尼达尼布的合成

间硝基苯甲酸甲酯(1)与氯乙酸甲酯反应制得4-甲氧基羰基甲基-3-硝基苯甲酸甲酯(2);2依次经催化氢化、乙酰化及与原苯甲酸三乙酯反应制得关键中间体(E)-1-乙酰基-3-(乙氧基-苯基-甲烯基)-2-氧-2,3-二氢-1H-吲哚-6-羧甲酸甲酯(5);N-甲基对硝基苯胺依次经氯乙酰化、取代和催化氢化反应制得N-(4-氨基苯基)-N-甲基-2-(4-甲基哌嗪-1-基)乙酰胺(9);5和9经拼合合成了治疗特发性肺纤维化药尼达尼布,总收率22.0%,纯度99.4%,其结构经1H NMR和MS确证。     

吲哚-4-甲醛的合成新方法

以2-甲基-3-硝基苯甲酸甲酯为原料,经硼氢化钠还原和铬酐-吡啶络合物氧化制得2-甲基-3-硝基苯甲醛(2),2用乙二醇保护醛基,经DMFDMA缩合、RaneyNi-水合肼环化、稀盐酸酸解等反应合成了吲哚4-甲醛(4),4及中间体的结构经^1H NMR确证。     

2-{[(2'-氰基联苯基-4-基)甲基]氨基}-3-硝基苯甲酸甲酯的合成

以3-硝基-2-氨基苯甲酸甲酯为原料,经三氟乙酰化、N-烷基化和脱保护反应制得坎地沙坦中间体2-{[(2'-氰基联苯基-4-基)甲基]氨基}-3-硝基苯甲酸甲酯,其结构经~1H NMR,~(13)C NMR和MS(ESI)确证。     

BCL-2选择性抑制剂——ABT-199的合成工艺改进

以3,3-二甲基环己酮(2)为原料,经5步反应制得中间体1-氯-4-［2-(氯甲基)-5,5-二甲基环己基-1-烯］苯（5）;以5-溴-7-氮杂吲哚为原料,经3步反应制得制得5-羟基-1-三异丙基硅基-7-氮杂吲哚（8）; 8与4-［3-氟-4-(甲氧基羰基)苯基］哌嗪-1-甲酸叔丁酯（9）经取代反应制得4-｛3-［(7-氮杂吲哚)氧］-4-(甲氧基羰基)苯基｝哌嗪-1-甲酸叔丁酯（10）;10脱保护后与5进行S_N2取代反应,所得中间体与3-硝基-4-｛［（四氢-2H-吡喃-4-基)甲基］氨基｝苯磺酰胺经缩合反应合成了BCL-2选择性抑制剂ABT-199,总收率28.4%,其结构经¹H NMR和ESI-MS确证。     

新型N-(2'-芳胺嘧啶-4'-基)-N,2,3-三甲基-2H-吲唑-6-胺衍生物的合成及其抗肿瘤活性

以3-甲基-6-硝基-1H-吲唑为原料,经N-甲基化、催化还原、亲核取代及烷基化反应制得关键中间体N-(2'-氯嘧啶-4'-基)-N,2,3-三甲基-2H-吲唑-6-胺(5);5与芳胺经亲核取代反应合成了一系列新型的N-(2'-芳胺嘧啶-4'-基)-N,2,3-三甲基-2H-吲唑-6-胺衍生物,其结构经1H NMR和MS确证。初步生物活性测试结果表明,部分化合物具有明显的抗肿瘤活性。     

新型含吲唑环嘧啶衍生物的合成

以6-硝基-1H-吲唑为原料,经氮原子甲基化、催化氢化还原、亲核取代以及烷基化反应制得关键中间体N(2′-氯嘧啶-4′-基)-N,1-二甲基-1H-吲唑-6-胺(5);5与芳香胺进行亲核取代反应合成了一系列新型取代氨基嘧啶衍生物——N-(2′-取代氨基嘧啶-4′-基)-N,1-二甲基-1H-吲唑-6-胺,其结构经1H NMR和MS表征.     

5-取代吲哚-2-酮的合成

4-取代苯胺依次与水合氯醛及盐酸羟胺反应制得4-取代异亚硝基乙酰苯胺(2a～2e);2在浓硫酸作用下环合制得5-取代靛红(3a～3e);3通过改进的Wolff-Kishner-黄鸣龙反应合成了重要的药物中间体——5-取代吲哚-2-酮(5a～5e);5a通过硝化制得5-硝基吲哚-2-酮(5f);5f被还原制得5-氨基吲哚-2-酮(5g)。其结构经1H NMR和MS确证。     

(S)-(4-溴-2-甲苯)(3-甲基吗啉)甲酮的合成

以(S)-2-氨基丙醇和氯乙酰氯为起始原料,经酰化和环合反应制得(S)-5-甲基吗啉-3-酮（4）; 4经还原制得(S)-3-甲基吗啉(5); 5与4-溴-2-甲基苯甲酸酰化缩合合成了(S)-(4-溴2-甲基苯基)(3-甲基吗啉)-甲酮,总收率57%,其结构经¹H NMR 和 ¹³C NMR确证。     

氘代AZD9291的合成

吲哚和2,4-二氯嘧啶经偶联反应制得3-(2-氯嘧啶-4-基)-1H-吲哚(1); 1与CD₃I 经取代反应制得3-(2-氯嘧啶-4-基)-1-(甲基-d₃)-吲哚(2); 2经两步亲核取代反应制得N′-(2-二甲基氨基乙基)-2-甲氧基-N′-甲基-N-{［4-(1-(甲基-d₃)吲哚-3-基)］嘧啶-2-基}-5-硝基苯-1,4-二胺(4); 4经还原反应后,与氯丙酰氯发生缩合反应合成了氘代AZD9291,总收率8.5%,其结构经¹H NMR, ¹³C NMR和ESI-MS表征。     

取代吲哚-3-甲酸类化合物的合成

吲哚-3-甲酸是一种重要的有机中间体,被广泛应用于医药与农药的合成.以取代邻硝基甲苯为原料,与N,N-二甲基甲酰胺二甲基缩醛(DMFDMA)反应制得取代2-硝基-β-二甲氨基苯乙烯,再经铁粉和冰乙酸还原环合生成取代吲哚,取代吲哚与三氟乙酸酐经酰化、碱性条件下水解制得5种取代吲哚-3-甲酸类化合物,该合成方法操作简单,条件温和,收率较高.     

福司氟康唑杂质——2-(2,4-二氟苯基)-1-(1H-1,2,4-三氮唑-1-基)-3-(4H-1,2,4-三氮唑-4-基)-2-丙基磷酸二氢酯的合成

以1,3-二氟苯为起始原料,依次经傅－克酰基化,1H-三氮唑取代,环氧化,胺解,4H-三氮唑环化,磷酸酯化和钯碳加氢反应等7步反应合成了福司氟康唑的主要杂质--2-(2,4-二氟苯基-1-(1H-1,2,4-三氮唑-1-基)-3-(4H-1,2,4-三氮唑-4-基)-2-丙基磷酸二氢酯,纯度98%,总收率7.8%,其结构经¹H NMR确证。     

阿法替尼的合成工艺改进

以2-氨基-4-氯苯甲酸为原料,经环合、硝化、氯代和胺化后,采用一锅两步法制得关键中间体4-［(3-氯-4-氟苯基)氨基］-6-硝基-7-［(S)-四氢呋喃-3-基氧基]-喹唑啉(4); 4依次经还原、酰胺化、HWE反应合成阿法替尼,总收率55.7%,含量98%,其结构经¹H NMR和LC-MS确证。     

泰地唑胺的合成工艺改进

以4-溴-3-氟苯胺为原料,用氯甲酸苄酯保护氨基后,采用一锅两步法制得关键中间体--N-苄氧羰基-3-氟-4-［2-(2-甲基四唑-5-基)吡啶-5-基］苯胺（6）; 6在二异丙基氨基锂作用下与(R)-丁酸缩水甘油酯经环合反应合成了泰地唑胺,总收率53.2%,含量98.5%,其结构经¹H NMR和LC-MS确证。     

The first complete identification of a diastereomeric catalyst-substrate (alkoxide) species in an enantioselective ketone hydrogenation. Mechanistic investigations

The enantioselective hydrogenations of the dialkyl 3,3-dimethyloxaloacetate ketone substrates (2, 3, and 4; alkyl = Me, (i)Pr, and (t)Bu, respectively) were catalyzed by [Ru((R)-BINAP)(H)(MeCN)(n)(sol)(3-n)](BF(4)) (1, n = 0-3, sol = THF or MeOH, (R)-BINAP = (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) in up to 82% ee (R). Reaction of the active catalyst 1 with 1 equiv of substrate (2, 3, or 4) in THF or MeOH solution formed the diastereomeric catalyst-alkoxide complexes [Ru((R)-BINAP)(MeCN)(OCH(CO(2)R)-(C(CH(3))(2)CO(2)R))](BF(4)) (5/6 R = Me, 8/9 R = (i)Pr, and 10 R = (t)Bu, respectively) via hydride addition to the ketone carbonyl carbon and ruthenium addition to oxygen. The absolute configurations at the alkoxide groups ((R)- for the major diastereomers 5, 8, and 10) were determined via cleavage of the ruthenium-alkoxide bond with 1 equiv of HBF(4).OEt(2). The solution structures of the major diastereomer catalyst-alkoxide complexes (5, 8, and 10) were unambiguously determined by variable-temperature NMR spectroscopy. The major diastereomers (5, 8, and 10) had the same absolute configuration as the major product enantiomers from the catalytic hydrogenation of 2, 3, and 4 with 1 as catalyst. The ratio of major to minor alkoxide diastereomers was similar to the ee of the catalytic hydrogenation. The catalyst-alkoxide complexes are formed at temperatures as low as -30 degrees C with no other precursors or intermediates observed by NMR showing that ketone-hydride insertion is likely not the turnover limiting step of the catalytic hydrogenation. Results from the stoichiometric hydrogenolysis of 5/6, 8/9, or 10 indicate that their formation is rapid and only partially reversible prior to the irreversible hydrogenolysis of the ruthenium-oxygen bond. The stereoselectivities of the formation and hydrogenolysis of 5/6, 8/9, and 10 sum up to equal the stereoselectivities of the respective catalytic hydrogenations of 2, 3, and 4. The rates of the hydrogenolysis were consistent with these diastereomers being true catalytic intermediates.     

Synthesis of nitro-substituted 4-methyl-2,3-dihydro- and 2,3,4,5-tetrahydro-1H-1,5-benzo-2-diazepinones

The nitration of 4-methyl-2,3-dihydro-1H-1,5-benzo-2-diazepinone gives the 7 nitro derivative. The 8-nitro isomer was obtained from 4-nitro-1,2-phenylenediamine. The catalytic hydrogenation of the nitrobenzodiazepinones gives the 7- and 8-amino derivatives. The nitrobenzodiazepinones exist in the enol form in alkaline media.     

A three-step synthesis of 4-(4-iodo-1H-pyrazol-1-yl)piperidine, a key intermediate in the synthesis of Crizotinib

4-(4-Iodo-1H-pyrazol-1-yl)piperidine is a key intermediate in the synthesis of Crizotinib. We report a robust three-step synthesis that has successfully delivered multi-kilogram quantities of the key intermediate. The process includes nucleophilic aromatic substitution of 4-chloropyridine with pyrazole, followed by hydrogenation of the pyridine moiety and subsequent iodination of the pyrazole which all required optimization to ensure successful scale-up.     

Phosphine-Catalyzed [4+1] Cycloadditions of Allenes with Methyl Ketimines,Enamines, and a Primary Amine

Unprecedented phosphine-catalyzed [4+1] cycloadditions of allenyl imides have been discovered using various N-based substrates including methyl ketimines, enamines, and a primary amine. These transformations provide a one-pot access to cyclopentenoyl enamines and imines, or (chiral) γ-lactams through two geminal C−C bond or two C−N bond formations, respectively. Several P-based key intermediates including a 1,4-(bis)electrophilic α,β-unsaturated ketenyl phosphonium species have been detected by ³¹P NMR and HRMS analyses, which shed light on the postulated catalytic cycle. The synthetic utility of this new chemistry has been demonstrated through a gram-scaling up of the catalytic reaction as well as regioselective hydrogenation and double condensation to form cyclopentanoyl enamines and fused pyrazole building blocks, respectively.     

常山酮中间体的合成工艺改进

以2-乙酰呋喃为起始原料,经扩环、甲基化、去质子化、亲核加成、缩酮化、Rh/C催化氢化及水解等反应合成了常山酮中间体--1-(3-甲氧基哌啶-2-基)丙酮,总收率40.2%,其结构经¹H NMR和ESI-MS确证。     

Synthesis,characterization and catalytic activity of Rh (PPh3)2 (en)Cl complex

Ethylenediamine bis(triphenylphosphine) monochlororhodium has been prepared by the interaction of Wilkinson's catalyst and ethylenediamine in benzene. The complex has been isolated and characterized by conventional and spectroscopic methods. The catalytic activity of the complex was investigated for the hydrogenation of 1-octene as a model reaction at a hydrogen pressure of 1 atmosphere (101 kPa) using methanol as a solvent. The influence of various factors such as catalyst, substrate concentrations and temperature have been studied. The hydrido complex has been identified as an intermediate product by IR and NMR studies. The experimental data are in accordance with a rate expression of the form: .     

苯嘧磺草胺的新合成方法

设计并完成苯嘧磺草胺及其关键中间体的合成工艺路线,使其具备工业化生产潜力。采用氯磺酰异氰酸酯、叔丁醇、N-甲基-N-异丙基胺等作为起始原料,制备了关键中间体N-甲基-N-异丙基氨基磺酰胺,3步反应总收率~75%;采用2-氯-4-氟苯甲酸为原料,经过硝化、酰氯化、缩合、催化氢化还原、氨酯交换、甲基化反应制备了苯嘧磺草胺。共计8步反应制备得到苯嘧磺草胺,总收率为48.6%,纯度98.6%,产物与中间体经NMR、MS等进行了表征。