Synthesis of 5-aryl-2-oxazolepropionic acids and analogs. Antiinflammatory agents

Condensation of 2-bromoacetophenones with sodium succinimide gave N-phenacylsuccinimides ( 1 ) which were opened with sodium hydroxide to N-phenacylsuccinamic acids ( 2 ). The latter were cyclized to 5-aryl-2-oxazolepropionic acids ( 3 ) in sulfuric acid. Similar cyclization of N-phenacylphthalamic acid ( 5 ) and succinic acid 2-benzoylhydrazide ( 7 ) gave o-(5-phenyl-2-oxazolyl)benzoic acid ( 6 ) and 5-phenyl-1,3,4-oxadiazole-2-propionic acid ( 8 ). The succinamic acids 2 and the phthalamic acid 5 were observed to recyclize to the corresponding imides ( 1 and 4 ) on heating, and the succinic acid hydrazide 7 was similarly cyclized to N-benzamidosuccinimide ( 9 ) with acetic anhydride. Antiinflammatory screening data are reported for 3 , 6 and 8 .     

Tetronic acids and derivatives. Part V. Synthesis of 5-hydroxy-1H-pyrazoles via 4-hydrazino-5H-furan-2-ones. Reaction of hydrazines on tetronic acids

The conversion of tetronic acids 1 to 3(1-hydroxy alkyl)-5-hydroxy-1H-pyrazole derivatives 3, 5, 7 and 12 is described. The formation is shown to proceed via base-catalyzed rearrangement of the intermediate 4-hydrazino-5H-furan-2-one derivatives.     

On pyrrolidine derivatives I. An efficient synthesis of 3-substituted (2S,5S)-pyrrolidine-2, 5-dicarboxylic acids

(2S,5S)-3-Alkylpyrrolidine-2, 5-dicarboxylic acid derivatives I were stereoselectively synthesized by means of an efficient method starting from L-aspartic acid ( 1 ). Dieckmann reaction of 4-benzyl 1-t-butyl N-t-butyl-oxycarbonyl-N-ethoxycarbonylmethyl-L-aspartate ( 4 ) provided product 5 which consisted of a mixture of (2S,5S)- and (2R,5S)-1-t-butyloxycarbonyl-3-oxopyrrolidine-2, 5-dicarboxylates in a ratio of 95:5. Treating 1-t-butyl 6-ethyl 2-L-(t-butyloxycarbonyl)anuno-5-diazo-4-oxoadipate ( 8 ), prepared from 1 , with rhodium(II) acetate dimer also afforded a good yield of 5 . The Wittig reaction of 5 , followed by catalytic hydrogenation and then deprotection provided compound I .     

Synthesis of ω-substituted 5-alkylorotic acids

The lactone of 5 - -hydroxyethylorotic acid, the thiolactone of 5-(-mercaptoethyl)orotic acid, and 5-(-benzamidobutyl)orotic acid were synthesized from substituted 5-carb-ethoxymethylenehydantoins obtained by the condensation of urea with -ethoxalyl derivatives of -butyrolactone, -thiobutyrolactone, and ethyl -benzamidocaproate. The lactam of 5-(-aminoethyl)orotic acid was synthesized by the ammonolysis of the lactone of 5 -(-hydroxyethyl)orotic acid. The acid hydrolysis of 5-(-benzamidobutyl)orotic acid gave 5-(-aminobutyl)orotic acid.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1280–1282, September, 1971.     

Synthesis of 5-dialkylaminothiocarbonylthiobarbituric acids and 5-diethyiaminothiocarbonylthio-6-aminouracil

The title compounds are obtained by three different methods. The aminothiocarbonylthiolation of barbituric acids 1 and aminouracil ( 5 ) can be accomplished in one step by reaction with thiuram disulfides in the presence of potassium carbonate. On the other hand, compounds 4 can be obtained via the salt of chloro derivative 2 or the corresponding iodonium ylides 3 . The aminouracil derivative 7 was obtained in a similar fashion from 5 directly or via iodonium betaine 6 .     

Synthesis of 5-methyl-4-oxo-quinolinecarboxylic acids

A series of 5-methyl-4-oxo-3-quinolinecarboxylic acids was prepared in which the eight-position was substituted with fluorine, chlorine, methyl, or hydrogen. These quinolones were synthesized from the appropriate 2-methyl-3,4,6-trifluorobenzoic acids which were derived from oxazolines 8 and 16 . The oxazoline moiety served as both an ortho-director (where feasible) and a protecting group; a trimethylsilyl moiety was used to block the most acidic site in the molecule.     

Further evaluation of 5-alkyl-5-deaza antifolates. 5-propyl- and 5-butyl-5-deaza analogues of aminopterin and methotrexate

5-Propyl-5-deaza and 5-butyl-5-deaza analogues of classical antifolates were synthesized by extensions of a previously reported general route which proceeds through 2,4-diamino-5-alkylpyrido[2,3-d]pyrimidine-6-carbonitrile intermediates followed by reductive condensation with diethyl N-4-(aminobenzoyl)-L-glutarnate to give diethyl esters of 5-alkyl-5-deazaaminopterin types. N¹⁰-Methyl derivatives, i.e., derivatives of 5-alkyl-5-deazamethotrexate, were also prepared by reductive methylation of the N¹⁰-H compounds. 5-Ethyl-5-deazamethotrexate was prepared using an alternative route through 6-(bromomethyl)-2,4-diamino-5-ethylpyrido[2,3-d]pyrimidine. These antifolates were evaluated for inhibition of dihydrofolate reductase (DHFR) from L1210 cells, their effect on L1210 and S180 tumor cell growth in culture, and carrier-mediated transport through L1210 cell membranes. Inhibitory effect on DHFR was lowered relative to methotrexate in 5-propyl-5-deazaaminopterin and 5-propyl-5-deazamethotrexate by 2- to 3-fold (K_i = 9.3 and 11.7 pM, respectively, vs. 4.3 pM for methotrexate) and by 17- to 18-fold in 5-butyl-5-deaza-aminopterin and 5-butyl-5-deazamethotrexate (K_i = 74 and 78 pM, respectively). Molecular modeling using graphics derived from human DHFR show the propyl and butyl compounds interacting with the enzyme in conformations that account for these slight decreases in binding.     

4,5-Dihydro-5-thioxo-]H-tetrazoie-l-alkanoic and alkanesulfonic acids and their amide derivatives

Homologous 4,5-dihydro-5-thioxo-1H-tetrazole-l-alkanoic and alkanesulfonic acids were prepared by reaction of sodium azide with methyl (carboxyalkyl)- and (sulfoalkyl) carbamodithioates, respectively. 4,5-Dihydro-5-thioxo-1H-tetrazole-i-alkanamides were derived from the corresponding alkanoic acids by aminolysis of their acid chlorides or imidazolides. Analogous alkane-sulfonamides were synthesized by the reaction of methyl [[[(1,1-dimethylethyl) amino]sulfonyl]-alkyljcarbamodithioates with sodium azide followed by removal of the 1,1-dimethylethyl group with trifluoroacetic acid.     

Synthesis of 4-aminothieno[2,3-b] pyridine-5-carboxylie acids

2-Amino-3-cyanothiophenes were reacted with ethyl aminocrotonate in the presence of catalytic amounts of p-toluensulfonic acid. The intermediates 2-[N-(3′-ethoxycarbonyl-2′-propenylamino]-3-cyanothiophenes obtained were cyclized with sodium ethoxide to give the desired ethyl 4-aminothieno[2,3-b] pyridine-5-carboxylate. Hydrolysis of the latter aminoesters afforded 4-aminothieno[2,3-b]pyridine-5-carboxylic acid. The overall yields were about 80%.     

Metal-cinnamic acids interactions. Part III. Synthesis and study of copper(II) complexes of 3, 4- and 3, 5-dimenthoxycinnamic acid

Summary Copper(II) complexes derived from substituted cinnamic acids 3, 4-dimethoxycinnamic acid (3, 4-DMCH) and 3, 5-dimethoxycinnamic acid (3, 5-DMCH), of the formula [Cu(3, 4-DMC)₂]·H₂O (1), [Cu(3, 5-DMC)₂]·H₂O (2) were prepared. The magnetic properties of the complexes suggest dimeric structures typical of copper(II) acetate monohydrate-like complexes. X-band e.s.r. spectra of polycrystalline samples at low temperature are typical of triplet state systems S=1. Their ability to catalyze the aerial oxidation of 3, 5-di-t-butylcatechol was measured spectrophotometrically at 30°C. The complexes are models for oxidases.     

5-Isoxazolylhydrazines. Reduction of 5-isoxazolones to isoxazoles

5-Isoxazolylhydrazines III were obtained from 5-isoxazolones I, via the 5-haloisoxazoles II. The decomposition of the tosyl derivatives of III results in unambigous syntheses of 3,4-disubstituted isoxazoles.     

Synthesis and Biological Evaluation of 14-Alkoxymorphinans. Part 10. 14-O-Methyl derivatives of 5-methylnaltrexone and 5-methylnaloxone

In several steps, 5, 14-O-dimethylnaltrexone ( 3 ) and 5, 14-O-dimethylnaloxone ( 4 ) were prepared starting from 5, 14-O-dimethyloxycodone ( 5 ). Compound 3 exhibited opioid agonism in vitro (guinea-pig ileum and mouse vas deferens preparations) and antagonism in vivo (AcOH-writhing test in mice), while compound 4 was found to be an agonist in vitro and in vivo.     

Pseudoesters and Derivatives. XXXI1. Synthesis of 5-Ethylthio-, 5-Ethylsulfinyl- and 5-Ethylsulfonylfuran-2(5H)-ones

Convenient syntheses of 5-(ethylthio) furan-2(5H)-ones 2a-k from the appropriate 5-methoxyfuran-2(5H)-one 1a-g are described. The oxidation to the corresponding sulfoxides 5a-c and sulfones 6a-f is also reported.     

Synthesis and interconversion of 6-aroyl-4-oxohexanoie acids and 5-aryl-2-furanpropionic acids. Antiinflammatory agents

A series of 6-aroyl-4-oxohexanoic acids ( 2 ) was prepared for intermediate use by acid-catalyzed solvolysis of substituted 3-(2-furyl)acrylophenones ( 1 ). This reaction occasionally gave 5-aryl-2-furanpropionic acids ( 3 ) instead of, or in addition to, the desired diketones ( 2 ). Equilibrium between 2 and 3 was observed in the case where Ar is m-nitrophenyl. A rationalization for the formation of 3 is offered, and published reports with which our results differ are discussed. Diketones ( 2 ) were cyclized to furans ( 3 ) and antiinflammatory screening data are reported for the latter.     

Synthesis of novel 2-substituted-5-oxycoumarans via A direct route to 2,3-dihydro-5-hydroxy-2-benzofuranacetic acids

A number of novel 2-substituted 2,3-dihydro-5-benzofuranols optionally protected on 5-OH group have been prepared via a simple two step route to racemic 2,3-dihydro-5-hydroxy-2-benzofuranacetic acids from hydroquinones and 4-bromocrotonates.     

Chemical modification of plant alkaloids. 5. Spirocyclic systems based on cotarnine and barbituric acids

Cotarnine was reacted with barbituric acid and its N-alkylbartituric and 1,3-dimethyl-2-thio analogs under forcing conditions to produce spirocyclic systems. Adducts, further transformations of which included skeletal rearrangements (a type of T-reaction) and subsequent deamination, were formed in the first step. The reaction of N-methylcotarnine and 1,3-dimethylbarbituric acid was analogous. The properties of the spirocyclic products were studied. They were further modified at the CH-acid and aromatic moieties. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 38–42, January–February, 2008.     

Synthesis and exchange reactions of 5-alkyl-2-oxo-6-thioxo-1,2,3,6-hexahydropyrimidine-4-carboxylic acids

An improved preparation of 2-oxo-6-thioxo-1,2,3,6-hexahydropyrimidine-4-carboxylic acid 3, a potent inhibitor of dihydroorotase is presented. Trans-5-alkyl-2-oxo-6-thioxohexahydropyrimidine-4-carboxylic acids 12a-c were synthesised via the thiation of the p-methoxybenzyl esters of 5-alkyldihydroorotic acids with Lawesson's reagent followed by subsequent de-protection. The corresponding cisisomers were prepared by reduction of 5-alkyl-6-thioxoorotic acids with zinc in acetic acid. The stability and exchange reactions of 12a-c under physiological conditions were investigated by ultra-violet and ¹H nmr spectroscopy. The attempted synthesis of 16 , a fused cyclopentyl derivative of 3 is also presented.     

Synthesis of some new benzimidazole-5(6)-carboxylic acids

The title compounds, 1,2-dialkyl-benzimidazole-5(6)-carboxylic acids 34–45 were prepared at four steps; 1) preparation of mono amide derivatives 1–11 by the reaction of methyl 3,4-diaminobenzoate and substituted phenyl or phenoxyacetic acid chlorides; 2) preparation of the methyl benzimidazolecarboxyl-ates 12–22 , with zinc chloride and dry hydrogen chloride gas; 3) alkaline hydrolysis of the esters 23–33 ; and 4) substitution of the imidazole ring with benzyl or p-fluorobenzyl bromide, in alkali medium. 2-Aryl-benzimidazole-5(6)-carboxylic acids 50–53 were prepared via the oxidative condensation of 3,4-diaminobenzoic acid and aromatic aldehydes with cupric ion.     

6(5H)-phenanthridinones. III. halo-6(5H)phenanthridinones

Halogenation of 6(5H)-phenanthridinone or its 3,8-dihalo derivatives with N-bromo or N-chlorosuccinimide in dimethylformamide gives the corresponding 2-halophenanthridinones (I,V,XI-XIV). Further halogenation of 2-halo-6(5H)-phenanthridinone with the appropriate N-halosuccinimide, in the same medium, gives the corresponding 2,4-dihalo derivatives (II,VI). NXS/DMF is found to be a very convenient halogenating system in these preparations. 1,3,8-Trihalo-6(5H)-phenanthridinones (XIX,XX) are prepared from the 1-nitro derivatives which are obtained by a Schmidt rearrangement of 2,7-dihalo-4-nitro-9-oxofluorenes. Similarly, rearrangement and further reaction of 2-nitro-5-chloro-9-oxofluorene (XXI) leads to 3,10-dichloro-6(5H)-phenanthridinone (XXIV). UV absorptions as well as selected IR absorptions of these 6(5H)-phenanthridinones are described.     

Benzo[b] thiophene derivatives. XXII. Synthesis of the isomeric 5-methyl-6-methoxy- and 5-methoxy-6-methylbenzo[b] thiophene-2-carboxylic acids

The two isomeric benzo[b] thiophene-2-carboxylie acids having methyl and methoxy groups at positions 5 and 6 have been prepared and characterized. Both acids have been decarboxylated to the corresponding isomeric 5,6-disubstituted benzo[b]thophenes, and esterified to their methyl esters. The intermediate rhodanines, α-mercaptocinnamic acids and corresponding disulfides are described. An unusual by-product in the oxidative cyclization of β-3-methyl-4-methoxyphenyl-α-mercaptoacrylic acid with iodine is shown to be trans-3-methyl-4-methoxycinnamic acid, which can also be formed directly from the mercaptoacrylic acid by reduction with hydrogen iodide.