Improved preparation method of alfacalcidol

Abstract

The invention discloses an improved preparation method of alfacalcidol. The preparation method is characterized by comprising the following steps: starting from 1 alpha-OH-3,5-cyclized vitamin D3, directly carrying out ring-opening hydrolysis without an acetate intermediate to obtain alfacalcidol and a trans-isomer thereof, carrying out a Diels-Alder reaction, selectively reacting with the trans-isomer, and carrying out column chromatography separation or methyl formate recrystallization to obtain a pure alfacalcidol product. The method is simple and convenient to operate, mild in reaction condition and high in total yield, and is suitable for large-scale synthesis of products.

Description

technical field [0001] The invention relates to the fields of organic chemistry and pharmacy, in particular to an improved preparation method of alfacalcidol. Background technique [0002] Alfacalcidol, the chemical name is 9,10-cyclocholesta-5Z,7E,10(19)-triene-1α,3β-diol, the English name is alfacalcidol, and the structural formula is: [0003] [0004] Alfacalcidol is an important active metabolite of vitamin D3, which is a kind of substance involved in the stability of calcium and phosphorus internal environment and the mineralization process of bone. It is suitable for the prevention and treatment of osteoporosis, nephrogenic bone disease (nephrotic rickets), hyperparathyroidism (with bone disease), hypoparathyroidism, rickets and osteomalacia caused by nutritional and absorption disorders, Pseudocalcium deficiency (D-dependent type I) rickets and osteomalacia, etc. my country's related products have been on the market since 1997, and there are mainly two dosage fo...

AI Technical Summary

Problems solved by technology

[0008] In the above synthetic route, starting from the intermediate 1α-OH-3,5-cyclized vitamin D3 (compound I), involving acetic acid ring-opening reaction, Diels-Alder reaction and potassium hydroxide alkali hydrolysis reaction, the final product needs further Refining and purification, cumbersome operation, and the glacial acetic acid solvent needs to be removed in vacuum at a higher temperature in the acetic acid ring-opening reaction, and strong alkali sodium hydroxide or potassium hydroxide is used in the alkaline hydrolysis reaction, which is less stable for alfacalcid The chemical structure of alcohol is destructive, more impurities are likely to be produced in the reaction, and the overall yield is not high. The crude product of alfacalcidol needs to be purified multiple times or purified by preparative liquid phase, which requires high equipment investment and is not conducive to scale-up production.

[0009] The most important problem in the synthetic route of alfacalcidol is the separation of its trans isomers, except that it can be separated smoothly after the above-mentioned reaction with Diels-Alder dienophiles (maleic anhydride, etc.), there are also documents (US4554105 , synlett, 2013, Vol24, No.19, 2606-2608) reported that the trans isomer is converted into the cis isomer by photoreaction. In the actual experiment, a photoreactor and a high pressure of a specific wavelength are required. Mercury lamps also need to add a photosensitizer. The most important thing is that the conversion rate of the cis isomer is difficult to control and other new photoreactive impurities are produced, which increases the difficulty of purifying the target product. Therefore, only the photoreaction is used to promote the trans The method of configuration conversion, after purification by conventional methods (column chromatography, recrystallization), the control of trans isomer impurities is difficult to reach the limit required by the Pharmacopoeia

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