3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酸的合成

以2,3-二氯吡啶为起始原料,通过水合肼亲核取代、马来酸二乙酯环合制得2-(3-氯-2-吡啶基)-5-氧-3-吡唑烷甲酸乙酯(5);5经苯磺酰氯酯化、溴化氢溴化制得3-溴-1-(3-氯-2-吡啶基)-4,5-二氢-1H-吡唑-5-甲酸乙酯(7);7经脱氢、水解合成了用于制备氯虫酰胺的关键中间体--3-溴-1-(3-氯-2-吡啶基)-1H-吡唑-5-甲酸,总收率39.5%,其结构经~1H NMR和MS确证.     

The use of anilinodihydrofurans in the synthesis of novel heterocyclic compounds

Alkyl 4-oxo-2-phenylamino-4,5-dihydrofuran-3-carboxylates were used for the preparation of alkyl 5-amino-7-aryl-2-{[aryl(hydroxy)methyl](phenyl)amino}-4,6-dicyano-1-benzofuran-3-carboxylates, 4-oxo-2-phenylamino-N-(p-tolyl)-4,5-dihydrofuran-3-carboxamide, and ethyl 4-chloro-5-formyl-2-(phenylamino)furan-3-carboxylate. The latter was used for the synthesis of ethyl 4-chloro-5-(hydrazinylidenemethyl)-2-(phenylamino)furan-3-carboxylate and diethyl 5,5'-(hydrazine-1,2-di-ylidenemethylylidene)bis[4-chloro-2-(phenylamino)furan-3-carboxylate].     

Novel,racemic or nearly-racemic antibacterial bromo- and chloroquinols and γ-lactams of the verongiaquinol and the cavernicolin type from the marine sponge Aplysina (= Verongia) cavernicola

Butanolic extracts of the Mediterranean sponge Aplysina (= Verongia) cavernicola have given, by reverse-phase HPLC, the antibacterial quinols (±)-3-bromoverongiaquinol (= (±)-3-bromo-1-hydroxy-4-oxo-2,5-cyclohexadine-1-acetamide; 1d) and (±)-3-bromo-5-chloroverongiaquinol (= (±)-3-bromo-5-chloro-1-hydroxy-4-oxo-2,5-cyclohexadine-1-acetamide; 1c ) besides the products of their formal cyclization 5-chlorohexadiene-1-acetamide; 1c ) besides the products of their formal cyclization 5-chlorocavernicolin (= 5-cloro-3,3a,7,7aβ-tetrahydro-3aβ-hydroxy-2,6(1H)-indoledione; 6) , the C(7)-epimerizing 7β-bromo-5-chlorocavernicolin (=7 β-bromo-5-chloro-3,3a,7,7aβ-tetrahydro-3aβ-hydroxy-2,6(1H)-indoledione; 4a and 7α-bromo-5-chlorocavernicolin (4b) , and the C(7)-epimerizing 5-bromo-7β-chlorocavernicolin ( = 5-bromo-7β-chloro-3,3a,7,7aβ-tetrahydro-3aβ-hydroxy-2,6(1H)-indoledione; 5a) and 5-bromo-7α-chlorocavernicolin (5b) . The latter four were isolated as mixtures of C(7)-epimerizing monoacetates 4a′/4b′ and 5a′/5b′. Both 1 and 1c proved to be racemic from NMR examination of their esterification products with (–)-methyl-oxyacetic acid, whilst 6 had a ca. 6% enantiomeric purity as shown by a ¹H-NMR study of its monoacetate 6′ in the presence of a chiral shift reagent. These chiroptical data of the first chiral quinols from the Verongida and of 6 suggest phenol oxidative routes from tyrosine precursors for their formation. In view of their bioactivities, 1d and 1c have been synthesized from (p-hydroxyphenyl)acetic acid byt phenol oxidative routes.     

Di-6R,7R1-4(3H)-Oxo-2-quinazolinyl-substituted Cyclobutanes from Pinic and sym-Homopinic Acids

The corresponding diamides were obtained from reaction of cis-3-carboxy-2,2-dimethylcyclobutylacetic acid (pinic acid) and of cis/trans-3-(carboxymethyl)-2,2-dimethylcyclobutylacetic acid (homopinic acid) dichlorides with two equivalents of 5-bromo-, 4-chloro-, and 4,5-dimethoxyanthranilic acids. Treatment of them with formamide leads to the formation of the corresponding 2,2-dimethyl-3-[4(3H)-oxo-2-quinazolinyl]methyl-1-[4(3H)-oxo-2-quinazolinyl]cyclobutanes and 2,2-dimethyl-1,3-di[4(3H)-oxo-2-quinazolinylmethyl]cyclobutanes.     

Synthesis and Biological Evaluation of Some Novel N,N ′-Bis-(1,2,4-Triazin-4-Yl)Dicarboxylic Acid Amides and Some Fused Rings with 1,2,4-Triazine Ring

Some of novel N , N '-bis-(1,2,4-triazin-4-yl)dicarboxylic acid amides ( 2-5 ) and thiadiazolo[2,3- b ][1,2,4]triazin-7-yl carboxylic acid derivatives ( 6 , 7 ) were prepared by heating 4-amino-6-methyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine ( 1 ) with different dicarboxylic acids (oxalic, malonic, fumaric, maleic, succinic, and phthalic acids respectively) in POCl 3 . Refluxing 1 with 1-chloro-2,4-dinitrobenzene in DMF yielded 3-methyl-6-nitro-10 H -benzo[1,2,4]thiadiazino[2,3- c ][1,2,4]triazin-4-one ( 8 ). Condensation of 1 with 2,4-pentandione in refluxing acetic acid furnished 6-methyl-4-(1-methyl-3-oxobut-1-enylamino)-3-thioxo-3,4-dihydro-2 H -[1,2,4]triazin-5-one ( 9 ). 3,8-D imethyl[1,2,4] triazino[3,4- b ][1,3,4]thiadiazine-4,7-dione ( 11 ) was prepared by refluxing 1 with 2-bromopropionyl bromide in anhydrous benzene to afford the corresponding N -acetylated derivative 10 , which was cyclized by using triethylamine. Also, some triazinylquinazolinones 13a , b were obtained by fusion of 1 with 6-bromo(and/or 6,8-dibromo)-2-methyl-3,1-benzoxazin-4 H -ones.     

Unique tandem Heck-lactamization naphthyridinone ring formation between acrylanilides and halogenated pyridines

The Heck coupling of acrylanilides with 4-bromo-2-chloro-3-iodo-pyridine using palladium acetate can produce bis-Heck products or undergo an unusual tandem Heck-lactamization ring formation to generate 5-chloro-1-aryl-1,6-naphthyridin-2(1H)-ones.     

Nucleophilic substitution in 1-alkyl-4,5-dichloro-3-nitropyridazin-6-ones

Treatment of 1-alkyl-4,5-dichloro-3-nitropyridazin-6-one with C-nucleophiles and with ambident nucleophiles (2-azahetarylacetonitriles) leads to a selective substitution of a chorine atom by the quaternary carbon atom of the carbanion formed from a substituted acetonitrile. The pK_a of the CH-acid 2-(1-alkyl-5-chloro-3-nitro-6-oxo-1,6-dihydro-4-pyridazinyl)malononitrile was determined by potentiometric titration. Reaction of 2-(1-alkyl-5-chloro-3-nitro-6-oxo-1,6-dihydro-4-pyridazinyl)-2-hetarylacetonitriles with primary amines gives 6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-7-ones. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 556–564, April, 2006.     

Synthesis of new azetidinonyl/thiazolidinonyl quinazolinone derivatives as antiparkinsonian agents

Several 3-amantadinyl-2-[(2-substituted benzylidenehydrazinyl)methyl]-quinazolin-4(3H)-ones (5a–5l) were prepared by the reaction of 3-amantadinyl-2-hydrazinylmethyl substituted quinazolin-4(3H)-ones (4a–4b) with various substituted aromatic aldehydes. Cycloaddition of compounds (5a–5l) with thioglycolic acid in the presence of anhydrous zinc chloride yielded 3-amantadinyl-2-[((substitutedphenyl)-4-oxo-thiazolidin-3-yl)methylamino]-quinazolin-4(3H)-ones (6a–6l). Compounds 5a–5l on further reaction with chloro acetyl chloride in the presence of triethylamine gave 3-amantadinyl-2-[((substitutedphenyl)-3-chloro-2-oxo-azetidin-1-yl)methylamino]-quinazolin-4(3H)-ones (7a–7l). The compounds 5a–5l, 6a–6l and 7a–7l were screened for their antiparkinsonian activity. The most active compound was 6g i.e. 3-amantadinyl-6-bromo-2-[((3,4-dimethoxyphenyl)-4-oxo-thiazolidin-3-yl)methylamino]-quinazolin-4(3H)-ones. Structures of the newly synthesized compounds were established on the basis of elemental and spectral (IR, ¹H NMR and mass) analysis.     

Computational and experimental investigation of the Diels-Alder cycloadditions of 4-chloro-2(H)-pyran-2-one

4-Chloro-2(H)-pyran-2-one undergoes thermal Diels-Alder cycloaddition with electron-deficient dienophiles to afford, without any significant selectivity, 6-endo- and 5-endo-substituted bicyclic lactone cycloadducts. In contrast to 3- and 5-bromo-2(H)-pyran-2-one, 4-chloro-2(H)-pyran-2-one does not undergo thermal cycloadditions with electron-rich dienophiles. The regio- and stereochemical preferences of the cycloadditions of 4-chloro-2(H)-pyran-2-one and other related 2(H)-pyran-2-ones are investigated computationally. Calculations were carried out on the transition states leading to the four possible regio- and stereoisomeric cycloadducts using density functional theory (B3LYP/6-31G). These studies allow prediction of the regio- and stereoselectivity in these reactions which are in line with experimental observations.     

Synthesis of 2-substituted-5-halo-2,3-dihydro-4(H)-pyrimidin-4-ones and their derivatization utilizing the Sonogashira coupling reaction in the enantioselective synthesis of alpha-substituted beta-amino acids

A convenient, one-pot procedure for the synthesis of 1-benzoyl-2(S)-substituted-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-ones by tandem decarboxylation/beta-iodination of the corresponding 6-carboxy-perhydropyrimidin-4-ones was developed. In addition, several 1-benzoyl-2(S)-substituted-5-bromo-2,3-dihydro-4(H)-pyrimidin-4-ones were readily prepared by bromination of 1-benzoyl-2(S)-substituted-2,3-dihydro-4(H)-pyrimidin-4-ones. Subsequently, Sonogashira coupling of the halogenated heterocyclic enones with various terminal alkynes produced 1-benzoyl-2(S)-isopropyl-5-alkynyl-2,3-dihydro-4(H)-pyrimidin-4-ones in good yields. Hydrogenation of the unsaturated C-C moieties in the Sonogashira products followed by acid hydrolysis afforded highly enantioenriched alpha-substituted beta-amino acids.     

新型Bluco类β-内酰胺酶分子探针的合成

以2-氰基-6-羟基苯并噻唑为原料,与溴乙醛缩二乙醇缩合制得缩醛后再水解合成中间体6-(2-羰乙基)苯并[d]噻唑-2-甲腈(2);7-苯乙酰氨基-3-氯甲基头孢菌烷酸二苯甲酯依次经碘代和Wittig反应得(Z)-3-[3-(2-氰基苯并[d]噻唑-6-氧)丙-1-烯]-8-羰基-7-(2-苯乙酰氨基)-5-噻-1-氮[4.2.0]辛-2-烯-2-甲酸二苯甲酯(5);5经脱保护、缩合和氧化反应合成了3个新的Bluco类似物,其结构经1H NMR,13C NMR和HR-MS(ESI)表征。     

Lipase-mediated kinetic resolution of rigid clofibrate analogues with lipid-modifying activity

The lipase-catalysed kinetic resolution of methyl esters of (±)-5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid, (±)-6-chloro-2,3-dihydro-4H-1-benzopyran-2-carboxylic acid, and (±)-6-chloro-2,3-dihydro-4H-1-benzopyran-3-carboxylic acid, rigid analogues of clofibrate, was effected with fair to moderate enantioselectivities (E=1.0–4.8), enantiomeric excesses of up to 86% and workable reaction rates. Enantiomerically pure (R)- and (S)-5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acids were obtained by fractional crystallisation of the diastereomeric salts of the corresponding racemic acid with (+)- and (−)-amphetamine from ethanol; the absolute configuration of the products were established by chemical correlation.     

Synthesis and Characterization of Some Novel 3-Bromo-2-acetylthiophene Chalcones and Biological Evaluation of Their Ethyl-4-(3-bromothien-2-yl)-2-oxo-6-(aryl)cyclohex-3-ene-1-carboxylate Derivatives

Novel chalcones 1-(3-bromothien-2-yl)-3-(aryl)prop-2-en-1-ones derived from 3-bromo-2-acetylthiophene and their cyclization product with ethylacetoacetate such as 4-(3-bromothien-2-yl)-2-oxo-6-(aryl)cyclohex-3-ene-1-carboxylate derivatives were synthesized and studied by X-ray, analytical, and spectral methods. Compounds were screened for their anti-inflammatory, analgesic, and antimicrobial activities. The compound ethyl-4-(3-bromothien-2-yl)-2-oxo-6-(4-propoxyphenyl) cyclohex-3-ene-1-carboxylate 5c exhibited promising anti-inflammatory, analgesic and antibacterial activities.     

Reactions of 1-Aryl-2,2-dibromobutan-1-ones with Zinc and Alkyl 6-Bromo-2-oxo-2-H-chromen-3-carboxylate

Zinc enolates formed from 1-aryl-2,2-dibromobutan-1-ones and zinc react with alkyl 6-bromo-2-oxo-2-H-chromen-3-carboxylates affording alkyl 1-aroyl-6-bromo-2-oxo-1-ethyl-1,7b-dihydrocyclopropa[c]-chromen-1a(2H)-carboxylates as a single isomer.     

5-Cyano-6-aryluracil and 2-thiouracil derivatives as potential chemotherapeutic agents. IV

A series of 5-cyano-6-aryluracils and 2-thiouracils 1a-h has been prepared and alkylated to 1,3-dialkyluracils 2a-d and 2-alkylthiouracils, 3, 4 and 6 , by electrophilic substitution with alkyl halides. Reaction of 1b with dibromoethane and 1,3-dibromopropane gave the corresponding bicyclic products, 7-aryl-6-cyano-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-ones 5a,b and 8-aryl-7-cyano-3,4-dihydro-2H-pyrimido[2,3-b][1,3]thiazin-6-ones 5c-g . Nucleophilic substitution on 6 with hydrazine led to 7 which on refluxing with formic acid gave 5-aryl-6-cyano-8-methyl-s-triazolo[3,4-b]pyrimidin-7-ones ( 9 ), while with acetic and propionic acids only 2-acylhydrazino-3-methyl-4-oxo-5-cyano-6-arylpyrimidines 8a,b were isolated. The hydrazine 7 undergoes cyclization with acetylacetone and methyl dimethylmercaptoacrylate providing 2-(pyrazol-1-yl)-3-methyl-4-oxo-5-cyano-6-substituted pyrimidines 10 , and 11 . Some of the compounds were screened for antibacterial-, antifungal- and antiviral activities and a few of them showed significant chemotherapeutical activities.     

Synthesis of novel acyclonucleosides. Reactions of 1-(2-oxopropyl)pyridazin-6-ones

Multi-substituted-1-(1-bromo-2-oxopropyl)pyridazin-6-ones 3, 4 , multi-substituted-1-(1,1-dibromo-2-oxopropyl)pyridazin-6-ones 7, 8 , and multi-substituted-1-(3-bromo-2-oxopropyl)pyridazin-6-ones 5, 6 were synthesized from the corresponding 1-(2-oxopropyl)pyridazin-6-ones 1, 2 by the selective bromination in acidic or neutral medium. And treatment of 1,1-dibromo-2-oxopropyl derivatives 7, 8 with aqueous potassium carbonate gave the corresponding pyridazin-6-ones 9, 10 by the dealkylation. Reaction of 1 with methanolic potassium cyanide afforded only the corresponding 4-methoxy derivative 11 , whereas reaction of 2 with methanolic potassium cyanide gave 4-methoxy derivative 12 and 2-cyano-2-hydroxypropyl derivative 13 . Reaction of 1 and 2 with hydroxylamine in methanol afforded the corresponding syn-2-hydroxyiminopropyl derivatives 14 and 15 .     

Synthesis and biological evaluation of some new substituted benzoxazepine and benzothiazepine as antipsychotic as well as anticonvulsant agents

Various 2-((2-((5-benzylideneamino)-1,3,4-oxa/thiadiazol-2-yl)methyl)hydrazinyl) methyl)benzo[b][1,4]oxa/thiazepin-4(5H)-ones (4a–4l), 2-((2-((5-(4-oxo-2-substitutedphenyl thiazolidin-3-yl)-1,3,4-oxa/thiadiazol-2-yl)methyl)hydrazinyl)methyl)benzo [b] [1,4]oxa/thiazepin-4(5H)-ones (5a–5l) and 2-((2-((5-(3-chloro-2-(substitutedphenyl)-4-oxoazetidin-1-yl)-1,3,4-oxa/thia diazol-2-yl)methyl)hydrazinyl)methyl)benzo[b][1,4]oxa/thiazepin-4(5H)-ones (6a–6l) have been synthesized. The structures of these compounds have been established by elemental (C, H, N) and spectral (IR, ¹H-NMR and Mass) analysis. The synthesized compounds were screened for their antipsychotic and anticonvulsant activities. Compound 5l was found to be the most active compound of this series.     

嘧啶酮衍生物的微波合成

在微波辅助下,Baylis-Hillman加成物与4-氨基-6-氯嘧啶或2-氨基-噻唑反应,快速合成了两类嘧啶酮衍生物——3-取代-7-氯-4H-嘧啶[1,2-b]哒嗪-4-酮和6-取代-5H-噻唑[3,2-a]嘧啶-5-酮,收率81%～98%,其结构经1H NMR,13C NMR,IR和MS确证。     

Reactions of zinc enolates derived from 1-aryl-2-bromo-alkanones and 1-aryl-2-bromo-2-phenylethanone with 3-aroyl-6-bromochromen-2-ones and 2-benzoylbenzo[f]chromen-3-one

3-Aroyl-6-bromochromen-2-ones and 2-benzoylbenzo[f]chromen-3-one reacted with zinc enolates derived from 1-aryl-2-bromoalkanones and 1-aryl-2-bromo-2-phenylethanone to give, respectively, 4-(1-alkyl-2-aryl-2-oxoethyl)-3-aroyl-6-bromochroman-2-ones and 1-(2-aroyl-1-methyl-2-oxoethyl)-2-benzoyl-1,2-dihydrobenzo[f]chromen-3-ones as a single stereoisomer. Treatment with acetic anhydride of the intermediate product obtained from 3-benzoyl-6-bromochromen-2-one and [1-(4-chlorophenyl)-2-phenylethen-1-yloxy]-zinc(II) bromide resulted in the formation of 3-(1-acetoxy-1-phenylmethylidene)-6-bromo-4-[2-(4-chlorophenyl)-2-oxo-1-phenylethyl]chroman-2-one.     

Synthesis and anti-inflammatory activity of some benzofuran and benzopyran-4-one derivatives

New series of furosalicylic acids 3a-c, furosalicylanilides 6a-n, furobenzoxazines 8a-f, 1-benzofuran-3-arylprop-2-en-1-ones 12a,b, 6-(aryl-3-oxoprop-1-enyl)-4H-chromen-4-ones 16a-c and 6-[6-aryl-2-thioxo-2,5-dihydropyrimidin-4-yl]-4H-chromen-4-ones 17a-c were synthesized. Anti-inflammatory activity evaluation was performed using carrageenan-induced paw edema model in rats and prostaglandin E(2) (PGE(2)) synthesis inhibition activity. Some of the tested compounds revealed comparable activity with less ulcerogenic effect than Diclofenac at a dose 100 mg/kg. All the synthesized compounds were docked on the active site of cyclooxygenase-2 (COX-2) enzyme and most of them showed good interactions with the amino acids of the active site comparable to the interactions exhibited by Diclofenac.