(2R,4R)-4-甲基-2-哌啶甲酸乙酯的合成工艺改进

目的 优化(2R,4R)-4-甲基-2-哌啶甲酸乙酯的合成工艺.方法 以S-(-)-α-甲基苄胺为原料,与乙醛酸乙酯反应得到[(S)-1-苯乙基亚胺基]乙酸乙酯,与异戊二烯进行环合后,再经不对称氢化和脱保护反应制得(2R,4R)-4-甲基-2-哌啶甲酸乙酯.结果 总收率从17.0％提高至47.6％.结论 本工艺可有效地降低生产成本.     

盐酸罗哌卡因的合成

(s)-2-哌啶甲酸在微波辅助下,依次与氯化亚砜反应20 min、2,6-二甲基苯胺反应30 min制得(S)-N-(2,6-二甲基苯基)-2-哌啶甲酰胺(5).5再与溴丙烷在DMF中,经微波辅助进行N-丙基化反应,制得盐酸罗哌卡因,总收率约56％.     

G蛋白偶联受体119激动剂MBX-2982的合成

目的改进G蛋白偶联受体119(GPR119)激动剂MBX-2982的合成工艺。方法以4-氰基哌啶-1-甲酸叔丁酯为起始原料,经过硫代、缩合、醚化、脱Boc保护以及取代反应制得MBX-2982。结果与结论经5步反应合成目标化合物MBX-2982,其结构经1H-NMR及MS谱确证。对多步反应条件进行了工艺考察及优化,总收率为42.8%(以4-氰基哌啶-1-甲酸叔丁酯计),高于文献收率(30.8%)。     

泽布替尼的合成工艺研究

目的 对小分子布鲁顿酪氨酸蛋白激酶(BTK)抑制剂泽布替尼的合成工艺进行优化。方法 以4-苯氧基苯甲酸为原料，依次经酰化、甲基化、环合反应制得中间体3-氨基-4-氰基-5-(4-苯氧基苯基)吡唑(4);以1-叔丁氧羰基-4-哌啶甲酸为原料，依次经酰胺化、亲核加成、缩合反应制得中间体4-[3-(二甲基氨基)丙烯酰基]哌啶-1-羧酸叔丁酯(8);中间体4和8经环合、还原、脱Boc保护、水解、手性拆分、酰胺化反应制得泽布替尼。结果与结论泽布替尼的结构经¹H-NMR、¹³C-NMR和MS谱确证，泽布替尼总收率为11.9%(以4-苯氧基苯甲酸计),纯度为99.60%(HPLC法),手性纯度为98.65%。与原研路线相比，该路线仅通过一次化学拆分即制得高手性纯度的泽布替尼，合成路线得以简化，收率得到提高。     

抗精神病药物伊潘立酮的合成工艺改进

目的改进抗精神病药伊潘立酮的合成工艺。方法以4-哌啶甲酸为起始原料,依次经过酰化、氯代、傅-克酰基化、水解、肟化、环合反应得到关键中间体6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐(10);以香草乙酮为起始原料,经与1-氯-3-溴丙烷反应制得中间体4-(3-氯丙氧基)-3-甲氧基苯乙酮(12);中间体10和12经亲核取代反应制得目标产物伊潘立酮,其结构经~1H-NMR、~(13)C-NMR、IR和MS谱确证。结果与结论确定了伊潘立酮的合成路线并进行了优化,总收率达37.4%(以4-哌啶甲酸计),目标物的纯度达99.89%。新工艺路线所用原料价廉易得、操作简便、条件温和,为伊潘立酮的工业化生产奠定了基础。     

盐酸噻加宾的合成

2-溴-3-甲基噻吩的格氏试剂与氯甲酸甲酯加成后“一锅”与环丙基溴化镁加成制得环丙基二（3-甲基-2-噻吩基）-甲醇，开环后与（R）-（一）-3-哌啶甲酸乙酯经缩合、水解和成盐反应制得盐酸噻加宾，总收率41％。     

伊立替康原料药中有关物质的合成

目的合成伊立替康原料药中的两种有关物质。方法 7-乙基-N-氧化喜树碱以喜树碱为起始原料经自由基乙基化反应、N-氧化反应制得;10-(4-哌啶基哌啶)甲酰氧基喜树碱以10-羟基喜树碱为起始原料与4-硝基苯基甲酰氯酯发生酯化反应,再与4-哌啶基哌啶发生胺解反应制得。结果与结论合成了伊立替康原料药质量标准中提及的两种有关物质,其化学结构经1H-NMR、质谱确证,质量分数经HPLC检测在99%以上,可作为伊立替康原料药质量控制的对照品。     

咪唑斯汀的合成工艺改进

由4-甲胺基-1-哌啶羧酸乙酯和甲硫尿嘧啶反应后水解脱羧得到的2-[(4-哌啶基)甲胺基]-4(1H-嘧啶酮，与2-氯-1-(4-氟苄基)-1H-苯并咪唑缩合制得咪唑斯汀，总收率49.5％。     

瑞格列奈的合成

邻氟苯甲醛经格氏反应得1-(2-氟苯基)-3-甲基丁醇,经NaOCl氧化制得1-(2-氟苯基)-3-甲基丁酮,再经哌啶胺解、成肟和NaBH_4还原制得3-甲基-1-[2-(1-哌啶基)苯基]丁胺,经N-乙酰-L-谷氨酸拆分、与3-乙氧基-4-乙氧羰基苯乙酸缩合、水解制得抗糖尿病药瑞格列奈,总收率为9.5%。     

瑞格列奈的合成

4-乙氧羰基-3-乙氧基苯乙酸(2)和对甲苯磺酰氯用碳酸钾为碱,氯化苄基三乙铵为相转移催化剂反应制得混酐,再与(S)-3-甲基-1-[2-(1-哌啶基)苯基]丁胺反应制得(S)-2-乙氧基-4- [2- [3-甲基-1-[2-(1-哌啶基)苯基]丁基氨基]-2-氧代乙基]苯甲酸乙酯,再在乙醇中经氢氧化钠水解即可制得瑞格列奈,总收率约74％(以2计).     

Porphyrin dimers as photosensitizers in photodynamic therapy

Porphyrin dimers 9 with either linkages and possible isomers bis[1-[6,7-bis[2-(methoxycarbonyl)ethyl]-1,3,5,8-tetramethyl-2- vinylporphin-4-yl]ethyl] ether (10) bis[1-[6,7-bis[2-(methoxycarbonyl)ethyl]-1,3,5,8-tetramethyl-4- vinylporphin-2-yl]ethyl] ether (11), and 1-[6,7-bis[2-(methoxycarbonyl)ethyl]-1,3,5,8-tetramethyl-2-vinylporph in- 4-yl]ethyl 1-[6,7-bis[2-(methoxycarbonyl)ethyl]-1,3,5,8-tetramethyl-4-vinylporph in- 2-yl]ethyl ether (12) were synthesized from the corresponding (1-hydroxyethyl)vinyldeuteroporphyrin IX dimethyl esters (Hvd). The pure Hvd isomers 2-(1-hydroxyethyl)-4-vinyldeuteroporphyrin IX dimethyl ester (7) and 4-(1-hydroxyethyl)-2-vinyldeuteroporphyrin IX dimethyl ester (8) were obtained from 2-acetyl-4-(1-hydroxyethyl) deuteroporphyrin IX dimethyl ester (3) and 4-acetyl-2-(1-hydroxyethyl)deuteroporphyrin IX dimethyl ester (4). Porphyrins 3 and 4 were prepared either by partial reduction of 2,4-diacetyldeuteroporphyrin IX dimethyl ester (2) or by oxidation of hematoporphyrin IX dimethyl ester (1) by using tetra-n-propylammonium perruthenate (Prn4N)(RuO4) with N-methylmorpholine N-oxide as an oxidizing agent. The in vivo photosensitizing ability and therapeutic ratios of dimers 9-12 were compared with that of Photofrin II in the SMT-F tumor growing subcutaneously in DBA/2 Ha mice. These dimers were found to have better tumoricidal activity than Photofrin II with reduced skin phototoxicity.     

布南色林关键中间体的合成

目的合成布南色林的关键中间体。方法布南色林为新的治疗精神分裂症药物,本文归纳了其合成方法,并提出了一种新的关键中间体合成方法:由对氟苯甲酸乙酯与乙酰乙酸乙酯反应得对氟苯甲酰乙酸乙酯,再经氨解制得3-(4-氟苯基)-3-氧代丙酰胺,然后与环辛酮环合得到4-(4-氟苯基)-5,6,7,8,9,10-六氢环辛烷并[b]吡啶-2(1H)-酮。结果用新方法合成了布南色林的关键中间体,总收率57.6%。结论该路线反应条件温和,适合工业化生产。     

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。     

奥扎格雷钠的合成

对甲基肉桂酸乙酯经N-溴代丁二酰亚胺溴化制得对溴甲基肉桂酸乙酯，在离子液体N-正丁基吡啶四氟硼酸盐中，与咪唑室温缩合后碱性水解，得抗血栓药奥扎格雷钠，总收率为67％。     

2-(3-氰基-4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯的合成

目的优化非布司他关键中间体2-(3-氰基-4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯(4)的合成方法。方法采用"一勺烩"方法,以4-羟基苯甲腈为起始原料,首先与硫氢化钠和无水氯化镁在N,N-二甲基甲酰胺中反应,所得中间体不经分离,直接加入2-氯乙酰乙酸乙酯进行环合反应,得到2-(4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯(2);然后通过六亚甲基四胺/三氟乙酸进行Duff反应,得到2-(3-甲酰基-4-羟基)苯基-4-甲基-5-噻唑甲酸乙酯(3);再经盐酸羟胺/甲酸/甲酸钠体系脱水得到目标化合物。结果经四步反应合成非布司他关键中间体4,总收率为22.6%,其结构经核磁共振氢谱、质谱确证。结论改进后的工艺终产品无需柱色谱纯化,适合工业化生产。     

氨噻肟酸乙酯的合成

4-氯-3-氧代丁酸乙酯经肟化、与硫脲环合制得2-（2-氨基-4-噻唑基）-2-羟基亚胺基乙酸乙酯，在相转移催化剂溴化四乙铵作用下用硫酸二甲酯醚化制得氨噻肟酸乙酯，总收率46％。     

Ethyl carbamate metabolism: in vivo inhibitors and in vitro enzymatic systems

The metabolism of ethyl carbamate and the localization of its metabolites have been shown to be almost completely inhibited by ethanol in the mouse [Waddell, Marlowe, Pierce: Food Chem. Toxicol.25, 527 (1987); Yamamoto, Pierce, Hurst, Chen, Waddell: Drug Metab. Dispos. 16, 355 (1988)]. The enzyme system catalyzing this metabolism which is inhibited by ethanol now has been further investigated in both in vivo and in vitro studies. There is a direct, highly significant relationship between the extent of metabolism of ethyl carbamate and covalent binding of metabolites to liver protein. Paraoxon, carbaryl, CCl4 ethanol, methimazole, 4-methylpyrazole, diethyl maleate, ethyl N-hydroxycarbamate, and t-butyl carbamate inhibit, to different extents, the metabolism of ethyl carbamate in vivo; SKF-525A, CoCl2, Cacyanamide, chloral hydrate, 2-oxo-4-thiazolidine carboxylic acid, allopurinol, and methyl carbamate do not. Porcine liver esterase, yeast aldehyde dehydrogenase and mouse liver catalase catalyzed the metabolism in vitro; dog or bovine catalase, acid phosphatase, alcohol dehydrogenase, or carbonic anhydrase did not under the conditions tested. Paraoxon, 4-methylpyrazole, carbaryl, and NaF significantly inhibited the hydrolytic activity of mouse liver homogenates toward p-nitrophenyl acetate; ethanol or ethyl carbamate did not. However, each of these, except 4-methylpyrazole, inhibited the metabolism of ethyl carbamate by mouse liver homogenate or porcine liver esterase to about the same extent. Ion exchange chromatography of mouse liver cytosol revealed that the fraction with ability to metabolize ethyl carbamate co-chromatographed almost exactly with the ability to hydrolyze p-nitrophenyl acetate. It is proposed that ethyl carbamate is metabolized in the mouse, at least partially, by esterases; however, metabolism by other enzyme systems cannot be excluded.     

达比加群酯的合成工艺改进

目的 改进达比加群酯的合成工艺,提高反应收率并简化操作。方法 以4-甲胺基-3-硝基苯甲酸为原料,与3-（吡啶-2-基氨基）丙酸乙酯缩合后,经催化氢化、酰胺化后闭环、成脒、与氯甲酸正己酯反应得到达比加群酯。结果与结论 目标化合物的结构经核磁共振氢谱、质谱确证。改进后的合成方法与原工艺相比,环境友好,收率提高了16.4%,总收率为33.75%(以4-甲胺基-3-硝基苯甲酸计)。     

Ester hydrolysis and conjugation reactions in intact skin and skin homogenate, and by liver esterase of rabbits.

1. Procaine, 2-chloroprocaine, ethyl aminobenzoate and methyl salicylate were added at various concentrations to liver esterase, supernatant of skin homogenate, or single-pass perfused ears of rabbits. 2. Vmax of product formation by purified liver esterase correlated with the rank order of the distribution coefficients (n-octanol/buffer) of the substrates and ranged between 11 and 1100 pmol/min per micrograms protein. Km values were between 20 and 50 microM. 3. No correlation was observed when the apparent enzyme kinetics, calculated by non-linear adaptation, were compared with each other after substrate administration to skin, arterial influx, or incubation with skin homogenate. 4. An acid labile conjugate of ethyl 4-aminobenzoate was found, mainly during arterial perfusion and in supernatant of skin homogenate, after administration of ethyl 4-aminobenzoate. 5. Acetamidobenzoic acid was observed in quantities of about 10% of the free 4-aminobenzoic acid during dermal or arterial application of procaine. This metabolite was not found with ethyl 4-aminobenzoate. 6. The results from isolated rabbit ear perfusion differ quantitatively and qualitatively with those obtained from supernatant of skin homogenate or purified liver esterase.