奈必洛尔全合成研究
|
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％NaHCO_3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NaBH_4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NaBH_4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／SiO_2，7，7a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(CH_3)_3S~+I~-代替原方法中的(CH_3)_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。
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% NaHCO_3 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 AlCl_3 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) by
treatment 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 ClCOOCH_2CH_3 to afford a mixed anhydride, and then the anhydride was directly used without purification to give the acohol 7 via NaBH_4, 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 and
convenient 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.
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％NaHCO_3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NaBH_4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NaBH_4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／SiO_2，7，7a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(CH_3)_3S~+I~-代替原方法中的(CH_3)_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。
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% NaHCO_3 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 AlCl_3 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) by
treatment 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 ClCOOCH_2CH_3 to afford a mixed anhydride, and then the anhydride was directly used without purification to give the acohol 7 via NaBH_4, 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 and
convenient 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.
引文
[1] 张青山，李爱英，郭炳南．新型降血压药奈必洛尔研究进展[J]．中国新药杂志，2003，12(7)：517-520．
[2] 王吉云．Nebivolol—具有调节NO释放特点的更高选择性β_1受体阻断剂[J]．中国医药导刊，2002，4(3)：200．
[3] 刘增娟，郝哲，王国胜．β受体阻滞剂[J]．医学理论与实践，2002，15(10)：1218-1219．
[4] 马虹，刘志军．β受体阻滞剂在治疗高血压病中的地位[J]．中华心血管病杂志，2006，34(7)：660-661．
[5] 刘国树．β受体阻滞剂及其治疗高血压现状[J]．中国药物应用与监测，2005，(1)：11-13．
[6] 苏哲坦．新一代β阻滞剂的代表—Nebivolol[J]．心血管病学进展，2000，21(6)：369-370
[7] Sacco G., Evangelista S., Criscuoli M., Goso C., Bigioni M., Binaschi M., Manzini S. and Maggi C. A.. Involvement of nitric oxide in both central and peripheral haemodynamic effect of d/1-nebivolol and its enantiomers in rats [J]. European Journal of Pharmacology,2005,511:167-174.
[8] Brehrn B. R., Wolf S. C., Gorner S., Buck-Muller N. and Risler T.. Effect of nebivolol on left ventricular function in patients with chronic heart failure: a pilot study[J]. The European Journal of Heart Failure, 2002,4:757-763.
[9] Fountoulaki K.. Effect of Nebivolol versus telmisartan on LVM[J]. The American Journal of Hypertension,2005, 18(2): 171-177.
[10] Corninacini L.. Nebivolol and its 4-keto derivative increase nitric oxide in endothelial cells by reducing its oxidative inactivation[J]. Journal of the American College of Cardiology,2003, 42(10): 1838-1844.
[11] Bundkirchen A., Nguyen Q., Brixius K., B61ck B., Mehlhom U. and Schwinger R. H. G.. Lack of inverse agonistic activity of nebivolol, its D-and L-enantiomers and of in vivo metabolized nebivolol in human myocardium[J]. European Journal of Pharmacology, 2003,476: 97-105.
[12] Galetta F., Franzoni F., Magagna A., Femia F.R., Pentimone F., G. Santoro and A. Carpi. Effect of nebivolol on QT dispersion in hypertensive patients with left ventricular hypertrophy[J]. Biomedicine & Pharmacotherapy, 2005,59:15-19.
[13] Bundldrchen A., Brixius K., Bolck B., Nguyen Q. and Schwinger R. H. G.. β_1-adrenoceptor selectivity of nebivolol and bisoprolol. A comparison of [~3H]CGP 12.177 and [~(125)I]iodocyanopindolol binding studies[J]. European Journal of Pharmacology, 2003,460:19-26.
[14] Kamp O., Sieswerda G. T. and Visser C. A.. Comparison of effects on systolic and diastolic left ventricular function of Nebivolol versus Atenotol in patients with uncomplicated essential hypertension[J]. The American Journal of Cardiology,2003, 92(3):344-348.
[15] 张青山，李爱英．(S，R，R，R)-奈必洛尔合成路线图解[J]．中国医药工业杂志，2003，34(7)：34-36．
[16] Johannes C. W., Visser M. S., Weatherhead G. S., Johannes C. W., Visser M. S., Weatherhead G. S. and Hoveyda A. H..Zr-catalyzed kinetic resolution of allylic ethers and Mo-catalyzed chromene formation in synthesis. Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol [J]. Journal of American Chemistry Society,1998, 120(33): 8340-8347.
[17] March J．著，陶慎熹译．高等有机化学反应、机理和结构(下册)[M]．第一版，高等教育出版社，1990．183-185．
[18] 石德清，黄文芳，丁明武，吴田捷．金属化的苄叉基膦叶立德与羰基化合物的Wittig反应的立体化学(英文)[J]．合成化学，2003，11：507-508．
[19] Tsuji J.. Synthetic application of the Palladium-catalysed oxidation of olefins to ketones [J]. Synthesis, 1984, 369.
[20] 恽魁宏．有机化学[M]．第二版，北京：高等教育出版社，2001．343-345．
[21] Chandrasekhar S. and Reddy M. V.. Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol[J]. Tetrahedron, 2000, 56(34): 6339-6344.
[22] Dess D. B. and Martin J. C.. A useful 12-I-5 triacetoxyperiodinane (the Dess-Martin eriodinane or the selective oxidation of primary or secondary alcohols and a variety of related 12-I-5 species [J]. J. Am. Chem. Soc., 1991, 113, 7277-7287.
[23] Sharpless K. B., Amberg W., Bennani Y. L., Crispino G. A., Hartung J., Jeong K.S., Kwong H. L., Morikawa K. and Wang Zh. M.. The osmium-catalyzed asymmetric dihydroxylation: a new ligand class and a process improvement[J]. J. Org. Chem., 1992, 57(10): 2768-2771.
[24] Fukuyama T., Cheung M., Jow C. K., Hidai Y. and Kan T.. 2,4-Dinitrobenzenesulfonamides: A simple and practical method for the preparation of a variety of secondary amines and diamines[J]. Tetrahedron Lett., 1997, 38: 5831-5834.
[25] Fukuyama T., Jow C. K. and Cheung M.. 2- and 4-Nitrobenzenesulfonamides: Exceptionally versatile means for preparation of secondary amines and protection of amines[J]. Tetrahedron Lett., 1995, 36: 6373-6374.
[26] 陈鹏，陈钢，张开元，李鹏．盐酸奈必洛尔的合成[J]．中国医药工业杂志，2006，37(5)：289-292．
[27] 北京师范大学，华中师范大学，南京师范大学无机化学教研室编．无机化学(上册)[M]．第二版，高等教育出版社，1982．423-424．
[28] 陈玉清，刘爱民．氰化物中枢神经毒性与钙稳态失调的关系[J]．劳动医学，2001，18(6)：357-358．
[29] Xhonneux R. M. and Van Lommen G. R. E.. Agents for lowering the blood pressure [P]. EP334429, 1989.
[30] Kurono M. and Kondo Y.. Hydantion derivatives for treating complications of diabetes [P]. EP0264586, 1989
[31] Van Lommen G. R. E. and De Bruyn M. F. L. Derivatives of 2,2'-iminobisethanol [P]. EP0145067, 1985.
[32] Loiodice F., Longo A., Bianco P. and Tortorella V.. 6-chloro-2,3-dihydro-4H-1-benzopyran carboxylic acids: synthesis, optical resolution and absolute configuration[J]. Tetrahedron: Asmmetry, 1995, 6 (4): 1001-1011.
[33] Kurono M. and Miura K.. 3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid derivative having optical activity and production thereof [P]. JP 63230373, 1988.
[34] Kurono M. and Kondo Y.. Process for the preparation of optically active 4-oxo-1-benzopyran-2-carboxylic acid derivatives and intermediates thereof [P]. EP 331078, 1989.
[35] Kurono M., Bama Y., and Unno R.. Manufacture of optically active (S)-4-oxochroman-2-carboxylic acid derivatives [P]. JP 6092956, 1994. [46]
[36] Koizu M. and Saito Y.. Preparation of 6-fluoro-4-chromanone-2-carboxylic acid as intermediate for aldose reductase inhibitors [P]. JP 2218674, 1990.
[37] Recanatini M., Bisi A., Cavalli A., Belluti F., Gobbi S., Rampa A., Valenti P., Palzer M., Palusczak A. and Hartmann R. W.. A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17-hydroxylase/C7, 20-lyaze[J]. J. Med. Chem., 2001, 44(5): 672-680.
[38] 杨运旭，王乃兴，盛瑞隆，张军平，于安光，汪武卫．6-氟-色满-2-羧酸的合成及其(R)-，(S)-光学异构体的拆分研究[J]．有机化学，2005，25(2)： 201-203．
[39] 孙宁玲，徐成冰．今日高血压[M]．第一版，北京：中国医药科技出版社，2000．302-306．
[40] 袁开基，夏鹏．有机杂环化学(基本原理与合成药)[M]．北京：人民卫生出版社，1984．201-214．
[41] 张惠斌，爱起利，黄文龙．苯并吡喃酯类化合物的合成及其生物活性．中国药物化学杂志，2000，10(3)：157-160．
[42] 孙宏斌，华维一，陈玲，彭司勋，王霆，刘国卿．钾通道启开剂研究‘Ⅰ-反式-4-氨基-3-羟基-3，4-二氢-2，2二甲基-2’-氢-1-苯并吡喃类化合物的合成及其心血管活性．高等学校化学学报，1997，18(5)：730-733．
[43] 张伟，徐杰，孙志强．芳香族含氟化合物的特性及合成[J]．精细与专用化学品，2005，13(16)：1-4
[44] 余慧，周琪．含氟有机化合物的生态迁移及转化[J]．四川环境，2005，24(4)，54-58．
[45] 陈德化，黄建华．含氟芳香、杂环化合物的开发与进展[J]．有机氟工业，1995，(1)：12-26．
[46] 张伟，徐杰，孙志强．芳香族含氟化合物的特性及合成[J]．精细与专用化学品，2005，13(16)：1-4．
[47] 梁世懿，成本诚．高等有机化学结构反应合成 [M]．第一版，高等教育出版社，1993．401-402．
[48] 梁世懿，成本诚．高等有机化学结构反应合成 [M]．第一版，高等教育出版社，1993．281-286．
[49] Kohichi F., Masafumi M. and Junko K.. Process for preparing optically active carboxylic acid derivative[P]. WO 022543, 2002.
[50] 叶秀林．立体化学[M]．北京：北京大学出版社，1999．109．
[51] 黄锁义，王麟生，赵海峰，王昭松．手性氨基酸的制备及生物活性研究进展[J]．化学研究与应用，2003，15(6)：758-762．
[52] 陈良，乐美卿．立体化学基础[M]．北京：化学化工出版社，1992．
[53] 任国宾，詹予忠，陈宜俍，郭士岭，徐军，卫东燕．对羟基苯甘氨酸的合成及拆分技术进展[J]．精细化工中间体，2002，32(1)：8-12．
[54] 黄蓓，杨立荣，吴坚平．手性拆分技术的工业应用[J]．化工进展，2002，21(6)：375-380．
[55] 尹国，刘振华，曾姗姗，朱国洪．手性异构体拆分方法的研究进展[J]．中国药物化学杂志，2001，11(1)：57-62．
[56] 胡晓燕，孟宪兴，刘丽秀．外消旋混合物的光学拆分—优先结晶法[J]．山东化工，2000，29(3)：18-20．
[57] 李俊，蔡水洪．手性化合物的拆分研究[J]．化学世界，2001，5：11．
[58] 徐诗伟，徐清．2-芳基丙酸类药物的拆分研究进展[J]．微生物学通报，1995，22(2)：95-101．
[59] 郑卫．手性技术在抗生素等医药工业中的应用[J]．中国抗生素杂志，2000，25(4)：241-249．
[60] 王道林，牛之猛，刘华东．光学活性拆分剂脱氢枞胺的制备性纯化及其表征[J]．北京理工大学学报，2004，24(4)：357-359．
[61] Gottstein W.J.. racemic momocarboxylic acid resolution using dehydeoabietylamine[P]. US 3454626, 1969
[62] Lee C. C.. Penicillin sales of amines derived from rosin [P]. US 2585436, 1952.
[63] Bellucci G., Berti G., Borraccini A. and Macchia F.. The preparation of optically active chlorofluoroacetic acid and chlorofluoroethanol[J]. Tetrahedron, 1969, 25(15): 2979-2985.
[64] 信息：脱氢枞胺及其醋酸盐中试与应用研究通过省级鉴定[J]．精细与专用化学品，1998，7(11)：7．
[65] 梁梦兰，叶建峰．松香衍生物的季铵盐阳离子表面活性剂的合成与性能测定[J]．化学世界，2000，41(3)：138-141．
[66] 周永红，谢晖，宋湛谦．松香甘油酯聚氧乙烯醚的合成及其性能[J]．南京 林业大学学报，2003，27(2)：25-28．
[67] 何曼，陆进华，沈德渊．脱氢枞胺键合交联聚苯乙烯树脂的制法和应用[J]．化工时刊，2002，12：25-29．
[68] 王延，宋湛谦．N-脱氢枞基-N，N-二羟乙基季铵盐类阳离子表面活性剂合成及性质研究[J]．林产业化学与工业，1997，17(1)：6-9．
[69] Menger F. M. and Smith J. H.. Mechanism of ester aminolysis in aprotic solvents[J]. American Chemical Society, 1972, 92(5): 3824-3829.
[70] Masayoshi M., Tadashi K., Kazuhiko H. and Gohfu S.. Metheod for producing an optically active 2,2-dimethylcyclopropanecarboxylic acid[P]. EP 0093511, 1985.
[71] 李媛，张萍，董玉环，周蕾，王亚英．羧酸的还原方法[J]．化学通报，2002，(7)：452-457．
[72] Burgstahler A. W., Worden L. R. and Lewis T. B.. Direct Reduction of Carboxylic Acids to Aldehydes by Lithium in Ethylamine [J]. J. Org. Chem., 1963, 28(10): 2918-2919.
[73] Corriu R. J. P., Lanneau G. F. and Perrot M.. The one-pot conversion of carboxylic acids to aldehydes via activated silyl carboxylates. [J]. Tetrahed. Lett., 1987, 28(34): 3941-3944.
[74] Carey F. A., Sundberg R.J.著，王积涛译．高等有机化学(B卷)[M]．高等教育出版社，1986，101-102．
[75] 李述文，范如霖编译．实用有机化学手册[M]．第一版，上海科学技术出版社，1981，285-287．
[76] McGear y R. P.. Facile and chemoselective reduction of carboxylic acids to alcohols using BOP reagent and sodium borohydride [J]. Tetrahed. Lett., 1998, 39(20): 3319-3322.
[77] Marini A. E., M. Roumestant L., Viallefont P., Razafindramboa D., Bonato M. and Follet M.. Synthesis of enantiomerically pure β- and γ-amino acids from aspartic and glutamic acid derivatives [J]. Synthesis, 1992, 11: 1104-1108.
[78] Finholt A. E., Bond A. C. and J. Schlesinger H. I.. Lithium aluminum hydride and lithium gallium hydride and some of their application in organic and inorganic chemistry[J]. J. Am. Chem. Soc., 1947, 69(5): 1199-1203.
[79] 车荣睿．硼氢化钠在有机合成中的应用[J]．化学试剂，1986，8(2)：94-96．
[80] Mariappan P. and Muniappan T.. Methods of enhancement of reactivity and selectivity of sodium borohydride for applications in organic synthesis[J]. J. Organomet. Chem., 2000, 609: 137-151.
[81] 王葆仁．有机合成反应(上册)[M]．北京：科学出版社，1982．139，15．
[82] Dalla V., Catteau J. P. and Pale P.. Mechanistic rationale for the NaBH_4 reduction of α-keto ester[J]. Tetrahedron Lett., 1999, 40: 51932-5196.
[83] 杨红文．三氧化铬二吡啶、三氧化铬吡啶盐酸盐—两种有效的专用氧化剂[J]．化学研究与应用，2000，12(1)：74-76．
[84] Tietze L.F., Eicher T．著．张进琪译．精细有机合成—有机化学实践中的反应与合成[M]．第一版，南京大学出版社，1990．69-70．
[85] 邢其毅，徐瑞秋，周政，裴伟伟．基础有机化学[M]．第二版，高等教育出版社，1992．1103-1105．
[86] 巨勇，赵国辉，席婵娟．有机合成化学与路线设计[M]．第一版，清华大学出版社，1992．119-122
[87] 周云．选择性氧化剂铬(VI)在有机合成中的应用[J]．昭通师范高等专科学校学报，2002，24(5)：29-31．
[88] L.F.Tietze, T.Eicher著．张进琪译．精细有机合成—有机化学实践中的反应与合成[M]．第一版，南京大学出版社，1990．75．
[89] 刘良先．Corey氧化剂及其在选择性氧化中的应用[J]．化学通报，1992，12(4)：17-25．
[90] Corey E. J. and William S. J.. Pyridinium chlorochromate, An efficient reagent for oxidation of primary and secondary alcohols to carbonyl compounds[J]. Tetrahedron Lette., 1975, 16(31): 2647-2650.
[91] Core E. J. and Suggs J. W.. Oxidation of alcohols effected by pyridinium chlorochromate [J]. Tetrahedron Lett., 1975, 16 (31): 2647-2650.
[92] Core E. J. and Schmidt G.. Useful procedures for the oxidation of alcohols involving pyridinium dichromate in aprotic media [J]. Tetrahedron Lett., 1979, 20 (5): 399.
[93] Yamaza K. S. and Yamaza K. Y.. Nickel catalyzed oxidation of allylic alcohols with K_2S_2O_8 [J]. Chem. Lett., 1989 (8): 1361-1364.
[94] Corey E. J., Gilman J. N. W. and Gamen B. E.. New method for the oxidation of aldehydes to carboxylic acids and esters [J]. J. Am. Chem. Soc., 1968, 90: 5616-5617.
[95] Col lins J. C., Hess W. W. and Frank F. J.. Dipyridine-chrominium (Ⅵ) oxide oxidation of alcohols in dichloromethane [J]. Tetrahedron Lett., 1968, 9(30): 3363-3366.
[96] 贾彦兴，吴滨，涂永强．手性3，7-二甲基-5，6-二羟基-辛-7-烯醛中间体的合成[J]．高等学校化学学报，2001，22(4)：584-586．
[97] Reetz M. T., Drewes M. W. and Schwicksrdi R.. Preparation of enantiomerical pure α-N, N-dibenzylamino aldehydes: S-2-(N, N-dibenzylamino)-3-phenylpropanal [J]. Organic Syntheses. Vol. 10, p.256.
[98] Reetz M. T., Drewes M. W. and Schwicksrdi R.. Preparation of enantiomerical pure α-N, N-dibenzylamino aldehydes: S-2-(N, N-dibenzylamino)-3-phenylpropanal [J]. Organic Syntheses. Vol. 76, p. 110.
[99] 何宗耀，郭勇．氧化法制备(E)-柠檬醛[J]．华南理工大学学报(自然科学版) 2000，28(4)：63-65．
[100] 张贵生．氯铬酸甲铵硅胶负载型氧化剂的制备及其对醇的氧化研究[J]．有机化学，1997，17(5)：450-453．
[101] Cainelli G., Cardillo G., Orena M. and Sandri S.. Polymer supported reagents. Chromic acid on anion exchange resins. A simple and practical oxidation of alcohols to aldehydes and ketones[J]. J. Am. Chem. Soc., 1976, 98 (21): 6737-6738.
[102] Frechet J. M. J., Darling P. and Farrall M. J.. Poly(vinylpyridinium dichromate): an inexpensive recyclable polymeric reagent[J]. J. Org. Chem., 1981, 46 (8): 1728-1730.
[103] 陈振初，黄宪．重铬酸季铵盐聚合物试剂的制备及其在醇氧化中的应用[J]．化学试剂，1980，2(5)：24-25．
[104] 王央贡，陈家威，杨细香．铬酸／硅胶受载试剂的制备及醇氧化的研究[J]．化学试剂，1985，7(3)：133-135．
[105] 逯兆庆，寻知磊．活性炭处理含铬废水的方法[J]．电镀与涂饰，2002，21(5)：42-44．
[106] 李英杰，纪智玲，候凤，李茂林，王红心．活性炭吸附法处理含铬废水的研究[J]．沈阳化工学院学报，2005，19(3)：184-187．
[107] 王清，江丽，陈志传，陈文衡，张迅．高浓度含铬废水的综合利用[J]．环境科学与技术，2003，26(5)：38-39．
[108] Mohrmann K. H., Reiser W., Linke S. W. and Rudolf Z.. Process for the preparation of oxiranes[P]. US 4898954, 1990.
[109] Jones R. V. H. and Simpson E. S. C.. Process for preparing epoxides from carbonyl using sulphonium or sulphoxonium ylides and intermediates useful therein[P]. US 5750740, 1998.
[110] Forrester J., Jones R. V. H. and Preston P. N. Simple, inexpensive synthesis of oxiranes from carbonyl compounds. Generation of sulfonium ylides from the ternary system methanol-sulfuric acid-dimethyl sulfide[J]. J. Chem. Soc. Perkin Trans., 1993, 115: 1937-1940.
[111] Rao A. S., Pakniker S. K., Kitane J. G.. Recent advances in the preparation and synthetic applications of oxiranes. [J]. Tetrahedron, 1983, 39(14): 2323-2361.
[112] Mohrmann K. H., Reiser W., Linke S. W. and Zerbes R.. Preparation of oxiranes[P]. US 4992565, 1991.
[113] Organic Syntheses, Coll. Vol. 5, p.755 (1973); Vol. 49, p.78 (1969).
[114] Bernard M．著．吴范宏译．高等有机化学反应和机理[M]．高等教育出版社，2005．398-419．
[115] Rosenberger M. and Mcdougal P., Saucy G.. New approaches to the synthesis of canthaxanthin[J]. Pure and appl. Chem., 1979, 55: 871-876.
[116] Volker F. and Driessen H. E.. Methylization by sulfonium ylides [J]. Tetrahedron lett., 1962, 15: 661-662.
[117] Othmer K.. Encyclopedia of Chemical Technology [M]. 3rd ed, 1983. 233-235.
[118] Marbet R.. Epoxides[P]. Swiss 614201, 1979.
[119] Rosenberger M.. Ionone epoxide[P]. US 0399856, 1976.
[120] Mosset P. and Gree R.. Trimethylsulfonium methylsulfate, a simple and efficient epoxidizing agent [J]. Synthetic Comm., 1985, 15(8): 749-757.
[121] Corey E. J and M. Chaykovsky. Dimethylsulfoxonium Methylide[J]. J. Am. Chem. Soc., 1962, 84(5): 867-868.
[122] Corey E. J and Chaykovsky M.. Dimethyloxosulfonium Methylide ((CH_3)_2SOCH_2) and Dimethylsulfonium Methylide ((CH_3)_2SCH_2). Formation and Application to Organic Synthesis[J]. J. Am. Chem. Soc., 1965, 87(6): 1353-1364.
[123] Volker F. and Driessen H. E.. Methylization by sulfonium ylides [J]. Tetrahedron lett., 1962, 15: 661-662.
[124] Johnson A. W. and LaCount R. B.. The chemistry of ylids Ⅵ dimethylsulfonium fluorenylide-A Synthesis of epoxides[J]. J. Am. Chem. Soc., 1961, 83(2): 417-423.
[125] Yano Y., Okonogi T. and Sunaga M. Oxiran formation in the base-catalysed reation of long-chain alkyldimethelsulphonium salts and carbonyl compounds in benzene-water[J]. Chem. Commucications, 1973, 7: 527-528.
[126] Britton E. C. and Hansen J. N.. Sulphonium salts[P]. US 2366176, 1942.
[127] Britton E. C. and Hansen J. N.. Sulphonium salts[P]. US 2402016, 1944.
[128] Gaertner V. R.. Sulphonium sulfonates[P]. US 2813898, 1957.
[129] Chistie J.. Sulphonium sulfonates and its use[J]. J. Org. Chem., 1983, 48: 2531-2534.
[130] Byrne B. and Lawter L. M. L.. The preparation of trimethylsulfonium chloride from methyl chloroformate and dimethyl sulfide [J]. Tetrahedron lett., 1986, 27(11): 1233-1236.
[131] Eugene L. and Cranford N. J.. Preparation of sulphonium compounds[P]. US 2252081, 1938.
[132] Nagubandi S.. Process for preparing organo-sulfonium halides [P]. US 4743403, 1988.
[133] Klaus J.. and Nagubandi S.. Process for preparing organo-sulfonium halides [P]. EP 0156177, 1985.
[134] Yoshimine M. and Hatch M. J.. The mechanism of the reaction of aqueous benzyldimethylsulfonium chloride and formaldehyde with sodium hydroxide[J]. J. Am. Chem. Soc., 1967, 89(8): 5831-5838.
[135] March J.. Advanced Organic Chemistry: Reactions Mechanisms and Structure[M]. 1968. 343.
[136] J．马奇．高等有机化学反应、机理和结构(上)[M]．人民教育出版社，1981．76．
[137] 尹冬冬．有机化学 上册[M]．北京师范大学出版社，2003．260-262．
[138] 傅相锴．高等有机化学[M]．高等教育出版社，2003．98-103
[139] 曾昭琼．有机化学[M]．第三版，高等教育出版社，1993．299．
[140] 韩卫荣，欧育湘．不同载体钯催化剂的结构特征及其在笼形叔胺脱N-苄基上的应用[J]．精细化工，2004，21(11)：819-822．
[141] 陈筱金．Pd／C催化剂失活原因分析与改进措施[J]．化学反应工程与工艺，2002，18(3)：275-278．
[142] 邱文革，余永忠．N-苄基的脱去[J]．合成化学，1998，6(1)：34-39．
[143] Tuchalski G., Emmerling E, Groger K., Hansicke A., Nagel T. and Gunter R.. X-ray investigations of nebivolol and its isomers[J]. Journal of Molecular Structure, 2006, 800: 28-44.
[2] 王吉云．Nebivolol—具有调节NO释放特点的更高选择性β_1受体阻断剂[J]．中国医药导刊，2002，4(3)：200．
[3] 刘增娟，郝哲，王国胜．β受体阻滞剂[J]．医学理论与实践，2002，15(10)：1218-1219．
[4] 马虹，刘志军．β受体阻滞剂在治疗高血压病中的地位[J]．中华心血管病杂志，2006，34(7)：660-661．
[5] 刘国树．β受体阻滞剂及其治疗高血压现状[J]．中国药物应用与监测，2005，(1)：11-13．
[6] 苏哲坦．新一代β阻滞剂的代表—Nebivolol[J]．心血管病学进展，2000，21(6)：369-370
[7] Sacco G., Evangelista S., Criscuoli M., Goso C., Bigioni M., Binaschi M., Manzini S. and Maggi C. A.. Involvement of nitric oxide in both central and peripheral haemodynamic effect of d/1-nebivolol and its enantiomers in rats [J]. European Journal of Pharmacology,2005,511:167-174.
[8] Brehrn B. R., Wolf S. C., Gorner S., Buck-Muller N. and Risler T.. Effect of nebivolol on left ventricular function in patients with chronic heart failure: a pilot study[J]. The European Journal of Heart Failure, 2002,4:757-763.
[9] Fountoulaki K.. Effect of Nebivolol versus telmisartan on LVM[J]. The American Journal of Hypertension,2005, 18(2): 171-177.
[10] Corninacini L.. Nebivolol and its 4-keto derivative increase nitric oxide in endothelial cells by reducing its oxidative inactivation[J]. Journal of the American College of Cardiology,2003, 42(10): 1838-1844.
[11] Bundkirchen A., Nguyen Q., Brixius K., B61ck B., Mehlhom U. and Schwinger R. H. G.. Lack of inverse agonistic activity of nebivolol, its D-and L-enantiomers and of in vivo metabolized nebivolol in human myocardium[J]. European Journal of Pharmacology, 2003,476: 97-105.
[12] Galetta F., Franzoni F., Magagna A., Femia F.R., Pentimone F., G. Santoro and A. Carpi. Effect of nebivolol on QT dispersion in hypertensive patients with left ventricular hypertrophy[J]. Biomedicine & Pharmacotherapy, 2005,59:15-19.
[13] Bundldrchen A., Brixius K., Bolck B., Nguyen Q. and Schwinger R. H. G.. β_1-adrenoceptor selectivity of nebivolol and bisoprolol. A comparison of [~3H]CGP 12.177 and [~(125)I]iodocyanopindolol binding studies[J]. European Journal of Pharmacology, 2003,460:19-26.
[14] Kamp O., Sieswerda G. T. and Visser C. A.. Comparison of effects on systolic and diastolic left ventricular function of Nebivolol versus Atenotol in patients with uncomplicated essential hypertension[J]. The American Journal of Cardiology,2003, 92(3):344-348.
[15] 张青山，李爱英．(S，R，R，R)-奈必洛尔合成路线图解[J]．中国医药工业杂志，2003，34(7)：34-36．
[16] Johannes C. W., Visser M. S., Weatherhead G. S., Johannes C. W., Visser M. S., Weatherhead G. S. and Hoveyda A. H..Zr-catalyzed kinetic resolution of allylic ethers and Mo-catalyzed chromene formation in synthesis. Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol [J]. Journal of American Chemistry Society,1998, 120(33): 8340-8347.
[17] March J．著，陶慎熹译．高等有机化学反应、机理和结构(下册)[M]．第一版，高等教育出版社，1990．183-185．
[18] 石德清，黄文芳，丁明武，吴田捷．金属化的苄叉基膦叶立德与羰基化合物的Wittig反应的立体化学(英文)[J]．合成化学，2003，11：507-508．
[19] Tsuji J.. Synthetic application of the Palladium-catalysed oxidation of olefins to ketones [J]. Synthesis, 1984, 369.
[20] 恽魁宏．有机化学[M]．第二版，北京：高等教育出版社，2001．343-345．
[21] Chandrasekhar S. and Reddy M. V.. Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol[J]. Tetrahedron, 2000, 56(34): 6339-6344.
[22] Dess D. B. and Martin J. C.. A useful 12-I-5 triacetoxyperiodinane (the Dess-Martin eriodinane or the selective oxidation of primary or secondary alcohols and a variety of related 12-I-5 species [J]. J. Am. Chem. Soc., 1991, 113, 7277-7287.
[23] Sharpless K. B., Amberg W., Bennani Y. L., Crispino G. A., Hartung J., Jeong K.S., Kwong H. L., Morikawa K. and Wang Zh. M.. The osmium-catalyzed asymmetric dihydroxylation: a new ligand class and a process improvement[J]. J. Org. Chem., 1992, 57(10): 2768-2771.
[24] Fukuyama T., Cheung M., Jow C. K., Hidai Y. and Kan T.. 2,4-Dinitrobenzenesulfonamides: A simple and practical method for the preparation of a variety of secondary amines and diamines[J]. Tetrahedron Lett., 1997, 38: 5831-5834.
[25] Fukuyama T., Jow C. K. and Cheung M.. 2- and 4-Nitrobenzenesulfonamides: Exceptionally versatile means for preparation of secondary amines and protection of amines[J]. Tetrahedron Lett., 1995, 36: 6373-6374.
[26] 陈鹏，陈钢，张开元，李鹏．盐酸奈必洛尔的合成[J]．中国医药工业杂志，2006，37(5)：289-292．
[27] 北京师范大学，华中师范大学，南京师范大学无机化学教研室编．无机化学(上册)[M]．第二版，高等教育出版社，1982．423-424．
[28] 陈玉清，刘爱民．氰化物中枢神经毒性与钙稳态失调的关系[J]．劳动医学，2001，18(6)：357-358．
[29] Xhonneux R. M. and Van Lommen G. R. E.. Agents for lowering the blood pressure [P]. EP334429, 1989.
[30] Kurono M. and Kondo Y.. Hydantion derivatives for treating complications of diabetes [P]. EP0264586, 1989
[31] Van Lommen G. R. E. and De Bruyn M. F. L. Derivatives of 2,2'-iminobisethanol [P]. EP0145067, 1985.
[32] Loiodice F., Longo A., Bianco P. and Tortorella V.. 6-chloro-2,3-dihydro-4H-1-benzopyran carboxylic acids: synthesis, optical resolution and absolute configuration[J]. Tetrahedron: Asmmetry, 1995, 6 (4): 1001-1011.
[33] Kurono M. and Miura K.. 3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid derivative having optical activity and production thereof [P]. JP 63230373, 1988.
[34] Kurono M. and Kondo Y.. Process for the preparation of optically active 4-oxo-1-benzopyran-2-carboxylic acid derivatives and intermediates thereof [P]. EP 331078, 1989.
[35] Kurono M., Bama Y., and Unno R.. Manufacture of optically active (S)-4-oxochroman-2-carboxylic acid derivatives [P]. JP 6092956, 1994. [46]
[36] Koizu M. and Saito Y.. Preparation of 6-fluoro-4-chromanone-2-carboxylic acid as intermediate for aldose reductase inhibitors [P]. JP 2218674, 1990.
[37] Recanatini M., Bisi A., Cavalli A., Belluti F., Gobbi S., Rampa A., Valenti P., Palzer M., Palusczak A. and Hartmann R. W.. A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17-hydroxylase/C7, 20-lyaze[J]. J. Med. Chem., 2001, 44(5): 672-680.
[38] 杨运旭，王乃兴，盛瑞隆，张军平，于安光，汪武卫．6-氟-色满-2-羧酸的合成及其(R)-，(S)-光学异构体的拆分研究[J]．有机化学，2005，25(2)： 201-203．
[39] 孙宁玲，徐成冰．今日高血压[M]．第一版，北京：中国医药科技出版社，2000．302-306．
[40] 袁开基，夏鹏．有机杂环化学(基本原理与合成药)[M]．北京：人民卫生出版社，1984．201-214．
[41] 张惠斌，爱起利，黄文龙．苯并吡喃酯类化合物的合成及其生物活性．中国药物化学杂志，2000，10(3)：157-160．
[42] 孙宏斌，华维一，陈玲，彭司勋，王霆，刘国卿．钾通道启开剂研究‘Ⅰ-反式-4-氨基-3-羟基-3，4-二氢-2，2二甲基-2’-氢-1-苯并吡喃类化合物的合成及其心血管活性．高等学校化学学报，1997，18(5)：730-733．
[43] 张伟，徐杰，孙志强．芳香族含氟化合物的特性及合成[J]．精细与专用化学品，2005，13(16)：1-4
[44] 余慧，周琪．含氟有机化合物的生态迁移及转化[J]．四川环境，2005，24(4)，54-58．
[45] 陈德化，黄建华．含氟芳香、杂环化合物的开发与进展[J]．有机氟工业，1995，(1)：12-26．
[46] 张伟，徐杰，孙志强．芳香族含氟化合物的特性及合成[J]．精细与专用化学品，2005，13(16)：1-4．
[47] 梁世懿，成本诚．高等有机化学结构反应合成 [M]．第一版，高等教育出版社，1993．401-402．
[48] 梁世懿，成本诚．高等有机化学结构反应合成 [M]．第一版，高等教育出版社，1993．281-286．
[49] Kohichi F., Masafumi M. and Junko K.. Process for preparing optically active carboxylic acid derivative[P]. WO 022543, 2002.
[50] 叶秀林．立体化学[M]．北京：北京大学出版社，1999．109．
[51] 黄锁义，王麟生，赵海峰，王昭松．手性氨基酸的制备及生物活性研究进展[J]．化学研究与应用，2003，15(6)：758-762．
[52] 陈良，乐美卿．立体化学基础[M]．北京：化学化工出版社，1992．
[53] 任国宾，詹予忠，陈宜俍，郭士岭，徐军，卫东燕．对羟基苯甘氨酸的合成及拆分技术进展[J]．精细化工中间体，2002，32(1)：8-12．
[54] 黄蓓，杨立荣，吴坚平．手性拆分技术的工业应用[J]．化工进展，2002，21(6)：375-380．
[55] 尹国，刘振华，曾姗姗，朱国洪．手性异构体拆分方法的研究进展[J]．中国药物化学杂志，2001，11(1)：57-62．
[56] 胡晓燕，孟宪兴，刘丽秀．外消旋混合物的光学拆分—优先结晶法[J]．山东化工，2000，29(3)：18-20．
[57] 李俊，蔡水洪．手性化合物的拆分研究[J]．化学世界，2001，5：11．
[58] 徐诗伟，徐清．2-芳基丙酸类药物的拆分研究进展[J]．微生物学通报，1995，22(2)：95-101．
[59] 郑卫．手性技术在抗生素等医药工业中的应用[J]．中国抗生素杂志，2000，25(4)：241-249．
[60] 王道林，牛之猛，刘华东．光学活性拆分剂脱氢枞胺的制备性纯化及其表征[J]．北京理工大学学报，2004，24(4)：357-359．
[61] Gottstein W.J.. racemic momocarboxylic acid resolution using dehydeoabietylamine[P]. US 3454626, 1969
[62] Lee C. C.. Penicillin sales of amines derived from rosin [P]. US 2585436, 1952.
[63] Bellucci G., Berti G., Borraccini A. and Macchia F.. The preparation of optically active chlorofluoroacetic acid and chlorofluoroethanol[J]. Tetrahedron, 1969, 25(15): 2979-2985.
[64] 信息：脱氢枞胺及其醋酸盐中试与应用研究通过省级鉴定[J]．精细与专用化学品，1998，7(11)：7．
[65] 梁梦兰，叶建峰．松香衍生物的季铵盐阳离子表面活性剂的合成与性能测定[J]．化学世界，2000，41(3)：138-141．
[66] 周永红，谢晖，宋湛谦．松香甘油酯聚氧乙烯醚的合成及其性能[J]．南京 林业大学学报，2003，27(2)：25-28．
[67] 何曼，陆进华，沈德渊．脱氢枞胺键合交联聚苯乙烯树脂的制法和应用[J]．化工时刊，2002，12：25-29．
[68] 王延，宋湛谦．N-脱氢枞基-N，N-二羟乙基季铵盐类阳离子表面活性剂合成及性质研究[J]．林产业化学与工业，1997，17(1)：6-9．
[69] Menger F. M. and Smith J. H.. Mechanism of ester aminolysis in aprotic solvents[J]. American Chemical Society, 1972, 92(5): 3824-3829.
[70] Masayoshi M., Tadashi K., Kazuhiko H. and Gohfu S.. Metheod for producing an optically active 2,2-dimethylcyclopropanecarboxylic acid[P]. EP 0093511, 1985.
[71] 李媛，张萍，董玉环，周蕾，王亚英．羧酸的还原方法[J]．化学通报，2002，(7)：452-457．
[72] Burgstahler A. W., Worden L. R. and Lewis T. B.. Direct Reduction of Carboxylic Acids to Aldehydes by Lithium in Ethylamine [J]. J. Org. Chem., 1963, 28(10): 2918-2919.
[73] Corriu R. J. P., Lanneau G. F. and Perrot M.. The one-pot conversion of carboxylic acids to aldehydes via activated silyl carboxylates. [J]. Tetrahed. Lett., 1987, 28(34): 3941-3944.
[74] Carey F. A., Sundberg R.J.著，王积涛译．高等有机化学(B卷)[M]．高等教育出版社，1986，101-102．
[75] 李述文，范如霖编译．实用有机化学手册[M]．第一版，上海科学技术出版社，1981，285-287．
[76] McGear y R. P.. Facile and chemoselective reduction of carboxylic acids to alcohols using BOP reagent and sodium borohydride [J]. Tetrahed. Lett., 1998, 39(20): 3319-3322.
[77] Marini A. E., M. Roumestant L., Viallefont P., Razafindramboa D., Bonato M. and Follet M.. Synthesis of enantiomerically pure β- and γ-amino acids from aspartic and glutamic acid derivatives [J]. Synthesis, 1992, 11: 1104-1108.
[78] Finholt A. E., Bond A. C. and J. Schlesinger H. I.. Lithium aluminum hydride and lithium gallium hydride and some of their application in organic and inorganic chemistry[J]. J. Am. Chem. Soc., 1947, 69(5): 1199-1203.
[79] 车荣睿．硼氢化钠在有机合成中的应用[J]．化学试剂，1986，8(2)：94-96．
[80] Mariappan P. and Muniappan T.. Methods of enhancement of reactivity and selectivity of sodium borohydride for applications in organic synthesis[J]. J. Organomet. Chem., 2000, 609: 137-151.
[81] 王葆仁．有机合成反应(上册)[M]．北京：科学出版社，1982．139，15．
[82] Dalla V., Catteau J. P. and Pale P.. Mechanistic rationale for the NaBH_4 reduction of α-keto ester[J]. Tetrahedron Lett., 1999, 40: 51932-5196.
[83] 杨红文．三氧化铬二吡啶、三氧化铬吡啶盐酸盐—两种有效的专用氧化剂[J]．化学研究与应用，2000，12(1)：74-76．
[84] Tietze L.F., Eicher T．著．张进琪译．精细有机合成—有机化学实践中的反应与合成[M]．第一版，南京大学出版社，1990．69-70．
[85] 邢其毅，徐瑞秋，周政，裴伟伟．基础有机化学[M]．第二版，高等教育出版社，1992．1103-1105．
[86] 巨勇，赵国辉，席婵娟．有机合成化学与路线设计[M]．第一版，清华大学出版社，1992．119-122
[87] 周云．选择性氧化剂铬(VI)在有机合成中的应用[J]．昭通师范高等专科学校学报，2002，24(5)：29-31．
[88] L.F.Tietze, T.Eicher著．张进琪译．精细有机合成—有机化学实践中的反应与合成[M]．第一版，南京大学出版社，1990．75．
[89] 刘良先．Corey氧化剂及其在选择性氧化中的应用[J]．化学通报，1992，12(4)：17-25．
[90] Corey E. J. and William S. J.. Pyridinium chlorochromate, An efficient reagent for oxidation of primary and secondary alcohols to carbonyl compounds[J]. Tetrahedron Lette., 1975, 16(31): 2647-2650.
[91] Core E. J. and Suggs J. W.. Oxidation of alcohols effected by pyridinium chlorochromate [J]. Tetrahedron Lett., 1975, 16 (31): 2647-2650.
[92] Core E. J. and Schmidt G.. Useful procedures for the oxidation of alcohols involving pyridinium dichromate in aprotic media [J]. Tetrahedron Lett., 1979, 20 (5): 399.
[93] Yamaza K. S. and Yamaza K. Y.. Nickel catalyzed oxidation of allylic alcohols with K_2S_2O_8 [J]. Chem. Lett., 1989 (8): 1361-1364.
[94] Corey E. J., Gilman J. N. W. and Gamen B. E.. New method for the oxidation of aldehydes to carboxylic acids and esters [J]. J. Am. Chem. Soc., 1968, 90: 5616-5617.
[95] Col lins J. C., Hess W. W. and Frank F. J.. Dipyridine-chrominium (Ⅵ) oxide oxidation of alcohols in dichloromethane [J]. Tetrahedron Lett., 1968, 9(30): 3363-3366.
[96] 贾彦兴，吴滨，涂永强．手性3，7-二甲基-5，6-二羟基-辛-7-烯醛中间体的合成[J]．高等学校化学学报，2001，22(4)：584-586．
[97] Reetz M. T., Drewes M. W. and Schwicksrdi R.. Preparation of enantiomerical pure α-N, N-dibenzylamino aldehydes: S-2-(N, N-dibenzylamino)-3-phenylpropanal [J]. Organic Syntheses. Vol. 10, p.256.
[98] Reetz M. T., Drewes M. W. and Schwicksrdi R.. Preparation of enantiomerical pure α-N, N-dibenzylamino aldehydes: S-2-(N, N-dibenzylamino)-3-phenylpropanal [J]. Organic Syntheses. Vol. 76, p. 110.
[99] 何宗耀，郭勇．氧化法制备(E)-柠檬醛[J]．华南理工大学学报(自然科学版) 2000，28(4)：63-65．
[100] 张贵生．氯铬酸甲铵硅胶负载型氧化剂的制备及其对醇的氧化研究[J]．有机化学，1997，17(5)：450-453．
[101] Cainelli G., Cardillo G., Orena M. and Sandri S.. Polymer supported reagents. Chromic acid on anion exchange resins. A simple and practical oxidation of alcohols to aldehydes and ketones[J]. J. Am. Chem. Soc., 1976, 98 (21): 6737-6738.
[102] Frechet J. M. J., Darling P. and Farrall M. J.. Poly(vinylpyridinium dichromate): an inexpensive recyclable polymeric reagent[J]. J. Org. Chem., 1981, 46 (8): 1728-1730.
[103] 陈振初，黄宪．重铬酸季铵盐聚合物试剂的制备及其在醇氧化中的应用[J]．化学试剂，1980，2(5)：24-25．
[104] 王央贡，陈家威，杨细香．铬酸／硅胶受载试剂的制备及醇氧化的研究[J]．化学试剂，1985，7(3)：133-135．
[105] 逯兆庆，寻知磊．活性炭处理含铬废水的方法[J]．电镀与涂饰，2002，21(5)：42-44．
[106] 李英杰，纪智玲，候凤，李茂林，王红心．活性炭吸附法处理含铬废水的研究[J]．沈阳化工学院学报，2005，19(3)：184-187．
[107] 王清，江丽，陈志传，陈文衡，张迅．高浓度含铬废水的综合利用[J]．环境科学与技术，2003，26(5)：38-39．
[108] Mohrmann K. H., Reiser W., Linke S. W. and Rudolf Z.. Process for the preparation of oxiranes[P]. US 4898954, 1990.
[109] Jones R. V. H. and Simpson E. S. C.. Process for preparing epoxides from carbonyl using sulphonium or sulphoxonium ylides and intermediates useful therein[P]. US 5750740, 1998.
[110] Forrester J., Jones R. V. H. and Preston P. N. Simple, inexpensive synthesis of oxiranes from carbonyl compounds. Generation of sulfonium ylides from the ternary system methanol-sulfuric acid-dimethyl sulfide[J]. J. Chem. Soc. Perkin Trans., 1993, 115: 1937-1940.
[111] Rao A. S., Pakniker S. K., Kitane J. G.. Recent advances in the preparation and synthetic applications of oxiranes. [J]. Tetrahedron, 1983, 39(14): 2323-2361.
[112] Mohrmann K. H., Reiser W., Linke S. W. and Zerbes R.. Preparation of oxiranes[P]. US 4992565, 1991.
[113] Organic Syntheses, Coll. Vol. 5, p.755 (1973); Vol. 49, p.78 (1969).
[114] Bernard M．著．吴范宏译．高等有机化学反应和机理[M]．高等教育出版社，2005．398-419．
[115] Rosenberger M. and Mcdougal P., Saucy G.. New approaches to the synthesis of canthaxanthin[J]. Pure and appl. Chem., 1979, 55: 871-876.
[116] Volker F. and Driessen H. E.. Methylization by sulfonium ylides [J]. Tetrahedron lett., 1962, 15: 661-662.
[117] Othmer K.. Encyclopedia of Chemical Technology [M]. 3rd ed, 1983. 233-235.
[118] Marbet R.. Epoxides[P]. Swiss 614201, 1979.
[119] Rosenberger M.. Ionone epoxide[P]. US 0399856, 1976.
[120] Mosset P. and Gree R.. Trimethylsulfonium methylsulfate, a simple and efficient epoxidizing agent [J]. Synthetic Comm., 1985, 15(8): 749-757.
[121] Corey E. J and M. Chaykovsky. Dimethylsulfoxonium Methylide[J]. J. Am. Chem. Soc., 1962, 84(5): 867-868.
[122] Corey E. J and Chaykovsky M.. Dimethyloxosulfonium Methylide ((CH_3)_2SOCH_2) and Dimethylsulfonium Methylide ((CH_3)_2SCH_2). Formation and Application to Organic Synthesis[J]. J. Am. Chem. Soc., 1965, 87(6): 1353-1364.
[123] Volker F. and Driessen H. E.. Methylization by sulfonium ylides [J]. Tetrahedron lett., 1962, 15: 661-662.
[124] Johnson A. W. and LaCount R. B.. The chemistry of ylids Ⅵ dimethylsulfonium fluorenylide-A Synthesis of epoxides[J]. J. Am. Chem. Soc., 1961, 83(2): 417-423.
[125] Yano Y., Okonogi T. and Sunaga M. Oxiran formation in the base-catalysed reation of long-chain alkyldimethelsulphonium salts and carbonyl compounds in benzene-water[J]. Chem. Commucications, 1973, 7: 527-528.
[126] Britton E. C. and Hansen J. N.. Sulphonium salts[P]. US 2366176, 1942.
[127] Britton E. C. and Hansen J. N.. Sulphonium salts[P]. US 2402016, 1944.
[128] Gaertner V. R.. Sulphonium sulfonates[P]. US 2813898, 1957.
[129] Chistie J.. Sulphonium sulfonates and its use[J]. J. Org. Chem., 1983, 48: 2531-2534.
[130] Byrne B. and Lawter L. M. L.. The preparation of trimethylsulfonium chloride from methyl chloroformate and dimethyl sulfide [J]. Tetrahedron lett., 1986, 27(11): 1233-1236.
[131] Eugene L. and Cranford N. J.. Preparation of sulphonium compounds[P]. US 2252081, 1938.
[132] Nagubandi S.. Process for preparing organo-sulfonium halides [P]. US 4743403, 1988.
[133] Klaus J.. and Nagubandi S.. Process for preparing organo-sulfonium halides [P]. EP 0156177, 1985.
[134] Yoshimine M. and Hatch M. J.. The mechanism of the reaction of aqueous benzyldimethylsulfonium chloride and formaldehyde with sodium hydroxide[J]. J. Am. Chem. Soc., 1967, 89(8): 5831-5838.
[135] March J.. Advanced Organic Chemistry: Reactions Mechanisms and Structure[M]. 1968. 343.
[136] J．马奇．高等有机化学反应、机理和结构(上)[M]．人民教育出版社，1981．76．
[137] 尹冬冬．有机化学 上册[M]．北京师范大学出版社，2003．260-262．
[138] 傅相锴．高等有机化学[M]．高等教育出版社，2003．98-103
[139] 曾昭琼．有机化学[M]．第三版，高等教育出版社，1993．299．
[140] 韩卫荣，欧育湘．不同载体钯催化剂的结构特征及其在笼形叔胺脱N-苄基上的应用[J]．精细化工，2004，21(11)：819-822．
[141] 陈筱金．Pd／C催化剂失活原因分析与改进措施[J]．化学反应工程与工艺，2002，18(3)：275-278．
[142] 邱文革，余永忠．N-苄基的脱去[J]．合成化学，1998，6(1)：34-39．
[143] Tuchalski G., Emmerling E, Groger K., Hansicke A., Nagel T. and Gunter R.. X-ray investigations of nebivolol and its isomers[J]. Journal of Molecular Structure, 2006, 800: 28-44.