3-乙酰硫基-2-甲基丙酰基-L-脯氨酸制备工艺的改进

目的缩短3-乙酰硫基-2-甲基丙酰基-L-脯氨酸的生产周期,降低生产成本,提高收率和质量。方法用Na2CO3作为催化剂,在L-脯氨酸溶液中滴加酰氯,经过滤,中和,冷却,制得3-乙酰硫基-2-甲基丙酰基-L-脯氨酸。结果以酰氯计,收率38%以上,mp82~84℃,纯度99.85%(HPLC法)。结论本法操作简便,收率高,成本低,适合工业化生产。     

消旋卡多曲有关物质的合成

为控制消旋卡多曲产品质量,制备了可能的6种有关物质:[(3-巯基-2-苄基丙酰基)氨基]乙酸(B)、[(3-乙酰巯基-2-苄基丙酰基)氨基]乙酸(C)、5,10-二苄基-4,11-二氧代-7,8-二硫基-3,12-二氮杂十四烷二酸(D)、2-[(2-苄基丙烯酰基)氨基]乙酸苄酯(F)、2-[(3-巯基-2-苄基丙酰基)氨基]乙酸苄酯(G)和5,10-二苄基-4,11-二氧代-7,8-二硫基-3,12-二氮杂十四烷二酸二苄酯(H),并经MS、1H NMR确证结构.     

6-甲氧基-2-丙酰基萘合成方法的改进

以二氯乙烷和硝基甲烷代替硝基苯作为制备6-甲氧基-2-丙酰基萘(1)的溶剂，革除了毒性较大的硝基苯．改进后的工艺操作方便，产物收率高，质量也有明显提高．是一种适合工业生产的方法。     

2-羟基-3-氯甲基-5-甲基苯乙酮的合成

目的:探索黄酮醋酸类化合物中间体的合成方法。方法:通过酰基化、Fries重排、氯甲基化合成2-羟基-3-氯甲基-5-甲基苯乙酮,并应用(HCHO)n/HCI系统进行氯甲基化,获得了满意的收率(90.4%)。结果:采用新方法合成了未见文献报道的新化合物2-羟基-3-氯甲基-5-甲基苯乙酮。结论:该方法具有反应时间短、操作简便、收率好等优点。     

抗肿瘤药物2′-脱氧-5-氟尿苷合成研究

目的:合成抗肿瘤药物2′-脱氧-5-氟尿苷。方法:以5-氟尿嘧啶核苷为原料,经丙酰溴酰化溴代得2′-溴代-3,′5′-O-二丙酰基-5-氟尿嘧啶核苷,然后氢化得产物2′-脱氧-3,′5′-O-二丙酰基-5-氟尿嘧啶核苷,最后经皂化合成2′-脱氧-5-氟尿苷。结果:以5-氟尿嘧啶核苷为起始原料经3步反应合成了2′-脱氧-5-氟尿苷。结论:本合成方法工艺简便,原料易得,条件温和,总收率为72.0%,适于工业制备。     

3-甲基-5-苯基-2-芳基-2-吗啉醇盐酸盐的合成

目的合成3-甲基-5-苯基-2-芳基-2-吗啉醇盐酸盐。方法以安非他酮在人体内的活性代谢物羟基安非他酮为先导化合物,利用化合物2-苯基-2-氨基-1-乙醇与2-溴-3-氯苯丙酮,2-溴苯丙酮,6-甲氧基-2-(2-溴丙酰基)萘反应,合成了吗啉环上5位含苯基的新型吗啉醇类化合物3-甲基-5-苯基-2-(3-氯苯基)-2-吗啉醇,3-甲基-2,5-二苯基-2-吗啉醇,3-甲基-5-苯基-2-(6-甲氧基-2-萘基)-2-吗啉醇,经氯化氢酸化后得到其盐酸盐。结果总收率分别为72.5%,78.6%,68.4%,目标化合物结构经IR,1H-NMR,MS确证。结论本法合成2-芳基-2-吗啉醇类化合物反应时间短,溶剂无毒性,具有较高的应用价值,为开发新的2-芳基-2-吗啉醇类抗抑郁症药物提供了一条新的合成工艺。     

11β，17α-二羟基-17-丙酰基-1，4-雄甾二烯-3-酮的合成

目的 制备17-丙酰基功能化的甾体化合物11β,17α-二羟基-17-丙酰基-1,4-雄甾二烯-3-酮.方法 以泼尼松龙为原料,经5步反应合成目标物.结果 和结论 总收率为67.4%,通过NMR、MS等确证了中间体和目标物的结构.     

丙戊茶碱的合成

目的　选择丙戊茶碱的合成路线,考察其重要中间体 6 -溴 - 2 -己酮的合成工艺。方法　以 1,3-二溴丙烷、乙酰乙酸乙酯缩合得 2 -甲基 - 3-吡喃酸乙酯,再与 6 3%氢溴酸反应得 6 -溴 - 2 -己酮,总收率:6 3 1%。以 3-甲基黄嘌呤为原料,经与溴丙烷、6 -溴 - 2 -己酮两步缩合,得到丙戊茶碱,总收率:73 96 %。结果　产品质量合格,收率达到文献水平。结论　6 -溴 - 2 -己酮和丙戊茶碱的合成工艺适用于工业生产。     

抗肿瘤药物2''''-脱氧-5-氟尿苷合成研究

目的合成抗肿瘤药物2'-脱氧-5-氟尿苷.方法以5-氟尿嘧啶核苷为原料,经丙酰澳酰化溴代得2'溴代-3',5'-O-二丙酰基-5-氟尿嘧啶核苷,然后氢化得产物2'-脱氧-3',5'-O-二丙酰基-5-氟尿嘧啶核苷,最后经皂化合成2'-脱氧-5-氟尿苷.结果以5-氟尿嘧啶核苷为起始原料经3步反应合成了2'-脱氧-5-氟尿苷.结论本合成方法工艺简便,原料易得,条件温和,总收率为72.0%,适于工业制备.     

2-甲基-4,6-二氯-5-氨基嘧啶的制备

乙酰胺基丙二酸二乙酯和乙脒盐酸盐在乙醇钠存在下经缩合闭环得2-甲基-4，6-二羟基-5-乙酰胺基嘧啶，再经氯化和水解得到抗高血压药莫索尼定中间体2-甲基-4，6-二氯-5-氨基嘧啶，总收率为62％。     

苯甲酰胺类抗精神病药物的研究:若干3α-去甲托品烷衍生物的合成

Reductive amination of8- benzyl-nortropinone(3 )with ammonium acetate andsodium cyanoborohydride yielded the 3 α-amino nortropane derivative 4 which was condensed withsubstituted benzoic acids using 2-bromo-N-methyl-pyridinium iodide as condensing reagent to give thetarget compounds 2a～ein an overall yield of 50～60%.Compound 2e showed marked and selectiveaffinity for D-2 receptor.Compound 2d showed definite affinity for D- 1 receptor besides markedaffinity for D-2 receptor.     

(S)-(-)-氨磺必利-D-(-)-酒石酸盐的合成

目的研究（S）-（-）-氨磺必利-D-（-）-酒石酸盐的制备方法。方法以4-氨基-2-甲氧基-5-巯基苯甲酸为原料,经乙基化、氧化得4-氨基-2-甲氧基-5-乙基磺酰基苯甲酸（4）,另由1-乙基-2-氨甲基吡咯烷经D-（-）-酒石酸拆分得S-（-）-1-乙基-2-氨甲基吡咯烷（6）,4与6缩合制得S-（-）-氨磺必利（7）,再与D-（-）-酒石酸成盐制得目标物S-（-）-氨磺必利-D-（-）-酒石酸盐（1）。总收率达25%（以4-氨基-2-甲氧基-5-巯基苯甲酸计算）。结果所得产物经元素分析,红外光谱、核磁共振谱及质谱确证了结构。结论本方法原料易得,反应条件温和,产品质量易控制。     

Polyelectrolyte complexes of Eudragit l30 d-55 and gelatin: antinociceptive activity of entrapped piroxicam

The electrostatic interaction between oppositely charged polyelectrolytes leads to the formation of polyelectrolyte complexes, which are of considerable interest because of their potential applications as both drug carriers or surface modifying agents. In this study, in vitro and in vivo studies were carried out on polyelectolyte complexes formulated with Eudragit L30 D-55 and gelatin. The complexes of Eudragit L30 D-55 and gelatin were formulated by nonstoichiometric method. The polyelectrolyte complexes formulated were then granulated and evaluated by percentage yield, particle size, and swelling behavior. The pharmacodynamic effects of piroxicam entrapped in the complexes were determined using healthy rats. Results showed that gelatin and Eudragit L30 D-55 formed polyelectrolyte complexes that prolonged the antinociceptive effects of piroxicam in experimental rats. The performance of the polyelectrolyte complexes could be stated in the following descending rank order: 1:1 > 2:1 > 1:2 ratios of Eudragit L30 D-55 and gelatin. Nonstoichiometric interactions of gelatin and Eudragit L30 D-55 could yield matrices with adequate characteristics for the formulation of sustained release systems of drugs.     

Effect of prolonged treatment with neuroleptics on dopamine D-1 and D-2 receptor density in corpus striatum of mice

The effects of long-term treatment with neuroleptics on D-1 and D-2 receptor parameters in corpus striatum were studied in mice. Mice were treated daily for 12 days with the selective D-1 antagonist, the benzazepine SCH 23390, the mixed D-1/D-2 antagonist zuclopenthixol or the selective D-2 antagonist haloperidol. Three days after withdrawal Bmax and KD for 3H-SCH 23390 binding to D-1 receptors and 3H-spiperone binding to D-2 receptors were determined. The study showed that the density of D-2 receptors increased after haloperidol whereas no changes were seen after SCH 23390 or zuclopenthixol. No changes in D-1 receptor density were seen after either treatment. The results are in full agreement with published behavioural results where haloperidol induces tolerance whereas SCH 23390 or zuclopenthixol do not. Some changes in KD values were seen. The cause and meaning of these changes await further investigation.     

头孢丙烯的合成

以7-苯乙酰胺基-3-氯甲基-3-头孢烯-4-羧酸二苯甲酯为起始原料,经7-位酰胺基水解、在DCC作用下与侧链D-2-叔丁氧羰基氨基-2-(4-羟苯基)乙酸缩合、3-位氯甲基置换为碘甲基后与三苯膦成内鎓盐,与乙醛进行Wittig反应在3-位形成丙烯基,最后在三氟乙酸作用下脱去7-位侧链氨基和4-位羧基的保护基制得头孢丙烯,总收率16.4%.     

Synthesis and dopamine receptor affinities of 2-(4-fluoro-3- hydroxyphenyl)ethylamine and N-substituted derivatives

The synthesis of 2-(4-fluoro-3-hydroxyphenyl)ethylamine (26) and of some N,N-dialkyl derivatives (27-30) starting from 4-fluoro-3-hydroxytoluene and their in vitro binding affinities for dopamine (DA) receptor are reported. The amine 26 can be regarded as a molecular modification of DA in which the para hydroxyl group is replaced by fluorine. The new compounds 26-30 were evaluated for their affinity at D-1 and D-2 DA receptor subtypes by displacement of [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective). The amine 26 had about 2-fold less affinity for D-1 and D-2 binding sites than DA. The substitution of the amino group with ethyl, n-propyl, and 2-phenylethyl groups decreased the affinity for D-1 binding sites but greatly enhanced the effectiveness on D-2 binding sites. The N-ethyl- (28) and N-n-propyl-N-(2-phenylethyl)-2-(4-fluoro-3- hydroxyphenyl)ethylamine (30) were the most potent members of the series with high selectivity for D-2 binding sites. A similar effect was observed with isomeric N-n-propyl-N-(2-phenylethyl)-2-(3-fluoro-4-hydroxyphenyl)ethylamine (31) which was approximately 65 times more selective for D-2 sites vs D-1 sites. The introduction of a 2-phenylethyl group on the nitrogen atom induce the highest effect, perhaps as a consequence of an increased liposolubility or of binding to a complementary lipophilic site on the receptor.     

Synthesis and pharmacological characterization of 2-(4-chloro-3-hydroxyphenyl)ethylamine and N,N-dialkyl derivatives as dopamine receptor ligands.

2-(4-Chloro-3-hydroxyphenyl)ethylamine (4) and some derivatives were synthesized as dopamine (DA) receptor ligands. Amine 4 retains the dopaminergic pharmacophore 2-(3-hydroxyphenyl)-ethylamine, and the chlorine atom replaces the "para" hydroxyl group of DA. The derivatives 18a-e were obtained by introducing on the nitrogen of amine 4 the n-propyl and 2-phenylethyl or 3-phenylpropyl groups which can be accommodated by the D-2 receptor lipophilic sites 3C and pi 3, respectively. The affinity and selectivity of these compounds for D-1 and D-2 subtypes was determined in radioligand competition assays for the DA receptors of rat striatum membranes using [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective) as radioligands. The amine 4 shows about 7-fold lower affinity than DA for both sites and is not able to discriminate between the two subtypes of DA receptors. The introduction of two n-propyl groups (18a) on the nitrogen atom reduces by one-half and doubles the affinity for D-1 and D-2 binding sites, respectively. The substitution of an n-propyl group with different alkylphenyl groups, to give compounds 18b-e, increases the affinity for the D-2 subtype from 19-fold to 36-fold. These compounds have the same affinity at the D-2 site as the DA agonist N-n-propyl-N-(2-phenylethyl)-2-(3-hydroxyphenyl)-ethylamine (2a) and are about 20 times more selective than DA for this binding site. In the assay for D-2 receptor mediated inhibition of adenylate cyclase activity, all the tested compounds behaved as D-2 agonists; N-n-propyl-N-[2(4-hydroxyphenyl)ethyl]- (18d) and N-n-propyl-N-(2-phenyl-ethyl)-2-(4-chloro-3-hydroxyphenyl)ethylamine (18b) were more effective than DA or 2a. On the other hand, all compounds were less effective than DA in stimulation of adenylate cyclase activity in rat striatal homogenates, a kind of effect which is mediated by the D-1 subtype of DA receptors. These results suggest that the nitrogen substitution enhances the affinity and selectivity for the D-2 receptor. In the adenylate cyclase assay, the compounds behave as potent D-2 agonists.     

Fluorescent probes for dopamine receptors: synthesis and characterization of fluorescein and 7-nitrobenz-2-oxa-1,3-diazol-4-yl conjugates of D-1 and D-2 receptor ligands

Fluorescent probes have been designed and developed for dopamine D-1 and D-2 receptors. Fluorescein and/or NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl) derivatives of PPHT (D-2 agonist), spiperone (D-2 antagonist), SKF 38393 (D-1 agonist), and SKF 83566 (D-1 antagonist) were synthesized via their amino-functionalized analogues and all ligands were pharmacologically evaluated by measuring their ability to displace [3H]SCH 23390 and [3H]spiperone from D-1 and D-2 receptor sites in caudate putamen of monkeys (Macaca fascicularis). The fluorescein derivatives of PPHT and SKF 83566 and the NBD derivatives of spiperone and SKF 83566 retained the high affinity and selectivity of the parent ligands. The NBD derivatives of PPHT showed higher D-2 receptor affinity and selectivity than their parent ligands. The enantiomers of the fluorescent derivatives of PPHT were also synthesized and were found to exhibit stereoselectivity in binding to the D-2 receptor, with the S enantiomers having a considerably higher affinity than their R analogues. In contrast to these results, the fluorescein derivative of SKF 38393 showed only a low affinity for the D-1 receptor. These fluorescein- and NBD-coupled D-1 and D-2 receptor ligands have considerable significance as potential probes in the study of distribution of the receptors at the cellular/subcellular level and of their mobility in membranes in normal/diseased states by use of fluorescence microscopic and fluorescence photobleaching recovery techniques, respectively. The development of these novel fluorescent probes should also provide new leads for the design and synthesis of additional fluorescent ligands with better fluorescent properties and/or higher affinity/selectivity for the DA receptors.     

Directed biosynthesis of new enniatins.

New cyclohexadepsipeptides of the enniatin type with potential anthelmintic properties were produced by two different strategies: 1. In vitro synthesis by use of the multienzyme enniatin synthetase, and 2. in vivo precursor feeding of enniatin producing strains Fusarium scirpi and Fusarium sambucinum. The compounds were analyzed by HPLC, various NMR measurements and mass spectrometry. The three N-methyl L-amino acid positions in the enniatin B molecule could be gradually replaced by other (N-methyl) L-amino acids, e.g. alanine, cysteine, threonine and serine. The latter two amino acids yield new enniatins with functional groups in the hydrophobic side chains. Similarly the three D-2-hydroxyisovalerate residues, present in all naturally occuring enniatins, could be substituted by D-2-hydroxybutyric acid and D-lactic acid. Despite its lower yield the in vitro synthesis has the advantage of a broader variety of products formed.     

Characterization of antinociceptive activity of novel endomorphin-2 and morphiceptin analogs modified in the third position

In the present study we investigated and compared the in vivo analgesia of centrally administered endomorphin-2 and morphiceptin, and their analogs modified in position 3. Two series of analogs were synthesized by introducing unnatural aromatic amino acids in the D configuration: 3-(1-naphthyl)-D-alanine (D-1-Nal), 3-(2-naphthyl)-D-alanine (D-2-Nal), 3-(4-chlorophenyl)-D-alanine (D-ClPhe), 3-(3,4-dichlorophenyl)-D-alanine (D-Cl2Phe). Antinociceptive activity of endomorphin-2, morphiceptin, and their analogs was compared in the mouse hot-plate test, performed after i.c.v. administration of the peptides at a dose of 10 microg/animal. The best results were obtained for two morphiceptin analogs, [D-Phe3]morphiceptin and [D-1-Nal3]morphiceptin, which showed greatly improved analgesic activity, as compared to morphiceptin. In the endomorphin-2 series none of the modifications produced analogs more potent than the parent compound, but [D-1-Nal3]endomorphin-2 was the best analog. Antinociception induced by endomorphin-2 was reversed by concomitant i.c.v. administration of [D-Phe3]endomorphin-2, [D-2-Nal3]endomorphin-2, and [D-2-Nal3]morphiceptin, indicating that these analogs were weak mu-opioid antagonists.