New synthesis of 5H-pyrrolo[3,2-d]pyrimidines via pyrimido[5,4-c]pyridazines

Klein, Robert S.; Lim, Mu-Ill; Tam, Steve; Fox, Jack J.

doi:10.1021/jo00406a053

Cited by 43 publications

(11 citation statements)

References 7 publications

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“…2-Amino-4,6-dihydroxy-5-methylpyrimidine and 4-amino-6-hydroxy-2-methylpyrimidine dihydrate were purchased from Acros. 2,5-Diamino-4-hydroxypyrimidine, 29 2,5-diamino-4,6-dihydroxypyrimidine, 30 9-deazaguanine, 31 32 were prepared according to the literature procedures. -6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine was prepared by a slight modification of the route reported by Gangjee 33 and Secrist.…”

Section: Methodsmentioning

confidence: 99%

Structure-Based Design and Characterization of Novel Platforms for Ricin and Shiga Toxin Inhibition

et al. 2001

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Ribosome inhibiting proteins, RIPs, are a widespread family of toxic enzymes. Ricin is a plant toxin used as a poison and biological warfare agent; shiga toxin is a homologue expressed by pathogenic strains of E. coli. There is interest in creating effective antidote inhibitors to this class of enzymes. RIPs act by binding and hydrolyzing a specific adenine base from rRNA. Previous virtual screens revealed that pterins could bind in the specificity pocket of ricin and inhibit the enzyme. In this paper we explore a range of compounds that could serve as better platforms for inhibitor design. This establishes the importance of key hydrogen bond donors and acceptors for active-site complementarity. 8-Methyl-9-oxoguanine is a soluble compound that has the best inhibitory properties of any platform tested. The X-ray structure of this complex revealed that the inhibitor binds in an unexpected way that provides insight for future design. Several inhibitors of ricin were also shown to be inhibitors of shiga toxin, suggesting this program has the potential to develop effective antidotes to an important form of food poisoning.

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Section: Methodsmentioning

confidence: 99%

Structure-Based Design and Characterization of Novel Platforms for Ricin and Shiga Toxin Inhibition

et al. 2001

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“…Synthesis of 9-Deazahypoxanthine and Its 9-Substituted Derivatives Previously, 3 had been prepared by dichlorination of 1 with phosphorus oxychloride followed by partial alkaline hydrolysis of 6-chloro substituent and the subsequent removal of 2-chloro by hydrogenation with palla-dium on carbon, 9) or by the condensation of isoxazole and diethyl aminomalonate to form pyrrole derivative followed by reaction with formamidine acetate, 15) or by palladium-catalyzed cross-coupling of 4-methoxy-5-nitro-6-iodopyridine and trimethyl(tributylstannylethynyl)silane to form 4-methoxy-5-nitro-6-trimethylsilylethynylpyridine followed by construction of an annulated pyrrole ring. 16) However, in the routes to synthesize intermediates of 1 and 2, 6,8-dioxo-7H-2phenylpyrimido[5,4-c]pyridazine 8) and 6-amino-8-oxo-2phenylpyrimido[5,4-c]pyridazine, 8) respectively, by modifying Klein's procedure 8) using TFA as solvent, we found a simple two-step synthesis of 3 with an overall yield of 50%. This new method involved the reaction of 4-hydroxy-5phenylazo-6-methylpyrimidin-2-thione, 25, 17) with triethyl orthoformate in TFA at 70°C to give 8-oxo-7H-2phenylpyrimido[5,4-c]pyridazin-6-thione, 26.…”

Section: Resultsmentioning

confidence: 92%

“…Usually, the last step in these processes was the construction of the pyrimidine or pyrrole ring of the deazapurine base. [3][4][5][6][7] In order to find a simple and effective method to explore more PNP inhibitors, a facile synthesis of these analogues was developed based on the strategy of the direct aroylation or arylmethylation of available building blocks, such as 9-deazaxanthine (1), 8) 9-deazaguanine (2), 8,9) or 9-deazahypoxanthine (3). 9) The aroylated compounds could be converted to the corresponding arylmethyl derivatives or vise versa.…”

mentioning

confidence: 99%

Facile Synthesis of 9-Substituted 9-Deazapurines as Potential Purine Nucleoside Phosphorylase Inhibitors.

Shih

Cottam

Carson

2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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A facile synthesis of 9-substituted 9-deazapurines as potential inhibitors of purine nucleoside phosphorylase has been achieved by the direct Friedel-Crafts aroylation or arylmethylation of 9-deazapurines using trifluoromethanesulfonic acid as catalyst. The aroylated 9-deazapurines could be transformed into the corresponding 9-aryimethyl derivatives by the Wolff-Kishner reaction. A novel synthesis of 9-deazahypoxanthine was also developed by treatment of 4-hydroxy-5-phenylazo-6-methylpyrimidin-2-thione with triethyl orthoformate in trifluoroacetic acid (TFA) to yield 8-oxo-7H-2-phenylpyrimido[5,4-c]pyridazin-6-thione followed by Raney nickel reduction.

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“…91 In some cases the desired condensation reaction is accompanied by transformations of other functional groups present in the molecule (eqs 22 and 23). 77 Weakly acidic heteronucleophiles substitute for the alkoxy group in aminal esters. Thus hydrocyanic acid, 83 terminal alkynes, 93 and thiols 94 afford cyano, alkynyl, and alkylthio aminals (eq 24).…”

Section: Willi Kantlehner Universität Stuttgart Stuttgart Germanymentioning

confidence: 99%

t-Butoxybis(dimethylamino)methane

Kantlehner

Bowers

2007

Encyclopedia of Reagents for Organic Synthesis

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1 tert-Butoxybis(dimethylamino)methane 1 CH RO NMe 2 NMe 2 (1; R = t-Bu) (t-BAE) [5815-08-7] C 9 H 22 N 2 O (MW 174.33) InChI = 1/C9H22N2O/c1-9(2,3)12-8(10(4)5)11(6)7/h8H,1-7H3 InChIKey = HXRAMSFGUAOAJR-UHFFFAOYAR (2; R = Me) (MAE) [1186-70-5] C 6 H 16 N 2 O (MW 132.24) InChI = 1/C6H16N2O/c1-7(2)6(9-5)8(3)4/h6H,1-5H3 InChIKey = NCIMAYPZWJQYGN-UHFFFAOYAO (aminal esters reactive as aminomethylenating reagents (formylating reagents) for CH 2 -and NH 2 -acidic compounds. The t-butyl analog is somewhat more reactive than the methyl derivative; bis(dimethylamino)carbene can be generated from both compounds) Alternate Name: Bredereck's reagent. Physical Data: (1) bp 50-52 • C/12 mmHg; n 20 D = 1.4250. (2) bp 128 • C/760 mmHg; 32-33 • C/25 mmHg; n 20 D = 1.4158. Solubility: miscible with nonpolar aprotic waterfree solvents (benzene, toluene, cyclohexane, diethyl ether, etc.); react with protic solvents like water (hydrolysis to DMF) or alcohols (alcoholysis affords DMF acetals). Even common solvents like acetonitrile or acetone which are weakly CH-acidic react with the aminal esters on heating. Form Supplied in: colorless to weak yellow, strong aminesmelling liquids. Analysis of Reagent Purity: the best method is 1 H NMR spectroscopic examination of a neat sample. Handling, Storage, and Precautions: both compounds should be handled in a fume hood, with strict exclusion of atmospheric moisture. They should be stored in tightly sealed containers in a refrigerator under an atmosphere of dry nitrogen or argon.Introduction. Alkoxybis(dimethylamino)methanes can be obtained in good yields from N,N,N ,N -tetraalkylformamidinium salts and alcohol-free alkoxides. 2 The reactions have to be conducted in inert, strictly anhydrous solvents like cyclohexane, hexane, ether, or THF, in which unfortunately both reagents are insoluble. As a consequence it is necessary to use relatively large amounts of the solvent and long reaction times (eq 1). In the patent literature it is claimed that by the use of a mixture of DMF and mesitylene as solvent, the yields can be improved to about 95%. 3 In another method, 4 bis(dimethylamino)acetonitrile is used as the starting compound. Alcohol-free alkoxides suspended in absolute ether substitute the cyano group to give the corresponding aminal ester (eq 2). In contrast to the aforementioned method,

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New synthesis of 5H-pyrrolo[3,2-d]pyrimidines via pyrimido[5,4-c]pyridazines

Cited by 43 publications

References 7 publications

Structure-Based Design and Characterization of Novel Platforms for Ricin and Shiga Toxin Inhibition

Structure-Based Design and Characterization of Novel Platforms for Ricin and Shiga Toxin Inhibition

Facile Synthesis of 9-Substituted 9-Deazapurines as Potential Purine Nucleoside Phosphorylase Inhibitors.

t-Butoxybis(dimethylamino)methane

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