2-(2-氨基-4-噻唑基)-2-(Z)-羟亚胺基乙酸的合成

以乙酰乙酸甲酯为原料,经亚硝化,硫酰氯氯化,环合,水解,精制五步反应制备了2-(2-氨基-4-噻唑基)-2-(Z)-羟亚胺基乙酸,总收率38.8%。本品是合成头孢克肟、头孢他啶、头孢地尼等的重要中间体。     

(R)-(-)-1-(2-萘基)-2-N-甲基氨基乙醇的合成

目的研究拟β-肾上腺素(R)-(-)-1-(2-萘基)-2-N-甲基氨基乙醇(1)的合成方法.方法以β-萘乙烯(2)为原料,通过烯烃的Sharpless不对称双羟化、环化、选择性开环、催化氢化、甲酰化、还原等6步反应制备目标产物.结果与结论设计的合成路线以β-萘乙烯计,6步反应总收率为39.3%,ee值高达97%～99%,合成路线易行.目标产物的结构经质谱、红外光谱、1H-NMR和13C-NMR确证.     

Transporter-mediated actions of R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane

R-(-)-1-(Benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP] is a catecholaminergic and serotonergic activity enhancer that increases impulse-evoked catecholamine and serotonin release from nerve terminals, and is a candidate for symptomatic treatment of early Parkinson's disease. We now report the catecholamine and serotonin transporter-mediated actions of (-)-BPAP. The effects of (-)-BPAP on inhibition of neurotransmitter uptake and radioligand binding were assessed using human embryonic kidney 293 cells (HEK 293 cells) expressing cDNA for the human dopamine transporter (hDAT), norepinephrine transporter (hNET), and serotonin transporter (hSERT). The IC(50) values for the effects of (-)-BPAP on [3H]dopamine, [3H]norepinephrine, and [3H]serotonin uptake were 42+/-9, 52+/-19, and 640+/-120 nM, respectively. The IC(50) values for the effects of (-)-BPAP on [125I]3 beta-(4-iodophenyl)tropane-2 beta-carboxylic acid methyl ester ([125I]RTI-55) binding to hDAT, hNET, and hSERT were 16+/-2, 211+/-61, and 638+/-63 nM, respectively. The effects of (-)-BPAP on spontaneous and tyramine-induced norepinephrine and dopamine release from rat brain synaptosomes using a superfusion system were also assessed. Tyramine but not (-)-BPAP potentiated norepinephrine release. Furthermore, (-)-BPAP inhibited tyramine-induced norepinephrine release. Thus, (-)-BPAP may block tyramine-induced adverse effects such as hypertensive crisis. The actions of (-)-BPAP on the spontaneous and tyramine-induced dopamine release resembled its effects on norepinephrine release. We conclude that (-)-BPAP is not only catecholaminergic and serotonergic activity enhancer, but also a norepinephrine and dopamine uptake inhibitor and a weak serotonin uptake inhibitor that does not possess a tyramine-like action on catecholamine release, and is an inhibitor of tyramine-induced release of norepinephrine.     

Synthesis of (Z)-2-(2-formamido-4-thiazolyl)-2-(substituted alkoxyimino) acetic acids

(Z)-2-(2-formamido-4-thiazolyl)-2-(substituted alkoxyimino) acetic acids were synthesized by a new method based on the following sequence of reactions: treatment of the tert-butyl acetoacetate with sodium nitrite, alkylation of the oxime formed with an appropriate alkyl halide, halogenation of methyl alpha-keto group and simultaneous cleavage of tert-butyl ester with sulfuryl chloride, protection of the obtained acid function with diphenyldiazomethane, formation of the 2-aminothiazole ring by the Hantzsch method with thiourea, formylation of the amino group and selective final cleavage of the diphenylmethyl ester by treatment with trifluoroacetic acid and anisol. The developed procedure allows the synthesis of (Z)-2-(2-formamido-4-thiazolyl)-2-(substituted alkoxyimino) acetic acids, with an ester function in the alkoxyimino group employing a simple method and obtaining higher yields in comparison with the habitually used classic method.     

Production of 1-(1-adamantyl)-2-[4-(2-chloropyrimidinyl)]-1,2,3,4-tetrahydroisoquinoline

A multistage synthesis of a new derivative of 1,2,3,4-tetrahydroisoquinoline is described. Synthesis of title compound is based on the Bischler-Napieralski reaction.     

Synthesis, antiviral and cytotoxic activity of 2'-deoxyuridines, 2'-fluoro-2'-deoxyuridines and 2'-arabinouridines containing 5-(1-hydroxy-2-halo-2-ethoxycarbonylethyl)-, 5-(1-hydroxy-2-iodo-2- carboxyethyl)- and 5-[1-hydroxy (or methoxy)-2-iodoethyl] substituents.

The 5-[1-hydroxy-2-chloro-2-(ethoxycarbonyl)ethyl]-2'-deoxyuridine (7) and 5-[1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl]-2'- fluoro-2'-deoxyuridine/uridine nucleosides (8, 9) were synthesized by the regiospecific addition of HOX (X = Br or Cl) to the vinyl substituent of the respective (E)-5-[2-(ethoxycarbonyl)-vinyl]-2'-deoxyuridines (6a-b) and uridine (6c). A related reaction of (E)-5-(2-carboxyvinyl)-2'-deoxyuridines (10a-b) and uridine (10c) with iodine and potassium iodate afforded the 5-(1-hydroxy-2-iodo-2-carboxyethyl) derivatives (11-13). 5-(1-Hydroxy-2-iodoethyl)-arabinouridine (18) was obtained by the reaction of (17) with iodine in the presence of the oxidizing agent iodic acid. Treatment of (18) with methanolic sulfuric acid afforded 5-(1-methoxy-2-iodoethyl)-arabinouridine (19) in 65% yield. Of the newly synthesized compounds, 7, 11 and 12 showed activity in vitro against HSV-1. The most active compound (12, ID50 = 0.1 microgram/ml) was 10 times less active than acyclovir (ID50 = 0.01 microgram/ml) against HSV-1. Compounds 7 and 11 were cytotoxic to L1210 cells in culture, exhibiting an ED50 of 7.2 and 4.7 micrograms/ml respectively, relative to melphalan (ED50 = 0.15 microgram/ml), but were inactive against the KB cell line.     

2-(2-(3-(2-(7-氯-2-喹啉基)乙烯基)苯基)-3-氧代丙基)苯基丙醇的合成工艺

目的对2-(2-(3-(2-(7-氯-2-喹啉基)乙烯基)苯基-3-氧代丙基)苯基)丙醇的合成工艺进行研究。方法以间氰基苯甲醛和邻甲基苯乙酮分别作为起始原料,经过缩合、格氏反应、羟基保护、羟甲基反应、卤化反应,缩合得到最终目标产物。结果总收率为质量分数47.5%。结论该工艺原料易得,降低了制备成本、简化了反应操作条件、提高了产率,更适合工业化生产。     

含氧叔丁基三唑醇类化合物的合成及其体外抗真菌活性

目的设计合成含氧取代的叔丁基三唑醇类化合物并研究其体外抗真菌活性。方法以一氯频那酮为起始原料经多步反应合成目标化合物,化合物结构经1H-NMR谱、IR谱确证;选择8种真菌为实验菌株,按国际标准抗真菌敏感性实验方法测定体外抑菌活性。结果与结论合成了12个新化合物。所有目标化合物对8种真菌均具有一定的抑制作用。可以将现有的三唑醇类抗真菌药物结构中的2,4-二氟苯基替换成其他疏水性基团来设计抗真菌化合物。     

Functional group metabolism of dopamine-2 agonists: conversion of 4-(2-di-n-propylaminoethyl)-2-(3H)-indolone to 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone

In the previous report, we reported the results of absorption, protein binding, and pharmacokinetics of the dopamine-2 agonists (D2-agonists) 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone, N-(2'-hydroxy-5'-[N,N-di-n-propylaminoethylphenyl])methanesulfonamide, and 4-(di-n-propylaminoethyl)-2-(3H)-indolone. Both phenolic compounds, 1 and 2, were subject to more rapid metabolism than the nonphenol 3. In the present study, we investigated the metabolic basis of the differences in the pharmacokinetics of these compounds. In both rats and dogs, the principal urinary metabolite of 1 and 2 was the corresponding glucuronide. In contrast, 3 was first converted to 1 which then was converted to a glucuronide. On the basis of the urinary excretion of 1 and its glucuronide after intravenous administration of 1 and 3, approximately 78% of the dose of 3 in rats and 58% in dogs was converted to 1. The depropyl analogue of 3 was identified as a minor urinary metabolite. 4-(2-Di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone was found in the plasma of rats, dogs, and cynomolgus monkeys treated with 3. The concentration of 1 declined in parallel with that of 3 in dogs and monkeys, indicating that the true half-life of 1 is shorter than or equal to that of 3. On the basis of plasma concentrations of 1 in dogs, the apparent conversion of 3 to 1 was 9%.(ABSTRACT TRUNCATED AT 250 WORDS)     

2-(2-苄氧羰基氨基噻唑-4-基)-5-(3-甲基-2-丁烯氧羰基)-2-戊烯酸的合成

对头孢布烯的关键中间体2-(2-苄氧羰基氨基噻唑-4-基)-5-(3-甲基-2-丁烯氧羰基)-2-戊烯酸(1)的合成工艺进行了研究。选用国内易得的(2-氨基噻唑-4-基)乙酸甲酯(2)作为起始原料,经过氨基保护、M ichae l加成-消除和选择性酯化三步反应制得目标化合物1,反应总收率63.0%。该工艺操作简单,生产成本低,适合工业化生产。     

Synthesis and antiviral activity of the carbocyclic analogues of (E)-5-(2-halovinyl)-2'-deoxyuridines and (E)-5-(2-halovinyl)-2'-deoxycytidines

The carbocyclic analogues of the potent and selective antiherpes agents (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU), and (E)-5-(2-bromovinyl)-2'-deoxycytidine (BVDC) were synthesized by conventional methods with use of carbocyclic 2'-deoxyuridine as starting material. C-BVDU, C-IVDU, and C-BVDC were equally selective, albeit slightly less potent, in their antiherpes action than BVDU, IVDU, and BVDC. Although resistant to degradation by pyrimidine nucleoside phosphorylases, C-BVDU did not prove more effective than BVDU in the systemic (oral, intraperitoneal) or topical treatment of HSV-1 infections in mice.     

2-氨基-2-[2-(4-正辛基苯基)乙基]-1,3-丙二醇盐酸盐的合成工艺改进

目的 合成新型免疫抑制剂2-氨基-2-[2-（4-正辛基苯基）乙基]-1，3-丙二醇盐酸盐（FTY-720）。方法 以苯和正辛酰氯为起始原料，经傅克酰基化、还原、酰化、缩合、还原羰基、还原酯基、去乙酰化和成盐反应得到目的化合物FTY-720，总收率为12．0％。结果与结论 目标化合物的结构经^1H-NMR、IR和MS确证，中间体的^1H-NMR谱和mp值与文献值相符。该合成路线成本低廉，操作简单。