Method for synthesizing pitavastatin calcium intermediate by micro-channel reactor

Abstract

The invention discloses a method for synthesizing a pitavastatin calcium intermediate through a micro-channel reactor. The pitavastatin calcium intermediate is ethyl 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dyhydroxyl-6-heptylate. The preparation method comprises the following steps: dissolving hydroxylamine hydrochloride into a mixed solution of water, alcohol and acetone; then, adding tert-butyl 6-[[(1E)-2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-vinyl]-2,2-dimethyl-1,3-dioxane-4-acetate, dissolving the added substance, filtering the obtained solution, feeding the solution toa micro-channel reactor preheating module, introducing the preheated reaction liquid into a reaction module, collecting the reaction liquid flowing out of a cooling module, and performing extraction and purification to obtain pitavastatin tert-butyl ester. The method provided by the invention has the advantages of small organic reagent dosage and high yield.

Description

technical field [0001] The invention belongs to the technical field of synthesizing statin lipid-lowering drugs in the pharmaceutical chemical industry, and in particular relates to a method for synthesizing pitavastatin calcium intermediates using a microchannel reactor. Background technique [0002] The chemical name of pitavastatin calcium is +bis{(3R,5S,6E)-7-[2-cyclopropyl-4-(fluorophenyl)quinoline-3-phenyl]-3,5-dihydroxy -6-heptenoic acid ethyl ester} calcium salt (2:1), the chemical structural formula is as follows: [0003] [0004] Pitavastatin Calcium is the first fully synthetic HMG-CoA reductase inhibitor jointly developed by Nissan Chemical and Kowa Co., Ltd. Inhibition of the liver enzyme Chemicalbook to reduce the ability of the liver to produce cholesterol, so as to improve the elevated blood cholesterol level, mainly used to treat patients with hypercholesterolemia and familial hypercholesterolemia, because of its very good lipid-lowering effect, Known ...

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Problems solved by technology

[0011] (2) The toluene used in the post-treatment of method two belongs to flammable, explosive and toxic chemicals, which requires relatively high protection requirements for production operators, and there is a certain danger in the production process, and this method produces pitavastatin calcium intermediates. low yield;

[0012] (3) The cost of L-camphorsulfonic acid used in method three is relatively high, and it belongs to sulfur-containing compounds. The sulfur-containing wastes produced in the production process have great pressure on environmental protection. The pitavastatin calcium intermediate is produced by this method. low yield;

[0013] (4) Method 4 will use a large amount of organic reagents in the process of synthesizing the pitavastatin calcium intermediate, and the post-processing steps are long and complicated, and the yield is low

[0014] There are still problems such as long reaction time, poor selectivity, low yield, poor purity, and large amount of solvent used in the production process of the above traditional kettle-type process.

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