- Manganese-Promoted Regioselective Direct C3-Phosphinoylation of 2-Pyridones
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A highly efficient and regioselective manganese-induced radical oxidative direct C?P bond formation between 2-pyridones and secondary phosphine oxides was developed. The C3-selective phosphinoylation was conveniently achieved through a combination of substoichiometric manganese and persulfate oxidant under mild conditions. Various 3-phosphinoylated pyridone products can be obtained in moderate to high yields. Preliminary mechanistic studies suggest that the reaction is likely to involve a radical pathway induced by catalytically active Mn3+ species.
- Chantarojsiri, Teera,Kittikool, Tanakorn,Phakdeeyothin, Kunita,Yotphan, Sirilata
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Read Online
- Preparation method of high-purity pirfenidone
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The invention relates to the technical field of drug synthesis, and discloses a preparation method of high-purity pirfenidone. The preparation method at least comprises the following steps: (1) uniformly mixing 2-amino-5-methylpyridine, a diazotization reagent and water, cooling to a temperature of -4 DEG C to 3 DEG C, adding an acid solution, and carrying out a thermal insulation reaction; heating for hydrolysis after the reaction is completed, cooling, then adjusting the pH value to 6.5-7.5 by using a sodium hydroxide solution with the mass fraction of 30%, extracting an organic phase by using a first solvent, drying, and concentrating under reduced pressure to obtain a 2-hydroxy 5-methylpyridine crude product; (2) adding a second solvent into the 2-hydroxy 5-methylpyridine crude productfor recrystallization to obtain a 2-hydroxy 5-methylpyridine pure product; (3) uniformly mixing the 2-hydroxy 5-methylpyridine pure product, iodobenzene, a catalyst and anhydrous potassium carbonate,heating and reacting, carrying out suction filtration, and carrying out vacuum concentration to obtain a pirfenidone crude product; and (4) adding a third solvent into the pirfenidone crude product,heating to dissolve, cooling to -5 to 5 DEG C, crystallizing for 1 to 1.5 hours, carrying out suction filtration, and drying to obtain a pirfenidone pure product.
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Paragraph 0062-0242
(2020/05/02)
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- Method for preparing anti-fibrotic drug
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The invention relates to a method for preparing an anti-fibrotic drug. The method for preparing pirfenidone is characterized by comprising the following steps of: hydrolyzing a starting material 2-amino-5-methylpyridine by adopting a reverse diazotization hydrolysis method, extracting by using an extraction solvent and recrystallizing by using a recrystallization solvent to obtain 2-hydroxy-5-methylpyridine; in the presence of anhydrous potassium carbonate and active copper, mixing with iodobenzene and heating to carry out nucleophilic substitution reaction to produce a target compound: pirfenidone crude product; and sequentially carrying out recrystallization and purification by using a recrystallization solvent: ethyl acetate and absolute ethanol to finally obtain a pirfenidone pure product. The method disclosed by the invention has the following characteristics that: the initial raw material: the 2-amino-5-methylpyridine is a commercially available chemical product which is cheap and easy to obtain; the reverse diazotization is adopted to replace conventional diazotization reaction and the operation is simple and convenient; the purification methods of the 2-hydroxy-5-methylpyridine and the final product pirfenidone are easy to operate and high in yield; and the processing method is low in energy consumption and the production cost is reduced.
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Paragraph 0016; 0018
(2019/04/27)
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- 5-alkyl-N-substituted aryl pyridone derivative, preparation method thereof and application of derivative
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The invention provides a compound as shown in a formula I, or pharmacologically acceptable salt of the compound, or a prodrug of the compound, or a hydrate or solvate of the compound or a crystal form of the compound. The invention further provides a preparation method and an application of the compound. The structurally novel 5-methyl-2(1H) pyridone derivative as shown in the formula I has an obvious inhibiting effect on fibroblast proliferation and fibroblast secretory fiber binding protein (Fn), and the inhibiting effect is more significant than that of a positive drug pirfenidone (PF). The compound has an excellent application prospect in preparation of drugs for treating or preventing diseases such as fibrosis diseases and tumors.
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Paragraph 0082; 0085-0087; 0100-0101
(2019/10/04)
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- A process for preparing 2 - chloro -5 - methyl pyridine method (by machine translation)
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The invention belongs to the technical field of organic chemical industry, relates to 2 - chloro - 5 - methyl pyridine preparation method, more specifically, relates to a 5 - methyl - 3, 4 - dihydro pyridine - 2 (1 H) - one (hereinafter referred to as the: pyridone) and chlorine gas, first synthesis of 2 - hydroxy - 5 - methyl pyridine (hereinafter referred to as: synthetic azo), re-chlorinated preparing 2 - chloro - 5 - methyl pyridine. (by machine translation)
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Paragraph 0012; 0017-0019; 0025; 0028; 0032; 0036
(2019/07/04)
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- 5 - Methyl - 2 (1 H) pyridone derivative and its preparation and use
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The invention discloses 5-methyl-2(1H)pyridone derivatives represented by the formula (I), crystal form, pharmaceutically-acceptable salt, hydrate, solvate, or prodrug thereof, wherein in the formula (I), the R represents a hydrogen atom, a halogen atom,
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Paragraph 0076-0079
(2018/04/03)
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- IMPROVED PROCESS FOR THE PREPARATION OF PIRFENIDONE
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The present invention relates to improved process for the production of Pirfenidone which is comprises reacting the compound of 5-methyl-2(1H)-pyridone of formula (III) with bromobenzene (IV) in polar solvent, in presence of base and activated Cu powder to obtain the compound of formula (I). The present invention is also related to purification of Pirfenidone.
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Page/Page column 5
(2018/10/25)
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- A highly efficient Suzuki-Miyaura methylation of pyridines leading to the drug pirfenidone and its CD3 version (SD-560)
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Efficient introduction of methyl or methyl-d3 into aromatic and heteroaromatic systems still presents a synthetic challenge. In particular, we were in search of a non-cryogenic synthesis of the 5-CD3 version of pirfenidone (4d, also known as Pirespa, Esbriet or Pirfenex), one of the two drugs approved to date for retarding idiopathic pulmonary fibrosis (IPF), a serious, rare and fatal lung disease, with a life expectancy of 3-5 years. The methyl-deuterated version of pirfenidone (4e, also known as SD-560) was designed with the objective of attenuating the rate of drug metabolism, and our goal was to find a green methylation route to avoid the environmental and economic impact of employing alkyllithium at cryogenic temperatures. The examination of several cross-coupling strategies for the introduction of methyl or methyl-d3 into methoxypyridine and pyridone systems culminated in two green and nearly quantitative Suzuki-Miyaura cross-coupling routes in the presence of RuPhos ligand: the first, using commercially available methyl boronic acid or its CD3 analog and the second, employing potassium methyl trifluoroborate or CD3BF3K, the latter obtained by a new route in 88% yield. This led, on a scale of tens of grams, to the synthesis of pirfenidone (4d) and its d3 analog, SD-560 (4e), at 99% isotopic purity.
- Falb, Eliezer,Ulanenko, Konstantin,Tor, Andrey,Gottesfeld, Ronen,Weitman, Michal,Afri, Michal,Gottlieb, Hugo,Hassner, Alfred
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supporting information
p. 5046 - 5053
(2017/11/09)
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- 5-methyl-2(1H) pyridone derivative and preparation method and application thereof
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The invention discloses a 5-methyl-2(1H) pyridone derivative shown in the formula I or salt, a hydrate, a solvate or a pro-drug thereof, which are pharmaceutically acceptable and have the same crystal form. In the formula I, X is selected from S or NH; R1
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Paragraph 0077; 0078; 0079
(2017/04/12)
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- 5 - methyl - 2 (1 H) pyridone derivative and its preparation and use
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The invention discloses 5-methyl-2(1H)pyridone derivatives disclosed as Formula I, or crystal forms, pharmaceutically acceptable salts, hydrates, solvates or pro-drugs thereof. In the formula I, R is selected from hydroxy group, mercapto group, amino grou
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Paragraph 0078-0080
(2017/09/12)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF PIRFENIDONE
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The present invention is relates to an improved process for the preparation of pure pirfenidone. The present invention also relates to a crystalline form of pirfenidone and its pharmaceutical composition thereof.
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Page/Page column 9
(2017/08/07)
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- 5 - methyl - 2 (1 H) pyridone derivative and its preparation and use
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The invention discloses 5-methyl-2(1H)pyridone derivatives represented by the formula (I), crystal form, pharmaceutically-acceptable salts, hydrates, solvates, or prodrugs thereof. In the formula (I), the R1 represents a hydrogen atom, a halogen element,
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Paragraph 0080; 0081; 0082; 0083
(2017/09/12)
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- Pirfenidone derivative and preparation method and use thereof
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The invention relates to a pirfenidone derivative and a preparation method and use thereof and discloses a compound shown as in formula I or its pharmaceutically acceptable salt, crystal, hydrate or solvate, wherein R1 is selected from H or C1-C8 alkyl, R2, R3, R4, R5 and R6 are selected respectively or all from H or halogen, and at least one of the R2, R3, R4, R5 and R6 is halogen. The novel compound of the invention is significantly better than pirfenidone in anti-fibrosis activity and has an inhibitory rate of higher than 42% for fibroblast proliferation, as much as 5 times higher than 8.15% of pirfenidone, and the derivative has good industrial prospect.
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Paragraph 0063; 0064; 0065
(2016/10/24)
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- Pirfenidone derivative and preparation method thereof
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The invention discloses a compound shown in the formula I or pharmaceutically acceptable salt or a pharmaceutically acceptable crystal form or pharmaceutically acceptable hydrate or pharmaceutically acceptable solvate thereof. R1, R2, R3, R4 and R5 are selected from H, halogen, hydroxyl, nitryl and carbonyl or C1-C8 alkyl respectively or simultaneously; R6 and R7 are selected from H or C1-C8 alkyl respectively or simultaneously, and R6 and R7 are connected to form a five-membered ring or a six-membered ring containing 3-17 carbon atoms. Compared with pirfenidone, the novel compound has different ring structures, the anti-fibrosis activity of the novel compound is remarkably superior to that of pirfenidone, and especially, the inhibition ratio of the novel compound for fibroblast proliferation is increased by at least 30% compared with pirfenidone; meanwhile, the inhibition effect of the novel compound on fibroblast secretory fibronectin is remarkably superior to that of pirfenidone, and good industrial prospects are achieved. The formula I is shown in the specification.
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Paragraph 0049; 0050; 0051; 0052; 0053
(2017/04/19)
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- Pirfenidone derivative and preparation method thereof
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The invention discloses a compound shown in a formula I or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, wherein R1, R2, R3, R4 and R5 are respectively or simultaneously selected from H, halogen, hydroxyl, nitryl, carbonyl or C1-C8 alkyl; R6 and R7 are respectively or simultaneously selected from H, O=C-NH2, S=C-NH2, phenyl, methyl substituted phenyl, ethyl substituted phenyl, methoxy substituted phenyl and ethyoxyl substituted phenyl. Compared with pirfenidone, the new compound disclosed by the invention is of a specific C=N-N structure, and the anti-fibrosis activity of the new compound is obviously better than that of pirfenidone, especially, inhibition rate of the new compound on fibroblast proliferation is improved by at least 50% compared with pirfenidone; meanwhile, the inhibitory effect of the new compound on fibronectin secretion of the fibroblast is also obviously better than that of pirfenidone, so that the compound disclosed by the invention has a good industrial prospect.
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Paragraph 0050; 0051; 0052
(2017/04/12)
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- Application of pirfenidone derivative to pharmacy
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The invention discloses application of a compound as shown in a formula (I) (the formula can be seen in specification) or medically acceptable salt, the crystal form, aquo-complex or solvent thereof to preparation of anti-fibrosis drugs and/or antineoplastic drugs; wherein R1, R2, R3, R4 and R5 are separately or simultaneously selected from H, halogen, hydroxyl, nitro, carbonyl or a C1 alkyl group, a C2 alkyl group, a C3 alkyl group, a C4 alkyl group, a C5 alkyl group, a C6 alkyl group, a C7 alkyl group or a C8 alkyl group; R6 and R7 are separately or simultaneously selected from H, O=C-NH, S=C-NH, phenyl, methyl-substituted phenyl, ethyl-substituted phenyl, methoxyl-substituted phenyl and ethyoxyl-substituted phenyl. The invention provides application of the novel compound as shown in the formula (I) (the formula can be seen in specification) or medically acceptable salt, the crystal form, aquo-complex or solvent thereof to preparation of anti-fibrosis drugs and/or antineoplastic drugs, compared with pirfenidone, the novel compound has a specific C=N-N structure, anti-fibrosis activity of the novel compound is remarkably better than that of pirfenidone, and the novel compound has good industrialized prospect.
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Paragraph 0045-0047
(2017/06/10)
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- Asymmetric Homogeneous Hydrogenation of 2-Pyridones
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An asymmetric homogeneous hydrogenation of 2(1H)-pyridones has been developed, using a ruthenium complex bearing two chiral N-heterocyclic carbene (NHC) ligands. To the best of our knowledge, the presented reaction is the first example of a homogeneous asymmetric conversion of 2-pyridones into the corresponding enantioenriched 2-piperidones.
- Wysocki, Jedrzej,Schlepphorst, Christoph,Glorius, Frank
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supporting information
p. 1557 - 1562
(2015/06/30)
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- THE DERIVATIVES OF PYRIDONE AND THE USE OF THEM
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The present invention provides N-substituted-2(1H) pyridones or the pharmaceutical acceptable salts thereof, and the pharmaceutical preparations containing the compounds. The compounds of the present invention can be used to treat various fibrotic diseases effectively, e.g., hepatic fibrosis.
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Page/Page column 7
(2008/06/13)
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- (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors
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The invention encompasses the novel compound of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases. STR1 The invention also encompasses certain pharmaceutical compositions for treatment of cyclooxygenase-2 mediated diseases comprising compounds of Formula I.
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- (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors
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The invention encompasses the novel compound of Formula A that is useful in the treatment of cyclooxygenase-2 mediated diseases. STR1 The invention also encompasses certain pharmaceutical compositions for treatment of cyclooxygenase-2 mediated diseases comprising compounds of Formula A.
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- 3,4-diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs to COX-2 inhibitors
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The invention encompasses the novel compound of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases. STR1 The invention also encompasses certain pharmaceutical compositions for treatment of cyclooxygenase-2 mediated diseases comprising compounds of Formula I.
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- Azetidinone compounds useful in the preparation of carbapenem antibiotics and process for preparing carbapenem and penem compounds
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Compounds of formula (I): STR1 wherein: R1 is hydrogen or a hydroxy-protecting group; R2 is alkyl, alkoxy, halogen, optionally substituted phenyl or optionally substituted phenoxy; R3 is optionally substituted pyridyl, optionally substituted quinolyl or phenyl group which has a substituent of formula --CYNR5 R6, where Y is oxygen or sulfur, and R5 and R6 are each alkyl, aryl or aralkyl, or R5 and R6 and the nitrogen to which they are attached together form a heterocyclic group; is R4 hydrogen or an amino-protecting group; and Z is sulfur or oxygen; are valuable intermediates in the preparation of carbapenem compounds and retain a desirable configuration during conversion to such carbapenem compounds. Penem and carbapenem compounds having a group of formula --SA' are prepared from a corresponding compound having a substituted thio, sulfinyl or sulfonyl group at this position by reaction with a compound A'SH (where A' is an organic group) in the presence of a salt of a metal of Group II or III of the Periodic Table.
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- Process for the preparation of 2-substituted 5-alkyl-pyridines
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The title compounds of the formula STR1 can be prepared by cyclization of aminomethylenated 2-pentenoic acid derivatives of the formula STR2 where R, X, R1, R2 and Z have the meaning given in the description, in the presence of acids or ammonia. Preferably, aminomethylenated pentenoic acid derivatives are employed which can be prepared from pentenoic acid derivatives of the formula or with ortho-amides of the formula STR3 The meanings of A and B are also given in the description.
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- NITROGEN-CONTAINING SPIROCYCLES
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Spirocycles of general structural formula: STR1 are Class III antiarrhythmic agents.
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- Synthesis of 2-substituted-5-methylpyridines from methylcyclobutanecarbonitrile, valeronitrile and pentenonitrile intermediates
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3-Methyl-2-alkylamino-1-halo-1-cyano cyclobutanes are cleaved under acid conditions to form 2-halo-4-formylvaleronitrile and 4-formyl-2-pentenonitrile which can be cyclized to form 2-substituted-5-methylpyridine derivatives. These pyridine derivatives are useful as starting materials in the manufacture of herbicides such as fluazifop-butyl.
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- OXYGENATION OF THE UNACTIVATED PYRIDINE SYSTEM BY ACETYL HYPOFLUORITE MADE DIRECTLY FROM F2
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Acetyl hypofluorite was found capable of activating the usually unreactive pyridine by substituting the hydrogen at the 2 position by an acetoxy group which then was hydrolyzed to the corresponding pyridinone.Substitutents at 3, 4 or 5 position do not interfere with the reaction, but compounds with substituents at 2 (with the exception of aromatic ones) either do not react or produce tars.The reaction conditions are very mild and the yields are very good for this kind of substitution.Quinolines and pyrazines also react very satisfactorily.
- Rozen, Shlomo,Hebel, David
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p. 249 - 258
(2007/10/02)
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- Nucleophilic Displacement of N-Aryl and Heteroaryl Groups. Part 5. Conversion of 2-Aminopyridines into 2-Pyridones
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2-Ethoxycarbonyl-1-(2-pyridyl)pyridinium cations (3) (easily prepared from 2-aminopyridine and the appropriate pyrylium salt) are converted by dilute NaOH at 25 deg C into 1-(substituted 2-pyridylcarbonyl)-2-pyridones (7).Compounds (7) are readily hydrolysed to 2-pyridones.
- Katritzky, Alan R.,Awartani, Radi
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p. 2623 - 2627
(2007/10/02)
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- Anion-Mediated Fragmentation Reactions. Mechanistic and Synthetic Aspects of the Fragmentation and Rearrangement Reactions of Pyrimidinedione-Alkyne Photoadducts
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The acetone-sensitized photocycloadditon reactions of uracil, thymine, 5-fluorouracil, and 5-(trimethylsilyl)uracil with alkynes afford 2,4-diazabicyclooct-7-ene-3,5-diones.It is noteworthy that 5-(trimethylsilyl)uracil gives very high yields in th
- Kaminski, Victor V.,Comber, Robert N.,Wexler, Allan J.,Swenton, John S.
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p. 2337 - 2346
(2007/10/02)
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- The Mechanisms of Thermal Eliminations. Part 11. Rate Data for Pyrolysis of 2-Alkoxypyridines to 2-Pyridone, and of 2-Ethoxypicolines to 2-Picolones: Nature and Polarity of the Transition State
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The rates of thermal elimination of 2-ethoxy-, 2-isopropoxy-, 2-t-butoxy-pyridine to 2-pyridone and the corresponding alkene, and of the 2-ethoxy derivatives of 3-, 4-, 5-, and 6-methylpyridines to ethylene and the corresponding 2-picolines have been measured over at least 50 deg for each compound, between 585.1 and 721.1 K.The respective log (A/s-1) and Ea/kJ mol-1 values for the former three compounds are 12.20, 196.5; 12.68, 187.6; and 12.33, 161.0, and these are similar to those for the corresponding acetates.The relative rates of the first-order unimolecular decomposition at 600 K are: Et(1.0), Pri(18.0), But(1645) compared with 1.0:28.8:3316 for the acetates.The polarity of the transition state is thus less than for ester elimination.The difference in the rate ratios k(Pri)/k(Et) for alkoxypyridine and acetate pyrolyses is greater than the difference in the k(But)/k(Pri) ratios and is interpreted in terms of the difference in polarity of the transition states for primary, secondary, and tertiary elimination.Methyl substituents in the 3-, 4-, 5-, and 6-positions of the pyridine ring change the rate at 600 K by factors of 1.57, 1.02, 0.74, and 1.08, respectively.These show the decomposition does not take place via N-alkylpyridone tautomers, and that the reaction is, like ester pyrolysis, sterically accelerated.
- Al-Awadi, Nouria,Ballam, John,Hemblade, Paul R.,Taylor, Roger
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p. 1175 - 1178
(2007/10/02)
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- SYNTHESIS OF PYRIDINE N-OXIDE-SbCl5 COMPLEXES AND THEIR INTRAMOLECULAR AND OXYGEN-TRANSFER REACTION
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Mixing with equimolar solutions of pyridine N-oxide or its homologs and SbCl5 in CCl4 deposited 1:1 complexes as colorless crystals in high yield.On thermolysis, these complexes underwent intramolecular oxygen transfer to give selectively the corresponding 2-pyridone derivatives.N,N-Dimethylaniline N-oxide and SbCl5 also gave a crystalline 1:1 complex which on termolysis yield o-dimethylaminophenol in good yield.
- Yamamoto, Jiro,Imagawa, Masahiro,Yamauchi, Sigeyuki,Nakazava, Osamu,Umezu, Masahiro,et al.
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p. 1871 - 1873
(2007/10/02)
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- Kinetic Study of the Acid-Promoted Hydrolysis of Some Representative 2-Fluoro Nitrogen Heterocycles
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The acid-promoted hydrolysis of the 2-fluoro derivatives of pyridine, the four isomeric picolines, quinoline, pyrimidine, 4-methylpyrimidine, and 4,6-dimethylpyrimidine have been studied in hydrochloric acid over the concentration range of 0.05-8.0 F HCl.At each acid concentration, the reactions followed pseudo-first-order kinetics, and at low concentrations of acid, the rate of reaction increased linearly with h0.However, at higher acid concentrations negative deviations from linearity were observed for all the substrates and rate maxima for all but the pyrimidines.These results were correlated with the decline in water activity by means of the Bunnett ω and ω* relationships, as well as the Bunnett-Olsen LFER.The slopes of these correlations were suggestive of a proton transfer role for water in the reactions of the less activated 2-fluoropyridines and of 2-fluoroquinoline, while the correlations indicate a nucleophilic role for water in the reactions of the more highly activated pyrimidines.Entropies of activation, calculated both from the pseudo-first-order rate constants, and from the values of k2* obtained from the intercepts of the LFER plot, were significantly more negative for the pyridine and quinoline systems for the pyrimidines.The above results are interpreted as consistent with nucleophilic attack by water in the rate-determining step for the reaction of the pyrimidines, while for the less activated substrates nucleophilic attack may be assisted by proton transfer to additional water molecules.
- Clark, H. R.,Beth, L. D.,Burton, R. M.,Garrett, D. L.,Miller, A. L.,Muscio, O. J.
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p. 4363 - 4369
(2007/10/02)
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