Shakubiqu intermediate, Shakubiqu intermediate and preparation method of Shakubiqu

Abstract

The invention discloses a sacubitril intermediate and a preparation method of the sacubitril intermediate and sacubitril, and belongs to the technical field of organic synthesis of drugs. On one hand, the invention discloses a novel compound-sacubitril intermediate compound B and a preparation method thereof, and on the other hand, the invention discloses a novel preparation method of the sacubitril. The sacubitril intermediate and the preparation method of the sacubitril intermediate and the sacubitril have the following advantages that the synthesizing route is short, the product can be prepared only through four steps of chemical reactions, and the steps of existing patent routes all exceed nine steps; the dicarbonyl compound is prepared through Reformasky condensation supplied by the method, and the cost is low; a first chiral center is introduced by fully utilizing a chiral compound L-(S)-ethyl lactate which is low in cost and easy to obtain in the natural world, and the cost is low; a second chiral center is constructed through a biological enzyme catalysis technique, the optical selectivity reaches up to 99.9%, the quality is good, and the cost is low. By means of the technological means, the total yield of the prepared sacubitril is increased, and the quality of the sacubitril is improved.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis of medicines, and in particular relates to a sacubiqu intermediate, a sacubiqu intermediate and a preparation method of sacubiqu. Background technique [0002] Sacubitril (Sacubitril) is an anti-heart failure drug developed by Novartis. The compound and valsartan were co-crystallized to obtain LCZ696. The industry believes that the outstanding performance of LCZ696 has made this drug the most popular drug in the field of cardiology in the past 10 years. At the same time, in the next few years, there will be no drug in the cardiovascular field that can compete with LCZ696. Some analysts predict peak sales of LCZ696 as high as $8 billion, while analysts at Deutsche Bank expect the drug's peak sales to reach $6 billion given its superior performance in reducing key cardiovascular risks. Although there are slight differences in the data of various parties, there is no doubt that LCZ696 will...

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Problems solved by technology

[0008] The patent US5217996 uses chiral D-tyrosine derivatives as the preparation method of the substrate, which requires the use of relatively expensive raw materials such as trifluoroacetic anhydride, phenylboronic acid, triphenylphosphine palladium, lithium tetrahydrogen aluminum, etc. The use of a large amount of lithium tetrahydrogen in the process is also a very dangerous operation, and the process safety is expected to be improved. The total yield of this method is low, and the most critical thing is that the reaction selectivity in the hydrogenation of the final double bond is not high. Structural impurities are difficult to effectively control

[0009] Patent WO2014032627 uses chiral epichlorohydrin as a substrate for the preparation method, which requires the use of relatively expensive raw materials such as diethyl azodicarboxylate (DIAD), 4-bromobiphenyl, and phosphine ylide reagents, and there are also reactions The overall yield is not high, the hydrogenation reduction selectivity is not good, and the isomer impurities are difficult to effectively control, etc.

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