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Method for preparing tacalcitol

A technology of tacalcitol and compounds, which is applied in the field of compound preparation, can solve the problems of long route, unfavorable industrial production, and easy occurrence of dangerous environmental pollution, etc., achieves high stereoselectivity, easy scale-up preparation, and reduces the effect of preparation risk

Active Publication Date: 2015-04-08
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many deficiencies in this synthetic route: 1) the sulfone compound containing the VD analog core used in the synthesis needs to be synthesized from the VD analog as a raw material, and the cost is high, and the VD analog raw material must be subjected to light reaction to obtain; 2) Sodium amalgam reagent is used in the second step of sulfone removal, which is prone to danger during scale-up operation and will produce metallic mercury that pollutes the environment; 3) Although the epoxy compound used to construct the side chain has a structure Simple, but because of its low boiling point and poor stability, it has not been industrialized, so it is difficult to achieve cheap and easy to obtain
Although this route has avoided using light reaction and sodium amalgam, there are still following deficiencies in this scheme: 1) route is long, is unfavorable for suitability for industrialized production; Reagents with high toxicity are not conducive to the scale-up of production
[0012] In summary, there are factors restricting industrial scale-up production in the reported synthetic routes of tacalcitol

Method used

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  • Method for preparing tacalcitol
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  • Method for preparing tacalcitol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: the preparation of compound IIIa

[0047]

[0048] Compound II (13 g, 66.6 mmol) and anhydrous lithium chloride (3.85 g, 88.8 mmol) were dissolved in 300 mL of acetonitrile, triethylamine (10.2 g, 88.8 mmol) was added dropwise under nitrogen protection, and the temperature was raised to 50 degrees And keep the temperature for reaction for 1 hour, add compound Ia (14.4 g, 44.4 mmol), keep stirring at 50°C for 10 hours, TLC detects that the raw material spots disappear, and the reaction is complete. Quench the reaction with 200 mL of saturated ammonium chloride solution, extract twice with 200 mL of n-hexane, combine the organic phases, wash with 200 mL of saturated brine, wash with 200 g of anhydrous Na 2 SO 4 Drying and concentration under pressure gave 26 g of the crude product, which was chromatographed on a silica gel column to give 14.6 g of Compound III with a yield of 87%. 95% purity.

[0049] 1H NMR (400MHz, CDCl 3 ) δ=6.75 (1H, dd, J=15.4, 5...

Embodiment 2

[0050] Embodiment 2: the preparation of compound IIIb

[0051]

[0052] Acetonitrile (400 mL), lithium chloride (7.53 g, 177.6 mmol) and compound II (26 g, 133.2 mmol) were added to a dry 1 L three-necked flask, and triethylamine (22.4 g, 221.8 mmol), heated to 50°C and the reaction solution was dissolved until clear, kept stirring at 50°C for 1 h, added compound Ib (14.4 g, 44.36 mmol) in dichloromethane solution, kept stirring at 50°C for 13 hours, TLC detected that the raw material spots disappeared , quenched by adding 500 mL of saturated NH4Cl aqueous solution, extracted three times with 300 mL of n-hexane, combined the organic phases, washed with 200 mL of saturated NaCl aqueous solution, dried with 200 g of anhydrous Na2SO4, concentrated under reduced pressure to obtain 20 g of crude yellow oil, passed through a silica gel column layer 13.8 g of yellow oil was separated out, the yield was 79.3%, and the purity was 95%.

[0053] 1H NMR (400MHz, CDCl 3 ) δ=6.75 (1H, ...

Embodiment 3

[0054] Embodiment 3: the preparation of compound IIIc

[0055]

[0056] Add acetonitrile (300 mL), lithium chloride (10.5 g, 250 mmol) and compound II (4838 g, 250 mmol) into a dry 1 L three-necked flask, and add triethylamine (38 g, 250 mmol ), heated to 50°C and the reaction solution was dissolved until clarified, kept stirring at 50°C for 1 h, added a dichloromethane solution of compound Id (20 g, 50 mmol), kept stirring at 50°C for 13 hours, TLC detected that the raw material spots disappeared, Quenched by adding 500 mL of saturated NH4Cl aqueous solution, extracted three times with 300 mL of n-hexane, combined the organic phases, washed with 200 mL of saturated NaCl aqueous solution, dried with 200 g of anhydrous Na2SO4, concentrated under reduced pressure to obtain 16 g of crude yellow oil, passed through a silica gel column layer 11.4 g of compound IIIc was obtained with a yield of 89% and a purity of 98%.

[0057] 1H NMR (400MHz, CDCl 3 ) δ=6.75 (1H, dd, J=15.4, 5...

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Abstract

The invention discloses a method for preparing tacalcitol. The method comprises the following steps: with a compound I as a starting raw material, carrying out Wittig reaction, CBS catalytic asymmetric reduction, hydroxy protection, hydrogenation reduction, desilication ether protection and oxidation reaction to prepare a compound VIII, carrying out Wittig Horner reaction on the compound VIII and a known compound IX for coupling, and carrying out dehydroxylation protection to obtain the target compound, namely tacalcitol. With cheap raw materials as the starting point, the method disclosed by the invention is simple, convenient and safe, steps unfavorable to amplification, such as illumination reaction and sodium amalgam reduction reaction, are avoided, and industrial production is facilitated.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a method for preparing tacalcitol. Background technique [0002] Vitamin D (vitamin D) is a sterol derivative with anti-rickets effect, also known as anti-rickets vitamin. At present, it is considered that vitamin D is also a steroid hormone, and the most important members of the vitamin D family are VD2 (ergocalciferol) and VD3 (cholecalciferol). Vitamin D is a derivative of different provitamin D after ultraviolet irradiation. A 40-year study by American scientists found that taking a daily dose of vitamin D can cut the risk of breast, colon and ovarian cancer in half. When the sun shines on the skin, the body produces vitamin D, which accounts for 90% of the body's vitamin D supply. [0003] In recent years, more and more evidence has shown that a lack of vitamin D can be extremely harmful to the body. Diseases such as heart disease, lung disease, cancer, diabetes, h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C401/00
CPCY02P20/55
Inventor 郑保富高强张宪恕丁福斗李洪坤
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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