Preparation method of chiral intermediate for synthesizing statins

Abstract

The invention discloses a preparation method of a chiral intermediate for synthesizing statins. The preparation method comprises the following steps: 1, in the presence of a solvent, enabling (3R)-3-[(t-butyldimethylsilane)oxy]-glutarate monoester and 4-nitrophenyl chloroformate to react with alkali so as to obtain 1,5-p-nitrocarbobenzoxyalkyl-(3S)-3-[(t-butyldimethylsilane)oxy]-glutarate diester; 2, in the presence of a solvent, enabling triphenyl methyl phosphonium bromide to react with alkali and then react with 1,5-p-nitrocarbobenzoxyalkyl-(3S)-3-[(t-butyldimethylsilane)oxy]-glutarate diester to obtain a target product, namely (3R)-3-[(t-butyldimethylsilane)oxy]-5-oxo-6-triphenylphosphine caproate. According to the preparation method disclosed by the invention, the reaction process is more stable, the raw material utilization ratio is relatively high, and the yield is obviously improved. More importantly, due to the reduction of impurities, the product can obtain purity according with industrial production through simple crystallization operation, so that the production efficiency is greatly improved, the cost is saved, and the environment friendliness is ensured at the same time.

Description

technical field [0001] The invention relates to a preparation method of a chiral intermediate synthesized by statin drugs. Background technique [0002] Statins, namely 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are a class of oral lipid-lowering drugs widely used in clinical practice, the main function is to reduce low-density lipoprotein cholesterol in blood Level, to achieve the purpose of prevention and treatment of cardiovascular diseases (such as hypercholesterolemia, coronary heart disease). [0003] As the main cause of atherosclerosis and coronary heart disease, hypercholesterolemia poses a serious threat to people's life and health. Hydroxymethylglutaryl-CoA reductase inhibitors, namely statins, are a new class of lipid-lowering drugs that have been marketed in recent years. By inhibiting and controlling the activity of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis in the body, it can block or reduce the synthesis...

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Problems solved by technology

[0015] The study found that the chemical purity and yield of (1) in the existing method cannot be guaranteed, and there are technical difficulties in commercial large-scale production

It is reflected in the low yield and a large amount of impurities in the obtained product. Generally, the product obtained by conventional separation and purification methods is an oily substance. The purity detected by HPLC is usually between 75-80%. It is necessary to further improve the purity to more than 95% by column chromatography. To obtain white to light yellow solid powder crystals

As we all know, the column chromatography process consumes a large amount of solvent for industrial production, causing large pollution and low production efficiency. In addition, it is difficult to precisely control the operation, and the obtained product is still oily due to insufficient purity.

Oily products generally contain a large amount of unknown impurities, have poor stability, and the purity of long-term storage will decrease significantly, which will have a very obvious adverse effect on the subsequent production of statin compounds

[0016] The main factor causing the chemical purity and yield of (1) is that the reaction reagent used—methyl (ethyl) chloroformate—is too active in chemical properties, and many side reactions occur in the reaction process, and it is very easy to decompose and destroy, resulting in The intermediate (8) contains a large amount of impurities, which directly affects the chemical purity of the product (1), making the product (1) directly produced by the general purification method an oily substance

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