Chinese Journal of Pharmaceuticals

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Synthesis of Aprepitant

SU Wenrou1, NI Feng1, ZHANG Jin1, ZHU Ben2, LI Jianqi1*

2014, 45(10): 901-905.

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(R)-Phenylethylamine reacted with 2-bromoethanol to give (R)-2-[(1-phenylethyl)amino]ethanol hydrobromide, which was subjected to cyclization with 1-(4-fluorophenyl)-2,2-dihydroxyethanone followed by reduction to afford optical-pure isomer (2S,3R)-3-(4-fluorophenyl)-4-[(R)-1-phenylethyl]morpholin-2-ol(5).
Isomer 5 underwent nucleophilic substitution, deprotection and recrystallization to provide (2R,3R)-2-[(1R)-1-[3,5-di(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine hydrochloride, which was transformed to its (2R,3S)-diastereomer(9) hydrochloride via dehydrogenation and reduction process. Aprepitant was finally obtained by condensation of 9 hydrochloride with 5-(chloromethyl)-2,4-dihydro-1,2,4-triazol-3-one with an overall yield of about 21％[based on (R)-phenylethylamine].

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Synthesis of Apixaban

HE Chao, HOU Yunlei, ZHU Yan, MA Longsheng, ZHAO Yanfang*

2014, 45(10): 906-910.

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The key intermediate 3-(4-morpholinyl)-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one(5) was obtained via amidation, cyclization, dichlorination and elimination with 4-nitroaniline as the starting material. While another intermediate ethyl 2-chloro-2-[2-(4-methoxyphenyl)hydrazono]acetate(6) was prepared from 4-anisidine by diazotization and Japp-Klingemann reaction with ethyl 2-chloro-3-oxobutanoate. Apixaban, a factor Ⅹa direct inhibitor,was synthesized from 5 and 6 by 1,3-dipolar cycloaddition, olefination, reduction, amidation, cyclization and aminolysis with an overall yield of 25％ (based on 4-nitroaniline) and an HPLC purity of 99％. The improved process had several advantages over those reported procedures, such as mild conditions, simple operations and more suitable for industrial production.

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Synthesis of Adrafinil

XU Jie1, PENG Xuedong2, ZHANG Mei2, TANG Rupei1*

2014, 45(10): 910-912.

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Adrafinil was synthesized from benzophenone by reduction with KBH4 to give diphenylcabinol,which was subjected to condensation with thioglycolic acid, oxidation by H2O2, esterification with CH3OH and amidation with hydroxylamine hydrochloride with an overall yield of about 76％.

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Synthesis of Prasugrel

WANG Xiangquan1, YUE Shanshan2, LI Jindu3*, CHANG Sen2, SUN Tiemin1

2014, 45(10): 913-916.

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Prasugrel was synthesized from ethyl 2-(2-fluorophenyl)acetate by bromination, condensation with 2-[(tert-butyldimethylsilyl)oxy]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(3) and Grignard reaction to give 2-[(tertbutyldimethylsilyl)oxy]-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(5),which was subjected to deprotection and acetylation with an overall yield of 48％(based on compound 3).

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Convenient Synthesis of Baicalein

JING Linlin1, FAN Xiaofei1,2, MA Huiping1, FAN Pengcheng1, JIA Zhengping1*

2014, 45(10): 916-918.

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5,7-Dimethoxyflavone was prepared from chrysin by 5,7-dimethylation, which was subjected to selective bromination with N-bromosuccinimide (NBS) and reaction with sodium methoxide in DMF with CuBr as catalyst at 120 ℃ for 4 h to obtain 5,6,7-trimethoxyflavone. Finally, baicalein was prepared by demethylation and Wessely-Moser rearrangement with an overall yield of 56％.

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Asymmetric Synthesis of (3aS,6aR)-1,3-Bis(4-methoxybenzyl)-tetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione

LI Dan, XIONG Fangjun, XIONG Fei, CHEN Fener*

2014, 45(10): 919-923.

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An asymmetric synthesis of (3aS,6aR)-1,3-bis(4-methoxybenzyl)-tetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione, the key intermediate of (+)-biotin, was achieved from fumaric acid by bromine addition,condensation, cyclization with triphosgene and dehydration to give (3aS,6aR)-1,3-bis(4-methoxybenzyl)-dihydro-1Hfuro[3,4-d]imidazole-2,4,6(6aH)-trione(12), which was subjected to catalytic asymmetric alcoholysis, regioselective reduction and thiolation with an overall yield of 44％.

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Discovery and Synthesis of 6-Methylamino Impurity in Adenosine

ZHANG Chao, CHEN Daoxin, LI Zongling

2014, 45(10): 923-924.

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An impurity was found in adenosine. After separation by column chromatography, it was identified as 6-methylaminopurine riboside by MS, 1H NMR and 13C NMR. It was identical with the product from the substitution of 6-chloro-9-β-D-ribofuranosyl adenine with methylamine.

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Improvement of Fermentation Technology of Rapamycin by Actinoplanes sp.

CHEN Changfa, HUANG He, ZHANG Changqing, HU Haifeng*

2014, 45(10): 925-928.

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The fermentation medium composition was optimized in flasks to improve the production of rapamycin by Actinoplanes sp. SIPI-8011. The results showed that it could increase the productivity of rapamycin by adding glycerol as the carbon resource, as well as controlling pH value during the period. Meanwhile, it could reduce the formation of the byproduct 27-O-demethylrapamyci by adding betaine. The improved medium was investigated in a 50 L jar-fermentor, and the titre of rapamycin reached 920 μg/ml, which was a 38.8％ increase compared to the original conditions. The amount of 27-O-demethylrapamycin was reduced by 83.5％ at the same time.

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Improvement of β-Carotene Production by Overexpression MEP Pathway

CHEN Xiping, XIE Liping, ZHANG Qi, HU Youjia*

2014, 45(10): 929-933.

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An upstream pathway named methyl-erythrose 4-phosphate(MEP) pathway was constructed, and two kinds of recombinant plasmid pET32a(+)-dxs-idi-ispDF and pTrcHis2B-dxs-idi-ispDF were obtained. Then the upstream pathway and a downstream β-carotene-forming pathway were transformed into Escherichia coli to get two kinds of recombinant strains. The results suggested that the β-carotene production of the recombinant strains contained MEP pathway were significantly improved.

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Comparison and Identification of Succinum and Its Adulterants

CHENG Song1, LUO Xiaojuan1, WANG Weining2, PAN Yingni1, LIU Xiaoqiu1*

2014, 45(10): 933-935.

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Succinum and its adulterants were distinguished by character identification, microscopic identification and physiochemical identification. The main component was isolated by various column chromatography methods, and the structure was identified as caryophyllene oxide by spectra analysis. Succinum and its adulterants were identified by TLC with the main component as the reference substance. The methods for the identification were simple, reproducible,specified and reliable for the quality control of Succinum.

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Preparation and Preliminary Evaluation of 9-Nitrocamptothecin Hydroxypropyl-β-cyclodextrin Inclusion Complexes

LU Shanshan1, CHEN Jun1, YANG Xixiong2*, GU Wei1, LI Wei1

2014, 45(10): 936-940.

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To improve the solubility of 9-nitrocamptothecin(1), the inclusion complexes of 1 with hydroxypropyl-β-cyclodextrin (HP-β-CD) were prepared by saturated aqueous solution method. The inclusion process was optimized by orthogonal design. The optimal process was as follows: the molar ratio of 1 to HP-β-CD was 1∶120, the inclusion was carried out at 60 ℃ for 2 h, the concentration of HP-β-CD was 507 mmol/L. Moreover, the formation of inclusion complexes was verified by differential scanning calorimetry (DSC) and X-ray diffraction method. After inclusion, the solubility of 1 was increased from 0.01 mg/ml to 3.85 mg/ml. Furthermore, the proportion of the lactone form of 1 in the fresh prepared inclusion complexes was 99％. Compared with the free drug, the lactone form was more stable in the inclusion complexes.

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Preparation of Nimodipine Nanosuspension by Wet Milling

ZENG Longbiao1,2, LIAN Yunfei2, ZHANG Jundong2, TANG Wenyan2, LI Juan1*

2014, 45(10): 941-945.

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The nimodipine nanosuspension was prepared by wet milling technique to improve the solubility of nimodipine. The formulation and preparation process were optimized by single factor test with particle size, polydispersity index (PDI) and ζ potential as indexes. The particle size, PDI and ζ potential of the optimal product were (261.2±5.7)nm,0.160±0.022 and -32 mV, respectively. The results of X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) showed that nimodipine in the lyophilized nanosuspension still existed in crystalline form. Compared with the bulk drug, the solubility of nimodipine in the lyophilized nanosuspension was increased by nearly 60 times.

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Preparation of Lyophilized Oleanolic Acid Liposomes and Protective Effect on Cl4-Induced Acute Hepatic Injury in Mice

NI Bin1, LI Xiang2, ZHANG Jing1?, LIAO Zhenggen1, LIU Jing3

2014, 45(10): 946-949.

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The oleanolic acid liposomes were prepared by ethanol injection methd, followed by surface odification with self-synthesized trimethyl chitosan. Through comparing of appearances and physicochemical properties f the liposomes before and after lyophilization, the lyophilized process parameters, kinds and amounts of lyoprotectants ere optimized. The results showed that lyophilized liposomes with good appearance and reconstitution were obtained by sing 6％ trehalose as lyoprotectant, pre-freezing at -80 ℃ for 6 h and lyophilizing for 30 h. The encapsulation efficiency,particle size and ζ potential of the liposomes before and after lyophilization were (96.8±1.7)％ and (97.1±0.9)％,(164.0±4.2) and (195.5±5.9)nm, (23.8±0.2) and (20.3±1.1) mV, respectively. The mprovement of the product on iochemical markers of mice with acute hepatic injury induced by CCl4 was investigated. Compared with model group,
the liposomes could significantly decrease the ALT and AST activities in serum and malondialdehyde level in liver,showing promising protective efficacy on liver injury.

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Determination of Aminomethylbenzoic Acid Injection and Its Related Substances by HPLC

ZHOU Xueping, YIN Yiping*, FAN Xiaoqing, CAO Hongbing

2014, 45(10): 956-958.

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An HPLC method was established for the determination of aminomethylbenzoic acid injection and its related substances. A C18 column was used with the mobile phase of 0.153 mol/L sodium dihydrogen phosphate solution (containing 0.83％ triethylamine and 0.23％ sodium lauryl sulfate, adjusted to pH 2.5 with phosphoric acid)∶methanol (60∶40), at the detection wavelength of 230 nm. Aminomethylbenzoic acid was successfully separated from its degradation products. It was linear in the ranges of 0.2 - 4 and 8 - 120 μg/ml. The average recovery was 100.25％, with RSD of 0.51％.

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Determination of 9-Propenyladenine in Tenofovir Disoproxil Fumarate by LC-MS

CHEN Dan1, KANG Lijuan2, ZHANG Lin1, JIANG Ye1*

2014, 45(10): 959-961.

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An LC-MS method was established for the determination of 9-propenyladenine in tenofovir disoproxil fumarate. A YMC-Pack ODS-AQ column was used with the mobile phase of acetonitrile∶0.01 mol/L ammonium acetate solution (40∶60) in SIM mode with positive ionization. The MS detection was carried out by monitoring m/z 176.2 with DP of 50 V. It was linear in the range of 0.5 - 50 ng/ml. The average recoveries were 97.8％ - 99.2％, with RSDs no more than 5.0％.

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Determination of Aconitine, Hypaconitine and Mesaconitine in Xiaotong Patches by HPLC

MEI Xin, PAN Jinhuo*, YANG Jing

2014, 45(10): 962-964.

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An HPLC method was established for the determination of aconitine, hypaconitine and mesaconitine in Xiaotong patches. A Hedera ODS-2 column was used, with the mobile phase A of acetonitrile∶tetrahydrofuran(25∶15) and the mobile phase B of 0.1 mol/L ammonium acetate solution (adding 0.5 ml of glacial acetic acid per liter) by gradient elution, at the detection wavelength of 235 nm. The calibration curves were linear in the ranges of 0.07 -0.42 μg, 0.15 - 0.88 μg and 0.05 - 0.32 μg for aconitine, hypaconitine and mesaconitine. Their average recoveries were 92.7％, 92.1％ and 93.0％, with RSDs of 3.37％, 2.09％ and 3.14％.

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Determination of Related Substances in 4-(2-Methylpropoxy)-1,3-dicyanobenzene by GC

YANG Weihan, ZHANG Li, LI Qirong

2014, 45(10): 965-967.

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A GC method was established for the determination of the related substances in 4-(2-methylpropoxy)-1,3-dicyanobenzene (1), the key material of febuxostat. A DB-5 capillary column was used with temperature programming. It was linear for 1 in the range of 2.5 - 6 000 μg/ml, while that was linear for its impurities Ⅰ, Ⅱ, Ⅲ and Ⅳ in the range of 1.5 - 15 μg/ml. Their low limits of detection were 1.0, 0.7, 0.8, 0.8 and 0.8 μg/ml, respectively.

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Enzyme Activity Determination of Recombinant Arginine Deiminase

LIU Ying, DAI Jue, HU Haifeng*

2014, 45(10): 968-970.

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An assay method was established for the enzyme activity determination of recombinant arginine deiminase (ADI) expressed by E. coli. The effects of reaction solution volume, substrate concentration, reaction time and pH value of reaction solution on enzyme activity were investigated. The optimized conditions were as follows: 20 mmol/L arginine, pH 6.5, reaction time of 20 min and reaction volume of 100 μl (test tube method). The calibration curve of ADI was linear in the range of 10 - 25 μg/ml with CV less than 10％.

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Determination of Daptomycin for Injection by HPLC

GONG Wei1, WANG Jiandong1, CHAI Jun1, FENG Jun2

2014, 45(10): 971-972.

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An HPLC method was established for the determination of daptomycin for injection. A C8 column was used with the mobile phase of acetonitrile∶0.5％ ammonium dihydrogen phosphate solution(35∶65) at the detection wavelength of 220 nm. It was linear in the range of 0.01 - 1 mg/ml. The average recovery was 100.0％, with RSD of 0.4％.

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Continuous Crystallization Process of Methionine

LI Tao1, REN Guobin2*

2014, 45(10): 973-977.

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Crystallization can be carried out in batch or continuous process. The continuous crystallization process has the advantages of small equipment size, improved process efficiency and crystal characteristics easy to control. Continuous crystallization of methionine was studied in this paper. The results indicated that compared with the products of batch crystallization, continuous crystallization resulted in bigger crystal size, narrowsize distribution, significantly reduced agglomeration. Dynamics of continuous crystallization of methionine was determined as to provide some references for the scale-up and crystallizer design.

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Research Progress on Isomerization of Double Bond in Cephalosporin Pharmacophore

YAO Liuduan, JIN Guoyou, LIU Xiaohong, LIU Xuebin

2014, 45(10): 978-985.

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The Δ2 isomers of cephalosporin have been proved to be antibacterially inactive. However, the structural modification of cephalosporin may result in the isomerization of the double bond in the cephem nucleus.Sometimes the isomerization also occurs in the hydrolysis of the cephalosporin prodrug in vivo. In this paper, the research progress in the isomerization mechanism, the different properties, the synthesis and converse technology between the Δ3 ceph-3-em and Δ2 ceph-2-em, is reviewed.

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Progress in Injectable Microsphere Formulations of Peptide Drugs

XU Xiaohan, WU Wenzhe*

2014, 45(10): 985-990.

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Because of the limitation of the materials, complicated preparation methods and the intrinsic unstable property of biological macromolecules, the marketed injectable microsphere formulations are more concentrated in peptide drugs with molecular weight no more than 1 500, while few protein drugs with larger molecular weight and more complicated structure can be found currently in the market. This paper reviews the recent progress of long-acting injectable microspheres of peptide and protein drugs, including the applications of novel materials and preparation methods as well as the market situation.

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Graphical Synthetic Routes of Eldecalcitol

ZHAO Guodong, LIU Zhaopeng*

2014, 45(10): 994-998.

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Learning American and European Union Experience to Perfect Re-registration of Drugs in China

ZHENG Yangyang1，DONG Zhi1*，XIA Yongpeng2

2014, 45(10): 999-45123.

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