Investigation of amodiaquine bulk drug impurities by liquid chromatography/ion trap mass spectrometry

Three unknown impurities in an amodiaquine bulk drug sample were detected by reversed-phase high-performance liquid chromatography with ultraviolet detection (HPLC/UV). A liquid chromatography/tandem mass spectrometry (LC/MS(n)) method is described for the investigation of these impurities. Mass spectral data were acquired on an LCQ ion trap mass analyzer equipped with an electrospray ionization (ESI) source operated in positive ion mode. The fragmentation behavior of amodiaquine and its impurities has been studied. Based on the mass spectral data and the specifics of the synthetic route, the possible structures of these impurities were elucidated as 4-[(5-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol (impurity I), 4-[(7-chloroquinolin-4-yl)-amino]phenol (impurity II) and 4-[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)-N(1)-oxy]phenol (impurity III). The structures were confirmed by their independent synthesis and NMR spectral assignment.     

Synthesis of azoles from 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides

Condensation of 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides with 2,4-pentanedione, phenyl isocyanate or phenyl isothiocyanate (with subsequent work up of the semicarbazides obtained by base), and carbon disulfide gave respectively: 1-(3,5-dimethyl-1H-1-pyrazolyl)-3-[3-(3,5-dimethyl-1H-1-pyrazolyl)-3-oxopropylanilino]-1-propanone, 3-(2-{[2-(5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]anilino}ethyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-one and its thio analog, and 5-(2-{[2-(2-thioxo-2,3-dihydro-1,3,4-oxadiazol-5-yl)ethyl]anilino}ethyl)-2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione plus their methyl derivatives. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1353–1358, September, 2007.     

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).     

8-羟基喹啉席夫碱衍生物及其金属配合物的合成及荧光性质研究

设计合成了三种新的8-羟基喹啉席夫碱衍生物4-(8-羟基喹啉-5-亚胺甲基)-7-甲氧基苯并吡喃-2-酮(3a),4-(8-羟基喹啉-5-亚胺甲基)-7-己氧基苯并吡喃-2-酮(3b)和4-(8-羟基喹啉-5-亚胺甲基)-7-十八烷氧基苯并吡喃-2-酮(3c)及其铝、锌配合物,产物结构经1H(13C)NMR,MS,HRMS,IR和元素分析表征,研究了它们的荧光发光性能.     

Synthesis, characterization and fluorescence studies of novel bi-phenyl based acrylate and methacrylate

4-[(1E)-3-(biphenyl-4-yl)buta-1,3-dien-1-yl]phenyl prop-2-enoate (ACH) and 4-[(1E)-3-(biphenyl-4-yl)buta-1,3-dien-1-yl]phenyl 2-methylprop-2-enoate (MCH) was synthesized from biphenyl in three steps and their structures were confirmed by elemental analysis, IR, NMR (1H, 13C, DEPT135, 1H-1H COSY, 1H-13C HSQC and 1H-13C HMBC) spectroscopic techniques. In this present study, various physicochemical characteristics we demonstrate solubility, color, absorbance and fluorescence property of novel biphenyl based acrylate and methacrylate measured in different solvents like benzene, dichloromethane, tetrahydrofuran, acetonitrile, dimethylsulfoxide and ethanol.     

Synthesis and total 1H- and 13C-NMR assignment of cephem derivatives for use in ADEPT approaches

We report the synthesis and total NMR characterization of 5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid-3-[[[(4'-nitrophenoxy)carbonyl]oxy]-methyl]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (5), a new cephalosporin derivative. This compound can be used as the carrier of a wide range of drugs containing an amino group. The preparation of the intermediate product, 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (6), as well as the synthesis of the antimalarial primaquine prodrug 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]- 5-dioxide (7) are also described, together with their total (1)H- and (13)C-NMR assignments.     

Synthesis of new bis-1,2,4-triazole derivatives

A series of new 1,2/1,3-bis[o-(N-methylidenamino-3-aryl-5-phenyl-4H-1,2,4-triazole-4-yl)phenoxy]ethane/propane derivatives 4 were prepared in good yields by treatment of 4-amino-3-aryl-5-phenyl-4H-1,2,4-triazoles 2 with certain bis-aldehydes 1.Compounds 4 were reduced with NaBH(4) to afford the corresponding 1,2/1,3-bis[o-(N-methylamino-3-aryl-5-phenyl-4H-1,2,4-triazole-4-yl)phenoxy]ethane/propane derivatives 5. All new compounds were characterized by IR, (1)H-NMR, (13)C-NMR and mass spectral data.     

Synthesis and antimicrobial activity of some derivatives of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide

(7-Hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide (2) was prepared from (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid ethyl ester (1) and 100% hydrazine hydrate. Compound 2, is the key intermediate for the synthesis of several series of new compounds such as Schiff's bases 3a-l, formic acid N'-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)acetyl] hydrazide (4), acetic acid N'-[2-(7-hydroxy-2-oxo-2H-chromen-4- yl)-acetyl] hydrazide (5), (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid N'-[2-(4- hydroxy-2-oxo-2H-chromen-3-yl)-2-oxoethyl] hydrazide (6), 4-phenyl-1-(7-hydroxy-2- oxo-2H-chromen- 4-acetyl) thiosemicarbazide (7), ethyl 3-{2-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)-acetyl]hydrazono}butanoate (8), (7-hydroxy-2-oxo-2H-chromen-4-yl)- acetic acid N'-[(4-trifluoromethylphenylimino)methyl] hydrazide (9) and (7-hydroxy-2- oxo-2H-chromen-4-yl)acetic acid N'-[(2,3,4-trifluorophenylimino)-methyl] hydrazide (10). Cyclo- condensation of compound 2 with pentane-2,4-dione gave 4-[2-(3,5- dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-7-hydroxy-2H-chromen-2-one (11), while with carbon disulfide it afforded 7-hydroxy-4-[(5-mercapto-1,3,4-oxadiazol-2-yl)methyl]-2H- chromen-2-one (12) and with potassium isothiocyanate it gave 7-hydroxy-4-[(5- mercapto-4H-1,2,4-triazol-3-yl)methyl]-2H-chromen-2-one (14). Compound 7 was cyclized to afford 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)-N -(4-oxo-2-phenylimino- thiazolidin-3-yl) acetamide (15).     

Alpha-glucosidase inhibitory constituents from Cuscuta reflexa

Two new compounds, 7'-(3',4'-dihydroxyphenyl)-N-[(4-methoxyphenyl)ethyl]propenamide (4), and 7'-(4'-hydroxy,3'-methoxyphenyl)-N-[(4-butylphenyl)ethyl]propenamide (5) have been isolated from Cuscuta reflexa along with five known compounds, 6,7-dimethoxy-2H-1-benzopyran-2-one (1), 3-(3,4-dihydroxyphenyl)-2-propen-1-ethanoate (2), 6,7,8-trimethoxy-2H-1-benzopyran-2-one (3), 3-(4-O-beta-D-glucopyranoside-3,5-dimethoxyphenyl)-2-propen-1-ol (6), 2-(3-hydroxy-4-methoxyphenyl)-3,5-dihydroxy-7-O-beta-D-glucopyranoside-4H-1-benzopyrane-4-one (7), reported for the first time from this species. Structures of these compounds were determined by spectral analysis. These compounds showed strong inhibitory activity against alpha-glucosidase.     

1H and 13C NMR spectral study of some 3,5-bis[(E)-thienylmethylene]piperidin-4-ones

(1)H and (13)C NMR spectra have been recorded for 3,5-bis[(E)-thienylmethylene]piperidin-4-one (1a), 3',3″-dimethyl-3,5-bis[(E)-thienylmethylene]piperidin-4-one (1b), 5',5″-dibromo-3,5-bis[(E)-thienylmethylene]piperidin-4-one (1c), their 1-methyl derivatives 2a-c and 3,5-bis[(E)-thienylmethylene]-2r,6c-diphenylpiperidin-4-one (3a). For selected compounds 2D spectra have been recorded. The spectral data are used to study the configuration and conformation of these molecules. The chemical shifts are discussed in light of steric, electronic and magnetic anisotropic effects. The magnetic anisotropic effects of thiophene ring and phenyl group are noteworthy. (1)H-(1)H COSY spectrum of 2b suggests that long-range (1)H-(1)H coupling, up to seven bonds, is possible in it. HMBC spectrum of 2b displays the magnetic nonequivalence of C-2 and C-6 and protons at these carbons.     

Synthesis of [1-15N,2-13C]-labeled difloxacin

Abstract  

The synthesis of [1-¹⁵N,2-¹³C]-difloxacin, an arylfluoroquinolone antibacterial agent, is reported. As a crucial initial step, the starting materials ethyl 2,4,5-trifluorobenzoylacetate, [formyl-¹³C]-triethyl orthoformate, and [¹⁵N]-4-fluoroaniline were reacted to ethyl [¹⁵N,3-¹³C]-3-(4-fluoroanilino)-2-(2,4,5-trifluorobenzoyl)acrylate. After cyclization and ester cleavage, the resulting intermediate was reacted with 1-methylpiperazine to [1-¹⁵N,2-¹³C]-1-(4-fluorophenyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, i.e., [1-¹⁵N,2-¹³C]-difloxacin. The overall yield was 62% based on the non-labeled and 43% based on the labeled starting materials (both used in 1.4 molar excess). The product was identified by ¹H-, ¹³C-, and ¹⁵N-NMR spectroscopy and by cochromatography (TLC, HPLC) with an authentic reference; its purity (HPLC) was above 98%. Prior to synthesis of [1-¹⁵N,2-¹³C]-difloxacin, non-labeled difloxacin was synthesized in order to optimize procedures and to identify and characterize all intermediates.     

Synthesis and biological activities of new 1,4-benzothiazine derivatives.

New 2H-1,4-benzothiazin-3(4H)-one derivatives possessing (4-phenyl-1-piperazinyl)alkyl moieties at the 2-position were synthesized and tested for calcium antagonistic and calmodulin antagonistic activities. Antihypertensive effects in spontaneously hypertensive rats were also evaluated. In general, these compounds were rather weak calcium channel blockers, although, in contrast, many of them had moderate to potent calmodulin antagonistic activity, and 2-[3-(4-(4-fluorophenyl)-1-piperazinyl]propyl]-2H-1,4-benzothiazin -3 (4H)-one derivatives 45, 74 and 75 showed potent antihypertensive effects.     

Synthesis of new 1H-1,2,4-triazolylcoumarins and their antitumor and anti-HIV activities

A variety of 7-[(1,5-dialkyl-1H-1,2,4-triazolyl)methoxy(and methyl)]coumarins were synthesized from cycloaddition of 2-(2H-benzopyran-7-yloxy)acetonitrile and 2-(5-methoxy-4-methyl-2H-benzopyran-7-yloxy)acetonitrile, respectively, with various reactive cumulene intermediates via spontaneous rearrangements. The anticancer (breast, lung, CNS cancers) and antiviral (HIV-1, HIV-2) properties of some compounds were investigated in vitro. 5-Methoxy-4-methyl-7-[(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-yl)methyl]coumarin showed some inhibition of HIV-1. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 669–678, May, 2006.     

Design, synthesis, and 1,3-dipolar cycloaddition of (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1,4-oxazin-2-one N-oxides as chiral (E)-geometry-fixed alpha-alkoxycarbonylnitrones

Optically pure (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1, 4-oxazin-2-one N-oxides [(5R)- and (5S)-2] were designed as chiral (E)-geometry-fixed alpha-alkoxycarbonylnitrones 1. The nitrones (5R)- and (5S)-2 were synthesized by three-step oxidation of (R)- and (S)-phenylglycinols [(R)- and (S)-3], condensation of the resulting (R)- and (S)-2-hydroxylamino-2-phenylethanols [(R)- and (S)-5] with glyoxylic acid, and cyclization of the intermediary nitrones (R)- and (S)-6b. The nitrone (5R)-2reacted with olefins 7-14 under mild conditions to afford the corresponding cycloadducts 15-22 as the main products via the least sterically demanding exo modes. Cycloadduct 30 obtained from (5S)-2 and cyclopentadiene was effectively elaborated to (1S,4S, 5R)-4-benzyloxycarbonylamino-2-oxabicyclo[3.3.0]oct-7-en-3-one (28), the key synthetic intermediate of carbocyclic polyoxin C.     

Synthesis and thermal behaviour of new benzo-1,2-thiazine long-chain aryl-piperazine derivatives

A series of potential biologically active 2-[3-(4-phenyl-1-piperazinyl)propyl]-3-(4-substituted-benzoyl)-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxides was synthesized in a straightforward manner by condensation of respective 3-substituted-4-hydroxy-1,2-benzothiazine 1,1-dioxides with 1-(1-chloropropyl)-4-phenylpiperazine. The structures of all of the newly formed compounds were identified by elemental analysis, FTIR and ¹H NMR. The synthesized compounds were subjected to preliminary evaluation using differential scanning calorimetry (DSC) to determine the existence of multiple crystal forms. The DSC scans for all compounds show more than one endothermic effect, which might suggest dynamic proton transfer between two or three possible tautomeric forms: O-keto/O-enol, O-enol/O-keto and O-keto/O-keto/CH₂ in crystals 2-[3-(4-phenyl-1-piperazinyl)propyl]-3-(4-substituted-benzoyl)-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxides.     

Oxacalix[3]arene complexes with the ReI(CO)3 fragment

Oxacalix[3]arenes p-methyloxacalix[3]arene (L(1)), p-isopropyloxacalix[3]arene (L2), and p-ethoxycarbonyloxacalix[3]arene (L3) are able to bind the Re(I)(CO)3 moiety with two of their three phenol-O atoms and one of their ether-O atoms. The monoanionic complexes were isolated in the salts (DBUH)[Re(CO)3(L1H-2)].L1 (1) and (NEt4)[Re(CO)3(L2H-2)].L2.0.5 MeCN (2) (DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene). Over the course of its reaction with (NEt4)(2)[Re(CO)3Br(3)] and DBU, p-ethoxycarbonyloxacalix[3]arene decomposes to form [{Re(CO)3(L4H-2)}2] (3) {L4 = 1-(5-ethoxycarbonyl-2-hydroxy-3-hydroxymethyl-benzyl)-2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-a]azepin-1-ium. The expected monoanion [Re(CO)3(L3H-2)]- (4) was identified by 13C NMR and mass spectra.     

Studies on antibacterial agents. II. Synthesis and antibacterial activities of substituted 1,2-dihydro-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acids

A series of substituted 1,2-dihydro-6-oxo-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acids for the treatment of systemic infections was synthesized via 7-bromo-3-ethylthio-4,5-difluoro-2-methylindole (3), which was prepared by Gassman's indole synthesis in excellent yield. The synthesized pyrroloquinolines were tested for their antibacterial activities. 8-Fluoro-1,2-dihydro-2-methyl-9-(4-methyl-1-piperazinyl)-6-oxo-6H- pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid showed a potent antibacterial activity against gram-positive and gram-negative bacteria.     

Preparation of palladium complexes of 1,3-di(2-pyridyl)propane derivatives and their use in norbornene polymerization

A variety of neutral palladium(II) complexes [Pd(L–L)Cl₂] containing 1,3-di(2-pyridyl)propane (1), 1,3-bis(2-pyridyl)-2-pentylpropane (2), 1,3-bis(2-pyridyl)-2-phenylpropane (3a), 1,3-bis(2-pyridyl)-2-tolylpropane (4), and 1,3-bis(2-pyridyl)-2-ferrocenylpropane (5) as chelate ligands (L–L) have been synthesized. The crystal structures of 1,3-diphenyl-2,4-di-pyridin-2-yl-butan-1-ol (3b), 5, [(2)PdCl₂], [(4)PdCl₂], and [(5)PdCl₂] have been determined and show a square planar geometry at palladium(II). The neutral complexes were tested in the polymerization of norbornene and copolymerization of norbornene with norbornene derivatives. The complex bearing the pentyl group exhibited high reactivity to give up to 5.9×10⁵ in molecular weight for the homopolymerization. When [(4)PdCl₂] or [(5)PdCl₂] was used as a catalyst, homopolymers insoluble at 150 °C in trichlorobenzene were obtained. However, copolymerization of norbornene with norbornene derivatives 8a–d catalyzed by [(4)PdCl₂] gave soluble copolymers with molecular weights up to 5.1×10⁵.     

The first (ferrocenylmethyl)imidazolium and (ferrocenylmethyl)triazolium room temperature ionic liquids

N-(Ferrocenylmethyl)imidazole (3a), 1-(ferrocenylmethyl)-1,2,4-triazole (3b), 1,1'-bis[(1H-imidazol-1-yl)methyl]ferrocene (8a), 1,1'-bis([1H-(2-methyl)imidazol-1-yl]methyl]ferrocene (8b), and 1,1'-bis[(1H-1,2,4-triazol-1-yl)methyl]ferrocene (8c) were synthesized in moderate yields. These compounds were quaternized with methyl iodide to form 1-(ferrocenylmethyl)-3-methylimidazolium iodide (4a), 1-(ferrocenylmethyl)-4-methyl-1,2,4-triazolium iodide (4b), 1,1'-bis([1-(2,3-dimethyl)imidazolium]methyl)ferrocene diiodide (9b), and 1,1'-bis([1-(4-methyl)-1,2,4-triazolium]methyl)ferrocene diiodide (9c), respectively, in excellent yields. Compounds 4a, 4b, 9b, and 9c were metathesized with bis(trifluoromethanesulfonyl)amide to give high yields of 5a, 5b, 10b, and 10c. With potassium hexafluorophosphate, 9b forms 10d. Salts 5a, 5b, and 10c are the first room-temperature ionic liquids with cations containing an organometallic moiety that exhibit T(g) values well below room temperature, i.e., -32, -16, and -11 degrees C. The compounds were characterized by (1)H, (19)F, and (13)C NMR, MS, and elemental analyses. T(g) values and melting points were determined by DSC. T(d) values (5% weight loss temperature) were recorded by TGA. X-ray single-crystal structures show that 9c and 10d crystallize in the triclinic space group P.     

Palladium catalyzed C-C coupling reactions of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one

Palladium catalyzed Suzuki-Miyaura, Stille, and Sonogashira coupling reactions are reported for the electron-deficient heterocyclic scaffold 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (1). Furthermore, 3,5-di(thien-2-yl)-4H-1,2,6-thiadiazin-4-one (7m) is further elaborated to afford the tetrathienyl 3,5-bis[(2,2'-bithien)-5-yl]-4H-1,2,6-thiadiazin-4-one (9). All compounds are fully characterized.