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Synthetic Research of Plerixafor and Laquinimod

Author: QiangBin
Tutor: ZhuoGuangLan
School: Zhejiang University of Technology
Course: Organic Chemistry
Keywords: Plerixafor antineoplastic drug Laquinimod multiple sclerosis synthesis optimization yield
CLC: TQ463
Type: Master's thesis
Year: 2014
Downloads: 1
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The synthetic methods of Plerixafor and Laquinimod were studied on the basis ofthe view of domestic and international literature. Because of different disadvantagesand drawbacks of the existing methods reported in literatures, two new modifiedsynthetic methods for Plerixafor and Laquinimod was proposed in the thesis, and eachsynthetic step was optimized.Plerixafor (trade name Mozobil) is an antagonist of CXC chemokine receptor type4(CXCR4) which is developed by Genzyme company. It is a drug that when used incombination with granulocyte-colony stimulating factor (G-CSF) may help increasethe hematopoetic stem cells in the blood that can be collected for autologous stem celltransplant in patients with non-Hodgkin’s lymphoma (NHL) or multiple myeloma(MM). The optimum synthetic route and process conditions were studied in the firstpart of the dissertation.We choose bis(3-aminopropyl)ethylene diamine as the starting material, whichundergoes sulfonylation, cyclization with ethylene bis(p-toluenesulphonate),deprotection with concentrated sulfuric acid to give1,4,8,11-tetraazacycloteradecanewith high total yield of about53.8%. On the basis, cyclam was subjected to protectionfollowed by condensation with α,α’-dibromo-p-xylene and then deprotection to givePlerixafor with high total yield of about55.7%. Therefore, the overall yield is about30.0%. The improved procedure could reduce the cost, simplify the synthesis andimprove the yield.Laquinimod is an effective, safe drug for multiple sclerosis, which is nowundergoing a phase Ⅲclinical trial. Through changing the cytokine balancemodulation of immune and improvement of clinical symptoms could be praticallyavailable. The optimum synthetic route and process conditions were studied in thesecond part of the dissertation.Taking2-amino-6-chlorobenzoic acid as the raw material, Laquinimod wasobtained after a series of chemical reactions including cyclization, methylation,condensation, and amidation reaction. The overall yield is about48.0%. The improved procedure could reduce the cost, simplify the synthesis and improve the yield.The optimization experiment was conduct on these aspects such as alteringreaction times, temperature, molar ratio, solvent and reagents. The structures ofPlerixafor, Laquinimod and their intermediates are confirmed by1H-NMR,13C-NMRand MS. In a word, the improved process is a high yield, simple operation, low costand suitable for scale production.

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CLC: > Industrial Technology > Chemical Industry > Pharmaceutical chemical industry > Production of organic compounds in drug
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