【作者】 柏一慧；

【导师】 陈新志；

【作者基本信息】 浙江大学 ， 化学工程与技术， 2007， 博士

【摘要】 本文对奈必洛尔的全合成进行了研究。奈必洛尔（Nebivolol）是兼有心血管扩张作用的新型降压药物。本文综述了奈必洛尔的合成策略，在现有的奈必洛尔的合成方法中，以杨森（Janssen）公司开发的色满酸拆分合成法最易工业化，但该方法亦由于其合成方法有限，成本较高使得奈必洛尔的推广受到了限制。本文以优化工业化条件为目标，对杨森公司方法进行了改进，对该合成体系中关键中间体的合成以及奈必洛尔全合成方法进行了研究，具体内容和结果如下：1)采用4-氟苯酚为原料自行合成了关键中间体6-氟-3，4-二氢-2H-1-苯并吡哺-2-甲酸6，该中间体在杨森公司方法中为原料。顺丁烯二酸酐法：以4-氟苯酚为原料，经酚羟基甲基化、与顺丁烯二酸酐发生Friedel-Crafts酰基化反应、在碱性条件下Michael加成环合，合成了6-氟-4-氧代-3，4-二氢-2H-1-苯并吡喃-2-甲酸，再经催化氢化得到6。研究了各步反应条件，得到了较合适的反应条件。环合为关键步骤，其较合适的条件为以10％NaHCO₃为催化剂，回流温度，反应15min。该方法共4步，总收率67.0％。乙二酸二乙酯法：以4-氟苯酚为起始原料，经酯化、Fries重排、环化、氢化等6个步骤得到目标产物，总收率27.3％。4-氟苯酚与乙酸酐酯化得4-氟苯基乙酸酯35，35在三氯化铝催化下Fries重排得4-氟-2-乙酰基苯酚36，二步总收率61.0％；36与酰化试剂乙二酸二乙酯经酰化、环合及碱性水解得到6-氟4-氧代-4H-1-苯并吡喃-2-甲酸34，用一种试剂完成了酰化、环化并引入羧基，三步总收率52.2％；34在乙酸介质中，以10％Pd／C催化加氢得外消旋6-氟-3，4-二氢-2H-1-苯并吡喃-2-甲酸6，产率85.7％。两种方法均具有条件温和、试剂常见易得、易于工业化的特点，其中顺丁烯二酸酐法少量制备更理想，而乙二酸二乙酯法生产环境更友好，本文选用前者作为制备6的方法。2)采用天然拆分试剂脱氢枞胺对外消旋6-氟-3，4-二氢-2H-1-苯并吡喃-2-甲酸进行了拆分。以廉价的松香胺为原料，分离提纯得到纯度为98.8％、光学纯度98.3％的拆分试剂脱氢枞胺，研究了以脱氢枞胺拆分外消旋6的工艺。脱氢枞胺：外消旋6／mol=1∶1形成非对映体酰胺；分别依次选择乙醇、甲醇作为结晶溶剂，分步结晶得到纯非对映异构体酰胺，产率分别为31.3％、30.0％，总收率61.3％；酰胺在酰胺：乙酸：浓盐酸／g=0.15∶2∶1，回流40 h条件下水解分别得到（-）-（R）-6（6a）和（+）-（S）-6（6b），拆分总收率从原方法中的20.1％提高到29.7％，光学纯度均大于97％。首次给出了酰胺的光谱及物理性质并初步研究了6的消旋化，非对映异构体酰胺在KOH催化下于乙二醇中回流可水解得到6的消旋体，并借此对拆分母液进行回收，6的回收率51.6％。该工艺条件相对于杨森方法具有价格更低的拆分试剂、更高的收率以及可循环回收的拆分母液，更适于工业化。3)采用常温、常压条件合成了关键中间体6-氟-3，4-二氢-2H-1-苯并吡喃-2-甲醛8。采用NaBH₄还原混合酸酐法制备得到6-氟-3，4-二氢-2H-1-苯并吡喃-2-甲醇7。酸6，6a和6b与氯甲酸乙酯形成混合酸酐，该混合酸酐无需分离直接经NaBH₄还原即可得到7，（-）-（R）-7（7a）和（+）-（S）-7（7b），产率90％以上。选择无机吸附剂制备得到活性更高、操作更方便、污染少的负载型氧化剂PCC／SiO₂，7，7a和7b在该氧化剂作用下得到醛8，8a和8b，产率80％以上。两步反应均在常温常压下进行，两步总收率达75％以上；反应过程中底物构型保持不变；该氧化反应后处理简单，氧化后残渣可再生处理，所制得的氧化剂对其它醇的氧化也有较好的结果。（原方法采用二异丁基氢化铝直接还原酸，产率50％，该反应还原剂昂贵、不稳定，反应条件苛刻。）4)合成了中间体6-氟-3，4-二氢-2H-1-苯并吡喃-2-环氧乙烷9。采用环氧化试剂（CH₃）₃S⁺I^-代替原方法中的（CH₃）₃SO⁺I^-，分别通过8、8a和8b的环氧化反应合成了外消旋6-氟-3，4-二氢-2H-1-苯并吡喃-2-环氧乙烷（9）、（R，R）-9（9a）和（S，R）-9（9b），产率分别为99.5％，20.5％，38.8％。5)制备得到奈必洛尔。9a与苄胺反应得到（R，R）-α-[（苯甲基）氨基]亚甲基]-6-氟-3，4-二氢-2H-1-苯并吡喃-2-甲醇10a，10a和9b经取代反应将两边的苯并吡喃环连接起来，再经氢化脱苄最终得到终产物。所有关键中间体及目标产物的相关光谱图均给出，表明产物结构正确。更多还原

【Abstract】 In this thesis, the total synthesis of Nebivolol was stdudied.Nebivolol is a new kind of drug for lowering blood pressure with additional effect for dilatating cardiovasculars. There are several filed synthetic methods for Nebivolol, among which the one invented by Janssen Pharmaceutica Institution via the optical resolution of a chroman carboxylic acid is the most suitable one to be industrialized. But it is still restricted by synthetic routes and high cost ,which makes Nebivolol difficult to be widely used. In this thesis, the synthesis of the main intermediates and the whole synthetic system of Nebivolol were studied, aiming to optimize the industrialized conditions . Following are the contents and results:1) The key intermediate 6-fluro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid （6）, which was the raw material in the Janssen’s, was synthesized from 4-fluoro phenol as follows:Maleic anhydride method: 6-fluoro-4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid （5） was synthesized from 4-fluoro phenol, via methylization, Friedel-Crafts reaction with Maleic anhydride and then Michael addition at basic condition to be cyclized . 5 was hydrogenolysised in catalyst to give 6 . Conditions were studied, and the optimized one was achieved. The key step was cyclization, whose yield was found best in condition of 10% NaHCO₃ catalyzing and refluxing for 15 min. The yield overall was 67.0%.Diethyl oxalate method: It involves 6 steps including esterification, rearrangment, acylation, cyclization, hydrolyzation and hydrogenation with an overall yield of 27.3%. First, 4-fluoro phenol（2） was esterified with acetic anhydride to give 4-fluorophenyl acetate（3）, then 3 was rearranged in the presence of anhydrous AlCl₃ to afford 4-fluoro-2-acetyl phenol （35） , these two steps yielded 61.0%. 35 was transformed into 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid （34） bytreatment with diethyloxalate via acylation, cyclization and then hydrolyzation, using a single reagent to finish three steps. The title product, 6 was finally obtained by reducing 34 with hydrogen and 10% Pd/C in acetic acid.Both the two methods upon have the potential perspective to be industrialized due to the mild conditions and readily available reagents. The former is better when in small scale, and the latter will have a better plant environment . In this thesis, the former was selected.2) A practical process for the resolution of racemic 6 was studied as follows: （+）-dehydroabietylamine, the chiral resolving reagent, was separated from rosin amine with a purity of 98.8% and the optical purity 98.3%. Dehydroabietylamine and racemic 6 in ratio of 1 :l（mol） were used to form the diastereomeric amides; the pure diastereomer 40a was got from ethanol by fractional crystallization in a yield of 31.3%; and 40b from methanol in 30.0% , totally yielding 61.3%; the optical acid 6a was got by hydrolysis of 40a under a 40-h-refluxing with amide:acetic acid: concentrated HCl/g=0.15:2:1, and so was 6b by hydrolysis of 40b. The total yield of resolution was raised from 20.1% to 29.7% . For a first time, the spectral and physical properties of the diastereomers were given, and the racemization of 6 was studied. The diastereomeric amides were found hydrolyzed to give racemic 6 in boiling glycol with KOH. Based on this, 6 was recovered from the mother liquor in resolution in a yield of 51.6%. This resolving process is more suitable to be industrialized with easier gained chiral reagent, higher yield and recyclable mother liquor.3) The key intermediate 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehy-de （8） was prepared at room temperature and normal pressure as follows:6 was reacted with ClCOOCH₂CH₃ to afford a mixed anhydride, and then the anhydride was directly used without purification to give the acohol 7 via NaBH₄, the yield of 7 was 90.2%; and so was 6a to 7a and 6b to 7b. A coated PCC oxidant was invented by a selected inorganic absorber with PCC, which was more reactive andconvenient to be used than uncoated one. 7 was oxidized to give 8 by this oxidant with a yield of more than 80%, and so was 7a to 8a and 7b to 8b. The two steps were both done at room temperature and normal pressure without any changes in the stereo structures, totally yield to 75%. （Janssen’s method: expensive and unstable DIBAL-H as reductant, -78℃, yielding 50%.）4) Racemic 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran （9） was prepared by 8, via dimethylsulfonium methylide instead of dimethyloxosulfonium methylide, yielding 99.5%; and so was （R,R）-9 （9a） by 8a, yielding 20.5%; and （S,R）-9 （9b） by 8b, yielding 38.8%.5) （S,R,R,R）-Nebivolol was got as follows:9a was reacted with benzylamine to give （R,R）-6-fluoro-3,4-dihydro -α-[[（phenylmethyl）amino]methyl]-2H-1-benzopyran-2-methanol （10a）, 10a was coupled with 9b to give 42, and then 42 was desamidizated via hydrogenlysis to give the goal product.The corresponding spectra of all the main intermediates and the goal product were given, which identified the structures of the products.更多还原