Pyrimethamine

Base Information

• Chemical Name: Pyrimethamine
• CAS No.: 58-14-0
• Molecular Formula: C12H13ClN4
• Molecular Weight: 248.715
• Hs Code.: 29335990
• European Community (EC) Number: 200-364-2
• NSC Number: 757306,3061
• UN Number: 2811
• UNII: Z3614QOX8W
• DSSTox Substance ID: DTXSID9021217
• Nikkaji Number: J4.589F
• Wikipedia: Pyrimethamine
• Wikidata: Q421072
• NCI Thesaurus Code: C788
• RXCUI: 9010
• Pharos Ligand ID: G5NUG5N82974
• Metabolomics Workbench ID: 42609
• ChEMBL ID: CHEMBL36
• Mol file: 58-14-0.mol

Synonyms:Chloridin;Daraprim;Malocide;Pyrimethamine;Tindurine

Chemical Property of Pyrimethamine

Chemical Property:

• Appearance/Colour: white solid
• Vapor Pressure: 8.34E-10mmHg at 25°C
• Melting Point: 233-234°C
• Refractive Index: 1.655
• Boiling Point: 491.5 °C at 760 mmHg
• PKA: pKa 7(t=20.0) (Uncertain)
• Flash Point: 251 °C
• PSA: 77.82000
• Density: 1.305 g/cm³
• LogP: 3.68620
• Storage Temp.: 0-6°C
• Solubility.: Prepare the solution immediately before use. Dissolve 0.25 g in a mixture of 1 volume of methanol R and 3 volumes of methylene chloride R and dilute to 10 mL with the same mixture of solvents. The solution is clear (2.2.1) and not more intensely coloured than reference solution BY6 (2.2.2, Method II).
• Water Solubility.: <0.01 g/100 mL at 21℃
• XLogP3: 2.7
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 4
• Rotatable Bond Count: 2
• Exact Mass: 248.0828741
• Heavy Atom Count: 17
• Complexity: 243
• Transport DOT Label: Poison

Purity/Quality:

99% ^*data from raw suppliers

Pyrimethamine ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xn
• Hazard Codes: Xn
• Statements: 22-36
• Safety Statements: 26

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CCC1=C(C(=NC(=N1)N)N)C2=CC=C(C=C2)Cl
• Recent ClinicalTrials: Pyrimethamine as an Inhibitor of NRF2 in HPV-negative Locally Advanced Head and Neck Squamous Cell Carcinoma
• Recent EU Clinical Trials: A Phase I/II Open-Label Study to Evaluate the Safety, Tolerability and Recommended Phase II Dose (RP2D) of GLG-801 in patients with Advanced Solid Tumors (Phase I); and safety, tolerability and anticancer activity of GLG-801 in patients with Metastatic TNBC (Phase II).
• Recent NIPH Clinical Trials: OPEN-LABEL, CROSSOVER EXPLORATORY STUDY TO ASSESS THE DOSE DEPENDENT EFFECT OF PYRIMETHAMINE ON EXOGENOUS AND ENDOGENOUS MATE1/2K SUBSTRATES
• Uses: For the treatment of toxoplasmosis and acute malaria; For the prevention of malaria in areas non-resistant to pyrimethamine. Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum malaria with pyrimethamine alone is therefore not recommended. Most strains of Plasmodium vivax have remained sensitive. Pyrimethamine is also used in combination with a sulfonamide for the treatment of Toxoplasmosis. It is slowly absorbed from the gastrointestinal tract with peak plasma levels 4–6 hours after dosing. Pyrimethamine is bound to plasma proteins and is extensively metabolized before excretion. Its elimination half-life is 3–5 days. This powerful inhibitor of dihydrofolate reductase is used for preventing and treating malaria caused by plasmodia P. vivax, P. malariae, P. ovale, including P. falciparum. Pyrimethamine, an antagonist of folic acid, exhibits antimicrobial action against causative agents of malaria and simultaneously possesses sporontocide action. It is also effective with respect to the causative agent of toxoplasmosis. It is used for preventing malaria and treating toxoplasmosis. It can only be used for preventative measures; however, because resistance develops quickly and because of the fact that the maximal effect is achieved by using it in combination with sulfadoxine, a combined drug which is prescribed under the name fansidar, which contains a pyrimethamine–sulfadoxine ratio of 1:20. A combination of pyrimethamine, sulfonamide, and quinine is the drug of choice for acute attacks of malaria and its chloroquine-resistant forms. Pyrimethamine in combination with sulfadiazine or trisulfapyrimidine is the drug of choice for toxoplasmosis. A synonym of this combined drug is daraprim. Dihydrofolate reductase inhibitor; generally used in combination with other antimicrobial agents. Antiprotozoal (Toxoplasma); antimalarial
• Indications: Pyrimethamine (Daraprim) is the best of a number of 2,4- diaminopyrimidines that were synthesized as potential antimalarial and antibacterial compounds. Trimethoprim (Proloprim) is a closely related compound. Pyrimethamine is well absorbed after oral administration, with peak plasma levels occurring within 3 to 7 hours. An initial loading dose to saturate nonspecific binding sites is not required, as it is with chloroquine. However, the drug binds to tissues, and therefore, its rate of renal excretion is slow. Pyrimethamine has a half-life of about 4 days. Although the drug does undergo some metabolic alterations, the metabolites formed have not been totally identified.
• Clinical Use: Pyrimethamine has been recommended for prophylactic use against all susceptible strains of plasmodia; however, it should not be used as the sole therapeutic agent for treating acute malarial attacks. As mentioned previously, sulfonamides should always be coadministered with pyrimethamine (or trimethoprim), since the combined antimalarial activity of the two drugs is significantly greater than when either drug is used alone. Also, resistance develops more slowly when they are used in combination. Sulfonamides exert little or no effect on the blood stages of P. vivax, and resistance to the dihydrofolate reductase inhibitors is widespread. In addition to its antimalarial effects, pyrimethamine is indicated (in combination with a sulfonamide) for the treatment of toxoplasmosis.The dosage required is 10 to 20 times higher than that employed in malarial infections.
• Drug interactions: Potentially hazardous interactions with other drugs Increased antifolate effect with sulphonamides, trimethoprim, methotrexate and pemetrexed. Antiepileptics: anticonvulsant effect of fosphenytoin and phenytoin antagonised, also increased antifolate effect. Antimalarials: avoid concomitant use with artemether/lumefantrine; increased antifolate effect with proguanil.

Technology Process of Pyrimethamine

There total 29 articles about Pyrimethamine which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 85.0%

2,4-diamino-5-(3-azido-4-chlorophenyl)-6-ethylpyrimidine (95458-40-5) → 2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidine (58-14-0)

Guidance literature:

With hydrazine hydrate; for 0.25h; Heating;

DOI:10.1039/P19870002217

Reference yield: 76.0%

4-Chlorophenylboronic acid (1679-18-1) + 2,4-diamino-6-ethyl-5-iodopyrimidine (514854-13-8) → 2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidine (58-14-0)

Guidance literature:

With dipotassium hydrogenphosphate; Pd(OAc)2(dppf)2; In 1,2-dimethoxyethane; for 24h; Heating;

Reference yield: 74.0%

5-(4-chlorophenyl)pyrimidine-2,4-diamine (17039-14-4) + Ethyl boronic acid (4433-63-0) → 2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidine (58-14-0)

Guidance literature:

5-(4-chlorophenyl)pyrimidine-2,4-diamine; With acetic acid; trifluoroacetic acid; In acetonitrile; at 20 ℃; for 0.166667h; Green chemistry;

Ethyl boronic acid; With oxygen; In acetonitrile; at 110 ℃; for 10h; under 760.051 Torr; Green chemistry;

DOI:10.1021/acs.orglett.7b03297

upstream raw materials:

diazomethane

α-(4-chlorophenyl)-α-propionylacetonitrile

6-ethyl-2-amino-5-(4-chloro-phenyl)-3H-pyrimidine-4-thione

N-[4-ethyl-6-chloro-5-(4-chloro-phenyl)-pyrimidin-2-yl]-acetamide

Downstream raw materials:

2,4-diamino-5-(4-chloro-3-nitrophenyl)-6-ethylpyrimidine

C₆H₁₀O₄*C₁₂H₁₃ClN₄

C₇H₁₂O₄*C₁₂H₁₃ClN₄

C₂₆H₂₁ClN₄O₂

Refernces

• 1、 Zhang, Lizhi,Liu, Zhong-Quan. "Molecular Oxygen-Mediated Minisci-Type Radical Alkylation of Heteroarenes with Boronic Acids". . p. 6594 - 6597. Retrieved 2017/12/26.
• 2、 Tarnchompoo, Bongkoch,Sirichaiwat, Chawanee,Phupong, Worrapong,Intaraudom, Chakapong,Sirawaraporn, Worachart,Kamchonwongpaisan, Sumalee,Vanichtanankul, Jarunee,Thebtaranonth, Yodhathai,Yuthavong, Yongyuth. "Development of 2,4-diaminopyrimidines as antimalarials based on inhibition of the S108N and C59R+S108N mutants of dihydrofolate reductase from pyrimethamine resistant Plasmodium falciparum". . p. 1244 - 1252. Retrieved 2007/10/03.