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Synthesis of Rosuvastatin Calcium and Tenofovir Disoproxil Fumarate

Author: ChenXiong
Tutor: LiPing
School: East China Normal University
Course: Organic Chemistry
Keywords: Rosuvastatin calcium Tenofovir Disoproxil Fumarate HMG-CoAReductase Inhibitor hepatitis B
CLC: TQ463
Type: Master's thesis
Year: 2011
Downloads: 37
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Abstract


This paper relates to a research into a route of synthesizing a lipid-lowering medicine Rosuvastatin calcium and anti-hepatitis B medicine Tenofovir disoproxil fumarate.Rosuvastatin was discovered by Shionogi and Astrazeneca, November2002licensed to market in Netherlands. It is a synthetic inhibitor of the HMG-CoA reductase and the effect of lipid-lowering batter than other statins. With the good safety and tolerability, it is called "super statin".In the synthesis, we use4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-pyrimidine carboxaldehyde and (R)-3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-λ5-phosphanylidene)-hexanoic acid methyl ester as raw materials. Stating from Wittig reaction, silyl group deprotection, asymmetric reduction, hydrolization, acidification, formation of amine salt, formation of Calcium salt, etc.8steps finish the synthesis of Rosuvastatin calcium. The purity of the product more than99.5%.During experiment, we improve the post-processing of Wittig reaction. Through the use of methyl t-butyl ether/n-hexane/water/ethanol system phase separation can effectively remove the byproduct triphenyl-phosphine oxide, avoid column chromatography and the artificial steps can apply to industrial production. In reduction reactions, We through change the mass of sodium borohydride and diethyl methoxy borane, made the content of the diasteromer impurities drop to0.7%; We also research the purity of Rosuvastatin calcium. In this process, we take Rosuvastatin sodium salt acidification, formation of amine salt. Through the ammonium salt precipitation removed the diasteromer impurities.Tenofovir Disoproxil Fumarate(TDF) is HBV-DNA polymerase and HIV reverse transcriptase inhibitor, TDF licensed to market in united states in2001as a AIDS drug. In2008, European Union approved TDF as chronic hepatitis B drugs licensed to market in27members.In the synthesis, I use adenine and (R)-(+)propylene carbonate as raw materials after five steps get the final product. The purity of the product more than99.6%. In the experiment, We studied (R)-9-(2-hydroxypropyl)adenine alkyl substituted reaction, through the use of hydrogenated sodium, we get the key intermediate (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine; we also reseach Tenofovir Disoproxil react with different organic acids, recrystallization in different solutions,at last we determined the optimum conditions.

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