A study on kinetics of heterogeneous synthesis of piperacillin

doi:10.11949/0438-1157.20211095

Abstract

Abstract:

Piperacillin is an important antibiotic, which can be synthesized by the reaction of ampicillin aqueous solution and methylene chloride solution of 4-ethyl-2, 3-dioxy-1-piperazine formyl chloride (EDPC) at the oil-water interface. In this paper, the constant interface cell is used to study the apparent synthesis reaction kinetics at the interface, and it is determined that it conforms to the first-order reaction kinetic model. The effects of stirring rate, specific boundary area, pH and temperature on the reaction rate were discussed in details. The experimental results showed that when the stirring rate was greater than 250 r/min, there is a "flat zone" of chemical reaction control which is independent of the stirring strength. Under the "flat zone", the reaction rate constant increases with the increase of specific boundary area, pH and temperature. Through the relationship between temperature and reaction rate constant, the kinetic and thermodynamic data of the reaction were obtained, and then the reaction mechanism was deduced by combining with density functional theory (DFT).

Key words: constant interface cell, interface, multiphase reaction, N-acylation, reaction kinetics, computer simulation

摘要：

哌拉西林是一种重要的抗生素，它是利用氨苄西林水溶液和4-乙基-2，3-二氧-1-哌嗪甲酰氯(EDPC)的二氯甲烷溶液在油水界面处反应得到的。利用恒界面池研究界面表观合成反应动力学，确定符合一级反应动力学模型。详细讨论了搅拌速率、比界面积、pH、温度对反应速率的影响，实验结果表明，当搅拌速率大于250 r/min时出现与搅拌强度无关的化学反应控制“坪区”，在“坪区”下，反应速率常数随比界面积、pH、温度增大而增大。通过温度与反应速率常数的关系，得到反应的动力学数据与热力学数据，并通过与密度泛函理论(DFT)结合推导反应机理。

关键词: 恒界面池, 界面, 多相反应, N-酰基化反应, 反应动力学, 计算机模拟

CLC Number:

TQ 465.1

Yu XIE, Yujun WANG. A study on kinetics of heterogeneous synthesis of piperacillin[J]. CIESC Journal, 2021, 72(12): 6254-6261.

谢煜, 王玉军. 哌拉西林非均相合成反应动力学的研究[J]. 化工学报, 2021, 72(12): 6254-6261.

Figures/Tables 14

Fig.1 The synthetic pathway of piperacillin

Fig.2 Schematic diagram of experimental device

Table 1 Mobile phase gradient

时间/min	流动相A/%	流动相B/%
0	90	10
5	85	15
10	65	35
35	55	45
60	35	65
65	90	10
75	90	10

Fig.3 Change of piperacillin concentration in aqueous phase with time at different rotational speeds

Fig.4 Change of piperacillin content with time at different initial concentrations

Fig.5 Fitting diagram of first-order reaction kinetics at different initial concentrations

Fig.6 Fitting diagram of reaction rate constant k under different boundary areas

Fig.7 The effect of specific interfacial area on the rate constant k

Fig.8 Fitting diagram of reaction rate constant k at different pH

Fig.9 The effect of pH on the reaction rate constant k

Fig.10 Fitting diagram of reaction rate constant k at different temperatures

Fig.11 Effect of temperature on the reaction rate constant k

Fig.12 Fitting diagram of ln(k/T)-T-1

Fig.13 Free energy changes, intermediate and transition state structures during the synthesis of piperacillin with ampicillin and EDPC

References 35

1	Livermore D M. Current epidemiology and growing resistance of gram-negative pathogens[J]. The Korean Journal of Internal Medicine, 2012, 27(2): 128-142.
2	Gin A, Dilay L, Karlowsky J A, et al. Piperacillin-tazobactam: a beta-lactam/beta-lactamase inhibitor combination[J]. Expert Review of Anti-Infective Therapy, 2007, 5(3): 365-383.
3	Drawz S M, Bonomo R A. Three decades of beta-lactamase inhibitors[J]. Clinical Microbiology Reviews, 2010, 23(1): 160-201.
4	Hawkey P M, Warren R E, Livermore D M, et al. Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party[J]. Journal of Antimicrobial Chemotherapy, 2018, 73(): iii2-iii78.
5	Livermore D M. Beta-lactamase-mediated resistance and opportunities for its control[J]. The Journal of Antimicrobial Chemotherapy, 1998, 41(): 25-41.
6	李明华, 李明杰, 张万义, 等. 氧哌嗪青霉素钠的合成[J]. 黑龙江医药, 1996, 9(6): 327-328.
	Li M H, Li M J, Zhang W Y, et al. Synthesis of oxpiperazine penicillin sodium [J]. Heilongjiang Medical Journal, 1996, 9(6): 327-328.
7	Steimecke G, Teubner T H, Lierathe E, et al. Prepn. of piperacillin from ampicillin in high yield-by reacting benzyl-penicillin with piperazine deriv., useful in treatment of e.g. lung inflammation and meningitis: DD295162-A[P]. 1991-10-24.
8	李忠华. 哌拉西林钠的合成新工艺[J]. 山西医科大学学报, 2002, 33(4): 333-334.
	Li Z H. New process for the synthesis of piperacillin sodium[J]. Journal of Shanxi Medical University, 2002, 33(4): 333-334.
9	王玉军, 黄国明, 张建辉, 等. 一种利用微反应器合成哌拉西林的方法: 110294769B[P]. 2020-10-30.
	Wang Y Z, Huang G M, Zhang J H, et al. Method for synthesizing piperacillin by using micro-reactors: 110294769B[P]. 2020-10-30.
10	Maruko Seiyaku K K. New2,3-di:oxo:piperazine derivs.- useful as intermediates for piperacillin having antibacterial activity: JP2032075-A[P]. 1990-02-01.
11	Xie Y, Huang G M, Wang Y J, et al. Synthesis of piperacillin with low impurity content using a new three-feed membrane dispersion microreactor[J]. Chemical Engineering Journal, 2020, 387: 124178.
12	Xie Y, Chen Q, Huang G M, et al. Scaling up microreactors for kilogram-scale synthesis of piperacillin: experiments and computational fluid dynamics simulations[J]. AIChE Journal, 2021, 67(6): e17231.
13	Xie Y, Huang G M, Hu W G, et al. Effects of piperacillin synthesis on the infterfacial tensions and droplet sizes[J]. Chinese Journal of Chemical Engineering, 2021, 38(10): 53-62.
14	Yoshida J I, Kim H, Nagaki A. Green and sustainable chemical synthesis using flow microreactors[J]. ChemSusChem, 2011, 4(3): 331-340.
15	Katritzky A R, Suzuki K, Singh S K. N-acylation in combinatorial chemistry[J]. ChemInform, 2005, 36(17). DOI:10.1002/chin.200517250. DOI
16	Wang P J, Wang K, Zhang J S, et al. Kinetic study of reactions of aniline and benzoyl chloride in a microstructured chemical system[J]. AIChE Journal, 2015, 61(11): 3804-3811.
17	周曌. 水相中的达参反应及N-酰基化反应研究[D]. 重庆: 重庆大学, 2018.
	Zhou Z. Investigation on darzens reaction and N-acylation reaction in aqueous phase[D]. Chongqing: Chongqing University, 2018.
18	李洲. 萃取动力学研究实验装置的评介 (一)恒界面池的型式和操作特性[J]. 化工冶金, 1987(3): 47-57.
	Li Z. A review on experimental installations for research of extraction kinetics(1): Constant interfacial area cell(Lewis cell) and its mass-transfer characteristics[J]. Engineering Chemistry & Metallurgy, 1987(3): 47-57.
19	彭小五, 李丽娟, 时东, 等. 2-丁基-1-正辛醇萃取硼酸的动力学研究[J]. 盐湖研究, 2020, 28(3): 79-84.
	Peng X W, Li L J, Shi D, et al. Kinetics of extraction of boric acid with 2-butyl-1-n-octanol[J]. Journal of Salt Lake Research, 2020, 28(3): 79-84.
20	周革菲, 张曼平, 黄凯美. 恒界面池法研究TBP从盐酸中萃取铁的动力学[J]. 莱阳农学院学报, 2000, 17(3): 199-202.
	Zhou G F, Zhang M P, Huang K M. Study on the kinetic of tri-n-butyl phosphate as a extractant for extraction of iron in toluene by the method of invariable interface[J]. Journal of Laiyang Agricultural College, 2000, 17(3): 199-202.
21	孙思修, 薛梅, 杨永会, 等. 溶剂萃取动力学研究方法: 恒界面池法[J]. 化学通报, 1996, 59(7): 50-52.
	Sun S X, Xue M, Yang Y H, et al. Research methods for solvent extraction kinetics: constant interfacial cell method[J]. Chemistry, 1996, 59(7): 50-52.
22	刘向楠, 党亚固, 费德君, 等. 乳化液膜萃取Cr(Ⅲ)的内相反萃步骤动力学研究[J]. 化学工程, 2015, 43(11): 25-29.
	Liu X N, Dang Y G, Fei D J, et al. Stripping reaction at internal phase of extracting Cr(Ⅲ) by emulsion liquid membranes[J]. Chemical Engineering (China), 2015, 43(11): 25-29.
23	金士威, 易琼, 张旭, 等. 应用恒界面池法研究磷酸三丁酯萃取磷酸的动力学[J]. 武汉工程大学学报, 2011, 33(2): 34-37.
	Jin S W, Yi Q, Zhang X, et al. Studies on extraction kinetics of phosphoric acid by tributyl phosphate using method of constant interfacial area stirred cell[J]. Journal of Wuhan Institute of Technology, 2011, 33(2): 34-37.
24	Liu K K, Xin H L, Han M H. Elucidation of key factors in nickel-diphosphines catalyzed isomerization of 2-methyl-3-butenenitrile[J]. Journal of Catalysis, 2019, 377: 13-19.
25	Liu K K, Wang T F, Han M H. Rational design of efficient steric catalyst for isomerization of 2-methyl-3-butenenitrile[J]. Molecular Catalysis, 2020, 498: 111259.
26	Scalmani G, Barone V, Mennucci B, et al. Gaussian 09, Revision E.01[CP]. Gaussian, Inc.,2009.
27	Becke A D. Density-functional exchange-energy approximation with correct asymptotic behavior[J]. Physical Review A, 1988, 38(6): 3098-3100.
28	Lee C, Yang W, Parr R G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density[J]. Physical Review. B, Condensed Matter, 1988, 37(2): 785-789.
29	Becke A D. Density-functional thermochemistry (III): The role of exact exchange[J]. The Journal of Chemical Physics, 1993, 98(7): 5648-5652.
30	Krishnan R, Binkley J S, Seeger R, et al. Self-consistent molecular orbital methods (XX): A basis set for correlated wave functions[J]. The Journal of Chemical Physics, 1980, 72(1): 650-654.
31	Mó O, Yáñez M. Influence of polarization functions on molecular electrostatic potentials[J]. Theoretica Chimica Acta, 1978, 47(4): 263-273.
32	Fukui K. The path of chemical reactions—the IRC approach[J]. Accounts of Chemical Research, 1981, 14(12): 363-368.
33	Fukui K. Formulation of the reaction coordinate[J]. The Journal of Physical Chemistry, 1970, 74(23): 4161-4163.
34	Yang X L, Zhang J W, Fang X H. Extraction kinetics of niobium by tertiary amine N235 using Lewis cell[J]. Hydrometallurgy, 2015, 151: 56-61.
35	Zhou R, Li T T, Su Y, et al. Removal of sulfanilic acid from wastewater by thermally activated persulfate process: oxidation performance and kinetic modeling[J]. Journal of Chemical Technology & Biotechnology, 2019, 94(10): 3208-3216.

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