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54-62-6

Supplier Related Products Identification Chemical Properties Safety Data Hazard Information Material Safety Data Sheet(MSDS) Spectrum Detail Well-known Reagent Company Product Information

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Identification

Name
Aminopterin
CAS
54-62-6
Synonyms
4-AMINOFOLIC ACID
4-AMINO-PGA
4-AMINOPTEROYLGLUTAMIC ACID
4-AMINOPTEROYL-L-GLUTAMIC ACID
AMINOPTERIN
AMINOPTERINE
4-amino-4-deoxypteroylglutamate
4-amino-folicaci
4-aminofolicacid[qr]
4-amino-pga[qr]
4-aminopteroylglutamicacid[qr]
4-diamino-6-pteridinyl)methyl)amino)benzoyl)-n-(p-(((l-glutamicaci
AGPA
ai3-26079[qr]
aminopteridine
aminopterinum
aminopterinum[qr]
a-ninopterin
apga
apga[qr]
EINECS(EC#)
200-209-9
Molecular Formula
C19H20N8O5
MDL Number
MFCD00036692
Molecular Weight
440.41
MOL File
54-62-6.mol

Chemical Properties

Appearance
Aminopterin is a white to yellow powder; commonly used as the dihydrate which forms clustersof yellow needles
Melting point 
225 °C
mp 
228-235 °C (dec.)

alpha 
18 º (c=1% in 0.1N NaOH)
Boiling point 
551.67°C (rough estimate)
density 
1.4378 (rough estimate)
refractive index 
1.6910 (estimate)
Fp 
87℃
storage temp. 
2-8°C

solubility 
2 M NaOH: 50 mg/mL

pka
pKa 5.5 (Uncertain)
form 
powder

color 
yellow

Usage
A folic acid antagonist. Its actively transported into cells by thefolate transporter. In the cell, its converted to a high molecular weight polyglutamate metabolite by folylpolyglutamate synthase, that, in turn, binds to dihydrofolate reductase a
Merck 
13,471
BRN 
69045
CAS DataBase Reference
54-62-6(CAS DataBase Reference)
EPA Substance Registry System
54-62-6(EPA Substance)

Safety Data

Hazard Codes 
T+
Risk Statements 
R61:May cause harm to the unborn child.
R28:Very Toxic if swallowed.
R63:Possible risk of harm to the unborn child.
R26/27/28:Very Toxic by inhalation, in contact with skin and if swallowed .
Safety Statements 
S53:Avoid exposure-obtain special instruction before use .
S28:After contact with skin, wash immediately with plenty of ... (to be specified by the manufacturer) .
S36/37:Wear suitable protective clothing and gloves .
S45:In case of accident or if you feel unwell, seek medical advice immediately (show label where possible) .
S36/37/39:Wear suitable protective clothing, gloves and eye/face protection .
S22:Do not breathe dust .
RIDADR 
UN 2811 6.1/PG 1

WGK Germany 
3

RTECS 
MA1050000


8-10-23
HazardClass 
6.1(a)
PackingGroup 
I
HS Code 
29339900
Safety Profile
Poison by ingestion and intraperitoneal routes. Human and experimental teratogenic data. Other experimental reproductive effects. Mutation data reported. Human systemic effects by ingestion: gastrointestinal. Questionable carcinogen with experimental tumorigenic data. When heated to decomposition it emits toxic fumes of NOx,.
Hazardous Substances Data
54-62-6(Hazardous Substances Data)
Toxicity
LDLo orl-rat: 2500 mg/kg JPETAB 95,303,49

Hazard Information

General Description
Clusters of yellow needles. Used as a rodenticide, medicine and rodenticide. Not registered as a rodenticide in the U.S.
Health Hazard
An antimetabolite; antagonizes the utilization of folic acid by the body. Highly toxic by ingestion.
Potential Exposure
Aminopterin is used as a medicine (as a folic acid antagonist), rodenticide, and agricultural chemical.
First aid
Move victim to fresh air. Call 911 or emergency medical service. Give artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; give artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved and take precautions to protect themselves. Medical observation is recommended for 24 to 48 hours after breathing overexposure, as pulmonary edema may be delayed. As first aid for pulmonary edema, a doctor or authorized paramedic may consider administering a drug or other inhalation therapy.
Shipping
UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required
Waste Disposal
It is inappropriate and possibly dangerous to the environment to dispose of expired or wastepharmaceuticals 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 properly label 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
Chemical Properties
Dark Yellow Solid
Chemical Properties
Aminopterin is a white to yellow powder; commonly used as the dihydrate which forms clustersof yellow needles
Originator
Aminopterin,Sigma Chemical Company
Uses
A folic acid antagonist. Its actively transported into cells by thefolate transporter. In the cell, its converted to a high molecular weight polyglutamate metabolite by folylpolyglutamate synthase, that, in turn, binds to dihydrofolate reductase and inhibits its activity.
Uses
antineoplastic, antirheumatic, folic acid antagonist
Definition
Differs slightly in structure from folic acid and antagonizes the utilization of folic acid by the body, an antimetabolite.
Manufacturing Process
2,4,5,6-Tetraaminopyrimidine·H2SO4·H2O (75.0 g, 0.293 mole) was added to a stirred solution of BaCl2·2H2O (71.5 g, 0.293 mole) in H2O (1.45 L) at 85- 90°C. The mixture was stirred rapidly at about 90°C for 15 min, cooled to 40°C, and filtered from BaSO4, which was washed thoroughly on a funnel withH2O. The clear, yellow filtrate was then diluted further with H2O to give a volume of 4.35 L. This solution of the tetraaminopyrimidine·2HCl was then added to a solution of NaOAc (4.35 L of 4 N) in which 1,3-dihydroxyacetone (79.3 g, 0.88 mole) and cysteine·HCl·H2O (51.5 g, 0.293 mole) had just been dissolved. The resulting solution was stirred mechanically at room temperature while a slow stream of air was continuously passed through it for 26 hours. (Yellow-orange solid began separating after 2 hours). The mixture was then kept in a refrigerator for 16 hours before the solid was collected, washed successively with cold H2O, EtOH, and Et2O before it was dried to constant weight in vacuo over P2O5 at 25°C. [The crude product mixture (47 g) was weighed in order to obtain an estimate of the volume of 48% HBr required to form hydrobromide salts]. A mechanically stirred mixture of the dried solid and EtOH (6.05 L) was heated to 70°C, and a solution of 48% HBr (28 ml) in EtOH (490 ml) was added in a thin stream while the mixture was maintained at 70-75°C. The mixture was then refluxed for about 5 min with rapid stirring while nearly all of the solid dissolved. The hot solution was treated with Norit and filtered through a Celite mat. The clear yellow filtrate was kept in a refrigerator overnight while a first crop of orange colored solid separated. The collected solid was washed with EtOH, then dried in vacuo (56°C over P2O5) to give 17.2 g of product. The filtrate was concentrated by evaporation (rotary evaporator) to about 2 L and then refrigerated to give a second crop of 10.2 g, which was dried as before; total yield of crude 2,4- diamino-6-pteridinemethanol hydrobromide 27.4 g (34%). The PMR spectrum of this material in CF3CO2D showed it to contain a barely detectable amount of methyl-substituted 2,4-diaminopteridine·HBr.
Bromine (59.6 g, 0.373 mole) was added dropwise over a 30 min to a stirred solution of triphenylphosphine (97.7 g, 0.373 mole) in anhydrous dimethylacetamide (486 ml) kept at 10°C (ice bath) and protected from atmospheric moisture. (Bromine remaining in the funnel was rinsed with 10 ml of dimethylacetamide). A smooth suspension containing finely divided, crystalline triphenylphosphine dibromide resulted. The 2,4-diamino-6- pteridinemethanol·HBr (25.4 g, 0.093 mole) described above was added in one portion through a powder funnel (with the aid of 10 ml dimethylacetamide). The ice bath was removed, and the stirred mixture was allowed to warm to 20-25°C. After about 1 hour, complete solution had occurred. The solution, which gradually developed a dark red color, was kept at 20-25°C for 1 hour longer and was then chilled (ice bath) before it was treated with EtOH (72 ml). After overnight refrigeration, the solvents were removed by evaporation in vacuo. The dark, semisolid residue was stirred with two 300 ml of C6H6 (to remove triphenylphosphine oxide), and each portion was removed from the C6H6 insoluble product by decantation. The solid that remained was dissolved with stirring in glacial AcOH (660 ml) which had been preheated to 80°C. The mixture was kept in a bath at 80°C until solution was complete. Tan crystalline solid separated as the dark solution was allowed to cool. Overnight refrigeration caused the AcOH to partially freeze. When it had thawed, the solid was collected, washed with chilled AcOH followed by Et2O, and dried in vacuo (over P2O5 and NaOH pellets) at successive temperatures of 25°C, 56°C, and 110°C. (The higher temperature was necessary for complete removal of AcOH). The yield was 15.3 g (49%). (Some runs afforded 60% yield). This sample was further purified by reprecipitation from MeOH solution (Norit) by addition of Et2O followed by drying in vacuo (25°C, P2O5), yield 13.0 g (42%) of 2,4-diamino-6-(bromomethyl)pteridine hydrobromide as A mixture of 2,4-diamino-6-(bromomethyl)pteridine hydrobromide (168 mg, 0.500 mmole) and N-(4-aminobenzoyl)-L-glutamic acid (400 mg, 1.50 mmoles) in dimethylacetamide (2 ml) was stirred at 25°C under N2 in a stoppered flask protected from light. Solution occurred after 2 hours. After 18 hours, the orange solution was mixed with H2O (15 ml) with stirring to give a finely divided, yellow precipitate. The mixture was centrifuged, and the supernatant removed by decantation. The yellow solid was stirred with four 15 ml portions of H2O, each of which was removed by decantation after centrifugation. The solid was then suspended in EtOH (15-20 ml), collected by filtration, washed with Et2O, and dried in vacuo (25°C, P2O5) to give hydrated N-[4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid (Aminopterin) hydrate (4:7) in 68% yield (160 mg). Examination by TLC revealed one UV-absorbing spot and no fluorescence at any point.
Therapeutic Function
Antineoplastic
Purification Methods
Purify aminopterin by recrystallisation from H2O. It has properties similar to those of methotrexate (above). It has UV at max 244, 290 and 355nm ( 18600, 21300 and 12000) in H2O at pH 1; 260, 284 and 370nm ( 28500, 26400 and 8600) in H2O at pH 13. [Seeger et al. J Am Chem Soc 71 1753 1949, Angier & Curran J Am Chem Soc 8 1 2814 1959, Blakley The Biochemistry of Folic Acid and Related Pteridines, North-Holland Publ Co., Amsterdam, NY, pp 157-163 1969.] For small quantities, chromatograph it on DEAE cellulose with a linear gradient of ammonium bicarbonate pH 8 and increase the molarity from 0.1 to 0.4. Monitoring is by following the UV absorption of the fractions. For larger quantities, a near boiling solution of aminopterin (5g) in H2O (400mL) is slowly treated with small portions of MgO powder (~0.7g, calcined magnesia) with vigorous stirring until a small amount of MgO remained undissolved and the pH rises from 3-4 to 7-8. Charcoal (1g) is added to the hot solution and filtered immediately through a large sintered glass funnel of medium porosity and lined with a hot wet pad of Celite (~2-3 mm thick). The filtrate is cooled in ice, and the crystals of the Mg salt are collected by filtration and recrystallised from boiling H2O (200mL). The crystals are washed with EtOH and dried in vacuo. The Mg salt is redissolved in boiling H2O (200mL) and carefully acidified with vigorous agitation with AcOH (2mL). Pure aminopterin (3g) separates in fine yellow needles (dihydrate) which are easily filtered. The solid is washed with cold H2O, then Me2CO and dried in vacuo. If a trace of impurity is still present as shown by DEAE cellulose chromatography or TLC, repetition of the process will remove it; see UV above. [Loo J Med Chem 8 139 1965, Beilstein 26 IV 3831.] CARCINOGENIC.

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Sigma Aldrich
54-62-6(sigmaaldrich)
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