不对称催化加氢合成（R）-2-羟基-4-苯基丁酸乙酯
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摘要
不对称催化反应是目前化学合成研究中最活跃的领域之一。对手性化合物的迫切需求,促使不对称催化合成的应用研究迅速发展,其中非均相不对称催化反应被认为是一种很有潜力的技术。本文选取血管紧张素转化酶抑制剂(ACEI)的重要中间体——(R)-2-羟基-4-苯基丁酸乙酯(R-EHPB)为研究对象,在近年来α-酮酯不对称加氢反应研究的基础上,通过2-氧代-4-苯基丁酸乙酯(EOPB)在 Pt-金鸡纳生物碱体系中的不对称催化加氢合成了R-EHPB。实验工作分为两部分:高压釜间歇操作和滴流床连续操作。
首先确定了反应体系和分析方法。由Pd/C催化L-辛可尼定合成了10,11-二氢辛可尼定(HCd)作为修饰剂,以乙醇为溶剂,EOPB在Pt负载型催化剂作用下进行不对称加氢。反应产物通过程序升温,在β-环糊精衍生物毛细管色谱柱上进行分析。
第一部分实验在高压釜反应器中进行。采用商品Pt/C(5%)催化剂时讨论了EOPB不对称加氢过程中催化剂被HCd预修饰方式对反应结果的影响,发现催化体系的预吸附和超声处理都使得转化率和光学收率降低;分别考察了HCd浓度、EOPB初始浓度、氢压和反应温度对不对称加氢结果的影响,结果表明在Pt/C作用下R-EHPB的光学收率均低于15%。
由浸渍法制备了约5%Pt/Al_2O_3催化剂,用于EOPB不对称加氢时光学选择性比Pt/C明显较好。采用Pt/Al_2O_3系统研究了各反应因素对加氢结果的影响,实验表明适宜的HCd浓度(约0.68 mmol.L~(-1))和EOPB初始浓度范围(0.2-0.6mol·L~(-1))对转化率和光学收率均有利;增加氢压能显著增加反应速率,但对光学收率影响不大,操作压力为5.0MPa较佳;温度升高使转化率增加,但对光学选择性不利,兼顾两者温度控制在333-343K为宜。
通过光学选择性规律和反应动力学研究,探讨了EOPB不对称催化加氢反应机理,认为HCd的喹啉环在催化剂Pt表面的平行吸附是反应具有立体选择性的关键。与丙酮酸乙酯在类似体系中的不对称加氢不同,本研究中反应底物(EOPB)与HCd之间存在明显的竞争吸附。根据反应机理和合理的假设推导出了不对称加氢反应速率方程,该方程能较好地描述实验结果。
Enantioselective catalytic reaction has received significant attention in recent years because of its potential impact on the synthesis of chiral Pharmaceuticals and other chemicals. Heterogeneous asymmetric catalysis is of special interest for its advantages in separation and reuse of catalysts. In this dissertation, the enantioseletive hydrogenation of ethyl 2-oxy-4-phenylbutyrate (EOPB) to ethyl (R)-2-hydroxy-4-phenylbutyrate (R-EHPB) on Pt catalysts modified by cinchona alkaloid was studied.The modifier, 10,11-dihydrocinchonidine (HCd) was prepared with Pd/C and ethanol was used as the reaction medium. Both conversion and enantiomeric excess (e.e.) were determined by a programmed temperature gas chromatograph with a chiral capillary column.The hydrogenation reaction can be conducted either in a stirred tank batch process, or in a trickle-bed continuous process. When the reactions were carried out in an autoclave, at first the commercial Pt/C was used and the effect of the pre-modified catalysts on hydrogenation results were investigated. It was found that conversion and e.e. both decreased if HCd was pre-adsorbed on catalyst or the catalyst was irradiated by ultrasonic. The e.e.'s were all less than 15% when the hydrogenation was catalyzed with Pt/C in our experiments.5wt% Pt/Al_2O_3 catalyst was prepared with impregnation method and it led to higher optical yields than Pt/C for the asymmetric hydrogenation of EOPB. The influences of some factors on conversion and e.e. were studied. Suitable reaction conditions are as follows: HCd concentration (approx. 0.68mmol.L~(-1)), initial concentration of EOPB (0.2-0.6mol.L~(-1)), temperature (333-343K) and hydrogen pressure (5.0MPa).Based on the kinetic feature, the enantioselective hydrogenation mechanism was proposed and the parallel adsorption of HCd via its quinoline ring on Pt surface was considered to be determinative on high enantioselectivity. Different from the asymmetric hydrogenation of ethyl pyruvate, the competitive adsorption between EOPB and HCd was found in our study. According to the mechanism and reasonable
postulations, a hydrogenation rate equation was obtained and it could depict the experimental results well.When a trickle-bed reactor was used, the e.e.'s decreased obviously if the modified Pt/A^Ch was transferred to the reactor. Conversion and e.e. can be kept in steady level when the mixed liquid containing HCd is introduced into the reactor at a constant velocity. In four catalyst beds, the effects of HCd concentration, gas velocity, liquid velocity, pressure and temperature on reaction results were discussed. The e.e. values increase with higher liquid velocity, but conversions are reduced. Higher pressure and temperature both lead to lower optical yields.The productivities obtained in trickle-bed reactor and autoclave were examined. It was found that higher productivities per unit mass of catalyst and per unit volume of reactor were obtained in the autoclave and the trickle-bed reactor, respectively.A partial wetting model was proposed and its simulations of conversion and e.e. were found to agree well with the experimental data in the range of operating conditions studied. In order to evaluate the significance of various parameters used in proposed model, a sensitivity analysis was performed. It was observed that the model was highly sensitive to the values of the effective diffusion coefficient and dynamic liquid-solid mass transfer coefficient.
首先确定了反应体系和分析方法。由Pd/C催化L-辛可尼定合成了10,11-二氢辛可尼定(HCd)作为修饰剂,以乙醇为溶剂,EOPB在Pt负载型催化剂作用下进行不对称加氢。反应产物通过程序升温,在β-环糊精衍生物毛细管色谱柱上进行分析。
第一部分实验在高压釜反应器中进行。采用商品Pt/C(5%)催化剂时讨论了EOPB不对称加氢过程中催化剂被HCd预修饰方式对反应结果的影响,发现催化体系的预吸附和超声处理都使得转化率和光学收率降低;分别考察了HCd浓度、EOPB初始浓度、氢压和反应温度对不对称加氢结果的影响,结果表明在Pt/C作用下R-EHPB的光学收率均低于15%。
由浸渍法制备了约5%Pt/Al_2O_3催化剂,用于EOPB不对称加氢时光学选择性比Pt/C明显较好。采用Pt/Al_2O_3系统研究了各反应因素对加氢结果的影响,实验表明适宜的HCd浓度(约0.68 mmol.L~(-1))和EOPB初始浓度范围(0.2-0.6mol·L~(-1))对转化率和光学收率均有利;增加氢压能显著增加反应速率,但对光学收率影响不大,操作压力为5.0MPa较佳;温度升高使转化率增加,但对光学选择性不利,兼顾两者温度控制在333-343K为宜。
通过光学选择性规律和反应动力学研究,探讨了EOPB不对称催化加氢反应机理,认为HCd的喹啉环在催化剂Pt表面的平行吸附是反应具有立体选择性的关键。与丙酮酸乙酯在类似体系中的不对称加氢不同,本研究中反应底物(EOPB)与HCd之间存在明显的竞争吸附。根据反应机理和合理的假设推导出了不对称加氢反应速率方程,该方程能较好地描述实验结果。
Enantioselective catalytic reaction has received significant attention in recent years because of its potential impact on the synthesis of chiral Pharmaceuticals and other chemicals. Heterogeneous asymmetric catalysis is of special interest for its advantages in separation and reuse of catalysts. In this dissertation, the enantioseletive hydrogenation of ethyl 2-oxy-4-phenylbutyrate (EOPB) to ethyl (R)-2-hydroxy-4-phenylbutyrate (R-EHPB) on Pt catalysts modified by cinchona alkaloid was studied.The modifier, 10,11-dihydrocinchonidine (HCd) was prepared with Pd/C and ethanol was used as the reaction medium. Both conversion and enantiomeric excess (e.e.) were determined by a programmed temperature gas chromatograph with a chiral capillary column.The hydrogenation reaction can be conducted either in a stirred tank batch process, or in a trickle-bed continuous process. When the reactions were carried out in an autoclave, at first the commercial Pt/C was used and the effect of the pre-modified catalysts on hydrogenation results were investigated. It was found that conversion and e.e. both decreased if HCd was pre-adsorbed on catalyst or the catalyst was irradiated by ultrasonic. The e.e.'s were all less than 15% when the hydrogenation was catalyzed with Pt/C in our experiments.5wt% Pt/Al_2O_3 catalyst was prepared with impregnation method and it led to higher optical yields than Pt/C for the asymmetric hydrogenation of EOPB. The influences of some factors on conversion and e.e. were studied. Suitable reaction conditions are as follows: HCd concentration (approx. 0.68mmol.L~(-1)), initial concentration of EOPB (0.2-0.6mol.L~(-1)), temperature (333-343K) and hydrogen pressure (5.0MPa).Based on the kinetic feature, the enantioselective hydrogenation mechanism was proposed and the parallel adsorption of HCd via its quinoline ring on Pt surface was considered to be determinative on high enantioselectivity. Different from the asymmetric hydrogenation of ethyl pyruvate, the competitive adsorption between EOPB and HCd was found in our study. According to the mechanism and reasonable
postulations, a hydrogenation rate equation was obtained and it could depict the experimental results well.When a trickle-bed reactor was used, the e.e.'s decreased obviously if the modified Pt/A^Ch was transferred to the reactor. Conversion and e.e. can be kept in steady level when the mixed liquid containing HCd is introduced into the reactor at a constant velocity. In four catalyst beds, the effects of HCd concentration, gas velocity, liquid velocity, pressure and temperature on reaction results were discussed. The e.e. values increase with higher liquid velocity, but conversions are reduced. Higher pressure and temperature both lead to lower optical yields.The productivities obtained in trickle-bed reactor and autoclave were examined. It was found that higher productivities per unit mass of catalyst and per unit volume of reactor were obtained in the autoclave and the trickle-bed reactor, respectively.A partial wetting model was proposed and its simulations of conversion and e.e. were found to agree well with the experimental data in the range of operating conditions studied. In order to evaluate the significance of various parameters used in proposed model, a sensitivity analysis was performed. It was observed that the model was highly sensitive to the values of the effective diffusion coefficient and dynamic liquid-solid mass transfer coefficient.
引文
1.戴立言,陆熙炎,朱光美,手性技术的兴起,化学通报,(1995),(6),15～22
2.尤启东,林国强,手性药物——研究与应用,化学工业出版社,北京,(2004)
3.危凤,纤维素三苯基氨基甲酸酯手性固定相的研制与奥美拉唑的手性色谱分离[博士学位论文] ,浙江大学,杭州,(2003)
4.孙志浩,手性技术与生物催化,生物加工过程,(2004),2(4),6～10
5.汪朝阳,手性技术,自然杂志,(2002),24(4),219～223
6. Tetsuo O, Hidemasa T, Masato K, Katsunori N, Ryoji N, Asymmetric hydrogenation of unsaturated carboxylic acids catalyzed by BINAP-ruthenium (Ⅱ) complexes, J. Org. Chem., (1987), 52 (14), 3174～3176
7.黄量,戴立言,杜灿屏,吴镭,手性药物的化学与生物学,化学工业出版社,北京,(2002)
8. Caner H, Groner E, Levy L, Agranat I, Trends in the development of chiral drugs, Drug Discov. Today, (2004), 9 (3), 105～110
9. Toyo'oka T, Resolution of chiral drugs by liquid chromatography based upon diastereomer formation with chiral derivatization reagents, J. Biochem. Biophys. Methods, 2002, 54(1-3), 25～56
10.何煦昌,不对称有机合成和反应的分类,合成化学,(2002),10(5),377～384
11.姜标,不对称合成技术,世界科学,(1996),(8),20
12.张梦军,廖春阳,兰玉坤,李声时,对催化不对称合成的重大贡献—2001年诺贝尔化学奖,化学教育,(2002),(1),5～13
13.廖春阳,孙立力,李声时,催化不对称合成—2001年诺贝尔化学奖简介,自然杂志,(2001),23(6),349～356
14. Scott J W, Topics in stereochemistry, Wiiey, New york, (1989), 19,209
2.尤启东,林国强,手性药物——研究与应用,化学工业出版社,北京,(2004)
3.危凤,纤维素三苯基氨基甲酸酯手性固定相的研制与奥美拉唑的手性色谱分离[博士学位论文] ,浙江大学,杭州,(2003)
4.孙志浩,手性技术与生物催化,生物加工过程,(2004),2(4),6～10
5.汪朝阳,手性技术,自然杂志,(2002),24(4),219～223
6. Tetsuo O, Hidemasa T, Masato K, Katsunori N, Ryoji N, Asymmetric hydrogenation of unsaturated carboxylic acids catalyzed by BINAP-ruthenium (Ⅱ) complexes, J. Org. Chem., (1987), 52 (14), 3174～3176
7.黄量,戴立言,杜灿屏,吴镭,手性药物的化学与生物学,化学工业出版社,北京,(2002)
8. Caner H, Groner E, Levy L, Agranat I, Trends in the development of chiral drugs, Drug Discov. Today, (2004), 9 (3), 105～110
9. Toyo'oka T, Resolution of chiral drugs by liquid chromatography based upon diastereomer formation with chiral derivatization reagents, J. Biochem. Biophys. Methods, 2002, 54(1-3), 25～56
10.何煦昌,不对称有机合成和反应的分类,合成化学,(2002),10(5),377～384
11.姜标,不对称合成技术,世界科学,(1996),(8),20
12.张梦军,廖春阳,兰玉坤,李声时,对催化不对称合成的重大贡献—2001年诺贝尔化学奖,化学教育,(2002),(1),5～13
13.廖春阳,孙立力,李声时,催化不对称合成—2001年诺贝尔化学奖简介,自然杂志,(2001),23(6),349～356
14. Scott J W, Topics in stereochemistry, Wiiey, New york, (1989), 19,209