乙氧甲叉丙二酸二乙酯制备方法的改进

乙氧甲叉丙二酸二乙酯是由丙二酸二乙酯和原甲酸三乙酯在乙酸酐和氯化锌催化下缩合而成的,收率97.3％(以丙二酸二乙酯计算)。原甲酸三乙酯的投料量是过量的,没反应的原甲酸三乙酯回收后套用在下一釜反应中。     

3,6-二甲氧基-2,5-二氢吡嗪-2-羧酸乙酯的合成

用苄氧羰基氨基乙酸在N-甲基吗啉的催化下与氯甲酸异丁酯反应后,无需分离直接与氨基丙二酸二乙酯盐酸盐反应得到(2-苄氧羰基氨基乙酰胺基)丙二酸二乙酯,经Pd/C催化氢解、环合后在二氯甲烷中与Me3OBF4反应制得α-取代丝氨酸的合成中间体3,6-二甲氧基-2,5-二氢吡嗪-2-羧酸乙酯,总收率35.1%.     

氟哌酸中间体—3-氯-4-氟苯胺亚甲基丙二酸二乙酯的合成工艺改进

3-氯-4-氟苯胺在适当的Lewis酸存在下,与原甲酸三乙酯及丙二酸二乙酯缩合,一步制得了3-氯-4-氟苯胺亚甲基丙二酸二乙酯(Ⅲ),反应收率几乎为100％,本方法可在氟哌酸的生产巾完全代替乙氧_亚甲基丙二酸二乙酯工艺。     

相转移催化反应在麝香酮合成中的应用

相转移催化是近年发展起来的一种化学合成方法。我厂合成麝香酮所用的中间体甲基丙二酸二乙酯如按一般烃化方法制取,所得产物中夹杂有副产物二甲基丙二酸二乙酯和未反应的丙二酸二乙酯各达10%以上,三者沸点接近,不易分离,严重影响了最终产品的质量和收率。我们采用相转移催化方法,加速反应使之更有选择性。并对溶剂、催化剂用虽和加料次     

3-氯-4-氟苯胺基亚甲丙二酸二乙酯制备的改进

3-氯-4-氟苯胺在 Lewis 酸存在下直接同原甲酸三乙酯、丙二酸二乙酯反应,除得到60～70%收率的主产物3-氯-4-氟苯胺基亚甲丙二酸二乙酯(1)外,还分离到三个产物,经 IR、MS、~1HNMR 及元素分析,证明其结构分别是甲脒3的盐酸盐、4和5。可用本法代替原用乙氧亚甲丙二酸二乙酯制备1的工艺。     

3-氯-4-氟苯胺基甲叉基丙二酸二乙酯的新合成方法

设计了以羟基甲叉基丙二酸二乙酯钠盐为原料合成３ 氯 ４ 氟苯胺基甲叉基丙二酸二乙酯的方法,收率为５１７％．     

丙二酸二乙酯的一次二乙基化

二乙基丙二酸二乙酯是生产催眠药巴比妥的重要中间体。丙二酸二乙酯次甲基上的两个活泼氢,从理论上讲可以在同一反应器中先后进行两次乙基化。伹目前各生产厂均分两次进行烷化反应才能得到合格的酯(d_4~(20) 0.9840～0.9860),致使生产周期长、需用设备多、能量消耗大和劳动生产率低。为此,我们参考了山东新华药厂巴比妥试验资料,进行了在同批反应中完成两次乙基化的试验。     

6,7-二氟-4-羟基-2-甲氧甲硫基-3-喹啉羧酸乙酯的合成

3,4-二氟苯胺在三乙胺存在下与二硫化碳生成芳基取代的二硫代氨基甲酸后与氯甲酸乙酯反应得到3,4-二氟苯基异硫氰酸酯,先后与由丙二酸二乙酯在无机碱中成的盐和氯甲基甲醚反应后加热环合,得到氟喹诺酮类抗菌剂普卢利沙星的中间体6,7-二氟-4-羟基-2-甲氧甲硫基-3-喹啉羧酸乙酯,总收率85.7%.     

盐酸金刚乙胺的合成

1-金刚烷甲酸经酰氯化后与丙二酸二乙酯乙氧基镁反应得到金刚烷甲酰丙二酸二乙酯,再经水解脱羧、肟化、还原、成盐等反应得到抗病毒药盐酸金刚乙胺,总收率约70%。     

褪黑激素的合成工艺改进

褪黑激素（ｍｅｌａｔｏｎｉｎ,１）,化学名：Ｎ－乙酰－５－甲氧基色胺,是人脑松果体分泌的一种物质,有多种生理作用,尤其同生物节律的关系日益受到人们的关注。目前国内外已将其开发为改善睡眠的保健品上市。文献［１～３］报道了１的合成,本文采用文献［３］的方法合成１,并进行改进。　　在制备２－氰乙基丙二酸二乙酯（２）时,文献［４］在醇钠与丙二酸二乙酯反应后于３５℃滴加丙烯腈,收率为６０％,另有２０％左右的二取代副产物二－（２－氰乙基）丙二酸二乙酯生成。现将醇钠使用量减少３０％,于２５℃滴加丙烯腈,收率达…     

S-Nitrosylation of sulfhydryl groups in albumin by nitrosating agents

The reaction of sulfhydryl groups in human serum ablumin with bacteriostatic and hypotensive nitrosating agents such as sodium nitroprusside and sodium nitrite has been examined. The low reactivity of sodium nitroprusside to sulfhydryl groups in albumin has been observed and the sterical inaccessibility of this agent to the site which sulfhydryl group resides was implicated. The reaction of sodium nitrite with albumin was highly influenced by pH and little reactivity was observed at physiological pH. On the other hand, the reaction between albumin and S-nitrosoglutathione, an intermediate induced from the reaction of glutathione and nitrosating agents, resulted in the rapid decrease of free sulfhydryl groups in albumin. S-Nitrosylation of the sulfhydryl group by S-nitrosoglutathione and the subsequent production of mixed disulfide is the probable route of modification. In the physiological system, S-nitrosoglutathione may act as an active intermediate in expressing reactivity of nitrosating agents to sulfhydryl groups in albumin.     

化学消除-分光光度法测定苯扎澳铵制剂含量

目的：建立苯扎溴铵消毒液中主药苯扎溴铵含量测定的新方法;方法：利用盐酸和亚硝酸钠反应生成亚硝酸,亚硝酸与脲反应生成二氧化碳和氮气,除去苯扎溴铵消毒夜中的亚硝酸钠,样品不经分离用紫外法直接测定 结果：不同生产批号、不同含量的药用原料苯扎溴铵均配制不同浓度的消毒液,用不同型号的分光光度计测定其合量 本法与药典法比较,结果无显著性差异 结论;本法简便、快速,适用于苯扎溴铵消毒液的含量测定     

Formation of a mutagenic diazoquinone by interaction of phenol with nitrite

Reaction of phenol with nitrite under mildly acidic conditions produced p-nitrosophenol, p-diazoquinone and o-diazoquinone. p-Diazoquinone showed mutagenicity in Salmonella typhimurium strains TA98 and TA100 without metabolic activation; the number of his+ revertant colonies in strain TA98 was 85 with a dose of 20 nmol (after deduction of the background (control) number of about 20). Higher doses of the compound were bactericidal. While the reaction of phenol with an equivalent amount of nitrite at pH 3 produced p-nitrosophenol in high yield, reaction with excess nitrite produced a high yield of p-diazoquinone. p-Nitrosophenol was converted to p-diazoquinone by reaction with nitrite. Formation of o-diazoquinone also increased with increasing amounts of nitrite. The formation of these compounds was not greatly affected by the presence of dimethylamine. Nitrosation of dimethylamine with nitrite was stimulated by phenol because of the formation of p-nitrosophenol and its stimulatory effect. Thus, the reaction of phenol with nitrite can produce mutagenic p-diazoquinone, and can also stimulate nitrosation of secondary amines by production of p-nitrosophenol.     

Synthesis and analysis of isotopically stable labeled nitrosamines as mass spectrometry standards for drug impurity quality control

We describe a simple and easy pathway to synthesize nitrosamine mass spectrometry standards in good to moderate yields. N-alkylation of Boc-protected primary or secondary amines using stable isotope labeled alkyl halides yielded the key intermediates that were deprotected, and then, the nitrosamine was formed with sodium nitrite and sodium hydrogensulfate. Special attention to safety, disposal of waste, and surface cleaning was carried throughout.     

Changes in biliary secretion and lactate metabolism induced by diethyl maleate in rabbits

Diethyl maleate is a compound which binds with glutathione by means of a glutathione S-transferase and is excreted into bile leading to a rapid depletion of hepatic glutathione. In the rabbit, the activity of the enzyme is fairly low and we were thus prompted to study the possible effects of diethyl maleate on biliary secretion and metabolic status in this species. The administration of diethyl maleate induced a transient choleresis followed by cholestasis. The choleresis coursed with increases in the biliary output of sodium and unaccounted anions, whereas those of chloride, bicarbonate and bile acids were unaffected. Our data seem to confirm that choleresis is due to the osmotic activity of diethyl maleate compounds excreted into bile, as has been reported in rats and dogs. The cholestasis observed coursed with falls in the outputs of sodium, chloride and bicarbonate though that of bile acids remained constant. Following diethyl maleate administration, a metabolic acidosis appeared with progressive increases of blood lactate concentration. In bile the concentration of this anion closely followed that of plasma. The cholestasis is attributed to a lowered biliary secretion of bicarbonate probably secondary to the metabolic alteration. The hepatic values of cytoplasmatic and mitochondrial NADH/NAD ratios and of adenine nucleotide concentrations suggest that the increase in blood lactate results rather from a fall in its hepatic utilization that from an increase in its production.     

Mutagenicity studies of selected antihistamines, their metabolites and products of nitrosation

Methapyrilene, four structurally related antihistamines, three metabolites of methapyrilene and two products of the reaction of methapyrilene with nitrite were all tested for mutagenicity to Salmonella typhimurium. The two products of the methapyrilene-nitrite reaction have also been identified as metabolites of methapyrilene. None was mutagenic alone, either with or without rat liver S-9 activation. After reaction with sodium nitrite in acetic acid solution (nitrosation), the products of five of the ten compounds were mutagenic. These compounds were methaphenilene, 2-thiophenemethanol, 2-thiophenecarboxylic acid, N-(2-pyridyl)-N'N'-dimethylethylenediamine and N-(2-thenylmethyl)-2-aminopyridine.     

Interaction of heparin sodium and dopamine hydrochloride in admixtures studied by microcalorimetry

Microcalorimetry was used to investigate the interaction between dopamine hydrochloride and heparin sodium in 5% dextrose injection and in 0.9% sodium chloride injection. Heat of reaction (in microjoules) was measured by flow calorimetry for the following combinations of solutions: dopamine hydrochloride solution and heparin sodium solution prepared from powdered forms of the drugs in water; solutions of the powdered drugs in 5% dextrose injection; solutions of the powdered drugs in 0.9% sodium chloride injection; solutions prepared in 5% dextrose injection from commercial dopamine hydrochloride injection and commercial heparin sodium injection; and solutions prepared in 0.9% sodium chloride injection from the commercial drug injections. Mixing the solutions of the powdered drugs in water caused heat to be evolved, as did mixing the solutions of the powdered drugs diluted with 5% dextrose injection and the commercial injections diluted with 5% dextrose injection. The interactions of the two drugs were believed to be ionic, based on the exothermic nature of the reaction. No heat of reaction was measurable when sodium chloride was used as the diluent. Based on this preliminary investigation, admixtures containing heparin sodium and dopamine hydrochloride should be mixed in 0.9% sodium chloride injection to minimize the risk of interaction between the two drugs.     

Studies on the reactability of chlordiazepoxide to its N-nitrosos derivative in physiological conditions (author's transl)]

It is shown that chlordiazepoxide readily reacts with sodium nitrite in an aqueous HCl solution as well as in human gastric juice to N-nitrosochlordiazepoxide with a high yield (up to 75%). For this reaction the pH optimum has been determined to be 1.4. After oral application of chlordiazepoxide alone or in combination with nitrite to rats, the drug as well as its N-nitroso derivative were recovered from serum and analysed by high-pressure liquid chromatography.     

Effect of simultaneous administration of saccharin or cyclamate and a nitrosamide (MNU) on bladder epithelium and the dominant lethal test

Three groups consisting of 150 Swiss male mice per group received orally sodium nitrite and methylurea daily. Two of these groups also received either sodium saccharin (about 3.4 g/kg) or sodium cyclamate (1.9 g/kg) while a fourth group served as control. After one week of this treatment, these animals were twice mated and a significant mutagenic induction (dominant lethals) was observed but this was solely due to the formation in the stomach of N-methylnitrosourea (MNU) from the sodium nitrite and methylurea administered. After further treatment for 90 days, no hyperplastic or neoplastic changes of the bladders were observed. In the lungs of some treated animals microscopic foci of nodular epithelial proliferation were observed but could only be related to the treatment with sodium nitrite and methyl urea.     

Kinetics of amyl nitrite-induced hemoglobin oxidation in cord and adult blood

The effect of amyl nitrite on the erythrocytes of adult and cord hemoglobin was examined in vitro. This study revealed that amyl nitrite caused oxyhemoglobin to become oxidized to methemoglobin wherein a rectangular hyperbolic curve was generated as the reaction progressed. This curve consisted of a reactionary log phase, and a terminal asymptotic phase only, with no inductionary lag phase. A comparative study of human cord blood oxidation times and adult blood was undertaken. It was revealed that cord blood erythrocytes were oxidized by amyl nitrite at a 5-6-fold greater rate than adult blood erythrocytes. Based on an independent Student's t-test, the time taken for cord blood erythrocytes to undergo oxidation was significantly shorter (P less than 0.05) than adult controls. This greatly enhanced reactivity of cord blood erythrocytes parallels earlier findings when sodium nitrite was used instead of amyl nitrite. However, this difference defies a simple explanation and must be attributed to many factors which may include pH, structural differences, and solubility phenomenon.