymphocytic leukemia in combination with prednisoneand as a single agent. The mechanisms of resistanceare the same as those seen for other agents of the class suchas mechlorethamine. The agent is well absorbed (75%) uponoral administration and highly protein bound. Metabolism ismediated by CYP and occurs extensively to give severalmetabolites, including the active phenylacetic acid–nitrogenmustard. The drug is eliminated via the kidneys with a terminalelimination half-life of 1.5 hours. Adverse effects includedose-limiting myelosuppression, which are seen asboth leucopenia and thrombocytopenia. Nausea and vomitingoccur less often than for mechlorethamine. Additionaladverse effects include hyperuricemia, azoospermia, amenorrhea,seizures, pulmonary fibrosis, and skin rash.

General Description

White to pale beige crystalline or granular powder with a slight odor. Melting point 65-69°C.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Chloroambucil is an alkylating agent. Reacts with proteins and a variety of nucleophilic compounds .

Fire Hazard

Literature sources indicate that Chloroambucil is nonflammable.

Biochem/physiol Actions

Chlorambucil is an anti-cancer drug that alkylates DNA and induces apoptosis. Death of chronic lymphocytic leukemia cells occurs via a p53-dependent mechanism.

Clinical Use

It is used in the palliative treatment of chronic lymphocytic leukemia, malignant lymphoma, and Hodgkin's disease.

Safety Profile

Confirmed carcinogen producing leukemia. Experimental carcinogenic and neoplastigenic data. Poison by ingestion, intravenous, intraperitoneal, and subcutaneous routes. Human systemic effects by ingestion: convulsions, cough, dyspnea, and interstitial fibrosis. Human reproductive effects by ingestion and possibly other routes: changes in spermatogenesis, menstrual cycle changes or disorders, and teratogenic effects of the fetal urogenital system. Experimental teratogenic and reproductive effects. Human mutation data reported. An anti-neoplastic agent. When heated to decomposition it emits very toxic fumes of Cland NOx.

Synthesis

Chlorambucil, 4-[p-[bis-(2-chloroethyl)amino]phenyl]butyric acid (30.2.1.7), is made from acetanilide and succinic anhydride. In the first stage of synthesis, acetanilide is acylated by succinic anhydride, giving 4-(4-acetaminophenyl)-4-ketobutyric acid (30.2.1.3). The keto group in this compound is reduced by hydrogen in a methanol solution using palladium on carbon as a catalyst. This results in the formation of the methyl ester of 4-(4-acetaminophenyl)-butyric acid (30.2.1.4). This is treated with an alkali in order to hydrolyze both the amide and ester parts of the molecule, which forms 4-(4-aminophenyl)butyric acid (30.2.1.5), which upon reaction with ethylene oxide gives 4-[p-[bis(2-hydroxyethyl) amino]phenyl]butyric acid (30.2.1.7). Replacing all of the hydroxyl groups in this compound using phosphoryl chloride and subsequent treatment with water to hydrolyze the resulting intermediate acid chloride to an acid gives chlorambucil (30.2.1.7).

Potential Exposure

Chlorambucil, an anticancer drug, is a derivative of nitrogen mustard. This drug is primarily used as an antineoplastic agent for treating lymphocytic leukemia; malignant lymphomas; follicular lymphoma; and Hodgkin’s disease. The treatments are not curative but do produce some marked remissions. Chlorambucil has also been tested for treatment of chronic hepatitis, rheumatoid arthritis; and as an insect chemosterilant. All of the chemical used in this country is imported from the United Kingdom. Work exposure in the United States would be limited to workers formulating the tablets, or to those patients receiving the drug.

Veterinary Drugs and Treatments

Chlorambucil may be useful in a variety of neoplastic diseases, including lymphocytic leukemia, multiple myeloma, polycythemia vera, macroglobulinemia, and ovarian adenocarcinoma. It may also be useful as adjunctive therapy for some immune-mediated conditions (e.g., glomerulonephritis, inflammatory bowel disease, nonerosive arthritis, or immune-mediated skin disease). It has found favor as a routine treatment for feline pemphigus foliaceous and severe feline eosinophilic granuloma complex due to the drug’s relative lack of toxicity in cats and efficacy.

Drug interactions

Potentially hazardous interactions with other drugs
Ciclosporin: ciclosporin concentration possibly reduced.
Patients who receive phenylbutazone may require reduced doses of chlorambucil.

First aid

Skin Contact: Flood all areas of body that havecontacted the substance with water. Do not wait to removecontaminated clothing; do it under the water stream. Usesoap to help assure removal. Isolate contaminated clothingwhen removed to prevent contact by others
Eye Contact: Remove any contact lenses at once. Flusheyes well with copious quantities of water or normal salinefor at least 20-30 min. Seek medical attention.
Inhalation: Leave contaminated area immediately; breathefresh air. Proper respiratory protection must be supplied toany rescuers. If coughing, difficult breathing or any othersymptoms develop, seek medical attention at once, even ifsymptoms develop many hours after exposure.
Ingestion: If convulsions are not present, give a glass ortwo of water or milk to dilute the substance. Assure that theperson’s airway is unobstructed and contact a hospital orpoison center immediately for advice on whether or not toinduce vomiting.

Carcinogenicity

Chlorambucil is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.

Environmental Fate

The mechanism of action of chlorambucil is thought to be an alkylating agent and an aromatic nitrogen mustard derivative; it interferes with DNA replication and RNA transcription by alkylation and cross-linking the strands of DNA.

Metabolism

Chlorambucil is extensively metabolised in the liver via the hepatic microsomal enzyme oxidation system, principally to phenylacetic acid mustard, which is pharmacologically active, and which also undergoes some spontaneous degradation to further derivatives.
Chlorambucil is excreted in the urine, almost exclusively as metabolites with less than 1% unchanged.

storage

Color Code—Blue: Health Hazard/Poison: Storein a secure poison location. Prior to working with chlorambucil you should be trained on its proper handling and storage. Store in cool, dry place. Store in sealed ampules or inamber screw-capped bottles or vials with Teflon? capliners. Solutions may be stored in bottles or vials with a silicone system having a Teflon? liner and sampled with needle and syringe. Prevent exposure to light. A regulated,marked area should be established where this chemical ishandled, used, or stored in compliance with OSHAStandard 1910.1045.

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.

Purification Methods

Chlorambucil is recrystallised from pet ether (flat needles) and has a solubility at 20o of 66% in EtOH, 40% in CHCl3, 50% in Me2CO but is insoluble in H2O [Everett et al. J Chem Soc 2386 1953]. [Beilstein 14 IV 1715.] CARCINOGEN.

Toxicity evaluation

The chemical is of a white to pale slight odorous powder, insoluble in water. It is very slightly dispersible in diethyl ether and acetone. It has a melting point of 69°C, boiling point of 424°C, and 5.75 pKa. The partition coefficient is 4.07 and has a molecular weight of 304.22 g mol^-1.

Incompatibilities

Moisture. Chlorambucil is an alkylating agent. Reacts with proteins and a variety of nucleophilic compounds. Compounds of the carboxyl group react with all bases, both inorganic and organic (i.e., amines) releasing substantial heat, water, and a salt that may beharmful. Incompatible with arsenic compounds (releases hydrogen cyanide gas), diazo compounds, dithiocarbamates, isocyanates, mercaptans, nitrides, sulfides (releasing heat, toxic, and possibly flammable gases), thiosulfates, and dithionites (releasing hydrogen sulfate and oxides of sulfur).

Waste Disposal

It is inappropriate and possibly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properlylabel and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged, and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator. Permanganate oxidation, high temperature incineration with scrubbing equipment, or microwave plasma treatment.

Chlorambucil(305-03-3)Related Product Information

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