Synthesis and Antioxidant Properties of Novel Polycycles with Tetrahydroquinoline and Chromane Fragments

Russian Journal of Organic Chemistry - The three-component acid-catalyzed cyclocondensation of arylamines with cyclopentadiene and 6-benzyloxy/hydroxy-(2,5,7,8-tetramethylchroman-2-yl)acetaldehyde...     

新型α-生育酚自旋标记衍生物的合成

以2-硝基丙烷为原料,经溴化、取代及还原反应合成了中间体2,3-二甲基-2,3-二羟胺基丁烷(3);α-生育酚与4-甲酰苯甲酸经酯化反应制得4-甲酰苯甲酸-2,5,7,8-四甲基-2-(4,8,12-三甲基十三烷基)-6-色满酯(4);3与4的加成反应产物经高碘酸钠氧化合成了一种新型的α-生育酚自旋标记衍生物——4-[2-(4,4,5,5-四甲基-1,3-二氧基-2-吡咯啉基)]苯甲酸-2,5,7,8-四甲基-2-(4,8,12-三甲基十三烷基)-6-色满酯,其结构经1H NMR,IR,HR-ESI-MS,元素分析和EPR表征。     

(6-Benzyloxy-2,5,7,8-tetramethylchroman-2-yl)acetaldehyde conjugates with 20-hydroxyecdysone,stachysterone B,and their 20,22-acetonides

Conjugates consisting of ecdysteroid and α-tocopherol analog fragments were synthesized for the first time from 20-hydroxyecdysone and (6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)acetaldehyde.     

Development of a 6-hydroxychroman-based derivatization reagent: application to the analysis of 5-hydroxytryptamine and catecholamines by using high-performance liquid chromatography with electrochemical detection

We developed a novel derivatization reagent, (2R)-2,5-dioxopyrrolidin-1-yl-2,5,7,8-tetramethyl-6-(tetrahydro-2H-pyran-2-yloxy)chroman-2-carboxylate (NPCA), for electrochemical (EC) detection in HPLC. NPCA was synthesized from (R)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (alpha-CA), which exhibits intense EC response. NPCA successfully yielded alpha-CA derivatives of primary amines by a two-step derivatization procedure. Following pre-column derivatization with NPCA, a simultaneous determination of alpha-CA derivatives of neuroactive monoamines [dopamine (DA), epinephrine, and 5-hydroxytryptamine (5-HT)], their monoamine oxidase metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindole-3-acetic acid) and their catechol-O-methyltransferase metabolites [3-methoxytyramine (3-MT) and normetanephrine (NMN)] was completely achieved using our HPLC-EC method. Using an HPLC equipped with coulometric electrode-array detection system, the resultant alpha-CA derivatives of NMN, 5-HT, DA and 3-MT showed intense EC responses, that were approximately 1.3, 1.4, 1.1 and 1.4-fold higher than the corresponding native forms, respectively. The detection limits were in the range of approximately 16-60 fmol on column (signal-to-noise ratio 3). The proposed HPLC method was applied to determine 5-HIAA, HVA, alpha-CA-5-HT and alpha-CA-DA in rat urine. As a consequence, these analytes were successfully determined with satisfactory precisions.     

Antioxidant properties of conjugates of 20-hydroxyecdysone derivatives with a polysubstituted chromanylaldehyde

The antioxidant properties of 20-hydroxyecdysone and its conjugates with (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetaldehyde are reported for initiated 1,4-dioxane oxidation as a model reaction. The antioxidant activity of these compounds is characterized in terms of the effective rate constant of inhibition, fk _In.     

Studies on hindered phenols and analogues. V. Synthesis, identification, and antidiabetic activity of the glucuronide of CS-045.

The glucuronide of a new oral antidiabetic agent, (+/-)-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl- methoxy)benzyl]thiazolidine-2,4-dione (CS-045) (1), was synthesized to confirm the structure of a metabolite in monkeys (Macaca fascicularis) and to examine its antidiabetic activity. The glucuronide also had antidiabetic activity in KK-mice.     

An analytical method for irinotecan (CPT-11) and its metabolites using a high-performance liquid chromatography: parallel detection with fluorescence and mass spectrometry

Irinotecan or 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) is an anticancer pro-drug used in the treatment of many types of cancer. We describe here the validation of an analytical method for CPT-11 and its metabolites, including an active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), its glucuronidated form, SN-38G, and several cytochrome P450 3A-mediated products such as 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) using a high-performance liquid chromatography connected to parallel fluorescence and mass spectrometry detection systems. This method is characterized as follows: (1) simple extraction of the analytes from biomaterials with perchloric acid/methanol; (2) sensitive quantitation of major metabolites (SN-38G, SN-38 and APC) with a fluorescence detector (FLD), where the limits of quantitation by FLD were 2.5 ng/mL for SN-38G and APC, 5 ng/mL for CPT-11 and 1 ng/mL for SN-38, respectively; (3) parallel selective monitoring of the metabolites including minor metabolites with a mass selected detector (MSD). There was no observed interference by other drugs expected to be co-administered. This method showed its usefulness by identifying a novel metabolite produced in human hepatic microsomes. The results indicate that this combination of FLD and MSD enables a highly selective analysis of CPT-11 and its metabolites, and is useful for studies both in vivo and in vitro.     

Formation of water-soluble vitamin derivatives from lipophilic vitamins by cultured plant cells

Glycosylation of vitamin E, its homologues, and vitamin A by cultured plant cells of Phytolacca americana and Catharanthus roseus was investigated to produce water-soluble vitamin derivatives. Two new compounds, that is, 2,5,7,8-tetramethyl-2-(4-methylpentyl)chroman-6-yl β-d-glucopyranoside and 2,5,7,8-tetramethyl-2-(4,8-dimethylnonyl)chroman-6-yl β-d-glucopyranoside, together with 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-6-yl β-d-glucopyranoside were isolated from the cultured cells of P. americana following administration of vitamin E and its homologues, that is, 2,5,7,8-tetramethyl-2-(4-methylpentyl)-6-chromanol, 2,5,7,8-tetramethyl-2-(4,8-dimethylnonyl)-6-chromanol and 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-6-chromanol (vitamin E). On the other hand, glycosylation by C. roseus gave two new compounds, that is, 2,5,7,8-tetramethyl-2-(4-methylpentyl)chroman-6-yl 6-O-β-d-glucopyranosyl-β-d-glucopyranoside and 2,5,7,8-tetramethyl-2-(4,8-dimethylnonyl)chroman-6-yl 6-O-β-d-glucopyranosyl-β-d-glucopyranoside, as well. Furthermore, conversion of vitamin A (retinol) by these cultured cells afforded retinyl β-d-glucopyranoside.     

The use of umbelliferone in the synthesis of new heterocyclic compounds

New coumarin derivatives, namely 7-[(5-amino-1,3,4-thiadiazol-2-yl)methoxy]-2H-chromen-2-one, 5-[(2-oxo-2H-chromen-7-yloxy)methyl]-1,3,4-thiadiazol-2(3H)-one, 2-[2-(2-oxo-2H-chromen-7-yloxy)acetyl]-N-phenylhydrazinecarbothioamide, 7-[(5-(phenylamino)-1,3,4-thiadiazol-2-yl)methoxy]-2H-chromen-2-one and 7-[(5-mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methoxy]-2H-chromen-2-one were prepared starting from the natural compound umbelliferone. The newly synthesized compounds were characterized by elemental analysis and spectral studies (IR, 1H-NMR and 13C-NMR).     

Totalsynthese von natürlichem α-Tocopherol. 4. Mitteilung. Aufbau des Chromanringsystems aus Trimethylhydrochinon und einem optisch aktiven C4- bzw. C5-Synthon

Total Synthesis of Natural α-Tocopherol Two independent syntheses of (S)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methanol ( 8b ), (Scheme 6 resp. 9) as optically active chroman moiety for the preparation of natural vitamin E via (S)-6-acetoxy-2,5,7,8-tetramethylchroman-2-carboaldehyde ( 2a ) (Scheme 1) and a corresponding side chain are described. Both reaction sequences use trimethyl-hydroquinone as starting material; one approach employs an optically active C₄ unit ( 10a ) (Schemes 5 and 6) to introduce the required configuration at C(2), the other uses an optically active C₅-synthon ( 11a ) (Schemes 8 and 9) to build the optically active chroman unit. The correct configuration and optical purity of the chroman synthesized is established by correlation with optically pure material of known configuration from which natural vitamin E had already been derived [2].     

Reaction of 2-(phenylamino)benzoic and 2-(phenylamino)- and 2-methyl-6-phenylpyridine-3-carboxylic acid hydrazides with succininc anhydride

Reactions of 2-(phenylamino)benzoic and 2-(phenylamino)- and 2-methyl-6-phenylpyridine-3-carboxylic acid hydrazides with succinic anhydride in organic solvents at room temperature gave the corresponding 4-(2-aroylhydrazinyl)-4-oxobutanoic acids. The reactions in boiling acetic acid afforded N-(2,5-dioxopyrrolidin-1-yl)benzamide or N-(2,5-dioxopyrrolidin-1-yl)pyridine-3-carboxamide.     

替格瑞洛的合成工艺改进

以2-丙硫基-4,6-二氢-5-氨基嘧啶和2-{［(3aR,4S,6R,6aS)-6-氨基-2,2-二甲基四氢-3aH-环戊基［d］［1,3］二氧-4-基］氧}-1-乙醇L-酒石酸盐为原料,经C-N偶联,亲核取代和环合反应制得2-{［(3aR,4S,6R,6aS)-6-(7-氯-5-丙硫基-3H-［1,2,3］三唑［4,5-d］嘧啶-3-基)-2,2-二甲基四氢-3aH-环戊基［d］［1,3］二氧-4-基］氧}-1-乙醇(4); 4与(1R,2S)-2-(3,4-二氟苯基)环丙胺D-扁桃酸盐经亲核取代反应后酸解脱除丙酮叉保护基合成替格瑞洛,总收率58.7%,纯度99.2%,其结构经¹H NMR, MS(ESI)和XRD确证。     

N-甲基-2-(4-取代哌嗪)-N-[3-(萘氧基)-3-(2-噻吩基)丙基]乙酰胺衍生物的设计与合成

以N-甲基-3-(1-萘氧基)-3-(2-噻吩基)-丙胺(度洛西汀)为原料,通过N-酰氯化反应和N-烷基化反应,合成了5个新型的N-甲基-2-(4-取代哌嗪)-N-[3-(萘氧基)-3-(2-噻吩基)丙基]酰胺衍生物,其结构经1H NMR,IR和MS表征。     

Synthesis and antioxidant activity of some new coumarinyl-1,3-thiazolidine-4-ones

A series of Schiff's bases (E)-N-2-aryliden-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetohydrazides 2a-l and N-(2-(substituted phenyl)-4-oxo-thiazolidin-3-yl)-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetamides 3a-l were synthesized and evaluated for their antioxidant activity by the phosphomolybdenum method. Most of the Schiff's bases and thiazolidine-4-ones bearing two hydroxyl groups on the phenyl ring showed excellent antioxidant activity in comparison with ascorbic acid. Preliminary investigation on cytotoxic and antifungal activity was done on some representative samples.     

13C CP/MAS NMR studies of vitamin E model compounds

13C cross-polarization magic angle spinning (CP/MAS) NMR data for 2,2,5,7,8-pentamethylchroman-6-ol (2), 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox c) (3) and its acetate (4), 2-methoxy-2,2,5,7,8-pentamethylchroman-6-ol (5), 2-hydroxy-2,2,5,7,8-pentamethylchroman-6-ol (6) and 2,2,5,7,8-pentamethylchroman (7) are reported. A deshielding of 7.7 ppm for the carboxylic carbon was observed in solid Trolox due to formation of intermolecular hydrogen bonds within cyclic dimers. Such crystal packing permits effective cross-polarization and fast relaxation (short T1rho(H)). The impact of the proton concentration on the CP dynamics is reflected by the longer T(CP) and T1rhoH for Trolox-d2 (deuterated at mobile proton sites). The calculated GIAO RHF shielding constants are sensitive to intramolecular effects: rotation around the C-6-O bond (changes of sigma up to 8 ppm) and conformation at C-2.     

Synthesis and characterization of new thiazolidinones containing coumarin moieties and their antibacterial and antioxidant activities

New coumarin derivatives, namely (2-(4-methyl-2-oxo-2H-chromen-7-yloxy)-N-(4-oxo-2-phenylthiazolidin-3-yl)acetamide, N-(2-(3-methoxyphenyl)-4-oxothiazolidin-3-yl)-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetamide, 2-(4-methyl-2-oxo-2H-chromen-7-yloxy)-N-(4-oxo-2-(2,3,4trimethoxyphenyl)thiazolidin-3-yl)acetamide and N-(2-(4-bromophenyl)-4-oxothiazolidin-3-yl)-2-(4-methyl-2-oxo-2H-chromen-7-yloxy)acetamide) were synthesized starting from 4-methyl-7-hydroxycoumarin. The structures of the obtained compounds were confirmed by analytical IR and NMR spectra to elucidate the different positions of protons and carbons and as well as theoretical studies (DFT/B3LYP). The new compounds were screened for antibacterial activity. Most of them are more active against E. coli S. aureus and B. subtilis than standard references.     

Studies on the Synthesis of (2R,4′R,8′R)-α-Tocopherol Alternative Syntheses of 2-Chroman-acetic Acid Intermediates

As an extension of previous studies on the total synthesis of (2R,4′R,8′R)-α-tocopherol ( 1 ) [1] [2], (S)-(?)-2-(6-benzyloxy-2,5,7,8-tetramethylchroman)acetic acid ( 6 ), a pivotal intermediate, possessing the absolute configuration required for construction of 1 was prepared by optical resolution of the racemic modification 11 . the latter substance was obtained by two routes, one emanating from the hydroxy acetal 7 [1] and the other based upon the Lewis acid mediated cycloaddition of trimethylhydroquinone to rac.-3-hydroxy-3-methylpent-4-en-l-yl acetate ( 16 ) giving rac. ethyl 2-(6-hydroxy-2,5,7,8-tetramethyl-chroman)acetate ( 12 ).     

Syntheses of (2R,4'R,8'R)-alpha-tocopherol and (2R,3'E,7'E)-alpha-tocotrienol.

Reaction of trimethyl-hydroquinone with methyl vinyl ketone in acidic methanol gave rac.-2-methoxy-2,5,7,8-tetramethyl-chroman-6-ol ( 8 ). This acetal was converted in four steps to rac.-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)acetic acid ( 13 ). Acid 13 was readily resolved with α-methyl-benzylamine to give the (S)-enantiomer 14 . Treatment of the unwanted (2 R)-isomer with acid regenerated 13 , thus leading to an efficient use of this compound. Employing a side chain derived from phytol, 14 was converted to (2R, 4′R, 8′R)-α-tocopherol ( 1d , ‘natural’ vitamin E). A reaction sequence from 14 involving two highly stereoselective Claisen rearrangements has provided the first total synthesis of (2R,'E,7′E)-α-tocotrienol ( 2d ).     

15N-labeled ionic probe attachment mass spectrometry of carbon clusters

An ionization method that uses metal-complex-based ionization probes, malonic acid 3-[2,6-bis(4,4-dimethyloxazolin-2-yl)pyridin-4-yloxy]propyl ethyl ester (EM-TMpybox) and potassium N-{3-[2,6-bis(4,4-dimethyloxazolin-2-yl)pyridine-4-yloxy]propyl} aminoacetate (Sar-TMpybox), was developed for isotope ratio analysis and the effective ionization of unsubstituted carbon clusters. The preparation of Sar-TMpybox and EM-TMpybox and their applications in cold-spray ionization mass spectrometry are reported. A probe applicable to a substituted fullerene is also demonstrated.     

Synthesis of 3-amino-3,4-dihydroquinazolin-4-one derivatives from anthranilic acid hydrazide and dicarboxylic acids

Treatment of anthranilic acid hydrazide with 2 equiv of ethoxalyl chloride gave the corresponding diester which underwent cyclization in acetic anhydride to produce ethyl 3-(ethoxalylamino)-4-oxo-3,4-dihydroquinazoline-2-carboxylate. Acylation of anthranilic acid hydrazide first with succinic anhydride and then with ethoxalyl chloride led to the formation of 4-[2-(2-{[ethoxy(oxo)acetyl]amino}benzoyl)hydrazino]-4-oxobutanoic acid whose cyclization in acetic acid afforded N-(2-ethoxycarbonyl-4-oxo-3,4-dihydroquinazolin-3-yl)succinamic acid, while in acetic anhydride ethyl 3-(2,5-dioxopyrrolidin-1-yl)-4-oxo-3,4-dihydroquinazoline-2-carboxylate was obtained. The latter was brought into reactions with amines and hydrazine hydrate and alkaline hydrolysis. Acylation of 2-[2-(2-aminobenzoyl)hydrazinocarbonyl]benzoic acid with ethoxalyl chloride gave ethyl N-[2-(phthalimidocarbamoyl)phenyl]oxamate, and with succinic anhydride, 3-[4-oxo-3-phthalimido-3,4-dihydroquinazolin-2-yl]propionic acid. 4-[2-(2-Aminobenzoyl)hydrazino]-4-oxobutanoic acid reacted with phthalic anhydride in boiling acetic acid to give phthalazino[1,2-b]quinazoline-5,8-dione via elimination of succinic acid residue.