Preparation method of pitavastatin calcium crude drug midbody
A technology of pitavastatin calcium and bulk drug, which is applied in the field of preparation of intermediates of pitavastatin calcium bulk drug with optical purity, can solve the problems of difficult separation and purification, low yield and the like, and achieves strong stereospecificity and high yield , conditioned response mild effect
Active Publication Date: 2014-04-30
江苏阿尔法集团福瑞药业(宿迁)有限公司
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Problems solved by technology
[0018] The purpose of the present invention is to solve the problem that the separation and purification of pitavastatin calcium bulk drug is difficult and the yield is low, and to provide a method for preparing pitavastatin calcium bulk drug with optical purity
Method used
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Embodiment
[0031] Embodiment: the preparation of a kind of high optical purity pitavastatin calcium bulk drug
[0032] 1: Into a 500ml three-neck reaction flask, stir it magnetically, put 2-amino-4′-fluorobenzophenone (10.7g), 80ml tetrahydrofuran, add 25ml concentrated sulfuric acid and 25ml acetic acid, and heat the system to 80°C. Slowly add bromomethylcyclopropyl ketone (12.225 g, 1.5 eq) dropwise. After the drop is complete, the reaction is continued for 1.5 hours and cooled to room temperature. The pH of the sodium hydroxide solution was adjusted to 6~7, the water phase was removed by layering, and the reaction solvent was finally removed to obtain 15.56 g of compound 3, with a yield of 94%.
[0033] 2: In a 500 ml three-necked reaction flask, mix compound 5-3 (15.56 g) and (3R)-3-p-toluenesulfonate-5-carbonyl-6-yne sodium heptanoate ethyl ester (21.6 g, 1.2eq) was dissolved in 120 ml of liquid ammonia solution and reacted for 1 hour at -70°C under nitrogen protection. Remove the...
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The invention discloses a preparation method of a pitavastatin calcium crude drug midbody, wherein a compound with a formula (1) and a compound with a formula (2) are subjected to condensation reaction to prepare a compound with a formula (3), then the compound with the formula (3) reacts with (3R)-3-p-alkyl besilate group-5-carbonyl-6-alkyne-sodium testosterone enanthate to obtain a compound with a formula (4), bi(2-methoxy-ethyoxyl group) aluminium sodium hydride is taken as a reducing agent to reduce alkynyl in the compound with the formula (4) to obtain trans-olefin of the compound with a formula (II), and finally, hydroboration reduction and hydrolysis reaction are carried out to prepare the pitavastatin calcium crude drug midbody. Compared with the prior art, the preparation method has the characteristics of being mild in reaction condition, strong in stereospecificity, good in environment friendliness, low in cost and the like, and is suitable for large-scale industrial production, and the yield is high.
Description
technical field [0001] The invention relates to a method for preparing an optically pure pitavastatin calcium bulk drug intermediate, which belongs to the field of medicine and chemical industry. Background technique [0002] Coronary heart disease is a common and frequently-occurring disease that threatens human health and life. Hypercholesterolemia characterized by elevated low-density lipoprotein (LDL) is one of the main risk factors for coronary heart disease. Pitavastatin Calcium, a new type of statin developed by Kowa, is known as a "super statin" because of its good cholesterol-lowering effect. Pitavastatin calcium has a strong inhibitory effect on hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, and can efficiently inhibit the process of cholesterol production in human liver cells HepG2, thereby hindering the synthesis of cholesterol. Pitavastatin calcium can induce the synthesis of low-density lipoprotein (LDL) receptor mRNA at an ultra-low concentration, incr...
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IPC IPC(8): C07D215/14
Inventor 石利平王艳尹晓龙吉民徐春涛万新强
Owner 江苏阿尔法集团福瑞药业(宿迁)有限公司