URACIL MUSTARD Chemical Properties

Melting point:

206°C (rough estimate)

Density 

1.6350 (rough estimate)

refractive index 

1.6100 (estimate)

solubility 

DMSO (Sparingly), Methanol (Slightly, Heated)

form 

Solid

pka

9.42±0.10(Predicted)

color 

Crystals from MeOH (aq)

IARC

2B (Vol. 9, Sup 7) 1987

EPA Substance Registry System

Uracil mustard (66-75-1)

Safety Information

RIDADR 

3249

HazardClass 

6.1(a)

PackingGroup 

I

Hazardous Substances Data

66-75-1(Hazardous Substances Data)

Toxicity

LD50 i.p. in rats: ~1.25-2.5 mg/kg (Chaube, Murphy)

URACIL MUSTARD Usage And Synthesis

Description

Uracil mustard appears as creamy/off-white, odourless, crystalline powder. It is used as an anti-cancer medicine. Uracil mustard is a chemotherapy drug that belongs to the class of alkylating agents. It is used for its anti-neoplastic properties. It works by damaging deoxyribonucleic acid (DNA), primarily in cancer cells that preferentially take up the uracil due to their need to make nucleic acids during their rapid cycles of cell division. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed. The DNA damage leads to apoptosis of the affected cells. Chemically it is a derivative of nitrogen mustard and uracil. Uracil mustard is a non-combustible substance itself; it does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Some are oxidisers and may ignite combustibles – wood, paper, oil, clothing, etc. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated.

Originator

Uracil Mustard,Upjohn,US,1962

Uses

Antineoplastic.

Definition

ChEBI: 5-[bis(2-chloroethyl)amino]uracil is a nitrogen mustard and an aminouracil.

Manufacturing Process

Preparation of 5-[bis(2-Hydroxyethyl)Amino] Uracil: 20 grams (0.157 mol) of 5-aminouracil was mixed with 350 ml of water, 23 ml of glacial acetic acid, and 160 ml of ethylene oxide in a one-liter flask immersed in an ice bath. The reaction mixture was stirred and allowed to come to room temperature slowly (as the ice melted), and stirring was continued for two days. A clear solution resulted to which was added 250 ml of water and 60 grams of Dowex-50 in the acid form. The mixture was stirred for 15 minutes, and the resin was collected on a filter. It was washed with water and the crude 5-[bis(2- hydroxyethyl)amino] uracil was eluted with a 10% aqueous solution of ammonium hydroxide. This eluate was evaporated to dryness, and the solid that remained was heated with 350 milliliters of isopropyl alcohol.Undissolved substances were removed by filtration and the filtrate was concentrated on a steam bath to a volume of about 125 ml and cooled to effect crystallization. After 20 hours at room temperature the crystals that had formed were recovered, washed with isopropyl alcohol, and dried, yielding 15.61 grams (46.2%) of crystalline 5-[bis(2-hydroxyethyl)amino] uracil having a MP of 157° to 163°C. An analytical sample, obtained by several recrystallizations from isopropyl alcohol, melted at 166° to 168°C.
Preparation of 5-[bis(2-Chloroethyl)Amino] Uracil: 13 ml of thionyl chloride was added to 52 ml of diethylene glycol dimethyl ether accompanied by stirring. Heat was generated, and sulfur dioxide and hydrogen chloride were liberated. The mixture was cooled and 5.58 grams of 5-[bis(2- hydroxyethyl)amino] uracil was added, followed by 8 ml of thionyl chloride, No evidence of reaction was noted, and the reaction mixture was heated to about 40°C, gas then being evolved. After one hour at 40°C, 5 ml of thionyl chloride was added, and after 30 minutes, another 3 ml was added. The mixture was then heated to 55°C, whereupon it darkened and all of the solid dissolved. After cooling and storage at room temperature for 20 hours, three volumes of benzene was added and a dark solid precipitated. After one hour, the dark solid was collected on a filter, washed with benzene, and dissolved in a minimum of boiling methanol. Crystals formed upon cooling; and after 18 hours in the refrigerator, they were recovered on a filter, washed with cold methanol, and dried under reduced pressure, yielding 2.96 grams of 5-[bis(2- chloroethyl)amino] uracil. The product was recrystallized by dissolving in a minimum of hot methanol and adding water until the solution became cloudy; 2.25 grams of 5-[bis(2-chloroethyl)amino] uracil was recovered after cooling the mixture to 4°C for 16 hours (MP 200° to 205°C). A small sample was recrystallized again, and it melted at 198° to 204°C.

Therapeutic Function

Cancer chemotherapy

General Description

Creamy white crystals or off-white powder. Used as an anti-cancer medicine.

Air & Water Reactions

Slightly soluble in water [Merck].

Reactivity Profile

URACIL MUSTARD (500 MG) (FOR U.S. SALE ONLY) reacts as a base.

Health Hazard

TOXIC; inhalation, ingestion or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution.

Fire Hazard

Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Some are oxidizers and may ignite combustibles (wood, paper, oil, clothing, etc.). Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated.

Safety Profile

Suspected carcinogen withexperimental carcinogenic and neoplastigenic data. Adeadly poison by ingestion and intraperitoneal routes.Mutation data reported. When heated to decomposition itemits very toxic fumes of Cl?? and NOx.

Carcinogenicity

Uracil mustard was reportedly carcinogenic in both mice and rats following multiple intraperitoneal injections. It produced a dose-related increase in lung tumor incidence in mice and tumors in a variety of other organs in both mice and rats. The IARC reviewed the preceding data and deemed it “sufficient evidence of carcinogenicity in animals.” Based on this information, its mutagenic potential, analogy to other nitrogen mustards, and a lack of carcinogenicity data in humans, the IARC classified uracil mustard in Group 2B (possibly carcinogenic to humans). Uracil mustard compared to nitrogen mustard itself in the same assay (lung tumor assay in strain A mice, intraperitoneal dosing) was found to be more potent as a tumorigen than nitrogen mustard. An in vitro assay to predict carcinogenicity gave a positive response predicting that uracil mustard would be a carcinogen in rodent test models. The assay used focus formation in a stable bovine papillomavirus type 1 DNA carrying a mouse fibroblast cell line that does not require transfection, infection with virus,isolation of primary cells from animals, or addition of a microsomal fraction.

URACIL MUSTARD (66-75-1)Related Product Information

• Bendamustine
• 5-(2'-CHLOROETHYL)AMINOURACIL
• URACIL MUSTARD
• bis(2-chloroethyl)ethylamine
• 5-(ETHYLAMINO)-URACIL
• 5-(DIETHYLAMINO)URACIL
• 2,6-DIHYDROXY-4-METHYL-5-[BIS(2-CHLOROETHYL)AMINO]PYRIMIDINE
• 2-[bis(2-chloroethyl)amino]acetaldehyde