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Improved preparation method of alfacalcidol

A technology of alfacalcidol and its compounds, which is applied in the field of improved preparation, can solve the problems of difficulty in controlling the conversion rate of cis-isomers, unfavorable scale-up production, and high requirements for equipment investment, so as to avoid the use of preparation liquid phase and facilitate The effect of product purification and labor cost reduction

Inactive Publication Date: 2020-04-28
SHANDONG HUBBLE KISEN BIOLOGICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0030] Add a mixed solvent of 30ml dimethyl sulfoxide and 24ml glacial acetic acid into the reaction flask, add 1αhydroxy-3,5-cyclovitamin D3 (9g, 21.7mmol) at room temperature, and react at 50°C for 1 hour under the protection of nitrogen. The solution was slowly poured into 500ml aqueous sodium bicarbonate solution pre-cooled to 5°C, extracted three times with ether (200ml), the combined organic phases were washed successively with saturated aqueous sodium bicarbonate solution (150ml) and saturated brine (150ml). Dry over magnesium sulfate, filter, and concentrate under reduced pressure to obtain a mixture of alfacalcidol and 5,6-trans-1α-OH-vitamin D3 (trans isomer of alfacalcidol, compound III), with a yield of 100% , used directly in the following reaction.

[0031] Add 100ml of ethyl acetate and maleic anhydride (2.12g, 21.7mmol) to the above reaction concentrate, react at 35°C for 24 hours under nitrogen protection, the reaction solution is concentrated under reduced pr...

Embodiment 2

[0034] Add a mixed solvent of 30ml dimethyl sulfoxide and 24ml glacial acetic acid into the reaction flask, add 1αhydroxy-3,5-cyclovitamin D3 (9g, 21.7mmol) at room temperature, and react at 50°C for 1 hour under the protection of nitrogen. The solution was slowly poured into 500ml aqueous sodium bicarbonate solution pre-cooled to 5°C, extracted three times with ether (200ml), the combined organic phases were washed successively with saturated aqueous sodium bicarbonate solution (150ml) and saturated brine (150ml). Dry over magnesium sulfate, filter, and concentrate under reduced pressure to obtain a mixture of alfacalcidol and 5,6-trans-1α-OH-vitamin D3 (trans isomer of alfacalcidol, compound III), with a yield of 100% , used directly in the following reaction.

[0035] Add 100ml of ethyl acetate and dimethyl butyndioate (3.08g, 21.7mmol) to the above reaction concentrate, react at 35°C for 24 hours under nitrogen protection, concentrate the reaction solution under reduced pr...

Embodiment 3

[0038] Add a mixed solvent of 30ml dimethyl sulfoxide and 24ml glacial acetic acid into the reaction flask, add 1αhydroxy-3,5-cyclovitamin D3 (9g, 21.7mmol) at room temperature, and react at 50°C for 1 hour under the protection of nitrogen. The solution was slowly poured into 500ml aqueous sodium bicarbonate solution pre-cooled to 5°C, extracted three times with ether (200ml), the combined organic phases were washed successively with saturated aqueous sodium bicarbonate solution (150ml) and saturated brine (150ml). Dry over magnesium sulfate, filter, and concentrate under reduced pressure to obtain a mixture of alfacalcidol and 5,6-trans-1α-OH-vitamin D3 (trans isomer of alfacalcidol, compound III), with a yield of 100% , used directly in the following reaction.

[0039] Add 100ml of ethyl acetate and 4-phenyl-1,2,4-triazoline-3,5-dione (3.8g, 21.7mmol) to the above reaction concentrate, react at 10°C for 2 hours under nitrogen protection , the reaction solution was concentra...

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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C401/00
CPCC07B2200/07C07C401/00C07C2601/14C07C2602/24
Inventor 钟强代飞郭太明王丽娟
Owner SHANDONG HUBBLE KISEN BIOLOGICAL TECH CO LTD
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