相转移催化合成乙痛新

乙痛新(Ethoheptazine)化学名:1-甲基-4-苯基六氢氮杂(艹卓)-4-甲酸乙酯(V)。本品为类似杜冷丁结构的非成瘾性镇痛药,能治疗多种疼痛,疗效较好。制备乙痛新一般均以苯乙腈为起始原料,经二甲氨基乙基化、氯丙基化、环合、消除和醇解而得。但前两步反应均以氨基钠为缩合剂,对生产不利,尤其对氯丙基化反应不易取得成功。我们进行了工艺改革,采用相转移催化反应,取得满意结果,为生产提供了有利条件。合成路线     

相转移催化反应合成咳必清中间体

咳必清生产中的重要中间体1-苯基环戊烷羧酸系用苯乙腈为原料,经烷基化-环合、水解制得。烷基化和环合反应激烈,需严格控制无水。生产中操作不当常会发生冲料、固罐。苯乙腈α-碳原子的烷基化 Makosza 作过很多报道。我们采用相转移催化反应对苯乙腈烷基化-环合工艺进行试验,对反应条件、加料次序、催化剂用量作了摸索。新工艺不需要无水操作,环合物可免去减压分馏,消除了冲料、固罐等事故,并具有反应条件温和、操作便利、收率高     

提取苯乙酸工艺改进

苯乙酸是青霉素工业钾盐生产的主要原料之一。在6-APA生产过程中，其中主要副产物为苯乙酸。它是在6一APA的萃取过程中存留于二氯甲烷相之中。本文主要目的是通过对提取苯乙政工艺中控制条件：温度、PH值、时间的变化，进一步优化苯乙酸的提取工艺，使生产出的苯乙酸质量达到青霉素工业钾盐的原料标准。本工艺已经应用于工业生产中，且收到了明显效果。     

帕米格雷的合成

目的：帕米格雷的合成及工艺优化。方法：以α-氨基-对甲氧基苯乙酸和苯甲醚为原料，经傅克酰化、缩合、取代3步反应制得帕米格雷。结果：合成目标化合物，总收率47％。结论：该方法原料易得，操作简单。     

咪达那新合成工艺的改进

目的：对咪达那新的合成工艺进行改进。方法：以二苯乙腈为起始原料,经缩合1、缩合2及水解得到目标产物。结果：经三步合成了目标产物,总收率为68%,目标化合物结构经1HNMR和MS确证。结论：本合成方法原料易得,反应条件温和,适合工业化生产。     

青霉素发酵前体应用的研究

目的：降低发酵成本,减轻劳动强度。方法：试验分析,在不影响原有发酵单位的情况下,用苯乙酸钠在青霉素发酵过程中替代苯乙酸钾。结果：由PAA—Na替代PAA—K,发酵生产水平有所提高,平均发酵成本降低。结论：提高发酵指数,可以应用于大型生产。     

西司他汀钠的合成工艺研究

以7-溴-2-氧庚酸为原料经与（＋）2，2-二甲基环丙烷甲酰氨缩合，再与半胱氨酸发生取代；两步反应合成西司他汀钠。终产物采用甲醇-丙酮混合溶剂重结晶；目标化合物经核磁共振氢谱、质谱等确证其化学结构为西司他汀钠。该工艺简便易行，为中试放大提供了依据。     

盐酸文拉法辛合成工艺改进

目的：改进盐酸文拉法辛的合成工艺。方法：以对甲氧基苯乙腈和环己酮为原料，经缩合得α-（1-羟基环己基）-对甲氧基苯乙腈，再经还原，最后甲基化制备盐酸文法拉辛。以甲醇钠代替氢化钾作为缩合剂，以盐酸乙醇代替氯化氢气体，以甲苯代替乙醚，对此工艺进行了改进。结果：得到较好的工艺条件。总收率达到47．4％。结论：改进后的工艺降低了生产成本，易于工业化生产。     

美沙拉嗪的合成

美沙拉⑤Mesalazin）,化学名为5一氨基水杨酸,即5－ASA,本品为治疗溃疡性结肠炎新药,疗效显著,不良反应轻微,安全性明显高于目前治疗结肠炎的首选药物柳氛皮肤毗峻I‘1．该药的合成方法很多,国内已有报道,大多是以水杨酸为起始原料,经硝化,还原合成！’］．虽然该合成路线仅两步反应,但由于水杨酸的硝化反应很不稳定,反应温度过低时,不易进行,反应温度过高时,因反应放热,温度不易控制而致使反应急剧升温、猛烈,极易发生冲料和爆炸的现象．因此我们采用对氨基苯乙酸为起始原料,以～锅煮”的方法得到5－ASA。该L艺路线…     

利血生合成工艺的改进

目的优化利血生的制备工艺。方法采用乙醇钠-石油醚反应体系代替钠-乙醚制备中间体α-甲酰基苯乙酸乙酯;采用乙酸钾调节环合反应体系碱度,在室温下环合生成利血生。结果高收率得到α-甲酰基苯乙酸乙酯以及终产物利血生,经1HNMR确证。结论改进后的工艺具有安全、高效、操作简便的特点,达到了对利血生工艺改进的目的。     

高效液相色谱法检测青霉素发酵液中苯乙酸残量

目的:检测青霉素发酵液中苯乙酸(PAA)残量.方法:采用高效液相色谱法.结果:方法准确可行,是检测青霉素发酵液中苯乙酸残量的经济、快捷的方法.本方法可用于青霉素发酵液中PAA残量的测定.     

Persistence of Candida sp. 115 during hydrolysis of penicillin G and metabolism of phenylacetic acid

The growth of Candida sp. 115 was investigated on the constituents of penicillin G hydrolysis reaction mixture. Neither penicillin G nor 6-aminopenicillanic acid was degraded or utilised for growth. The yeast accepted phenylacetic acid, sodium acetate and glucose as growth substrates. Phenylacetic acid was metabolised via p-hydroxy phenylacetic acid, which was the only accumulated metabolite. The enzymes responsible for hydroxylation of phenylacetic acid were induced by phenylacetic acid and sodium acetate.     

梯度渗漉法提取丹参有效成分的工艺

目的对渗漉方法提取丹参中有效成分丹参酮IIA、丹酚酸B进行研究。方法采用回流法、一般渗漉法与梯度渗漉法分别进行提取,应用正交实验设计和单因素考察的方法对提取工艺进行筛选,以HPLC法测定的丹参酮IIA、丹酚酸B的含量评价两种方式的提取效果。结果最佳提取工艺为梯度渗漉法,最佳的提取工艺条件为:取丹参药材粗粉,用适量95%乙醇溶胀2.5h,装入渗漉器材,用95%乙醇浸渍24h后,以4.5mL/min的速度开始渗漉,收集8倍药材量的渗漉液,提取丹参酮类脂溶性成分;再用50%乙醇,以4.5mL/min的速度渗漉,收集10倍药材量的渗漉液,提取丹参酚酸类水溶性成分,与HPLC测量结果比较,丹参酮IIA和丹酚酸B的提取率较高。结论梯度渗漉法提取丹参有效成分的最佳提取方式与一般渗漉法比较,提取率较高,完全适合丹参中有效成分的提取。     

DROLOXIFENE枸橼酸盐的工艺改进及其新的生物活性

目的　探索droloxifene的合成方法,并对其新的生物活性进行研究。方法和结果　以甲氧基苯和苯乙酸为原料,经酰氯化、付-克反应、烷基化、去甲基化、醚化、格氏加成、消除脱水、构型转化及成盐共9步反应,得droloxifene枸橼酸盐,8步收率14.7%(9.2%^［1］)。生物活性实验发现其具有缓解肿瘤细胞多药耐药性和诱导黄体细胞凋亡的两种新的生物活性。结论　本文对droloxifene的合成工艺进行了改进,反应步骤缩短两步,异构体分离、转化方法简便,原料及试剂易得,操作简便。两种新的生物活性的发现对新药研究及扩大临床应用提供了实验依据。     

Stabilization and HPLC analysis of betamethasone sodium phosphate in plasma

The analysis of corticosteroid prodrugs in pharmacokinetic (PK) studies poses the risk of overestimation of corticosteroid concentrations due to in vitro hydrolysis of prodrugs after sample collection. This study tests the effectiveness of enzyme inhibitors as stabilizers for betamethasone sodium phosphate (BSP) in pregnant sheep plasma samples collected during PK studies with betamethasone (BET) and provides simultaneous high-performance liquid chromatography analysis of BSP and BET. A rapid, sensitive, and specific ion-paired reversed-phase high-performance liquid chromatography assay for simultaneous measurement of BET and BSP in plasma was developed. This assay was used for analyzing samples from an in vitro prodrug hydrolysis study. Enzyme inhibitors tested were sodium arsenate (Na(2)HAsO(4)) and ethylenediaminetetraacetic acid. The BSP was administered intramuscularly to three pregnant sheep to assess in vivo PK. Samples were split with part treated with Na(2)HAsO(4) and part left natural. In vitro hydrolysis of BSP in plasma to BET could be completely inhibited by Na(2)HAsO(4), but not by ethylenediaminetetraacetic acid. The PK study showed lower concentrations of BET in samples with Na(2)HAsO(4) compared with natural samples. This study demonstrates that artifacts in PK profiles of corticosteroids due to in vitro prodrug hydrolysis can be prevented by sample treatment with enzyme inhibitors.     

盐酸罗匹尼罗的合成

2-甲基-3-硝基苯乙酸经氯代、酰胺化、还原得N,N-二丙基-2-甲基-3-硝基苯乙胺,与草酸二乙酯缩合、水解后还原得到2-硝基-6-[2-(二丙胺基)乙基]苯乙酸,最后经还原、缩合闭环及成盐反应制得盐酸罗匹尼罗,总收率约36%。     

Metabolism of 2-phenylethylamine to phenylacetic acid, via the intermediate phenylacetaldehyde, by freshly prepared and cryopreserved guinea pig liver slices

BACKGROUND: 2-Phenylethylamine is an endogenous amine, which acts as a neuromodulator of dopaminergic responses. Exogenous 2-phenylethylamine is found in certain foodstuffs and may cause toxic side-effects in susceptible individuals. MATERIALS AND METHODS: The present investigation examined the metabolism of 2-phenylethylamine to phenylacetic acid, via phenylacetaldehyde, in freshly prepared and cryopreserved liver slices. Additionally, it compared the relative contribution of aldehyde oxidase, xanthine oxidase and aldehyde dehydrogenase by using specific inhibitors for each oxidizing enzyme. RESULTS: In freshly prepared and cryopreserved liver slices, phenylacetic acid was the main metabolite of 2-phenylethalamine. In freshly prepared liver slices, phenylacetic acid was completely inhibited by disulfiram (inhibitor of aldehyde dehydrogenase), whereas isovanillin (inhibitor of aldehyde oxidase) inhibited acid formation to a lesser extent and allopurinol (inhibitor of xanthine oxidase) had no effect. In cryopreserved liver slices, isovanillin inhibited phenylacetic acid by 85%, whereas disulfiram inhibited acid formation to a lesser extent and allopurinol had no effect. CONCLUSION: In liver slices, 2-phenylethylamine is rapidly oxidized to phenylacetic acid, via phenylacetaldehyde, by aldehyde dehydrogenase and aldehyde oxidase with no contribution from xanthine oxidase.     

Free and chemically bonded phenolic acids in barks of Viburnum opulus L. and Sambucus nigra L

Liquid column chromatography, planar chromatography (TLC) on modified and unmodified silica layers, reversed-phase high-pressure liquid chromatography (HPLC), as well as ESI-TOF MS and 1H-NMR have been used for separation, purification and identification of phenolic acids in the barks of Sambucus nigra and Viburnum opulus (Caprifoliaceae). By the use of these procedures three cinnamic acid derivatives: caffeic acid, p-coumaric, and ferulic acid, four benzoic acid derivatives: gallic acid, protocatechuic acid, syringic acid, 3,4,5-trimethoxybenzoic acid, two phenylacetic acid derivatives: 3,4-dihydroxyphenylacetic acid, homogentisic acid, and two depsides: chlorogenic acid and ellagic acid were detected and identified in the bark of Viburnum opulus. Caffeic acid, p-coumaric acid, ferulic acid, gallic acid, syringic acid, 3,4,5-trimethoxybenzoic acid and chlorogenic acid were also detected and identified in the bark of Sambucus nigra. Except for chlorogenic acid, this is the first time these phenolic acids have been isolated, detected, and identified in the bark of V. opulus and S. nigra.     

Successful treatment of severe hyperammonemia using sodium phenylacetate powder prepared in hospital pharmacy

In order to treat a hyperammonemic patient with adult-onset type-II citrullinemia (CTLN2), sodium phenylacetate powder was prepared from chemical reagent grade phenylacetic acid in Gunma University Hospital. After purification by recrystalization, phenylacetic acid was neutralized with sodium carbonate and dried at 70 degrees C under reduced pressure. A solution of the prepared powder produced a single peak of m/z=181.0 (M+Na+) in electrospray-ionization-MS spectrogram. The content of phenylacetate was 74% of theoretical value, suggesting the existence of water of crystallization. The content of phenylacetate remained constant for 5 months under dark conditions at room temperature. The prepared sodium phenylacetate powder was orally administered to a 16-year-old patient with CTLN2 at a dosage of 12 g/d. The serum ammonia concentration of the patient, who did not show adequate response to intravenous arginine or oral sodium benzoic acid decreased remarkably to less than 100 microg/dl. Sodium phenylacetate powder should be an essential drug for the treatment of hyperammonemia caused by an inborn error of the urea cycle.     

正交设计法确定脂灵胶囊含量测定的水解条件

目的：建立脂灵胶囊的水解条件，以便准确测定脂灵胶囊中大黄酚的含量。方法：采用三因素三水平正交表，考察了盐酸浓度、加热时间、加酸量三因素对结合型蒽醌水解为游离型蒽醌的影响。结果：最佳水解条件为1．5mo1／ml盐酸10ml，水浴加热煮沸1．5h。