(2S,3R)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇的合成工艺研究

目的 对(2S,3R)- 1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇合成工艺进行研究.方法 以3-戊酮为起始原料,经Mannich反应、手性拆分、Grignard反应等步骤合成(2S,3R)-1-二甲氨基-3-(3-甲氧基苯基)-2-甲基戊-3-醇,并对化学拆分进行工艺优化.结果 合成(2S,3R)-1...     

天然化合物6-羟基-2-甲基-2-(4-甲基-3-戊烯基)-2H-苯并吡喃的合成

６羟基２甲基２（４甲基３戊烯基）２Ｈ苯并吡喃是从ＰｈａｃｅｌｉａｉｘｏｄｅｓＫｅｌｏｇｇ．中分离出的具有抗脂质氧化作用的天然化合物．报道以１，４环己二酮为起始原料经３步合成此天然化合物的过程．     

Novel 5-substituted 3-(2-naphthalenyl)-3-(1H-imidazol-l-ylmethy)-2-methylisoxazolidine derivatives

The synthesis and antifungal activity of a series of novel 5-substituted 3-(2-naphthalenyl)-3-(1H-imidazol-1-ylmethyl)-2- methylisoxazolidine derivatives are described. When tested in vitro in solid agar assays, some of the compounds demonstrated moderate to potent activity against Trichophyton rubrum and Candida albicans.     

NLNQ-1, a 2-[3-(2-nitro-1-imidazolyl) propylamino]-3-chloro-1,4-naphthoquinone, as a hypoxia-selective cytotoxin and radiosensitizer

BACKGROUND: Compounds bearing two independent redox centers are considered bis-bioreductive agents and usually demonstrate increased hypoxic selectivity with exposure time due to different requirements for reduction of each center. We have synthesized a novel 2-[3-(2-nitro-1-imidazolyl)propylamino]-3-chloro-1,4-naphthoquinone (NLNQ-1), through Michael addition. NLNQ-1, which combines a naphthoquinone (with a relatively high one electron reduction potential) with a 2-nitroimidazole (with a relatively low one electron reduction potential), could perform as a more potent hypoxia-selective cytotoxin and radiosensitizer. MATERIALS AND METHODS: NLNQ-1 was evaluated in V79 cells under hypoxic/normoxic conditions, alone or with radiation, by using the clonogenic assay. RESULTS: Clearly NLNQ-1 was a more potent cytotoxin than the 2-alkylsulfonyloxy-naphthoquinones (VH-compounds), developed previously in our lab, demonstrating hypoxic and aerobic IC50 values at microM rather than mM concentrations. As a radiosensitizer of hypoxic cells, NLNQ-1 was superior to the best bis-nitroimidazolic compound, NNB (which combines a 2-nitroimidazole with a 5-nitroimidazole), demonstrating a C1.6 value of 25.4 microM (ca. 25 fold lower than that of NNB), whereas its in vitro therapeutic index (IC50A/C1.6) ranged from 5.3-13.2. CONCLUSION: NLNQ-1 could be used as a novel scaffold for bis-bioreductive agents that can be properly modified for further optimization of their hypoxia-selective toxicity and radiosensitization properties.     

2-(3-aryl-3-oxopropen-1-yl)-9-tert-butyl-paullones: a new antileishmanial chemotype

A screening program directed to find new agents against Leishmania donovani, the parasite causing visceral leishmaniasis, revealed that paullones attenuate the proliferation of axenic amastigotes. Because these structures were not active in a test system involving infected macrophages, a structure optimization campaign was carried out. Concomitant introduction of an unsaturated side chain into the 2-position and a tert-butyl substituent into the 9-position of the parent scaffold led to compounds inhibiting also parasites dwelling in macrophages. By inclusion of the so elaborated scaffold into a chalcone substructure, the toxicity against uninfected host cells was significantly reduced. For the synthesis of this new compound class, a novel modification of the Heck-type palladium-catalyzed C,C-cross coupling strategy was used, employing a ketone Mannich base as precursor for the alkene reactant. The so-prepared compounds exhibited improved antileishmanial activity both on axenic amastigotes (GI50 < 1 microM) as well as on parasites in infected macrophages.     

Synthesis and pharmacological properties of some 2-(3-aminopropionyl)- and 2-(3-aminopropyl)-1-(3-pyridyl)-1,2,3,4-tetrahydro-beta-carbolines

Five derivatives of 2-(3-aminopropionyl)-1-(3-pyridyl)-1,2,3,4-tetrahydro-beta-carboline (2a-e) were obtained, which yielded, as a result of reduction with LiAlH4, five respective 2-aminopropyl-derivatives (3a-e). Pharmacological studies revealed that phenylpiperazine-derivatives 2d, 2e, 3d and 3e have sedative and analgesic properties. All compounds are devoided of neuroleptic, antidepressant, anxiolytic and antiparkinsonic activity.     

2-[3-[2-[(2S)-2-Cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]- 1,2,3,4-tetrahydroisoquinoline: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV

Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage. To achieve this, a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized. SAR studies resulted in a number of DPP-IV inhibitors, having IC(50) values of <50 nM with excellent selectivity over both DPP8 (IC(50) > 100 microM) and DPP-II (IC(50) > 30 microM). Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice. The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4), which is in clinical development.     

CoMFA, synthesis, and pharmacological evaluation of (E)-3-(2-carboxy-2-arylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acids: 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, a potent selective glycine-site NMDA receptor antagonist

(E)-3-(2-Carboxy-2-phenylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid, 1, is a potent and selective antagonist of the glycine site of the N-methyl-d-aspartate (NMDA) receptor. Using 3D comparative molecular field analysis (CoMFA) to guide the synthetic effort, a series of aryl diacid analogues of 1 were synthesized to optimize in vivo potency, duration of action, and binding activity. It was found that the incorporation of a substituted aromatic with an electron withdrawing group or a heterocyclic group at the 2-position of the 3-propenyl moiety of 1 gave compounds with better affinity and potency in the murine stroke model. Ultimately this led to the discovery of 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, 19, as a new potent selective glycine-site NMDA receptor antagonist.     

3-(3-氯丙基)-1,3,4,5-四氢-7,8-二甲氧基-2H-3-苯并氮杂 -2-酮合成工艺的改进

目的 改进3-(3-氯丙基)-1,3,4,5-四氢-7,8-二甲氧基-2H-3-苯并氮 -2-酮的合成工艺.方法 以3,4-二甲氧基苯乙酸为原料,先后经氯代、酰化、环和、取代和氢化等反应合成目标化合物.结果 与结论改进后的方法操作简单,易于纯化,试剂价廉易得,适合于工业化生产,总产率由44%提高到48%.     

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。     

7,8-二甲氧基-3-(3-碘丙基)-1,3-二氢-2H-3-苯并氮杂革-2-酮的制备

目的合成抗心绞痛的新药伊伐布雷定的关键中间体7,8-二甲氧基-3-(3-碘丙基)-1,3-二氢-2H-3-苯并氮杂--2-酮。方法以3,4-二甲氧基苯乙酸为原料,经卤化、酰化、环合、烷基化、碘取代等反应制得目标化合物。结果五步反应总收率为63.6%,产物经MS1、HNMR确证结构。结论所用工艺路线具有原料易得、操作简便、收率较高的特点,适用于该中间体的放大制备。     

Intramolecular nucleophilic amino attack in a monobactam: synthesis and stability of (2S,3S)- 3-[(2R)-2-amino-2-phenylacetamido]-2-methyl-4-oxo-1- azetidinesulfo nic acid

The potentially orally bioavailable arylglycine-substituted monobactam, (2S,3S)- 3-[(2R)-2-amino-2-phenylacetamido]-2-methyl-4-oxo-1- azetidinesulfonic acid, was prepared as a crystalline solid. No significant antibacterial activity [i.e., MICs were greater than 128 (micrograms/mL)] was found when the monobactam was tested against Gram positive and Gram negative bacteria. Solution instability (greater than 2,000 times less stable than aztreonam) due to intramolecular nucleophilic amine attack on the beta-lactam is believed to be a contributing factor to the poor microbiological activity.     

Synthesis and properties of 3-(2-hydroxyethyl)-3-n-pentyldiazirine, a photoactivable general anesthetic.

To overcome the difficulties of locating the molecular sites of general anesthetic action, we synthesized a novel photoactivable general anesthetic, 3-(2-hydroxyethyl)-3-n-pentyldiazirine (3-diazirinyloctanol), which anesthetized tadpoles with an ED(50) of 160 microM. Subanesthetic concentrations of 3-diazirinyloctanol enhanced GABA-induced currents in GABA(A) receptors, an effect that has been implicated in general anesthetic action. It also enhanced [(3)H]muscimol binding to this receptor. In muscle nicotinic acetylcholine receptors (nAcChoR), it inhibited the response to acetylcholine with an IC(50) of 33 microM. 3-Diazirinyloctanol's pharmacological actions were comparable to those of octanol. 3-(2-Hydroxyethyl)-3-[4,5-(3)H(2)]-n-pentyldiazirine photoincorporated into Torpedo nAcChoR-rich membranes mainly in the alpha subunit with 70% being in a proteolytic fragment containing the M4 transmembrane segment. Agonist enhanced the photolabeling 10-fold in a fragment containing the M1, M2, and M3 transmembrane segments. Thus, 3-diazirinyloctanol is a novel general anesthetic that acts on, and can be photoincorporated into, postsynaptic receptors.     

(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸的合成

目的 合成头孢唑兰中间体(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸。方法 以氰乙酰胺为起始原料,依次经甲氧亚氨化、加成、酯化、与硫氰化钾反应、构型转换和水解共6步反应制得目标化合物。结果和结论 目标化合物的结构经¹H-NMR和MS谱确证。该工艺路线原料易得,操作简便,总收率为29.8%,具有一定的工业化价值。     

Antihypertensive beta-adrenergic blocking agents: N-aralkyl analogues of 2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine

An interest in dual-acting antihypertensive agents, specifically those related to (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1), led us to probe the contribution of the side-chain amino substituent in this series. The ability of 1 and its various analogues to displace radiolabeled alpha 1 (WB-4101 and prazosin) and beta (dihydroalprenolol) adrenergic receptor ligands was assessed by receptor-binding techniques. Most of the compounds exhibited high beta-adrenoceptor binding affinities, but only the N-aralkylamino-substituted compounds showed high alpha 1-adrenoceptor affinities. Therefore, the vasodilation shown by 1 was not due to an interaction with the alpha 1 adrenoceptor. The aralkylamino analogues of 1 in spontaneously hypertensive rats and anesthetized dogs exhibited antihypertensive activity and alpha 1-adrenoceptor blocking properties. Unlike the preference shown by beta-adrenoceptors for S enantiomers in this oxymethylene class of beta blockers, the chirality at the secondary hydroxy center made only a minor contribution to the affinity for the alpha 1-adrenoceptor and even less of a contribution to the observed antihypertensive effects. This lack of chiral influence at the hydroxy center confirmed what had been previously observed in more limited studies with the isomers of both labetalol and medroxalol.     

3-(2-烷氧基-5-甲基苯基)-3-苯基丙胺类化合物的合成

目的 设计合成3－（2－烷氧基－5－甲基苯基）－3－苯基丙胺类化合物，从中筛选有抗尿失禁作用而无口干等不良反应的活性化合物。方法 以肉桂酸和对甲酚为起始原料，经环合、甲基化、酰胺化、还原或再经脱甲基化得目标产物。结果 共合成10个新化合物，经IR，^1H-NMR等确证其结构。     

3-（2-甲氧基-5-甲基苯基）-3-苯丙醇的合成

对甲苯酚和肉桂酸经脱水环合、水解甲基化制得3-(2-甲氧基-5-甲基苯基)-3-苯丙酸,用硼氧化钠在三氟化硼乙醚复合物作用下以无水THF为溶剂直接还原制得托特罗定中间体3-(2-甲氧基-5-甲基苯基)-3-苯丙醇,总收率89%.