Chemical and Pharmaceutical Bulletin
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ISSN-L : 0009-2363
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Volume 49, Issue 12
Displaying 1-32 of 32 articles from this issue
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Regular Articles
  • Evaluation of 13C-Phenylalanine and 13C-Tyrosine Breath Tests for the Measurement of Hepatocyte Functional Capacity in Patients with Liver Cirrhosis
    Toshihiro ISHII, Masaru FURUBE, Shuusuke HIRANO, Kazuhiko TAKATORI, Ka ...
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1507-1511
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1507
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    Liver disease is associated with an abnormal elevation of the plasma concentrations of the aromatic amino acids phenylalanine and tyrosine. The liver is the main site of aromatic amino acid metabolism, particularly the hydroxylation of phenylalanine to tyrosine and further tyrosine degradation. In the present study, we have examined the usefulness of the L-[1-13C]phenylalanine breath test (13C-PheBT) and L-[1-13C]tyrosine breath test (13C-TyrBT) for the detection of hepatic damage in patients with liver cirrhosis. First, the time courses of 13CO2 excretion after the administration of L-[1-13C]phenylalanine and L-[1-13C]tyrosine were compared. The peak times (the time expressed in minutes at which 13CO2 excretion was maximal) were 20 min in both breath tests, but 13C-TyrBT gave a higher peak than 13C-PheBT. Next, the parameters of 13C-PheBT and 13C-TyrBT were compared with biochemical liver function test values. These parameters were well correlated with several liver blood test values conventionally regarded as measures of hepatocyte functional reserve. Therefore, 13C-PheBT and 13C-TyrBT may be useful to assess the degree and progression of hepatic dysfunction.
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  • Measurement of the Length of the α Helical Section of a Peptide Directly Using Atomic Force Microscopy
    Seiji TAKEDA, Arkadiusz PTAK, Chikashi NAKAMURA, Jun MIYAKE, Masami KA ...
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1512-1516
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1512
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    Using atomic force microscopy (AFM), the length of the α-helix structure of poly-L-lysine was investigated by stretching the peptide directly, one molecule at a time. In the absence of urea, many rupturing points that seemed to be due to the breaking of some hydrogen bonds were observed in force-extension curves, while these points were never observed in the presence of 8 M urea. In the presence of 0.4 or 1.6 M urea, both force-extension curve types were observed. Total peptide elongation for each condition was calculated from force-extension curves reflecting the α-helix rupturing process. The experimental value of total elongation divided by the theoretical value of total α-helix elongation yields the α-helix content. This value was compatible with circular dichroism (CD) measurement results. This suggests that peptide conformation and content of the α-helix on a single molecule scale can be investigated by direct mechanical measurement using atomic force microscopy.
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  • Synthesis, Characterization, DNA Binding and Cytotoxic Studies of Platinum(II) and Palladium(II) Complexes of the 2,2'-Bipyridine and an Anion of 1,1-Cyclobutanedicarboxylic Acid
    Hassan MANSURI-TORSHIZI, Saeid GHADIMY, Niloofar AKBARZADEH
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1517-1520
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1517
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    Two neutral complexes of formula [M(bpy)(cbdca)] [where M is palladium(II) (Pd(II)) or platinum(II) (Pt(II)), bpy is 2,2'-bipyridine and cbdca is anion of 1,1-cyclobutanedicarboxylic acid] have been synthesized. These water soluble complexes have been characterized by chemical analysis and conductivity measurements as well as 1H-NMR, ultraviolet-visible and infrared spectroscopy. In these complexes the ligand cbdca coordinates to Pt(II) or Pd(II) as bidentate with two oxygen atoms. They are nonelectrolyte in conductivity water. These complexes inhibit the growth of P388 lymphocytic leukemia cells and their targets are DNA. They invariably show ID50 values less than cisplatin. [Pt(bpy)(cbdca)] and [Pd(bpy)(cbdca)] have been interacted with calf thymus DNA and bind to DNA through coordinate covalent bond. In addition, the influence of binding of these complexes on the intensity of EtBr-DNA have been studied. They bind to DNA via a nonintercalating mode.
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  • Constituents of Ophiuroidea. 1. Isolation and Structure of Three Ganglioside Molecular Species from the Brittle Star Ophiocoma scolopendrina
    Masanori INAGAKI, Motohiro SHIBAI, Ryuichi ISOBE, Ryuichi HIGUCHI
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1521-1525
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1521
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    Three ganglioside molecular species, OSG-0 (1), OSG-1 (2), and OSG-2 (3) have been obtained from the polar lipid fraction of the chloroform/methanol extract of the brittle star Ophiocoma scolopendrina. The structures of these gangliosides have been determined on the basis of chemical and spectroscopic evidence as 1-O-[(N-glycolyl-α-D-neuraminosyl)-(2→6)-β-D-glucopyranosyl]-ceramide (1), 1-O-[8-O-sulfo-(N-acetyl-α-D-neuraminosyl)-(2→6)-β-D-glucopyranosyl]-ceramide (2) and 1-O-[(N-glycolyl-α-D-neuraminosyl)-(2→8)-(N-acetyl- and N-glycolyl-α-D-neuraminosyl)-(2→6)-β-D-glucopyranosyl]-ceramide (3). The ceramide moieties were composed of heterogeneous unsubstituted fatty acid, 2-hydroxy fatty acid and phytosphingosine units. Compounds 2 and 3 represent new ganglioside molecular species.
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  • Effects of Dehydration Temperatures on Moisture Absorption and Dissolution Behavior of Theophylline
    Makoto ONO, Yuichi TOZUKA, Toshio OGUCHI, Keiji YAMAMOTO
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1526-1530
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1526
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    Anhydrous theophylline was prepared by heating theophylline monohydrate at temperatures between 60 °C and 140 °C. The effects of dehydration temperatures on the moisture absorption and dissolution behavior of anhydrous theophylline were investigated in this study. The hydration rate of anhydrous theophylline at 95% relative humidity and 25 °C decreased with increasing dehydration temperatures. From the fitting analysis of solid-state reaction models, the hydration reaction was found to be governed by the phase boundary reaction model for samples prepared at lower dehydration temperatures (<100 °C) but the reaction obeyed the growth of nuclei reaction model when samples were dehydrated at higher temperatures. The dissolution rates of various anhydrous theophylline samples were measured by the rotating disk method. The calculated solubility of anhydrous theophylline prepared by heating was about 2.5 times higher than that of theophylline monohydrate. The phase transformation rate from the anhydrous form to the monohydrate during dissolution tests decreased with higher dehydration temperatures. It was found that the anhydrous theophylline prepared at different dehydration temperatures transformed to the monohydrate by way of different growth of hydrate nuclei mechanism.
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  • Solution Properties and Photonuclease Activity of Cationic Bis-porphyrins Linked with a Series of Aliphatic Diamines
    Naoki YAMAKAWA, Yoshinobu ISHIKAWA, Tadayuki UNO
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1531-1540
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1531
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    The development of efficient photo-induced DNA cleavage agents has been of particular interest for biomedical applications such as cancer photodynamic therapy (PDT). Toward this objective, we synthesized a series of cationic bis-porphyrins with various lengths of diamino alkyl linkage, N,N'-bis{4-[10,15,20-tris(1-methylpyridinium-4-yl)porphyrin-5-yl]benzoyl}oligomethylenediamine hexaiodide. They were expected to show more efficient photocleavage of DNA than unichromophore meso-tetrakis(4-N-methylpyridiniumyl)porphine (TMPyP), which is well known to cleave DNA effectively on illumination. The cationic bis-porphyrins were found to self-aggregate in aqueous solution, and the aggregation property was accounted for by the formation of an intermolecular dimer. Because conservative-type circular dichroism spectra of the bis-porphyrins were induced in the Soret region on binding to calf thymus DNA, we assigned their binding mode to outside self-stacking on the DNA surface. Their photonuclease activity using plasmid DNA decreased as the number of their linker hydrocarbons increased, and was well correlated with their tendency for dimerization. The inhibitory effect of azide anion, N3-, and the enhancement effect of D2O suggest that singlet oxygen was probably involved in the photocleavage of DNA.
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  • Redox Reaction of Artemisinin with Ferrous and Ferric Ions in Aqueous Buffer
    Nathawut SIBMOOH, Rachanee UDOMSANGPETCH, Anake KIJJOA, Udom CHANTHARA ...
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1541-1546
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1541
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    Artemisinin, a sesquiterpene with endoperoxide bond, possesses potent antimalarial activity against the ring and late stage of chloroqine-resistant Plasmodium falciparum malaria both in vitro and in vivo. The mode of antimalarial activity of artemisinin is iron-dependent. The aim of this study was to investigate the reactions of artemisinin with ferrous and ferric ions in aqueous buffer. Artemisinin generated a cycle of iron oxidation and reduction. It oxidized ferrous and reduced ferric ions with similar rate of reaction (k=10±0.5 M-1·s-1 for ferrous and k=8.5±2.0 M-1·s-1 for ferric ion). The major active product was dihydroartemisinin which exhibited antimalarial activity at least 3 times more potent than artemisinin. Dihydroartemisinin preferably binds to ferric ion, forming ferric-dihydroartemisinin complex. The re-oxidation of the complex gives artemisinin and ferric ion. This suggests that in aqueous buffer, the reaction of artemisinin with iron may give rise to the active reaction products, one of them being dihydroartemisinin, which is responsible for antimalarial activity.
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  • Functional Modification of Cytochrome c by Peroxynitrite in an Electron Transfer Reaction
    Hidehiko NAKAGAWA, Yukiko OHSHIMA, Mitsuko TAKUSAGAWA, Nobuo IKOTA, Yu ...
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1547-1554
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1547
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    The redox reaction of cytochrome c after modification with peroxynitrite under physiological conditions was investigated. Cytochrome c was treated with a bolus of synthetic peroxynitrite at a sub-millimolar concentration, and then subjected to reduction by superoxide and oxidation by hydrogen peroxide. The ability for the membrane potential formation in the mitochondrial respiratory chain was also evaluated. After the treatment with peroxynitrite, the cytochrome c molecule was mono-nitrated mainly at a tyrosine residue, using liquid chromatography-electrospray ionizing mass spectrometry (LC-ESI-MS) and HPLC. Although the redox capacity of cytochrome c was not affected by the peroxynitrite treatment, the oxidation of ferrocytochrome c to ferricytochrome c by hydrogen peroxide was accelerated. When cytochrome c was treated with peroxynitrite in the presence of 5-methoxytryptamine, an inhibitor for the tyrosine nitration by peroxynitrite, the acceleration of hydrogen peroxide-mediated oxidation was suppressed. It was also found that the formation of membrane potential in the rat liver mitochondria was suppressed when peroxynitrite-treated cytochrome c was used instead of the intact cytochrome c in vitro. From these results, we concluded that the peroxynitrite-treated cytochrome c was nitrated at a tyrosine residue and became more susceptible to oxidation by hydrogen peroxide, concomitantly losing the ability to transfer electrons in the mitochondrial respiratory chain. It is suggested that the peroxynitrite-induced modification of cytochrome c increases the susceptibility to non-physiological oxidants, and may cause dysfunction of mitochondria by suppressing of membrane potential.
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  • Two New 2'-Oxygenated Flavones from Andrographis elongata
    Galla JAYAKRISHNA, Pennaka HARIKISHORE, Chunduri VENKATA RAO, Duvvuru ...
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1555-1557
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1555
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    Two new 2'-oxygenated flavones, 5,2',6'-trihydroxy-7-methoxyflavone (3) and skullcapflavone I 2'-O-β-D-(4''-E-cinnamyl) glucopyranoside (5), together with three known flavones, 7-O-methylwogonin (1), skullcapflavone I (2) and skullcapflavone I 2'-O-β-D-glucopyranoside (4) were isolated from the whole plant of Andrographis elongata, and the structures were elucidated by FAB-MS and one- and two-dimensional (1D- and 2D)-NMR spectral studies including 1H-1H correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond connectivity (HMBC) and rotating frame Overhauser enhancement spectroscopy (ROESY) experiments, and chemical studies.
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  • Medicinal Foodstuffs. XXVIII. Inhibitors of Nitric Oxide Production and New Sesquiterpenes, Zedoarofuran, 4-Epicurcumenol, Neocurcumenol, Gajutsulactones A and B, and Zedoarolides A and B, from Zedoariae Rhizoma
    Hisashi MATSUDA, Toshio MORIKAWA, Iwao TOGUCHIDA, Kiyofumi NINOMIYA, M ...
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1558-1566
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1558
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    A new eudesmane-type sesquiterpene, zedoarofuran, and six new guaiane- or seco-guaiane-type sesquiterpenes, 4-epicurcumenol, neocurcumenol, gajutsulactones A and B, and zedoarolides A and B, were isolated from aqueous acetone extract of Zedoariae Rhizoma together with 36 known sesquiterpenes and two diarylheptanoids. Their stereostructures were elucidated on the basis of chemical and physicochemical evidence. The effects of isolated components on nitric oxide production in lipopolysaccharide-activated mouse peritoneal macrophages were examined and 16 sesquiterpenes including gajutsulactones A and B, and bis(4-hydroxycinamoyl)methane were found to show inhibitory activity.
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  • New Bitter-Tasting Hemiterpene Glycosides from the Japanese Fern Hymenophyllum barbatum
    Masao TOYOTA, Yasushi OISO, Yoshinori ASAKAWA
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1567-1572
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1567
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    Hymenosides G—J were newly isolated from the Japanese fern Hymenophyllum barbatum, in addition to hymenosides A—F. The structures of hymenosides were elucidated by extensive two-dimensional nuclear magnetic resonance and/or chemical evidence. The structures of those aglycones were divided into three types, 1,4-dihydroxy-2-hydroxymethyl-but-2-ene, 1,4-dihydroxy-2-methyl-but-2-ene, and 3-hydroxy-5-hexanolide. The sugar moieties were also established by chemical and spectroscopic methods, which were acylated by phenylacetic acid derivatives. These glycosides had a bitter or weakly pungent taste.
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  • Synthesis and Nucleic Acid-Binding Properties of Water-Soluble Porphyrins Appending Platinum(II) Complexes
    Hiroki MUNAKATA, Toshiki KANZAKI, Shigeo NAKAGAWA, Hiroyasu IMAI, Yosh ...
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1573-1580
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1573
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    We synthesized two water-soluble porphyrins appending platinum(II) complexes [α,β-(4a) and α,α-(4b) 5,15-bis(2-trans-[PtCl(NH3)2]N-2-aminoethylaminocarbonylphenyl) 2,3,7,8,12,13,17,18-octamethylporphyrin] and studied their reactions with a variety of nucleic acids [disodium adenosine-5'-monophosphate (AMP), disodium guanosine-5'-monophosphate (GMP), disodium thymidine-5'-monophosphate (TMP), disodium cytidine-5'-monophosphate (CMP), synthetic polymer poly(dG)-poly(dC), poly(dA)-poly(dT)] by 1H-NMR, UV-vis and FAB-MS spectroscopies. Based on the denaturation experiments of synthetic nucleic acid polymers, we conclude that the presence of the porphyrins (5.6 μM) does not cause significant changes in the melting temperature of poly(dA)-poly(dT) (28 μM) (ΔT=1 °C) and shows reannealing. On the other hand, gradual melting of poly(dG)-poly(dC) (28 μM) occurs at a low temperature (ΔT=−27 °C) in the presence of the porphyrins (5.6 μM), and the solutions do not show reannealing phenomena. The results of UV-vis and 1H-NMR experiments revealed that the porphyrins bind to guanine bases and that the porphyrins bind to GMP more strongly than to the other nucleotides. The binding modes between the porphyrins and synthetic nucleic acids are affected more by the coordination of the nucleobase [poly(dG)-poly(dC)] to the Pt(II) in the porphyrins than by Coulomb and hydrophobic interactions.
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  • Total Synthesis of (S)-(+)-Curcudiol, and (S)-(+)- and (R)-(−)-Curcuphenol
    Machiko ONO, Yuuko OGURA, Kazumi HATOGAI, Hiroyuki AKITA
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1581-1585
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1581
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    A highly enantioselective synthesis of the versatile chiral synthons possessing one stereogenic center, (S)-and (R)-4-aryl-5-hydroxy-(2E)-pentenoate (3) was achieved based on the enzymatic reaction of (±)-3 with commercially available lipases MY-30 or OF-360 from Candida rugosa. Application of (S)-3 and (R)-3 to the total syntheses of (S)-curcuphenol (1), (S)-curcudiol (2), and (R)-curcuphenol (1), respectively, is described.
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  • A New Drug Delivery System Using Plasma-Irradiated Pharmaceutical Aids. VIII. Delayed-Release of Theophylline from Double-Compressed Tablet Composed of Eudragit as Wall Material
    Masayuki KUZUYA, Kousuke ITO, Shin-ichi KONDO, Yoshimitsu MAKITA
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1586-1592
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1586
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    The rapid release from a double-compressed tablet containing theophylline as a core drug with the pH-dependent water-soluble polymers, Eudragit L100, S100 or L100-55 used as a wall material was suppressed by argon plasma-irradiation due to an effect of inter-segmental cross-link reactions on the decrease in the surface polymer solubility of outer layer. In addition, the rapid theophylline release from the double-compressed tablet of Eudragit L100-55 with a lower glass transition temperature (Tg) has converted into the delayed-release system under a set of plasma operational conditions due to an additional effect of plasma heat flux on softening of Eudragit L100-55 surface resulting in the formation of the film-like surface with a particle-particle interlinking of the outer layer.
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  • Synthesis and Structure—Activity Relationships in a Series of Ethenesulfonamide Derivatives, a Novel Class of Endothelin Receptor Antagonists
    Hironori HARADA, Jun-ichi KAZAMI, Susumu WATANUKI, Ryuji TSUZUKI, Kats ...
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1593-1603
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1593
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    In the previous paper, we described a series of the 2-arylethenesulfonamide derivatives, a novel class of ETA-selective endothelin (ET) receptor antagonists, including the compounds 1a, b. Compound 1a showed excellent oral antagonistic activities and pharmacokinetic profiles, and the monopotassium salt of 1 (YM-598 monopotassium) is in clinical trials. In this paper, we wish to report the investigation of the further details of structure-activity relationships (SARs) of the 2-phenylethenesulfonamide region in 1a. It was found that methyl substitutions at the 2-, 4- and 6-positions of the phenyl group in 1a led to the discovery of the ETA/ETB mixed antagonist (6s) with an IC50 of 2.2nM for the ETA receptor. We also found that introduction of an ethyl group to the 1-position of the ethenyl group in 1a gave the ETA selective antagonist (6u) with an oral endothelin antagonistic activity in rats.
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  • Development of a Stereoselective Practical Synthetic Route to Indolmycin, a Candidate Anti-H. pylori Agent
    Atsushi HASUOKA, Yutaka NAKAYAMA, Mari ADACHI, Hidenori KAMIGUCHI, Kei ...
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1604-1608
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1604
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    A stereoselective practical synthetic route to indolmycin is described. The route is composed of the regioselective coupling of indolyl magnesium halide with a trans-epoxy ester, diastereoselective oxazolone ring formation with guanidine and amine exchange reaction with methylamine. In the coupling step, use of dichloromethane as co-solvent and conversion of the resulting hydroxy ester to the hydroxy acid for purification, make this process efficient and practical. The oxazolone ring is formed in good yield without epimerization at the C5 position by treatment with guanidine and potassium tert-butoxide in tert-butanol at room temperature. In the final step, the amino group is efficiently converted to the methylamino group in aqueous methylamine solution at 5 °C. After examination of the route with racemates, indolmycin was synthesized stereoselectively in 22% total yield from optically active trans-epoxy ester. This route was applied to the preparation of the metabolites of indolmycin.
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  • 1,6-Asymmetric Induction during the Conjugate Addition of Arylcopper Reagents to a Chiral Sulfinyl-Substituted Pyrrolyl α,β-Unsaturated Amide
    Yoshitsugu ARAI, Kimio UEDA, Jianhua XIE, Yukio MASAKI
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1609-1614
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1609
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    The asymmetric conjugate addition of arylcopper reagents derived from aryl Grignard reagents and copper(I) iodide to a chiral 1-[2-(p-tolylsulfinyl)]pyrrolyl cinnamide proceeded smoothly to give (3R)-adducts with high diastereoselectivities (≥92% de) in high yields. Conjugate additions either of the cinnamide with the alkyl Grignard reagent-copper(I) iodide combination or of the crotonamide derivative with aryl Grignard reagent-copper(I) iodide gave moderate to good diastereoselectivities. With these sulfinyl pyrrolyl α,β-unsaturated amides, the chiral auxiliary was efficiently recovered without any loss of optical purity after asymmetric conjugate addition.
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  • A New Drug Delivery System Using Plasma-Irradiated Pharmaceutical Aids. IX. Controlled-Release of Theophylline from Double-Compressed Tablet Composed of Cellulose Derivatives as Wall Material
    Kousuke ITO, Shin-ichi KONDO, Masayuki KUZUYA
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1615-1620
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1615
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    The rapid release from a double-compressed tablet containing theophylline with the water-soluble polymer, hydroxypropylmethylcellulose (HPMC) or hydroxypropylmethylcellulose phthalate (HPMCP), used as a wall material can be suppressed by argon plasma-irradiation and changed into the sustained-release system due to a decrease in solubility of the outer layer. It was shown that the release profiles can be varied so as to cause theophylline release at different rates, depending on the set of conditions chosen for tablet manufacture and for plasma operation.
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  • A Practical Preparation of Methyl 2-Methoxy-6-methylaminopyridine-3-carboxylate from 2,6-Dichloro-3-trifluoromethylpyridine
    Tamaki HORIKAWA, Yoshimi HIROKAWA, Shiro KATO
    Article type: scientific monograph
    2001 Volume 49 Issue 12 Pages 1621-1627
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1621
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    An effective and practical synthetic route to methyl 2-methoxy-6-methylaminopyridine-3-carboxylate (7), the key intermediate of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1), from 2,6-dichloro-3-trifluoromethylpyridine (12) was undertaken. Process improvements were highlighted by regioselectivity of 12 with a nitrogen nucleophile and conversion of the 3-trifluoromethyl group into the methoxycarbonyl group. The reaction of 12 with N-benzylmethylamine provided the 6-(N-benzyl-N-methyl)aminopyridine 26a and the regioisomer 26b in >98: <2 ratio in a quantitative yield. Treatment of 2-methoxy-6-methylamino-3-trifluoropyridine (14a) with a large excess of sodium methoxide followed by acid hydrolysis gave the pyridine-3-carboxylic ester 7 in an excellent yield. The potential application of this reaction is also described.
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