Chinese Journal of Pharmaceuticals

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Synthesis of Glipizide

LIU Bingpeng, WANG Zhaojie, MIN Qingxiang

2015, 46(10): 1053-1054. https://doi.org/10.16522/j.cnki.cjph.2015.10.001

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Glipizide, an antidiabetic agent, was synthesized from 4-(2-aminoethyl)benzenesulfonamide by condensation with 5-methylpyrazine-2-carboxylic acid to give 5-methyl-N-(4-sulfamoylphenethyl)pyrazine-2- carboxamide, which was subjected to esterification with isocyanatocyclohexane with an overall yield about 84％. This synthetic method did not require the protection and deprotection of the amino group, which simplified the reaction steps, improved the yield and saved raw materials. Its work-up was also simple. This method has brought enormous economic benefits for the industrial production.

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Synthesis of Levodopa via Copper-catalyzed Hydroxylation

ZHAI Ning, ZHOU Houyuan , ZHANG Fuli, WANG Hongbo

2015, 46(10): 1055-1057. https://doi.org/10.16522/j.cnki.cjph.2015.10.002

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A new synthesis of levodopa from L-tyrosine was described. Levodopa was prepared from L-tyrosine by bromization to give 3-bromo-L-tyrosine, followed by the ligand-free copper-catalyzed hydroxylation with an overall yield about 59％.

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Improved Synthesis of Ursodeoxycholic Acid

LU Maofang, YIN Weicheng, WANG Fudong, PENG Dongming*

2015, 46(10): 1058-1059. https://doi.org/10.16522/j.cnki.cjph.2015.10.003

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Ursodeoxycholic acid was synthesized from chenodeoxycholic acid by oxidization with sodium hypochlorite to give 3α-hydroxycholanate-7-one, which was subjected to hydrogenation with lithium in tert-butanol with an overall yield of 82％. The process was simple and suitable for the industrialized production.

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Preparation of Hydroxyethyl Vinyl Deuteroporphyrin Ⅸ

PU Yu, CHEN Xiaojie, CHEN Wenhui*

2015, 46(10): 1060-1062. https://doi.org/10.16522/j.cnki.cjph.2015.10.004

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Hydroxyethyl vinyl deuteroporphyrin Ⅸ (HVD) was prepared from hemin by addition reaction with HBr, nucleophilic substitution and dehydration. The pure products of 3-vinyl-8-(1-hydroxyethyl)deuteroporphyrin Ⅸ and 3-(1-hydroxyethyl)-8-vinyldeuteroporphyrin Ⅸ were obtained by medium and high pressure column chromatography, respectively. The structures were confirmed by MS, IR, 1H NMR, and 13C NMR.

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Synthesis and Structure Identification of Neratinib and Its Related Substances

WANG Haibo, LUO Hairong, KUANG Hongfu, ZHANG Wei, LI Danfeng

2015, 46(10): 1063-1068. https://doi.org/10.16522/j.cnki.cjph.2015.10.005

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According to literature, the antitumor drug neratinib was synthesized. Meanwhile, five related substances were synthesized: N-[4-[3-chloro-4-(pyridin-2-methoxyl)anilino]-3-cyano-7-ethoxylquinolin-6- yl]formamide (A), N1-[4-[3-chloro-4-(pyridin-2-methoxyl)anilino]-3-cyano-7-ethoxylquinolin-6-yl]-N2,N2-dimethylethanediamide (B), 2-[4-[3-chloro-4-(pyridin-2-methoxyl)anilino]-3-cyano-7-ethoxylquinolin-6-yl]amino- 2-oxoacetic acid (C), 3-cyano-4-[3-chloro-4-(pyridin-2-methoxyl)anilino]-7-ethoxyl-6-[(1-methylpyrrolidin-2- ylidene)amino]quinoline (D) and 3-cyano-4-[3-chloro-4-(pyridin-2-methoxyl)anilino]-7-ethoxyl-6-(2-hydroxyl-5- oxopyrrolidin-1-yl)quinoline (E). The chemical structures were confirmed by MS, 1H NMR, and 13C NMR.

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Synthesis of 2-(4-Isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-ol

AN Chenhong1, ZHANG Heming2, WANG Hui1, SHANG Zhenhua1*

2015, 46(10): 1069-1072. https://doi.org/10.16522/j.cnki.cjph.2015.10.006

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2-Methyl-3-amino-4-acethylanisole (2) was prepared from 2-methyl-3-nitrophenol via methylation, Friedel-Crafts reaction and reduction. 2-(4-Isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-ol, the key intermediate of anti-HCV drug simeprevir, was synthesized from 3-methyl-2-butanone by bromination, cyclization, Sandmeyer reaction, cyano-substitution, and hydrolysis to give 4-isopropylthiazole-2-formic acid (3), which was subjected to chlorination, N-acylation with 2, and cyclization in the presence of t-BuOK. The overall yield was about 9％(based on 3-methyl-2-butanone).

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Synthesis of 3'-Amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic Acid

龚彦春，周西朋，沙波，吕伏生，袁方*

2015, 46(10): 1073-1075. https://doi.org/10.16522/j.cnki.cjph.2015.10.007

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3'-Amino-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid, a key intermediate of eltrombopag, was synthesized from 2-bromo-4-chlorophenol via nitration to give 2-bromo-4-chloro-6-nitrophenol, followed by benzyl protection to afford 2-(benzyloxy)-1-bromo-5-chloro-3-nitrobenzene, which was subjected to Suzuki coupling reaction with 3-carboxyphenylboronic acid in the presence of catalyst Pd/C, followed by hydrogenation with an overall yield about 65％.

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Construction of Genetic Engineering Bacteria for the Synthesis of L-2-Aminobutyric Acid

GUO Hongyan1,2, LIANG Rui1, LI Hang3, CHEN Daijie2, SHAO Lei2*

2015, 46(10): 1076-1079. https://doi.org/10.16522/j.cnki.cjph.2015.10.008

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A system of the regeneration of NADH coupling with leucine dehydrogenase (LDH) was constructed. The formate dehydrogenase (FDH) gene was synthesized and cloned into vector pET28a to construct recombinant plasmid pFDH-pET28a, which was transformed into E. coli BL21(DE3). After induction by IPTG, the activity of crude FDH from the recombinant was about 10 u/ml. Subsequently, LDH gene was synthesized and cloned into vector pET21a to construct a recombinant plasmid pLDH-pET21a. It was co-transformed together with plasmid pFDH-pET28a into E. coli BL21(DE3) to express FDH and LDH. Finally, L-2-aminobutyric acid was obtained by catalysis of FDH, LDH and threonine deaminase(TD). The results showed that the yield was over 95％ at the feeding amount of 7 g/100 ml.

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Fabrication of Double-decked Carrier with Negatively Charged Shielding for Gene Transfection

WANG Min, TIAN Huihui, CHEN Jingxiao, CHEN Jinghua*

2015, 46(10): 1080-1086. https://doi.org/10.16522/j.cnki.cjph.2015.10.009

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In this paper, polyethyleneimine (PEI) and hyaluronic acid were conjugated with histidine to obtain PEI-His and HA-His conjugates, respectively. PEI-His could bind plasmid enhanced green fluorescent protein-N1 (pEGFP-N1) to form PEI-His/DNA complexes (PD complexes), then the PD complexes were furtherly adsorbed with HA-His to form (PEI-His/DNA)/HA-His complexes (HPD complexes) with double-decked and negatively charged shielding architecture, which could be used for gene delivery. The observation of TEM showed that the HPD complexes were spherical. The average size of HPD complexes after hydration was about 142 nm and the ζ potential was -28.9 mV. After adding 10％ fetal bovine serum into HPD complexes, the average size and ζ potential were 135 nm and -25.8 mV, which indicated that the HPD complexes might have good serum stability. The encapsulation efficiency of the HPD complexes was (91.9±1.15)％. The results also showed that the complexes could protect the DNA from DNases I degradation. The in vitro cytotoxicity of HPD complexes was significantly lower than that of PEI/DNA complexes in PEI concentration range of 5 - 20 μg/ml, and cell survival rates of the former could maintain at least 80％. Finally, transfection efficiency of the HPD complexes was 2.88％, which indicated that the carrier was able to induce cellular uptake and gene transfection.

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Preparation and in vitro Characterization of Surface Imprinted Nanoparticles with Specific Recognition of Helicobacter pylori

HAN Jiaying1,2, HOU Jiapeng1,2, WANG Yuyan3, LIU Yu1,2, PAN Jun1,2*

2015, 46(10): 1087-1091. https://doi.org/10.16522/j.cnki.cjph.2015.10.010

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Exploratory work was carried out in an effort to fabricate surface molecularly imprinted nanoparticles (MIPs) with specific recognition of Helicobacter pylori. The imprinted nanoparticles loaded with 5-carboxyfluorescein (FAM) were prepared via the inverse microemulsion polymerization method. The hydrophilic peptide template, abbreviated as NQA, an outer membrane protein of H. pylori, was modified with a long-chain fatty acid to assist in its localization on the surface of the nanoparticles upon polymerization. The in vitro interaction between MIPs and H. pylori was investigated via flow cytometry with H. pylori strain SS1 as bacterial model. An adhesion model of strain SS1 and AGS cells was established for better simulating the in vivo distribution of H. pylori. The interaction between nanoparticles and the adhesion model was investigated by fluorescence microscopy. The results indicated that MIPs could specifically
recognize the targeting point of H. pylori to realize the specific binding to H. pylori in vitro.

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Preparation and Pharmacodynamics of Cream Containing Ibuprofen β-Cyclodextrin Inclusion Complexes

LI Xiaojie, LIANG Yueqin, WANG Heng, WANG Chongjing, LI Zhongkun*

2015, 46(10): 1092-1095. https://doi.org/10.16522/j.cnki.cjph.2015.10.011

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The inclusion complexes of β-cyclodextrin with ibuprofen was prepared by saturated water solution method. Then the cream containing the above inclusion complexes for hemorrhoids treatment was prepared by adding stearic acid, liquid paraffin and glycerol, etc. The drug concentrations in inclusion complexes and cream were determined by UV method. The results showed that the content of ibuprofen in inclusion complexes with inclusion rate of 50.3％ was 8.25％, while in cream was 1％. The cream had good centrifugal stability as well as good heat resistance and cold resistance. In the perianal ulcer test, the ulcerous wound areas of the rats in both cream containing inclusion complexes group and positive control group (Ma Ying Long hemorrhoids ointment) were significantly decreased after administration for 6 d compared with those in model group. The ulcers healed in both treatment groups after administration for 10 d. Moreover, the cream had no irritation to the anal mucosa of mice.

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Determination of Dabigatran in Beagle Dog Plasma by UPLC-MS/MS

XIANG Zhixiong, MA Wendi, XIA Guangxin*

2015, 46(10): 1096-1099. https://doi.org/10.16522/j.cnki.cjph.2015.10.012

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A UPLC-MS/MS method was established for the determination of dabigatran in Beagle dog plasma. Dabigatran-d3 was chosen as the internal standard. A BEH C18 column was used, with the application of ESI ion source, in the positive ion mode, combined with multiple reaction monitoring (MRM) mode. It was linear in the range of 1 - 1 000 ng/ml. The intra- and inter-day RSDs were less than 15％. The drug concentration of dabigatran in Beagle dog plasma was determined, and the main pharmacokinetic parameters of dabigatran etexilate mesylate after oral administration to Beagle dogs were as follows: tmax (1.8±0.3) h, cmax (113.8±65.0) ng·ml-1, AUC0→t (657.4± 340.8) ng·h·ml-1, AUC0→∞ (716.5±397.8) ng·h·ml-1, MRT (8.7±2.2)h, t1/2 (5.9±1.9) h.

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On-line Blend Uniformity Monitoring of Mezlocillin Sodium and Sulbactam Sodium for Injection by Near-infrared Spectroscopy

WANG Fei1, JIANG Wei1, ZHANG Hui2, NIE Lei1, ZANG Hengchang1*

2015, 46(10): 1100-1104. https://doi.org/10.16522/j.cnki.cjph.2015.10.013

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A quantitative determination model for sulbactam sodium and a qualitative analysis model based on moving block standard deviation (MBSD) were built with the application of near-infrared (NIR) spectroscopy. These two models were combined for the on-line blend uniformity monitoring of mezlocillin sodium and sulbactam sodium for injection to achieve an effective judgement for a blending endpoint of the blending process. The results indicated that the blending process of mezlocillin sodium and sulbactam sodium for injection could be effectively monitored by this method, and the blending endpoint could be exactly determined by the NIR spectroscopy models.

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Determination of Vitamin C Tablets by Raman Spectroscopy

LAI Yuanfa1, HU Jia1, ZHANG Qiguo2, LI Ning1

2015, 46(10): 1105-1107. https://doi.org/10.16522/j.cnki.cjph.2015.10.014

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A Raman spectroscopy method was established for the determination of vitamin C tablets. The samples were extracted by 0.1 mol/L acetic acid, and was analyzed by smart laser Raman spectrometer. It was qualitatived by Raman characteristic peak shifts, and quantitatived by Raman index peak area. It was linear in the range of 20 - 250 mg/ml. The average recovery was 99.53％, with RSD of 1.12％.

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Comparison on Different Detectors for the Determination of Ethyl and Isopropyl Methanesulfonate in Dabigatran Etexilate Mesylate by Headspace Gas Chromatography

ZHANG Mengmeng1, YAO Xiaohua2, JIANG Yuansen2, PAN Hongjuan1*

2015, 46(10): 1108-1112. https://doi.org/10.16522/j.cnki.cjph.2015.10.015

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Headspace GC methods with different detectors were established and compared for the determination of ethyl and isopropyl methanesulfonate in dabigatran etexilate mesylate, including FID, ECD and MS detectors. Detailed comparisons and evaluations were conducted mainly from the sensitivity, interference and sample determination, in order to provide a reference for the establishment of determination methods for methanesulfonates in different APIs.

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Determination of the Related Substances in Lapatinib Ditosylate Monohydrate by HPLC

XU Jianhua

2015, 46(10): 1113-1116. https://doi.org/10.16522/j.cnki.cjph.2015.10.016

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An HPLC method was established for the determination of the related substances in lapatinib ditosylate. A C18 column was used, with the mobile phase of ammonium acetate buffer solution (dissolved 3.0 g of ammonium acetate in 1 L of water, adjusted to pH 4.0 by glacial acetic acid)∶acetonitrile by gradient elution at the detection wavelength of 260 nm. It was linear for the related substances A, B, C and lapatinib ditosylate in the concentration ranges of 0.15 - 1.0, 0.30 - 2.0, 0.15 - 1.0 and 0.50 - 10.0 μg/ml, respectively. Their average recoveries were 105.57％, 103.47％ and 105.08％, with RSDs of 1.49％, 5.85％ and 0.89％, respectively. The low limits of detection for the related substances A, B, C and lapatinib ditosylate were 0.05, 0.05, 0.10 and 0.08 μg/ml, respectively.

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Determination of Residual Organic Solvents in Sorafenib Tosylate by Ionic Liquids-headspace-gas Chromatography

ZHANG Sujuan, ZHANG Xu, YANG Lixia, DU Xiaoyan, LIANG Min*

2015, 46(10): 1119-1121. https://doi.org/10.16522/j.cnki.cjph.2015.10.018

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An ionic liquids-headspace-gas chromatography method was established for the determination of six residual organic solvents, such as ethanol, acetone, dichloromethane, ethyl acetate, tetrahydrofuran and N,Ndimethylformamide, in sorafenib tosylate. 1-Butyl-3-methylimidazolium tetrafluoroborate was chosen as the headspace solvent. An Agilent HP-1 capillary column was used with the application of FID detector and at equilibrium temperature of 130 ℃. Their average recoveries were 96.7％ - 100.0％, with RSDs less than 4.33％.

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Research Progress of Protein-based Chiral Stationary Phases and Their Applications to Chiral Drug Resolution

DU Jiangbo, CHEN Xiaoyan, ZHONG Dafang*

2015, 46(10): 1122-1130. https://doi.org/10.16522/j.cnki.cjph.2015.10.019

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Chromatographic resolution of chiral drugs includes three kinds of approaches, namely chiral derivatization approach, chiral mobile phase approach, and chiral stationary phase (CSP) approach. Along with the emerge of a large number of commercially available CSP columns, the CSP approach quickly dominates the field of chiral drug resolution, due to its various advantages of high speed, simplicity, and efficiency. Protein-based CSPs remain one of the most widely used CSPs, and exhibit enantioselectivity for a wide range of compounds because of multiple binding sites on the surface of chiral selectors and multiple binding interactions between chiral selectors and ligands. This review mainly focuses on the research progress of protein-based CSPs and their applications to chiral drug resolution in recent 3 years, with the emphasis on their enantioselective properties, application scope, the factors influencing drug resolution, and a chromatographic optimization scheme on these stationary phases.

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Application of Practical Isolation and Purification Techniques in Small Molecule Drugs

ZHANG Fuli

2015, 46(10): 1131-1138. https://doi.org/10.16522/j.cnki.cjph.2015.10.020

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This review outlined the major methods of chiral resolution and common separation techniques for drugs synthesis, and gave a brief introduction of telescoped process and TRIZ theory. Several case studies of pharmaceutical products such as carnitine, linezolid, ephedrine, chloroamphenicol, galantamine, fosfomycin, vitamin B6, olmesartan medoxomil, captopril, taurine, et al, were discussed to illustrate the application of these practical techniques in small molecule drugs.

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Graphical Synthetic Routes of Beraprost Sodium

HOU Dalong, SONG Heng, ZHANG Baozhen, WANG Ensi*

2015, 46(10): 1139-1142. https://doi.org/10.16522/j.cnki.cjph.2015.10.021

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Graphical Synthetic Routes of Nilotinib

DU Deping1,2, ZHANG Ling2, KANG Dongwei1, ZHAN Peng1, LIU Xinyong1*

2015, 46(10): 1143-1145. https://doi.org/10.16522/j.cnki.cjph.2015.10.022

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