氢溴酸西酞普兰的合成

对苯二甲酸和多聚甲醛制得的5-羧基苯酞,经酰氯化、酰胺化和脱水等反应制得5-氰基苯酞,再经两步格氏反应得到4-[4-二甲胺基-1-(4-氟苯基)-1-羟基丁基]-3-羟甲基苄腈,最后经闭环、成盐制得氢溴酸西酞普兰,总收率31%.     

厄贝沙坦的合成

环戊酮与氰化钠反应制得1-氨基环戊腈，成盐、水解成酰胺后与戊酰氯反应制得2-丁基-1，3-二氮杂螺[4-4]壬-1-烯-4-酮，相转移催化条件下与4’-溴甲基-2-氰基联苯反应制得2-丁基-3-[（2’-氰基联苯-4-基）甲基]-1，3-二氮杂螺[4-4]壬-1-烯-4-酮，最后与叠氮化钠反应制得厄贝沙坦，总收率约39％。     

5-氟-2,3-二氢苯并呋喃的合成

对氟苯酚经溴化制得的邻溴对氟苯酚,与1,2-二氯乙烷反应制得2-(2-溴-4-氟苯氧基)氯乙烷,再经格氏反应制得5-氟-2,3-二氢苯并呋喃,总收率79%.     

多沙唑嗪、特拉唑嗪及哌唑嗪的高效合成

用4-氨基-2-氯-6,7-二甲氧基喹唑啉与无水哌嗪反应制得4-氨基-2-哌嗪基-6,7-二甲氧基喹唑啉(2).另用2-氯-4,6-二甲氧基-1,3,5-三嗪(3)和4-甲基吗啉(4)反应后加入相应的羧酸,制得的中间体7再与2反应分别制得多沙唑嗪(1a)、特拉唑嗪(1b)和哌唑嗪(1c),总收率分别为82.3％、88.0％和86.4％(以3计).     

苯扎贝特的相转移催化法合成

对氯苯甲酰氯和对羟基苯乙胺反应制得N-(4-羟基苯乙基)-4-氯苯甲酰胺,再在相转移催化剂TEBA作用下、氢氧化钠溶液中加丙酮和氯仿反应制得降血脂药苯扎贝特,总收率约67%。     

盐酸诺拉曲塞的合成

2-溴-4-硝基甲苯经催化氢化、与水合氯醛和盐酸羟胺反应、环合制得4-溴-5-甲基靛红,再经Baeyer-Villiger反应、甲酯化、与盐酸氯甲脒环合、Ullmann反应、成盐结晶制得胸苷酸合成酶抑制剂盐酸诺拉曲塞二水合物,总收率为8%。     

4-氟-3-甲基吡啶-2-甲酸甲酯的合成

3-甲基吡啶-2-甲酸甲酯(2)经氧化、硝化和还原反应制得4-氨基-3-甲基吡啶-2-甲酸甲酯(5),然后经改进的Balz-Schiemann反应制得4-氟-3-甲基吡啶-2-甲酸甲酯(1),以2计总收率约18%。     

N-(4-氯-3-三氟甲基苯基)-N'-(4-溴苯基)脲的合成

4-氯-3-三氟甲基苯胺和三光气在乙酸乙酯中反应制得4-氯-3-三氟甲基苯异氰酸酯,不经分离纯化,直接与对溴苯胺反应制得抗肿瘤药索拉非尼的中间体N-(4-氯-3-三氟甲基苯基)-N'-(4-溴苯基)脲,总收率约75%,纯度99.8%.     

3-奎宁环酮的制备

4-哌啶甲酸在三甲基氯硅烷作用下酯化、与溴乙酸乙酯进行N-烷基化反应制得1-乙氧甲酰基甲基哌啶-4-甲酸乙酯，再经Dieckmann反应制得药物中间体3-奎宁环酮，总收率约70％。     

三氯生的合成

目的 合成三氯生，并进行工艺改进。方法 以对二氯苯和2，4-二氯苯酚为原料制得2，4，4′-三氯-2′-硝基二苯醚，再经还原、重氮化和水解制得三氯生。结果 经四步反应制得三氯生，反应总收率45．83％。产物结构经红外光谱、核磁共振谱及质谱确证。结论 原料易得，工艺简单，适合工业化生产。     

Hydroxy- and amino-substituted piperidinecarboxylic acids as gamma-aminobutyric acid agonists and uptake inhibitors

The syntheses of (3RS,4RS)-4-hydroxypiperidine-3-carboxylic acid (4), (3RS,5SR)-5-hydroxypiperidine-3-carboxylic acid (20), (3RS,4SR)-4-acetamidopiperidine-3-carboxylic acid (10), and (3RS,5SR)-5-acetamidopiperidine-3-carboxylic acid (18), related to the specific gamma-aminobutyric acid (GABA) uptake inhibitors (RS)-piperidine-3-carboxylic acid (nipecotic acid) and (3RS,4SR)-4-hydroxypiperidine-3-carboxylic acid (21), are described. Furthermore, (3RS,4SR)-3-hydroxypiperidine-4-carboxylic acid (14), related to the specific GABA agonist piperidine-4-carboxylic acid (isonipecotic acid), has been synthesized. The structures of 4, 10, 14, 18, and 20 have been established by 270-MHz 1H NMR spectroscopic analyses. The affinity of the compounds for the GABA receptors and for the neuronal (synaptosomal) GABA uptake system in vitro has been measured. Compound 14 interacts selectively with the GABA receptors but less effectively than isonipecotic acid and the cis-isomer 22. Compounds 4, 18, and 20 are inhibitors of the GABA uptake system, although much weaker than nipecotic acid and (3RS,4SR)-4-hydroxypiperidine-3-carboxylic acid (21). Compound 10 is inactive in both test systems.     

Metabolic fate of gallic acid orally administered to rats

The metabolic behavior of orally administered gallic acid was investigated by HPLC and 4-O-methyl gallic acid was found to be the main metabolite in rat peripheral blood and urine. After oral administration of gallic acid, maximum concentration in portal vein and inferior vena cava occurred at 15 and 30 min, respectively. In portal vein, gallic acid was preferentially detected relative to 4-O-methyl gallic acid, whereas gallic acid and 4-0-methyl gallic acid were equally detected in inferior vena cava. On the other hand, 4-O-methyl gallic acid but not gallic acid was found in liver. The contents of gallic acid and 4-O-methyl gallic acid in urine were nearly 100 times higher than those in blood. The ratio of 4-O-methyl gallic acid to total gallic acid metabolites in urine was from 0.55 to 0.76, indicating that a considerable amount of gallic acid was excreted without being metabolized. In this study we found that gallic acid administered orally existed in the blood for 6 h at most, and more than half was metabolized to 4-O-methyl gallic acid, followed by excretion into urine.     

HPLC法快速检测苦参素注射液中8种抑菌剂及苯甲醛

目的:建立快速筛查和同时测定苦参素注射剂中8种抑菌剂(苯甲醇、苯酚、苯甲酸、山梨酸、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯)及苯甲醇降解产物———苯甲醛含量的高效液相色谱法。方法:应用WelchMaterials XB-C18色谱柱(4.6 mm×250 mm,5μm);流动相为乙腈-0.02 mol.L-1醋酸铵(冰醋酸调pH至5.0)梯度洗脱,流速1.0 mL.min-1,检测波长为211 nm(苯甲醇、苯酚),225 nm(苯甲酸),248 nm(苯甲醛),256 nm(山梨酸、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯)。结果:9种成分的峰面积与浓度的线性关系良好(r>0.9998),加样回收率为95.6%～102.2%。结论:本方法灵敏,快捷,准确,重复性好,可用于注射剂中抑菌剂的快速筛查与含量分析。     

Excitatory amino acid receptor ligands. Synthesis and biological activity of 3-isoxazolol amino acids structurally related to homoibotenic acid.

The 3-isoxazolol amino acid (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA, 2) and the isomeric compound (RS)-2-amino-3-(3-hydroxy-4-methylisoxazol-5-yl)propionic acid (4-methylhomoibotenic acid, 4a) are potent agonists at the AMPA subtype of central excitatory amino acid receptors. Using 4a as a lead structure, the amino acids 4c-e, in which the 4-methyl group of 4a is replaced by substituents of different size and polarity, were synthesized. Attempts to synthesize 4-(bromomethyl)homoibotenic acid (4f), a potential receptor alkylating agent, were unsuccessful. 4-Butylhomoibotenic acid (4c) and 4-(2-hydroxyethyl)homoibotenic acid (4e) were equipotent as inhibitors of [3H]AMPA binding (IC50 = 2 microM) and showed similar excitatory activity in the rat cortical slice preparation. 4d did not show significant affinity for AMPA receptor sites, but turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist. However, like 4c,e, 4d did not significantly affect the binding of the competitive NMDA antagonist, [3H]CPP, or the noncompetitive NMDA antagonist, [3H]MK-801. None of the amino acids 4c-e showed detectable affinity for [3H]kainic acid binding sites. Like the parent compound 4a (IC50 = 0.18 microM), 4c (IC50 = 0.18 microM), 4e (IC50 = 0.14 microM), and in particular 4d (IC50 = 0.02 microM) were effective inhibitors of calcium chloride-dependent [3H]glutamic acid binding, whereas AMPA is inactive (IC50 greater than 100 microM) in this binding assay. Thus, 4d is an effective and highly selective inhibitor of calcium chloride-dependent [3H]glutamic acid binding and may be a useful tool for studies of the physiological relevance and pharmacological importance of this binding affinity.     

Synthesis of dipeptide 4-nitroanilides containing non-proteinogenic amino acids

A series of tert-butyloxycarbonyl amino acid 4-nitroanilides, including N-alkylated amino acids and (R)- thiazolidine-4-carboxylic acid, (S)-oxazolidine-4-carboxylic acid. (4S,5S)-5-methyloxazolidine-4-carboxylic acid, (4S,5R)-5-methyloxazolidine-4-carboxylic acid, (S)-azetidine-2-carboxylic acid, (S)-pipecolic acid and (S)-3,4-dehydroproline, were prepared conveniently by the isocyanate method or the mixed anhydride procedure. The resulting amino acid 4-nitroanilides were extended to corresponding dipeptide 4-nitroanilides with tert-butyloxycarbonyl-(S)-alanine. In the case of sterically hindered amino acid 4-nitroanilides the mixed anhydride procedure with diphenylphosphinyl chloride was successful.     

Antifungal chromans inhibiting the mitochondrial respiratory chain of pea seeds and new xanthones from Calophyllum caledonicum

Two new xanthones, caledonixanthone M 1 and caloxanthone L 2, and one new acid, caledonic acid 6 were isolated from the hexane-soluble extract of the stem bark of Calophyllum caledonicum. In the course of this phytochemical study, seven other known compounds - calothwaitesixanthone, calozeyloxanthone, allanxanthone, isoapetalic acid 3, calolongic acid 4, apetalic acid 5 and isocalolongic acid 7 - were isolated. Their antifungal activity against the growth of the human pathogenic fungus Aspergillus fumigatus was then investigated. The results indicated that the crude extract, calolongic acid 4 and isocalolongic acid 7 exhibited strong inhibitory effects with MIC (80) values of 8, 4, 2 microg/mL, respectively. Besides, calolongic acid 4, its lactone derivative 4a and isocalolongic acid 7 markedly reduced the respiration of pea seed mitochondria.     

Conceptual biotransformation of 4-oxo-all-trans-retinoic acid, 4-oxo-13-cis-retinoic acid and all-trans-retinoyl-beta-glucuronide in rat whole embryo culture.

In cultured rat conceptuses, intraamniotic microinjections of 2500 ng/mL of 4-oxo-13-cis-retinoic acid, 600 ng/mL 4-oxo-all-trans-retinoic acid or 4000 ng/mL all-trans-retinoyl-beta-glucuronide, produce qualitatively and quantitatively similar patterns of dysmorphogenesis as those reported after the intraamniotic microinjection of 250 ng/mL all-trans-retinoic acid [Lee et al., Teratology 44: 313-323, 1991; Creech Kraft et al., Teratology 45: 259-270, 1992]. In the present study, we utilized HPLC techniques to analyze retinoid levels in cultured rat conceptuses, 1.5 hr after intraamniotic microinjections of 4-oxo-13-cis-retinoic acid (2500 ng/mL), 4-oxo-all-trans-retinoic acid (600 ng/mL) or all-trans-retinoyl-beta-glucuronide (4000 ng/mL). Our findings show that, after the microinjections of 4-oxo-all-trans-retinoic acid or 4-oxo-13-cis-retinoic acid (at these selected concentrations), 4-oxo-all-trans-retinoic acid was predominant in the embryos proper at concentrations of about 200 nM. This was roughly equivalent to the levels of all-trans-retinoic acid assayed after microinjections of all-trans-retinoyl-beta-glucuronide (4000 ng/mL). We conclude from these studies that both 4-oxo-all-trans-retinoic acid and all-trans-retinoic acid behave as ultimate or proximate dysmorphogens.     

Evaluation of inhibitors of fatty acid oxidation in rat myocytes

The effects of 4-bromocrotonic acid, 2-bromopalmitic acid, 3-mercaptopropionic acid, 4-pentenoic acid, and 2-tetradecylglycidic acid on the oxidations of palmitate, octanoate, and pyruvate in adult rat myocytes were studied. Since all of these compounds inhibit the oxidation of palmitate but not of pyruvate, they are specific inhibitors of fatty acid oxidation. Fifty percent inhibition of palmitate oxidation was obtained when myocytes were preincubated for 10 min with one of the following: 0.1 microM 2-tetradecylglycidic acid, 60 microM 4-bromocrotonic acid, 60 microM 2-bromopalmitic acid, 100 microM 3-mercaptoproprionic acid, or 100 microM 4-pentenoic acid. Removal of the inhibitors from the medium after preincubation relieved the inhibition caused by 3-mercaptopropionic acid but did not reverse the effects of the other inhibitors. This study leads to the conclusion that 2-tetradecylglycidic acid is the compound of choice for inhibiting the mitochondrial uptake of fatty acids and thereby their oxidation, whereas 4-bromocrotonic acid is the best irreversible inhibitor of the mitochondrial beta-oxidation cycle.     

Two new phenolic acids from Drynariae rhizoma

To study the chemical constituents of Drynariae Rhizoma, nine phenolic acids were isolated from a 70% ethanol extract by using a combination of various chromatographic techniques including column chromatography over silica gel, ODS, Sephadex LH-20, and semi-preparative HPLC. By spectroscopic techniques including 1H NMR, 13C NMR, 2D NMR, and HR-ESI-MS, these compounds were identified as 4, 4'-dihydroxy-3, 3'-imino-di-benzoic acid (1), protocatechuic acid (2), gallic acid (3), p-hydroxybenzoic acid (4), (E)-caffeic acid (5), ethyl trans-3, 4-dihydroxycinnamate (6), caffeic acid 4-O-beta-D-glucopyranoside (7), p-coumaric acid 4-O-beta-D-glucopyranoside (8), and 23(S)-12-O-caffeoyl-12-hydroxyllauric acid glycerol ester (9), separately. Among them, 1 and 9 are new compounds, and 3, 4, and 6 were isolated from Drynaria species for the first time.     

Zur Stereochemie der 3-Oxo-5-phenyl-1-cyclopentancarbonsäuren, 5. Mitt. Zur stereoselektiven Synthese der stereomeren 5-Phenyl-dihydroisosarkomycine

Stereochemistry of 3-Oxo-5-phenylcyclopentanecarboxylic Acids, V: On the Stereoselective Synthesis of the Stereomeric 5-Phenyldihydrosarcomycines In connection with our attempts to synthesize stereoselectively the 5-phenyldihydroisosarcomycines 1–4 , the C-methylation of 3-oxo-t-5-phenyl-1,1,r-4-cyclopentanetricarboxylic acid trimethylester (5) was performed. The reaction yields t-4-methyl-3-oxo-c-5-phenyl-1,1,r-4-cyclopentanetricarboxylic acid trimethylester (7) with a high degree of stereoselectivity. The stepwise degradation of 7 by acidic or basic saponification and decarboxylation has been examined. Via the isolated intermediates t-1,t-4-dimethoxycarbonyl-c-4-methyl-3-oxo-t-5-phenyl-r-1-cyclopentanecarboxylic acid (10) and c-4-methoxycarbonyl-t-4-methyl-3-oxo-c-5-phenyl-r-1-cyclopentanecarboxylic acid (12) the acid 1 (t-4-methyl-3-oxo-c-5-phenyl-r-1-cyclopentanecarboxylic acid) was obtained stereoselectively. The trans-carboxylic acid (c-4-methyl-3-oxo-t-5-phenyl-r-1-cyclopentanecarboxylic acid) (3) is accessible by thermodynamically controlled rearrangement.