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%.     

达比加群酯的合成

4-甲胺基-3-硝基苯甲酸与3-(吡啶-2-基氨基)丙酸乙酯在羰基二咪唑的作用下反应形成3-[(4-甲胺基-3-硝基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯,经锌粉还原得到3-[(3-氨基-4-甲胺基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯,随后与N-(4-氰基苯基)甘氨酸在羰基二咪唑以及醋酸作用下一锅制得3-[[2-[(4-氰基苯胺基)甲基]-1-甲基-1H-苯并咪唑-5-羰基](吡啶-2-基)氨基]丙酸乙酯,再进行成脒化反应以及酰化反应后即可制得达比加群酯,总收率约48％.     

白藜芦醇的合成

以3，5-二羟基苯甲酸为原料，经保护羟基、还原、氯代后，与亚磷酸三乙酯反应生成3，5-二甲氧基苯甲基膦酸二乙酯，再与茴香醛进行Wittig—Homer反应后于吡啶盐酸盐中脱保护得到白藜芦醇。总收率约43％。     

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。     

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%.     

新型安眠药加波沙朵的合成

目的合成新型安眠药加波沙朵。方法以甘氨酸乙酯盐酸盐、氯化苄和γ-丁内酯为原料,合成N-苄基甘氨酸乙酯和4-溴丁酸乙酯,经环合得到N-苄基-3-氧代-4-甲酸乙酯哌啶盐酸盐,该盐经氢化、基团保护,再与羟胺反应环合得到3-羟基-6-甲酸乙酯-4,5,6,7-四氢异唑[5,4-c]吡啶,最后去保护得到目标产物。结果与结论中间体及产物结构经IR、^1H-NMR和^13C-NMR确认。     

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。     

2-(3-羟基-1-金刚烷基)-2-乙醛酸的合成

金刚烷经相继甲酸化、酰氯化后与丙二酸二乙酯乙氧基镁反应,得到1-金刚烷甲酰基丙二酸二乙酯,再经水解脱羧、高锰酸钾氧化得到沙克列汀中间体2-(3-羟基-1-金刚烷基)-2-乙醛酸,总收率约28%。     

UK-78282的合成

对甲氧基肉桂酸经LiAlH4还原、溴代得到3-(4-甲氧基苯基)溴丙烷,与4-哌啶甲酸乙酯反应得到的1-[3-(4-甲氧基苯基)丙基]哌啶-4-甲酸乙酯经还原后与二苯甲醇醚化,得到钾离子通道阻断剂UK-78282,总收率58%.     

盐酸芬戈莫德的合成

2-苯乙醇经氯代、傅-克酰化反应后与2-乙酰胺基丙二酸二乙酯(DEAM)反应得2-[2-(4-正辛酰基苯基)乙基]-2-乙酰胺基丙二酸二乙酯,再依次经Et3SiH/AlCl3和NaBH4/CaCl2还原得2-[2-(4-正辛基苯基)乙基]-2-乙酰胺基-1,3-丙二醇,最后经氢氧化锂水解、成盐得新型免疫抑制剂盐酸芬戈莫德,总收率约25％.     

Research on heterocyclic compounds, XXIX. Synthesis and antiinflammatory activity of imidazo[1,2-a]pyrazine derivatives.

The reaction in anhydrous ethanol of some substituted 2-aminopyrazines with ethyl 2-benzoyl-2-bromoacetate or with ethyl 3-bromo-4-oxopentanoate afforded a group of ethyl 2-phenylimidazo[1,2-a]pyrazine-3-carboxylates and a group of ethyl 2-methylimidazo[1,2-a]pyrazine-3-acetates, respectively. The corresponding acids obtained via alkaline hydrolysis were subjected to pharmacological testing in vivo in order to evaluate their antiinflammatory activity.     

Research on the connections of isoindole derivatives and ethyl esters of formic, acetic and propionic acids

A series of new derivatives of isoindole in the reaction of nucleophilic substitution with ethyl chloroformate, ethyl bromoacetate and ethyl 3-bromopropanoate were synthesized.     

COPE-Abbau in Lösung 2. Mitteilung

COPE-Degradation in Solution. Part II When heated with H₂O₂ in i-propanol the diastereomer ethyl 2-methyl-3-phenyl-3-N,N-dimethylamino-propionates are degraded to ethyl α-methylcinnamates over their amine oxides, the threo-form (2 RS, 3 SR) which gives stereo-spcifically the trans-ester four times quicker than the erythro-form (2 RS, 3 RS) which supplies the cis-ester. The differences in the reaction rate is due to steric hindrance in the transition state. The amine oxides of ethyl 3-phenyl-3-N,N-dimethylamino-propionate and ethyl 3-phenyl-2-N,N-dimethylamino-propionate inspite of two hydrogen atoms which can undergo COPE-degradation do not yield mixtures of cis and trans olefins. Moreover a transition state is formed which in its structure corresponds to the stereochemically favoured transition state during degradation of amine oxide of the threo-form. Thereby trans ethyl cinnamate results stereospecifically.     

吡嘧司特钾的合成

以氰乙酸乙酯为原料，与叠氮化钠环合得到四唑-5-乙酸乙酯，再与2-氨基-3-甲基吡啶缩合得到3-(3-甲基-2-吡啶氨基)-2-(1H-四唑-5-基)丙烯酸乙酯，之后经环合成盐得到吡嘧司特钾，总收率48％。     

美洛昔康的合成

糖精钠与氯乙酸乙酯缩合得到的3-氧代-1,2-苯并异噻唑啉-2-乙酸乙酯1,1-二氧化物,在乙醇钠存在下扩环重排、甲基化一锅反应得到4-羟基-2-甲基-2H-1,2-苯并噻嗪-3-羧酸乙酯1,1-二氧化物,再与2-氨基-5-甲基噻唑缩合制得非甾体抗炎药美洛昔康,总收率53%.     

3,5-二羟基-4-甲基己酸叔丁酯的合成

以2-甲基-3-碳基丁酸乙酯为原料，经3-经基-2-甲基丁酸乙酯和5-经基-4-甲基-3-碳基己酸叔丁酯合成了3，5-二经基-4-甲基己酸叔丁酯，总收率38％。     

Nitrogen bridgehead compounds, facile synthesis of bioactive cyanopyrimido[1,2-a]pyrimidinones

Synthesis of some new cyanopyrimido[1,2-a]pyrimidinones 5-22 have been achieved via interaction of 2-amino-6-anisyl-5-cyano-4(3H)-pyrimidinone (1) with some heterocycles having a vicinal chloroester, chlorocyano or mercaptocyano group, dimethyl acetylenedicarboxylate, active methylene compounds, ethyl 2-acetyl-3-anisylpropenoate, ethyl 3-aryl-3-cyanopropenoates, ethyl 2-cyano-3-ethoxyacrylate and some enones or enals. Some of the isolated products were subjected to biological screening tests.     

Structure and antipyretic-hypothermizing effect of various pyrazol/1,5-a/pyrimidines]

Structures of condensation products between 3-phenyl-5-aminopyrazole and ethyl ethoxymethylenacetoacetate and ethyl acetonoxalate are demonstrated, namely ethyl 2-phenyl-7-methylpyrazolo[1,5-a]pyrimidin-6-carboxylate and ethyl 2-phenyl-7-methylpyrazolo[1,5-a]pyrimidin-5-carboxylate. Studies on antipyretic and hypothermizing activity of the acid derived from the latter and of other compounds are reported.     

Human moricizine metabolism. I. Isolation and identification of metabolites in human urine

1. Using synthetic standards and or spectral data, seven moricizine metabolites were structurally identified in human urine. Two novel metabolites were identified as phenothiazine-2-carbamic acid and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate. Two novel human moricizine metabolites, 2-amino-10-(3-morpholinopropionyl) phenothiazine, a previously identified dog metabolite, and 2-aminophenothiazine, a previously identified rat metabolite, were also identified. Three additional human metabolites, phenothiazine-2-carbamic acid ethyl ester sulphoxide (P2CAEES), moricizine sulphoxide, and ethyl {10-[N-(2′-hydroxyethyl)3-aminopropionyl] phenothiazin-2-yl} carbamate, all previously described in the literature, were observed. 2. Both 2-amino-10-(3-morpholinopropionyl) phenothiazine and ethyl [10-(3- aminopropionyl) phenothiazin-2-yl] carbamate, and possibly ethyl {10-[N-(2′-hydroxyethyl)3-aminopropionyl]phenothiazin-2-yl} carbamate, possess the structural characteristics thought to be necessary for class 1 antiarrhythmic activity.     

抗痛风药非布索坦的合成工艺研究

目的研究非布索坦的合成工艺。方法 4-羟基硫代苯甲酰胺与2-氯乙酰乙酸乙酯经环合制得2-(4-羟基苯基)-4-甲基-5-噻唑甲酸乙酯(12),12经Duff-Bills反应得到2-(4-羟基-3-甲酰基苯基)-4-甲基-5-噻唑甲酸乙酯(13),13与盐酸羟胺经高温脱水得到2-(3-氰基-4-羟基苯基)-4-甲基-5-噻唑甲酸乙酯(14),14与溴代异丁烷缩合制得2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑甲酸乙酯(7),最后经碱水解、酸中和制得非布索坦(1)。结果与结论目标化合物的结构经1H-NMR、MS谱等确证,总收率为23%(以4-羟基硫代苯甲酰胺计)。改进后的成本约为每千克2.5万元,反应操作简单,更适合于工业化生产。