奥美拉唑的合成

2,3，5-三甲基吡啶经氧代、硝化、在乙酐中重排、水解及氯代制得2-氯甲基-3，5-二甲基-4-硝幕吡啶盐酸盐，与2-巯基-5-甲氧基苯并咪唑在甲醇钠作用下同时完成缩合、甲氧基化得到5-甲氧基-2-[（4-甲氧基-3，5-二甲基吡啶-2-基）甲硫基]-1H-苯并咪唑，最后氧化得到奥美拉唑，总收率约42％。     

H~+、K~+-ATP酶抑制剂Pantoprazole Sodium

合成反应是由3-甲氧基-2-甲基-4硝基吡啶-N-氧化物(Ⅰ)或4-氯-3-甲氧基-2-甲基吡啶-N-氧化物(Ⅱ)在热的甲醇中和甲醇钠反应产生3,4-二甲氧基-2-甲基吡啶-N-氧化物(Ⅲ),Ⅲ在90℃酸酐中异构化,并用NaOH水解转化为2-羟甲基-3,4-二甲氧基吡啶(Ⅳ),Ⅳ和SOCl_2在CH_2Cl_2起反应生成相应的2-氯甲基-3,4-二甲氧基吡啶鎓盐(Ⅴ);Ⅴ和5-二氟甲氧基-2-巯基苯并咪唑(Ⅵ),在热甲醇中通过NaOH缩合产生5-(二氟甲氧基)-2[[(3,4-二甲氧基-2-吡啶     

奥美拉唑产品中二种杂质的制备

为对奥美拉唑产品中的杂质进行定量控制,以2-巯基-5-甲氧基-IH-苯并咪唑和2-氯甲基-3,5-二甲基-4-甲氧基吡啶经缩合、氧化制得2个奥美拉唑杂质--5-甲氧基-2-[(4-甲氧基-3,5-二甲基吡啶-2-基)甲磺酰基]-1H-苯并咪唑和5-甲氧基-2-[(4-甲氧基-3,5-二甲基吡啶-2-基-1-氧化物)甲磺酰基]-1H-苯并咪唑,并经核磁共振和质谱确证结构.     

埃索美拉唑镁的合成

2-羟甲基-3,5-二甲基-4-硝基吡啶经氯化亚砜氯化后得2-氯甲基-3,5-二甲基-4-硝基吡啶盐酸盐(3),3与5-甲氧基-2-巯基苯并咪唑缩合得5-甲氧基-2[(3,5-二甲基-4-硝基-2-吡啶基)甲硫基]-1H苯并咪唑(4),4经不对称氧化得5-甲氧基-2-[[(3,5-二甲基-4-硝基-2-吡啶基)甲基]亚磺酰基]-1H-苯并咪唑(5),5再通过甲氧基化后得埃索美拉唑钠(6),最后6与氯化镁反应得埃索美拉唑镁,总收率约73.6％(以2-羟甲基-3,5-二甲基-4-硝基吡啶计).     

奥美拉唑杂质的合成

目的研究奥美拉唑杂质:2-[(5-甲氧基-1 H-苯并咪唑-2-亚磺酰基)甲基]-3,5-二甲基-4-羟基吡啶的合成方法。方法以2-氯甲基-4-甲氧基-3,5-二甲基吡啶盐酸盐(CMML)为原料,通过脱甲基、缩合、氧化三步反应制得2-[(5-甲氧基-1 H-苯并咪唑-2-亚磺酰基)甲基]-3,5]二甲基-4-羟基吡啶。结果合成的目标化合物经核磁共振氢谱、核磁共振碳谱及质谱确证。结论该合成通过三步得到目标化合物,收率约为23%。     

S-泮托拉唑钠的合成工艺改进

用2-甲基-3、4-二甲氧基吡啶为原料,经氯化亚砜氯化后得2-氯甲基-3、4-二甲氧基吡啶盐酸盐,再和5-二氟甲氧基-2-硫基-1H-苯并咪唑进行缩合反应,再经不对称氧化得S-泮托拉唑,再经氢氧化钠成盐后得S-泮托拉唑钠。     

艾司奥美拉唑钠有关物质的合成

目的合成艾司奥美拉唑钠产品中两个N-吡啶取代杂质,加强其质量控制。方法以奥美拉唑硫醚和2-氯甲基-3,5-二甲基-4-甲氧基吡啶盐酸盐为起始原料,经取代反应得到奥美拉唑硫醚N-吡啶取代物(A),再经不对称氧化反应得到N-(4-甲氧基-3,5-二甲基-2-吡啶)甲基艾司奥美拉唑(B)。结果与结论目标化合物的结构经过质谱、核磁确证,纯度均大于98.0%,可用于艾司奥美拉唑钠产品研究质量控制的对照品。本工艺所用原料易得,成本低,纯度高。     

新质子泵抑制剂吡美拉唑合成与表征

目的探究吡美拉唑的合成与表征。方法分别以廉价的2,3-二甲基吡啶和2,6-二氯吡啶为起始原料,制备了关键中间体2-氯甲基-4-(3-甲氧基丙氧基)-3-甲基吡啶盐酸盐和2-巯基-5-甲氧基咪唑[4,5-b]吡啶,进而得到了吡美拉唑。结果与结论目标产物吡美拉唑及部分中间体的化学结构经红外光谱、高分辨质谱和~1H-NMR以及~(13)C-NMR确证,与文献方法相比,该路线原料易得,操作简便,避开使用2,3-二甲基-4-氯吡啶-N-氧化物为原料,进而避开了高危险试剂氢化钠,相对于文献报道的路线,收率明显提高,适合工业化生产。     

抗肿瘤药物neratinib的合成

目的合成抗癌药neratinib。方法以2-氯-4-硝基苯酚和2-氯甲基吡啶为起始原料,经醚化、硝基还原得到3-氯-4-（吡啶-2-甲氧基）苯胺,3-氯-4-（吡啶-2-甲氧基）苯胺与3-氰基-6-乙酰氨基-7-乙氧基-4-氯喹啉反应得到3-氰基-6-乙酰氨基-4-[3-氯-4-（吡啶-2-甲氧基）苯氨基]-7-乙氧基喹啉,3-氰基-6-乙酰氨基-4-[3-氯-4-（吡啶-2-甲氧基）苯氨基]-7-乙氧基喹啉去乙酰保护基后,与（E）-4-二甲氨基-2-丁烯酰氯经酰化反应得到ner-atinib。结果与结论目标物neratinib的总收率为56.0%,其结构经核磁共振氢谱、质谱确证。     

罗氟司特的合成

3,4-二羟基苯甲醛与二氟一氯甲烷醚化得到3-羟基-4-二氟甲氧基苯甲醛,与氯甲基环丙烷醚化得到3-环丙基甲氧基-4-二氟甲氧基苯甲醛,再经氧化、氯代后与4-氨基-3,5-二氯吡啶反应,制得慢性阻塞性肺病治疗药罗氟司特,总收率约23％.     

奥美拉唑磺酰化物的制备

目的:提供一种制备奥美拉唑磺酰化物的简单方法.方法:2-巯基-5-甲氧基苯并咪唑和2-氯甲基-3,5-二甲基-4-甲氧基吡啶盐酸盐经缩合、氧化可制得奥美拉唑.奥美拉唑再用高锰酸钾氧化可得到奥美拉唑磺酰化物,产品经IR、1H-NMR、MS、UV确证结构.结果与结论:本方法步骤简单,条件温和,后处理方便,所得奥美拉唑磺酰化物纯度达99%以上.     

Synthesis and antiinflammatory activity of 6-oxo-1-(beta-D-ribofuranosyl)nocotinic acid and related derivatives

5-Substituted 1-(beta-D-ribofuranosyl)pyridine-2-ones (6-oxonicotinic acid nucleosides) were prepared by direct glycosylation of 5-ntrio-, 5-carbomethoxy-, 5-carboxamido-, 5-amino, 5-carbobenzyloxyamino-, and 5-acetamido-2-trimethylsilyloxy or corresponding 2-methoxypyridine derivatives by the Hilbert-Johnson method. The glycosylation products were deblocked by conventional procedures and substituents at the 5 position were modified to give the 5-carboxamide, carboxyhydrazide, and carboxylic acid. Only 1-(beta-D-ribofuranosyl)pyridin-2-one-5-carboxylic acid [1-(beta-D-ribofuranosyl)-6-oxonicotinic acid (12), showed significant activity in treating adjuvant-induced arthritis in rats.     

A computational insight into the molecular interactions of chlorpyrifos and its degradation products with the human progesterone receptor leading to endocrine disruption

Chlorpyrifos (CPF) is a widely used pesticide effective against a large number of target pests, which is used by farmers to protect food crops. Based on earlier epidemiologic reports, which indicate that CPF might interfere with the progesterone signaling pathway and can affect conception, the present study was undertaken to evaluate the binding interaction of CPF with the human progesterone receptor (hPR). Progesterone is one of the important hormones of the reproductive system and through its receptor, PR, the progesterone signaling pathway regulates important reproductive functions including reproductive cyclicity and initiation and continuation of pregnancy. The binding interactions of four major degradation products of CPF, viz. chlorpyrifos-oxon (CPYO), des-ethyl chlorpyrifos (DEC), 3,5,6-trichloro-2-methoxypyridine (TMP), 3,5,6-trichloro-2-pyridinol (TCP), were also studied to evaluate the possibility of endocrine disruption caused by these metabolites. Docking studies revealed that CPF, CPYO, and DEC were able to involve important interacting amino acid residues of the hPR during molecular interactions and are capable of competing with progesterone. Thus, CPF and its degradation products can act as potential xenoligands for the hPR and can disrupt normal progesterone signaling pathway.     

Pyrido[2,1-f]purine-2,4-dione derivatives as a novel class of highly potent human A(3) adenosine receptor antagonists

1H,3H-Pyrido[2,1-f]purine-2,4-diones, which can be described as fused xanthine structures, have been synthesized by a novel synthetic procedure, and their affinities for the human adenosine A(1), A(2A), and A(3) receptors have been evaluated in radioligand binding studies. The synthetic procedure employed was developed in our laboratory and involved a two-step one-pot reaction that consists of the treatment of 6-aminouracil derivatives with N-bromosuccinimide to generate a 5,5-dibromo-6-imino intermediate that reacts "in situ" with pyridine, 4-methoxypyridine, 4-tert-butylpyridine, or 4-phenylpyridine to afford the corresponding 1H,3H-pyrido[2,1-f]purine-2,4-diones (2-5). Functionalization at the N(3) position in compounds 2-5 was performed by reaction with DBU and different alkyl, alkenyl, alkynyl, or benzyl halides. Binding studies at human adenosine A(1), A(2A), and A(3) receptors revealed significant antagonist effects in the low nanomolar range, in particular against the A(3) receptor. Thus, the 1-benzyl-3-propyl-1H,3H-pyrido[2,1-f]purine-2,4-dione derivative 6, which can be considered a lead compound in this series, exhibited a K(i) value of 4.0 +/- 0.3 nM against the hA(3) receptor. Because xanthine derivatives have traditionally been considered poor A(3) antagonists, the described pyrido[2,1-f]purine-2,4-dione derivatives represent a new family of adenosine receptor antagonists which deserves further exploration.     

Synthesis and cytotoxicity of 4-amino-5-oxopyrido[2,3-d]pyrimidine nucleosides

A number of nucleoside analogues have been either used clinically as anticancer drugs or evaluated in clinical studies, while new nucleoside analogues continue to show promise. In this article, we report synthesis and cytotoxicity of a series of new pyrido[2, 3-d]pyrimidine nucleosides. 2-Amino-3-cyano-4-methoxypyridine was converted, in two steps, to 4-amino-5-oxopyrido[2,3-d]pyrimidine. A variety of 1-O-acetylated pentose sugar derivatives were condensed with silylated 4-amino-5-oxopyrido[2,3-d]pyrimidine, followed by protection, to afford a series of 4-amino-5-oxopyrido[2, 3-d]pyrimidine nucleosides. Further derivatizations provided an additional group of pyrido[2,3-d]pyrimidine nucleosides. These nucleosides were evaluated for in vitro cytotoxicity to human prostate cancer (HTB-81) and mouse melanoma (B16) cells as well as normal human fibroblasts (NHF). A number of compounds (1a,b, 2a-c,f, 3f+4d) showed significant cytotoxicity to cancer cells, with 4-amino-5-oxo-8-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine (1b) being the most potent proliferation inhibitor (EC(50): 0.06-0.08 microM) to all types of cells tested. However, a selective inhibition to the cancer cells was observed for 4-amino-5-oxo-8-(beta-D-xylofuranosyl)pyrido[2,3-d]pyrimidine (2b), which is a potent inhibitor of HTB-81 (EC(50): 0.73 microM) and has a favorable in vitro selectivity index (28).     

Synthesis, in vivo occupancy, and radiolabeling of potent phosphodiesterase subtype-10 inhibitors as candidates for positron emission tomography imaging

We have recently reported the phosphodiesterase 10A (PDE10A) inhibitor 2-[4-[1-(2-[(18)F]fluoroethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenoxymethyl]-quinoline ([(18)F]1a) as a promising candidate for in vivo imaging using positron emission tomography (PET). We now describe the synthesis and biological evaluation of a series of related pyridinyl analogues that exhibit high potency and selectivity as PDE10A inhibitors. The most interesting compounds were injected in rats to measure their levels of PDE10A occupancy through an in vivo occupancy assay. The 3,5-dimethylpyridine derivative 3 and the 5-methoxypyridine derivative 4 showed a comparable level of occupancy to that of 1a. Because these derivatives showed lower in vitro activity and are slightly less lipophilic than 1a, we hypothesized that they could behave as better PET imaging ligands. Compounds [(18)F]3, [(18)F]4, and [(11)C]4 were radiosynthesized and subjected to biodistribution studies in rats for a preliminary evaluation as candidate PET radioligands for in vivo imaging of PDE10A in the brain.     

2-苯基-1-丁醇与2-二甲氨基-2-苯基丁腈的合成

目的为马来酸曲美布汀的重要中间体2-二甲氨基-2-苯基-1-丁醇的合成奠定基础。方法苯乙腈与溴乙烷进行烃化反应得2-苯基-1-丁腈,所得产物经水解得2-苯基-1-丁酸,然后通过硼氢化钠-碘体系还原得2-苯基-1-丁醇;苯乙腈与N-溴代丁二酰亚胺进行卤代反应得溴代苯乙腈,所得产物与二甲胺进行烃化反应得2-二甲氨基苯乙腈,然后与溴乙烷进行烃化反应得2-二甲氨基-2-苯基丁腈。结果合成了2-苯基-1-丁醇和2-二甲氨基-2-苯基丁腈,总收率为分别为51%和59.4%。目标产物的结构经核磁共振氢谱、质谱确证。结论本合成方法原料易得,操作简单,收率较高,适合于工业化生产。     

2-(2-甲氧基苯氧基)乙胺的制备

2-(2-Methoxyphenoxy)ethanamine was synthesized from 2-aminoethanol and aceto-nitrile by cyclization to give 2-methyl-2-oxazoline which reacted with 2-methoxyphenol followed by hydro-lysis with phosphoric acid with an overall yield of 44%。     

Modulation of adjuvant arthritis in the rat by 2-methoxyestradiol: an effect independent of an anti-angiogenic action

Angiogenesis is a prominent feature in rheumatoid arthritis. 2-methoxyestradiol (2ME2) inhibits endothelial cell proliferation, and angiogenesis in vivo. We evaluated the effect of 2ME2 in rats with adjuvant arthritis (AA), an autoimmune T-cell-dependent polyarticular arthritis induced by immunization with Mycobacterium organisms. Rats were immunized with Mycobacterium butyricum and arthritis was assessed clinically, by radiolabeled blood neutrophil (PMNL) migration to joints and by histology. Treatment with 2ME2 (30 mg/kg/d or 100 mg/kg/d) from day 6 post-immunization inhibited arthritis severity on day 14 (vehicle clinical score=11.2; 2ME2 groups=7-8, p<0.05). When treatment was delayed until signs of clinical arthritis on day 10 post-immunization, 2ME2 treatment still inhibited arthritis severity. PMNL migration to the joints was significantly inhibited (by 35-40%; p<0.01) by early 2ME2 treatment (day 6-14). Treatment with 2ME2 inhibited PMNL migration to dermal inflammation induced by TNF-alpha but not by LPS or C5a. Joint histology revealed decrease in leukocyte infiltration and especially in cartilage damage. However, synovial vascularity was not affected by 2ME2 treatment. The marked splenomegaly, splenitis and lymphoid hyperplasia associated with AA were prevented by 2ME2 therapy. Furthermore, the ex vivo proliferative response to mycobacterial antigen (PPD) of lymphocytes from 2ME2-treated rats with AA was markedly diminished, although response to mitogens was unaffected. Thus 2ME2 has anti-arthritic properties with a disease-modifying action, separate from its anti-angiogenic properties. The selective inhibition of TNF-alpha-induced leukocyte recruitment, lymphoid hyperplasia and attenuated recall response to antigen suggests both immunomodulatory and anti-inflammatory actions of 2ME2.     

Mechanism underlying relaxations caused by prostaglandins and thromboxane A2 analog in isolated dog arteries

In helical strips of dog cerebral, coronary, mesenteric, and renal arteries treated with ONO3708, an inhibitor of vasoconstricting prostaglandin (PG) receptors, and previously contracted with serotonin, PGF2 alpha, PGD2 and epithio-methano thromboxane A2 (sTxA2), a TxA2 analog, caused a relaxation. The cerebral arterial relaxation was suppressed by treatment with indomethacin and abolished by diphloretin phosphate (DPP), a PG antagonist. On the other hand, the relaxation of mesenteric arteries was not influenced by indomethacin but was markedly attenuated by DPP. Removal of endothelium did not alter the relaxation. Relaxations of coronary and renal arteries by PGF2 alpha were suppressed by indomethacin and DPP, whereas the PGD2-induced relaxation was not affected by indomethacin but was abolished by DPP. Concentration--relaxation curves for PGI2 were shifted to the right by treatment with DPP. It is concluded that after ablation of the constrictor response, dog cerebral arteries relax in response to PGs and TxA2, probably due mainly to the release of PGI2-like substance from the arterial wall and to the action of PGI2 receptive sites, whereas the mesenteric arterial relaxation appears to be associated with their action on PGI2 receptors in smooth muscle cells. PGF2 alpha-induced relaxations in coronary and renal arteries may result from the release of PGI2, and relaxations by PGD2 from the action on PGI2 receptors.