- Synthesis method of 6-chloro-3-alkyl uracil
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The invention relates to a synthesis method of 6-chloro-3-alkyl uracil, which is characterized by comprising the following steps: by using malonic acid and N-alkyl urea as raw materials, carrying outthe cyclization reaction to generate alkyl tripyrimidone; and then carrying out chlorination on the alkyl tripyrimidone to generate the 6-chloro-3-alkyl uracil. Compared with an existing method, the method is mild in reaction and low in cost, high-cost and high-risk raw materials such as high-toxicity and high-boiling phosphorus oxychloride are not used, and industrial large-scale production is facilitated; meanwhile, the chemical purity obtained by the method is high, the yield is good, and the economic benefit is good.
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Paragraph 0030; 0032; 0047; 0049; 0050; 0052
(2019/12/02)
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- A curved geleg sandbank preparation method
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The invention claims a curved geleg sandbank preparation method, using methyl urea and malonic acid diethyl ester as an initial raw material for preparing 3 - methyl - 6 - chloro uracil, while at the same time by the 2 - hydroxymethyl - 4 - pentachloro as initial material to prepare 2 - chloromethyl - 4 - pentachloro, then the 3 - methyl - 6 - chloro uracil with 2 - chloromethyl - 4 - pentachloro prepared tune geleg sandbank, the material cost is low, the preparation process is easy to control, convenient for industrial production.
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Paragraph 0050; 0052; 0054; 0066; 0068; 0070; 0082; 0084
(2019/04/04)
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- Preparation method for trelagliptin
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The invention discloses a preparation method for trelagliptin and belongs to the field of organic synthesis. The preparation method comprises the following steps: (1) taking methylurea and diethyl malonate as initial raw materials and performing cyclization and chlorination reaction, thereby acquiring 3-methyl-6-chlorouracil; (2) acquiring 2-(6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-methyl)-4-fluorobenzonitrile from the nucleophilic substitution reaction of 3-methyl-6-chlorouracil and 2-bromine methyl-4-fluorobenzonitrile; (3) generating a target compound (R)-2-((6-(3-aminopiperidines-1-group)-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-group) methyl-4-fluorobenzonitrile (trelagliptin) through the reaction of 2-(6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-methyl)-4-fluorobenzonitrile and (R)-3-aminopiperidine. The preparation method has the characteristics of low-cost and easily acquired initial raw materials, convenient after-treatment, mild condition, operation convenience, and the like.
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Paragraph 0031; 0032
(2018/03/26)
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- Preparation method of 6-chloro-3-methyluracil
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The invention belongs to the technical field of medicine chemosynthesis, and relates to a preparation method of 6-chloro-3-methyluracil. The method comprises the following steps that 1, methylurea, anorganic solvent and alkali are added into a reaction container for stirring and dissolution, then malonic acid or malonic ester is added, heating and reflux are conducted, then cooling is conducted,acid is added to adjust a pH value of reaction liquid, water is added, the reaction liquid is cooled, suction filtration is conducted, and drying is conducted to obtain a white to off-white first intermittent in a shape of loose powder; 2, phosphorus oxychloride is used for chloridizing the first intermittent to obtain a crude product; 3, the crude product prepared in the step 2 is subjected to decoloration by means of activated carbon to obtain a finished product. According to the preparation method of the 6-chloro-3-methyluracil, the product in the step 1 precipitates in a form of sodium salt, that is to say, the first intermittent is 1-sodium methylbarbiturate, compared with the prior art where a first intermittent precipitates in a form of 1-methylbarbituric acid, the preparation method of the 6-chloro-3-methyluracil has the advantages that the yield is obviously improved, moreover, in the step 2, acetonitrile is used as the solvent, the phosphorus oxychloride usage is reduced, post-treatment is convenient, and meanwhile, the product has a good crystal form, and is easy to filter.
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Paragraph 0021; 0027; 0030-0033; 0036-0039; 0042-0045; 0048
(2019/01/08)
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- Convenient synthesis of toxoflavin that targets β-catenin/TCF4 signaling activities
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A rapid and improved route for synthesis of toxoflavin, an antibiotic and antitumor agent, is described. The method uses easily obtained materials and simple and practical reactions, including chlorination, condensation, and diazotization to produce toxoflavin in five steps with 14.2% yield and 98.6% purity (HPLC). This synthetic toxoflavin effectively inhibited β-catenin/Tcf4 driven TOP-luciferase activity with an IC50 of less than 0.5 μM and induced colon cancer cell death in a dose-dependent manner with an IC50 of 0.29 μM.
- Mao, Yongjun,Tian, Wang,Huang, Ziwei,An, Jing
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p. 594 - 597
(2014/06/10)
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- Planar chiral flavinium salts: Synthesis and evaluation of the effect of substituents on the catalytic efficiency in enantioselective sulfoxidation reactions
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A series of substituted planar chiral flavinium salts with a phenyl "cap" have been prepared as potential catalysts for enantioselective sulfoxidation reactions with hydrogen peroxide by using an approach based on the synthesis of (arylamino)uracils and their condensation with substituted nitrosobenzenes. The effect of substituents at various positions on the ability of the catalyst to promote enantioselective sulfoxidation recations was investigated. Introduction of the tyrosine group into the side-chain of the flavinium species or substitution of the nitrogen N-3 of the flavin unit by o-isopropylphenyl has a remarkably positive effect on the enantioselectivity of the sulfoxidation reactions of aromatic and aliphatic substrates, respectively. On the other hand, substitution of the phenyl "cap" led to a substantial decrease in the efficiency of the catalyst. In summary, optimisation of the structures of the planar chiral flavinium catalysts led to enantioselectivities of up to 61 % ee for aromatic sulfides and of up to 65 % ee for tert-butyl methyl sulfide. By making structural changes to the planar chiral flavinium catalysts, the enantioselectivities of the sulfoxidation of aryl methyl sulfides and tert-butyl methyl sulfide with hydrogen peroxide have been improved. Copyright
- Jurok, Radek,Hodacova, Jana,Eigner, Vaclav,Dvorakova, Hana,Setnicka, Vladimir,Cibulka, Radek
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supporting information
p. 7724 - 7738
(2013/12/04)
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- Planar chiral flavinium salts - Prospective catalysts for enantioselective sulfoxidation reactions
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A novel planar chiral flavinium salt, 3-benzyl-5-ethyl-10-(8- phenylnaphthalen-1-yl)isoalloxazinium perchlorate (2b), which bears a phenyl cap that covers one side of the isoalloxazinium skeleton plane, has been prepared as a potential catalyst for the enantioselective H2O2 oxidation of sulfides. The rate of H2O2 oxidation of sulfides in the presence of racemic 2b is comparable to that of the reaction catalysed by 5-ethyl-3,10-dimethylisoalloxazinium perchlorate, which indicates that the bulky shielding substituent does not influence the catalytic activity of the flavinium unit. The turnover frequency for the oxidation of thioanisole with hydrogen peroxide with 2b is 870 h-1. The enantiomerically pure salts (+)-2b and (-)-2b were prepared from the pure enantiomers (+)-3b and (-)-3b of 3-benzyl-10-(8-phenylnaphthalen-1-yl)isoalloxazine (3b) obtained by HPLC separation of racemic 3b on a chiral stationary phase. The enantiomerically pure salts (+)-2b and (-)-2b catalyse the H2O2 oxidation of para-substituted thioanisoles with enantiomeric excesses of 34-44%. The highest enantioselectivity (54% ee) was observed in the oxidation of methyl naphthyl sulfide.
- Jurok, Radek,Cibulka, Radek,Dvorakova, Hana,Hampl, Frantisek,Hodacova, Jana
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supporting information; experimental part
p. 5217 - 5224
(2010/11/02)
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- Microwave-assisted synthesis of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5, 7(1H,6H)-dione libraries: Derivatives of toxoflavin
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The parallel synthesis of a library of toxoflavin derivatives is described. The microwave-assisted approach involves the de novo generation of the heterocyclic scaffold and allows for facile introduction of a variety of fragments.
- Todorovic, Nick,Giacomelli, Andrew,Hassell, John A.,Frampton, Christopher S.,Capretta, Alfredo
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experimental part
p. 6037 - 6040
(2010/11/21)
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- ORGANIC COMPOUNDS
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1- or 2- or 7-(substituted)-3-(optionally hetero)arylamino-[lH, 2H]-pyrazolo[3,4-d] pyrimidine-4,6(5H, 7H)-dione derivatives, in free, salt or prodrug form, are useful as pharmaceuticals, particularly as phosphodiesterase 1 inhibitors, useful for the treatment of diseases involving disorders of the dopamine Dl receptor intracellular pathway, such as Parkinson's disease, depression, narcolepsy and damage to cognitive function, e.g., in schizophrenia or disorders that may be ameliorated through enhanced progesterone - signaling pathway, e.g., female sexual dysfunction.
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Page/Page column 76
(2009/07/17)
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- Synthesis, biological active molecular design, and molecular docking study of novel deazaflavin-cholestane hybrid compounds
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Novel deazaflavin-cholestane hybrid compounds, 3′,8′-disubstituted-5′-deazacholest-2,4-dieno[2,3-g]pteridine-2′,4′(3′H,8′H)-diones, have been synthesized by condensation reaction between 6-(monosubstituted amino)-pyrimidin-2,4(1H,3H)-diones and 2-hydroxymethylenecholest-4-en-3-one in presence of p-toluenesulfonic acid monohydrate and diphenyl ether. The antitumor activities against human tumor cell lines (CCRF-HSB-2 and KB cells) have been investigated in vitro, and many of these compounds showed promising antitumor activities. Furthermore, molecular docking study using LigandFit within the software package Discovery Studio 1.7 was done for lead optimization of these compounds as potential PTK inhibitors. In general, all of the synthesized steroid-hybrid compounds showed good binding affinities into PTK (PDB code: 1t46).
- Shrestha, Ajaya R.,Shindo, Takashi,Ashida, Noriyuki,Nagamatsu, Tomohisa
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body text
p. 8685 - 8696
(2009/04/11)
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- ORGANIC COMPOUNDS
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2-(optionally hetero)arylmethyl-3 -(optionally hetero)arylamino- [2H] -pyrazolo [3,4-d] pyrimidine-4,6(5H, 7H)-diones, in free, salt or prodrug form are useful as pharmaceuticals, particularly as phosphodiesterase 1 inhibitors.
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Page/Page column 23
(2008/06/13)
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- ORGANIC COMPOUNDS
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The invention provides novel 7,8-dihydro-imidazo[l,2-α]pyrazolo[4,3-e]pyrimidin-4- one compounds and 7,8,9-trihydro-[lHor 2/f]-pyrimido [l,2-a]pyrazolo[4,3- e]pyrimidin-4(5H)-one compounds, substituted at the 1 or 2 position with C2-g allcyl, C3-9 cycloalkyl, heteroarylalkyl, or substituted arylalkyl, in free, salt or prodrug form, processes for their production, their use as pharmaceuticals, particularly as PDEl inhibitors, and pharmaceutical compositions comprising them.
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Page/Page column 30
(2008/06/13)
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- Pyrazolo[3,4-d]pyrimidineone compounds
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PCT No. PCT/SE98/00640 Sec. 371 Date May 7, 1998 Sec. 102(e) Date May 7, 1998 PCT Filed Aug. 7, 1998 PCT Pub. No. WO98/46606 PCT Pub. Date Oct. 22, 1998The invention relates to pharmaceutically useful pyrazolo[3,4-d]pyrimidinedione compounds, processes for their production, pharmaceutical compositions containing them and their use for the treatment of various diseases.
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- Synthesis and reactivities of a novel flavoenzyme model, 5-deazaflavin with C2-symmetry
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The title model compound represents a redox property of the active site of flavoenzymes and an environmental effect of the apoproteins. Its stereostructure was elucidated by 1H-NMR spectra and energy minimum calculations. The stereoselectivity of this model was observed during the reaction with Me2PNPH, as NAD(P)H model.
- Yanada, Reiko,Yoneda, Yoshiyuki,Yazaki, Mikako,Mimura, Norio,Taga, Tooru,Yoneda, Fumio,Yanada, Kazuo
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p. 2319 - 2323
(2007/10/03)
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- Effects of 8-phenyl and 8-cycloalkyl substituents on the activity of mono-, di-, and trisubstituted alkylxanthines with substitution at the 1-, 3-, and 7-positions
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The effects of 8-phenyl and 8-cycloalkyl substituents on the activity of theophylline, caffeine, 1,3-dipropylxanthine, 1,3-dipropyl-7-methylxanthine, 3-propylxanthine, and 1-propylxanthine at A1 adenosine receptors of rat brain and fat cels and at A2 adenosine receptors of rat pheochromocytoma PC12 cells and human platelets are compared. An 8-phenyl substituent has little effect on the activity of caffeine or 1,3-dipropyl-7-methylxanthine at adenosine receptors, while markedly increasing activity of theophylline, 1,3-dipropylxanthine, 1-isoamyl-3-isobutylxanthine, 1-methylxanthine, and 3-propylxanthine. 8-Phenyl-1-propylxanthine is potent (K(i) = 20-70 nM) at all receptors. A p-carboxy or p-sulfo substituent, which is introduced on the 8-phenyl ring to increase water solubility, in most cases decreases the activity and selectivity for the A1 receptor. Among the 8-p-sulfo analogues, only 8-(p-sulfophenyl)theophylline and 1,3-dipropyl-8-(p-sulfophenyl)xanthine are selective for the A1 receptors. 8-p-Sulfophenyl derivatives of caffeine, 1,3-dipropyl-7-methylxanthine, and 3-propylxanthine are somewhat selective for the A2 receptors. 8-Cycloalkyl substituents (cyclopentyl, cyclohexyl) markedly increase activity of caffeine and 1,3-dipropyl-7-methylxanthine at the A2 receptor. 8-Cyclohexylcaffeine is potent (K(i) = 190 nM) and very selective for the human platelet A2 receptors, but is not as selective for the rat PC12 cell A2 receptor. Such A2 selectivity is in contrast to the marked A1 selectivity of 8-cycloalkyltheophyllines and 8-cycloalkyl-1,3-dipropylxanthines. The apparent selectivity of certain xanthines is dependent on the assay systems that are compared.
- Shamim,Ukena,Padgett,Daly
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p. 1231 - 1237
(2007/10/02)
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- PURINES AND PYRIMIDINES AND CONDENSED SYSTEMS BASED ON THEM. 2. SYNTHESIS OF 1-METHYL-9-AMINOXANTHINE AND 9-AMINOTHEOPHYLLINE
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The previously unknown 9-aminotheophylline and 1-methyl-9-aminoxanthine were synthesized from 3-methyl-5-amino-6-hydrazinouracil.In the case of 1-methyl-9-aminoxanthine an x-ray diffraction study of an N-amino derivative of an NH heterocycle was made for the first time.
- Kuz'menko, V. V.,Kuz'menko, T. A.,Aleksandrov, G. G.,Pozharskii, A. F.,Gulevskaya, A. V.
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p. 690 - 697
(2007/10/02)
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- Reactions of 4a-Peroxides and 4a-Pseudobases of N10- and N5-Phenethylflavins
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A number of N5,N10-dialkylisoalloxazines have been synthesized in which either the N5 or the N10 substituent is a meta-substituted phenethyl group.Some of these compounds have been subjected to experiments in order to determine whether an intramolecular transfer of oxygen can occur between the flavin and the phenethyl group (a model of monooxygenase).When in the 1,5-dihydro reduced state, N5-alkyl-substituted isoalloxazines react with molecular oxygen to dive 4a-hydroperoxy derivatives.The hydroperoxides of the N5-ethyl-N10-phenethylflavins provide 4a-pseudobases on spontaneous decomposition.These in turn undergo ring contraction in base to yield 10a-spirohydantoins (Scheme V).The structure of 10a-spirohydantoin (28b) is as established by X-ray crystallographic technique.Spontaneous decomposition of 4a-hydroperoxides is not accompanied by intramolecular oxygen transfer to the phenethyl substituent groups at N10 or N5 (eq.4) 10a-Spirohydantoins may also be obtained by base treatment of 4a-pseudobases that have been prepared separately from the oxidized isoalloxazine (i.e., flavinium cation). 4a-(Allylperoxy)flavin derivatives, obtained by addition of alkyl peroxides to flavinium cations, undergo both spontaneous and photochemocal conversion to 10a-spirohydantoin.These findings are discissed in therms of proposals which have been made for the mechanism of action of flavoenzyme monooxygenases.
- Iwata, Masaki,Bruice, Thomas C.,Carrell, H. L.,Glusker, Jenny P,
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p. 5036 - 5044
(2007/10/02)
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