- Mechanochemical Magnesium-Mediated Minisci C-H Alkylation of Pyrimidines with Alkyl Bromides and Chlorides
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A novel method to synthesize 4-alkylpyrimidines by the mechanochemical magnesium-mediated Minisci reaction of pyrimidine derivatives and alkyl halides has been reported. The reaction process operates with a broad substrate scope and excellent regioselectivity under mild conditions with no requirement of transition-metal catalysts, solvents, and inert gas protection. The practicality of this protocol has been demonstrated by the up-scale synthesis, mechanochemical product derivatization, and antimalarial drug pyrimethamine preparation.
- Wu, Chongyang,Ying, Tao,Yang, Xinjie,Su, Weike,Dushkin, Alexandr V.,Yu, Jingbo
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p. 6423 - 6428
(2021/08/30)
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- Molecular Oxygen-Mediated Minisci-Type Radical Alkylation of Heteroarenes with Boronic Acids
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The carbon-carbon bond formation via autoxidation of organoboronic acid using 1 atm of O2 is achieved in a simple, clean, and green fashion. The approach allows a technically facile and environmentally benign access to structurally diverse heteroaromatics with medicinally privileged scaffolds. The strategy also displays its practicality and sustainability in the resynthesis of marketed drugs Crestor and pyrimethamine.
- Zhang, Lizhi,Liu, Zhong-Quan
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p. 6594 - 6597
(2017/12/26)
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- Structure-based design, synthesis and preliminary evaluation of selective inhibitors of dihydrofolate reductase from Mycobacterium tuberculosis
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Tuberculosis is an increasing threat, owing to the spread of AIDS and to the development of resistance of the causative organism, Mycobacterium tuberculosis, to the currently available drugs. Dihydrofolate reductase (DHFR) is an important enzyme of the folate cycle; inhibition of DHFR inhibits growth and causes cell death. The crystal structure of M. tuberculosis DHFR revealed a glycerol tightly bound close to the binding site for the substrate dihydrofolate; this glycerol-binding motif is absent from the human enzyme. A series of pyrimidine-2,4-diamines was designed with a two-carbon tether between a glycerol-mimicking triol and the 6-position of the heterocycle; these compounds also carried aryl substituents at the 5-position. These, their diastereoisomers, analogues lacking two hydroxy groups and analogues lacking the two-carbon spacing linker were synthesised by acylation of the anions derived from phenylacetonitriles with ethyl (4S,5R)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane-4-propanoate, ethyl (4S,5S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane-4-propanoate, tetrahydrooxepin-2-one and 2,3-O-isopropylidene-d-erythronolactone, respectively, to give the corresponding α-acylphenylacetonitriles. Formation of the methyl enol ethers, condensation with guanidine and deprotection gave the pyrimidine-2,4-diamines. Preliminary assay of the abilities of these compounds to inhibit the growth of TB5 Saccharomyces cerevisiae carrying the DHFR genes from M. tuberculosis, human and yeast indicated that 5-phenyl-6-((3R,4S)-3,4,5-trihydroxypentyl)pyrimidine-2,4-diamine selectively inhibited M. tuberculosis DHFR and had little effect on the human or yeast enzymes.
- El-Hamamsy, Mervat H.R.I.,Smith, Anthony W.,Thompson, Andrew S.,Threadgill, Michael D.
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p. 4552 - 4576
(2008/03/12)
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- Structural studies on bioactive compounds. Part 37. Suzuki coupling of diaminopyrimidines: A new synthesis of the antimalarial drug pyrimethamine
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Suzuki reactions have been used successfully to effect cross-coupling of 5-halopyrimidines with 4-chlorobenzeneboronic acid and 2,4-diamino-5-(4-chloro-3-halo)-6-ethylpyrimidines with 4-methoxybenzeneboronic acid. The antimalarial drug pyrimethamine has been prepared by coupling 2,4-diamino-6-ethyl-5-iodopyrimidine with 4-chlorobenzeneboronic acid.
- Richardson, Marianne L.,Stevens, Malcolm F.G.
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p. 482 - 484
(2007/10/03)
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- 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
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The reduced binding of pyrimethamine to Serl08Asn (S108N) mutants of parasite dihydrofolate reductase (DHFR), which forms the basis of resistance of Plasmodium falciparum to pyrimethamine, is largely due to steric constraint imposed by the bulky side chain of N108 on Cl of the 5-p-Cl-phenyl group. This and other S108 mutants with bulky side chains all showed reduced binding to pyrimethamine and cycloguanil. Less effect on binding to some bulky mutants was observed for trimethoprim, with greater flexibility for the 5-substituent. S108N DHFR also binds poorly with other pyrimethamine derivatives with bulky groups in place of the p-Cl, and the binding was generally progressively poorer for the double (C59R+S108N) mutant. Removal of the p-Cl or replacement with m-Cl led to better binding with the mutant DHFRs. Pyrimethamine analogues with unbranched hydrophobic 6-substituents showed generally good binding with the mutant DHFRs. A number of compounds were identified with high affinities for both wild-type and mutant DHFRs, with very low to no affinity to human DHFR. Some of these compounds show good antimalarial activities against pyrimethamine-resistant P. falciparum containing the mutant DHFRs with low cytotoxicity to three mammalian cell lines.
- Tarnchompoo, Bongkoch,Sirichaiwat, Chawanee,Phupong, Worrapong,Intaraudom, Chakapong,Sirawaraporn, Worachart,Kamchonwongpaisan, Sumalee,Vanichtanankul, Jarunee,Thebtaranonth, Yodhathai,Yuthavong, Yongyuth
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p. 1244 - 1252
(2007/10/03)
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- Regioselective Deacylation of 2,4-Diacylaminopyrimidine Derivatives by Lewis Acids and Crystal Structures of Two Products
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Deacylation of 2,4-diacylamino derivatives of pyrimethamine and related diaminopyrimidines with tin(II) chloride or zinc chloride, in ethanol or propan-2-ol, affords 2-acyl-4-aminopyrimidines exclusively.Regioselective 4-deacylation was observed by 1H NMR spectroscopy and established by crystallographic analysis of the 2,4-dipropionylpyrimidine 11 and the corresponding 4-amino-2-propionylpyrimidine deacylation product 17.The latter exists in the solid state as an unusual base-pair dimer linked by two pairs of equivalent hydrogen bonds.
- Griffin, Roger J.,Lowe, Philip R.
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p. 1811 - 1820
(2007/10/02)
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- Stuctural Studies on Bio-active Compounds. Part 5. Synthesis and Properties of 2,4-Diaminopyrimidine Dihydrofolate Reductase Inhibitors bearing Lipophilic Azido Groups
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A series of 2,4-diamino-5-(azidoaryl)-6-alkylpyrimidines has been prepared.The azide (36) (MZP) can be reduced by thiol reagents to the corresponding amine (28) but reductive deazidation occured when the series of azidophenyl derivatives was heated with hydrazine hydrate.Degradation of azide (36) in a trifluoroacetic acid-trifluoromethanesulphonic acid mixture at 0 deg C affords a means of introducing the bulky trifluoromethylsulphonyloxy substituent into the hindered ortho-position of the 5-aryl substituent.The products formed from thermolysis and photolysis of the azide (36) and the planar analogue 2,4-diamino-6-azidoquinazoline (70) derive from the triplet nitrene reactive intermediates. The azido compounds are potent inhibitors of rat liver dihydrofolate reductase although not as active as metoprin.The azide (36), as its ethanesulphonic acid salt, was selected for clinical trial on the basis of its ease of synthesis and suitable biological and pharmaceutical properties, and has a shorter biological half-life than compounds of comparable hydrophobicity.
- Bliss, Edward A.,Griffin, Roger J.,Stevens, Malcolm F. G.
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p. 2217 - 2228
(2007/10/02)
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- Selective Reactions in the Triazene Series. Part 2. Protodediazoniation of Arenediazonium Salts with Formamide
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Treatment of performed arenediazonium tetrafluoroborates or arenediazonium trifluoroacetates (formed in situ) with formamide an base effects reduction to the corresponding arene in moderate to good yield in cases where an electron-withdrawing substituent is present on the aromatic ring.Other functionalities remain unaffected.The mechanism of the protodediazoniation is shown to involve transfer of the formyl hydrogen atom to the substrate and may proceed via a 1-aryl-3-formyltriazine.
- Threadgill, Michael D.,Gledhill, Adrian P.
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p. 873 - 876
(2007/10/02)
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- 3-Imino-1,2,4-benzotriazine-1-oxides
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New 3-Imino-1,2,4-benzotriazine-1-oxides of formula I SPC1 wherein R represents an alkyl, alkenyl or haloalkyl radical, a phenyl or aralkyl radical optionally substituted by alkyl, alkoxy, haloalkyl, halogen or hydroxy, X and Y each independently represent hydrogen, halogen, an alkyl or alkoxy radical, or one of the two symbols represents a phenoxy or phenylsulphonyl radical optionally substituted by halogen, alkyl, haloalkyl and/or alkoxy which are active against harmful microorganisms are disclosed.
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- Intermediates for the preparation of pyrimidine compounds
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There is disclosed a method of making compounds represented by the formula SPC1 And which are useful as antimalarial agents. The method includes reacting a keto nitrile with a polyhydroxy compound and then reacting the product with guanidine base. In the above X is a halogen atom or a nitro group, Y is a halogen atom or hydrogen and R is hydrogen or alkyl containing 1 to 10 and preferably is lower alkyl containing 1 to 4 carbon atoms.
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