头孢唑兰和头孢克定侧链酸合成研究

目的探讨侧链酸的合成工艺及结构确证。方法以氰基乙酰胺为起始原料,经烷化,羟肟化,环合、酰胺水解反应合成了头孢菌素类的关键中间体2-(5-氨基-12,4,-噻二唑-3-基)-2-甲氧基亚氨基乙酸。结果四步主要反应的收率分别是73.2%,66.3%6,2.5%3,3.3%,总收率为10.1%。结论该合成工艺操作简便,收率高,是合成侧链酸的较好方法。通过元素分析、红外吸收光谱及核磁共振谱确证了侧链酸的结构。     

5-溴甲基-2,1,3-苯并噻二唑的合成工艺改进

以4-甲基-1,2-苯二胺为原料,经环合、溴化两步反应合成目标化合物.将其中间体亚硫酰苯胺的合成改在甲苯中进行,并采用"一勺烩"法合成5-甲基-2,1,3-苯并噻二唑;5-甲基-2,1,3-苯并噻二唑的溴化改在低毒性的1,2-二氯乙烷中进行,革除了高毒性的四氯化碳.该法简化了操作过程,缩短了反应时间,提高了目标物的总收率.     

4,5-二溴-3,6-二异辛基邻苯二甲腈的合成

目的：为了筛选4，5-二溴-3，6-二异辛基邻苯二甲腈最佳合成工艺。方法：以3，6-二羟基邻苯二甲腈和溴代异辛烷为原料在不同条件下经溴化、烷基化反应合成标题化合物，考察不同因素(温度、溶剂种类和用量等)对产物收率的影响。结果：溶剂的种类和用量、反应温度及脱氧剂的种类对产物收率的影响较大。结论；最佳合成工艺条件为：溶剂CH3COOH／CH3COOK，温度100℃，脱氧剂NaH。     

3-(3-氯-1,2,5-噻二唑-4-基)吡啶的合成工艺改进

以3-吡啶甲醛为原料,与氰化钠、一氯化硫反应合成选择性M1受体激动剂占诺美林的关键中间体3-（3-氯-1,2,5-噻二唑-4-基）吡啶,目标化合物的结构经^1H-NMR谱确证。改进后的工艺操作简单,反应条件温和,收率由文献报道的40%提高到52%,更适合工业化生产。     

2-吡啶甲醛的制备

2-吡啶甲醛（1）为常用合成中间体,其制备方法较多,大多以2-甲基吡啶为原料。本研究以2-氰基吡啶（2）为原料,常压下在硫酸水溶液中钯炭催化加氢制得1（图1）,并考察了硫酸浓度及用量、投料比、反应温度和时间、催化剂用量等因素对收率的影响：15％硫酸用量为2的20倍（质量比），催化剂用量为2的7％，于60℃反应16h，1总收率可达92％。此法操作简单，收率高且对环境污染小。     

均匀设计法优化6,8-环二硫辛酸乙酯的合成工艺

本文采用均匀设计实验法对"万能抗氧化剂"硫辛酸的重要中间体-6,8-环二硫辛酸乙酯的合成进行了优化,考察了硫化钠和硫粉与6,8-二氯辛酸乙酯的摩尔比,反应温度和滴加时间等因素;经过多元线性回归分析,兼顾收率和杂质等指标,确定了最优的6,8-环二硫辛酸乙酯的制备工艺条件.     

2-（5-氨基-1，2，4-噻二唑-3-基）-2-（Z）-甲氧亚氨基乙酸S-苯并噻唑硫酯的合成

2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚氨基乙酰胺与2-巯基苯并噻唑为原料,哌啶为溶剂,在三乙胺催化下反应制得头孢菌素中间体2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚氨基乙酸S-苯并噻唑硫酯,收率约76%。     

噻二唑合成工艺的改进

目的：为了提高噻二唑的收率。方法：以水合肼为原料经酰化、成盐、环合、精制四步合成了药物中间体噻二唑。结果：总收率达68％。结论：本方法具有操作安全、工艺简单、收率高等特点。     

(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸的合成

目的 合成头孢唑兰中间体(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸。方法 以氰乙酰胺为起始原料,依次经甲氧亚氨化、加成、酯化、与硫氰化钾反应、构型转换和水解共6步反应制得目标化合物。结果和结论 目标化合物的结构经¹H-NMR和MS谱确证。该工艺路线原料易得,操作简便,总收率为29.8%,具有一定的工业化价值。     

4-[(4,4-二甲基-7-甲氧基-1,3-二氧代-异喹啉基)乙基]苯磺酰胺的合成

以2-羧基-4-甲氧基苯乙酸为原料经环合、二甲基化两步反应合成目标产物4-[(4,4-二甲基-7-甲氧基-1,3-二氧代-异喹啉基)乙基]苯磺酰胺,研完了反应时间、温度、物料配比等因素对各步反应产率的影响,找到了最佳工艺条件,并通过核磁谱图表征了目标产物的结构,在上述优化条件下,两步反应的总收率可达到70％以上.     

3-[(甲基-1-萘甲基)氨基]-1,2-环氧丙烷的制备

由N-甲基-1-萘甲胺与环氧氯丙烷反应生成的1-氯-3-[（甲基-1-蔡甲基）氨基]-2-丙醇在碱性条件下环氧化制得标题化合物，总收率83％。     

Synthetic studies of 1-beta-methylcarbapenem antibiotics

The diastereoselective synthesis of the 1-beta-methylcarbapenems, (1R,5R,6S)-6-((R)-1-hydroxyethyl)-2-((S)-1-acetimidoylpyrrolidin-3 - ylthio)-1- methyl-1-carbapen-2-em-3-carboxylic acid and sodium (1R,5R,6S)-6-((R)-1-hydroxyethyl)-2-(5-chloro-2-oxobenzoxazolin-3- y l)-1- methyl-1-carbapen-2-em-3-carboxylate has been achieved. The key step was an aldol reaction between the achiral boron enolate which was generated from dibutylboron triflate and 3-propionyl-2-oxobenzoxazoline, and (3R,4R)-4-acetoxy-3-((R)-1-hydroxyethyl)azetizin-2-one.     

Synthesis of some thiazole-, 1,3,4-thiadiazole-, and 4H-1,2,4-triazole derivatives of pyrazolo[3,4-b]quinoline

Three novel series of pyrazolo[3,4-b]quinolines were prepared, namely: 1-(3-substituted-4-phenylthiazolin-2-ylidene)hydrazinocarbonylm ethyl-1H-pyrazolo[3,4-b]quinolines 3a-d; 1-(5-substituted amino-1,3,4-thiadiazol-2-yl)methyl-1H-pyrazolo[3,4-b]quinolines 4b-d, and 1-(4-substituted-4H-5- thioxo-1,2,4-triazole-3-yl)methyl-1H-pyrazolo[3,4-b]quinolines 5a-d. These compounds were prepared by cyclization of the new key intermediates 1-(substituted thiocarbamoylhydrazinocarbonyl)methyl-1H- pyrazolo[3,4-b]quinolines 2a-d. The alkylthio, aralkylthio 6a-f as well as the Mannich bases 8a-f derived from compounds 5a-d were also prepared. The structures of the new compounds were elucidated by elemental analyses, IR, 1H-NMR-, and mass spectra. The antimicrobial as well as inotropic and chronotropic activities were studied.     

Biosynthesis and transformation of homoanatoxin-a in the cyanobacterium Raphidiopsis mediterranea Skuja and structures of three new homologues

The biosynthetic origin of the C-12 methyl group in homoanatoxin-a (1) was identified by the feeding experiment of L-[methyl-13C]-methionine in the culture of the cyanobacterium Raphidiopsis mediterranea Skuja strain LBRI 48. Remarkably high incorporation (80%) of 13C was observed at C-12. The in vivo enzymatic transformation of 1 was also examined by the prolonged culture of strain LBRI 48. The cells harvested at the stationary phase (15 days of incubation) gave higher contents of 4S-hydroxyhomoanatoxin-a (2), 4R-hydroxyhomoanatoxin-a (3), 2,3-epoxyhomoanatoxin-a (4), and 4-ketohomoanatoxin-a (5) than those from the cells collected at the late logarithmic growth phase (5 days). Compounds 2-5 would be transformed from 1 in the cells. The ratio of anatoxin-a and 1 was not significantly changed between two phases. Compound 5 was generated from 1 by air oxidation during storage even under dry and cool (-30 degrees C) conditions, but the oxidation was prevented in a water solution at both room temperature and -30 degrees C (frozen stock). Homoanatoxin-a (1) gave 2,3-dihydro-3-methoxyhomoanatoxin-a (6) during the separation procedures probably by the Michael reaction of methanol used as solvent. It should be noted that 4 was isolated for the first time from a cyanobacterium as the natural product. Compounds 3 and 5 were new members of the anatoxins.     

多尼培南的合成

反式-4-羟基-L-脯氨酸经酯化、保护、还原、SN2取代、Mitsunobu反应、醇解得到（2S,4S）-1-叔丁氧羰基-2-（N-叔丁氧羰基氨磺酰胺基）甲基-4-巯基吡咯烷（7）,收率50.8%.7与（1R,5S,6S）-6-[（1R）-1-羟乙基]-2-二苯氧磷酰氧基-1-甲基-1-碳代-2-青霉烯-3-羧酸对硝基苄酯（8）缩合、脱保护,得到多尼培南,收率50.5%（以7计）.总收率接近26%（以反式-4-羟基-L-脯氨酸计）.     

Facile synthesis of fused pyrazolo[1,5-a]pyrimidinepyrazolo [1,5-a]triazines and N-sulphonamidopyrazoles as antiinflammatory

Interaction of hydrazine hydrate with methyl (2-E)-2-cyano-3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]-3-(methylsulphanyl)-2-propenoate 2 which was obtained by the reaction of methyl-2-cyano-3,3-bis(methylsulphanyl) acrylate 1 with 4-amino-1-phenyl-2,3-dimethyl pyrazoline-5-one afforded methyl-5-amino-3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]-1H-pyrazole-4-carboxylate 3a. The pyrazolin derivative 3a is a good precursor for the synthesis of pyrazolo[1,5-a]pyrimidines which is based on the interaction of 3a with alpha,beta-unsaturated nitrile derivatives. The biological effects of some of the newly synthesized compounds were also investigated as antiinflammatory, analgesic and antipyretic drugs. Compounds 2b, 4a, 3a, 3b, 2a and 4b were found to have significant antiinflammatory activity in descending order in comparison to control groups phenylbutazone. Compounds 3a, 2a, 4b, 4a, 2b and 3b have analgesic activity in decreasing order. Compound 3a was the most potent and had 82.6% potency of Novalgin. Compounds 2b, 2a, 3b, 4b, 3a and 4a were found to have significant antipyretic activity in descending order. Compounds 2a, 4b induced no ulcerogenic activity, while compounds 3b, 2b, 4a and 3a showed only slight ulcerogenic activity.     

Synthesis of some new 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones and their anti-inflammatory activities.

Sixteen 1-(1-naphthyloxy)acetyl-4-substituted-3-thiosemicarbazides, 2-substituted amino-5-(1-naphthyloxy)methyl-1,3,4-oxadiazoles, 2-substitutedamino-5-(1-naphthyloxy) methyl-1,3,4-thiadiazoles and 3-(1-naphthyloxy)methyl-4-substituted-1,2,4-triazole-5-thiones were synthesized. The structures of the compounds have been elucidated by UV, IR, 1H-NMR, 13C-NMR spectra and elemental analysis. The anti-inflammatory activities of the compounds were evaluated by carregeenan induced hind paw edema and air-pouch inflammation tests in mice. In carrageenan induced hind paw edema test, compounds 1a, 1d, 3d, 4a showed equivalent or higher activity compared to naproxen and phenylbutazone. In the air-pouch inflammatory model, compounds 1a, 1b, 1d, 2c, 3c, 3d, 4a and 4d showed marked anti-inflammatory activity. The ED50 values of these compounds ranged between 24-36 mg/kg. Side effects of the compounds on gastrointestinal system and kidneys were examined and none of the compound showed significant side effects.     

2-甲基-3-硝基苯乙腈的新合成路线

目的改进2-甲基-3-硝基苯乙腈（合成罗匹尼罗所需的重要中间体）的合成路线。方法以2-甲基-3-硝基苯甲醛为原料,经还原、氯化和氰代等3步反应制取2-甲基-3-硝基-苯乙腈,新路线对文献报道的氯化和氰代进行了改进,用异丙醇/异丙醇铝代替了NaBH4,用二氯亚砜代替了三氯化磷或三溴化磷。结果 2-甲基-3-硝基苯乙腈单晶的结构经X-衍射得到确认,产率有了很大提高。结论采用新合成路线,原料易得,操作简便,成本低廉。     

Synthesis of some new hydrazone derivatives as biologically active agents

A series of [4-(6H/bromo-4-oxo-2-phenyl-3(4H)-quinazolinyl)phenoxy]acetic acid (1,2-dihydro-1-H/methyl-2-oxo-3H-indol-3-ylidene)hydrazides (VII1-16) were synthesised by condensing 1-H/methyl-5-substituted indoline-2,3-diones with [4-(6H/bromo-4-oxo-2-phenyl-3(4H)-quinazolinyl) phenoxy]acetic acid hydrazides (IV1-2) which in turn were obtained by reacting ethyl [4-(6H/bromo-4-oxo-2-phenyl-3(4H)-quinazolinyl)phenoxy]acetates (III1-2) with hydrazine hydrate. All the synthesised compounds (VIII1-16) were screened for their antibacterial, acetylcholinesterase enzyme inhibitory and antiviral activities.     

维生素B1催化合成1-(3-甲氧基-4-丙氧基-5-硝基苯基)-4-(3,4,5-三甲氧基苯基)-1,4-二酮

研究以NaCN和维生素B1为催化剂合成MK-287的关键中间体1-(3-甲氧基-4-丙氧基-5-硝基苯基)-4-(3，4，5-三甲氧基苯基)-1，4-二酮（1）的催化效果。结果表明：维生素B1较文献报道的催化剂ETB具有反应时间短、成本低廉的优点，可代替ETB合成目的化合物。