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Preparation method of calcipotriol

A technology based on calcipotriol and triisopropylsilyl, applied in the field of preparation of calcipotriol

Active Publication Date: 2016-07-13
SHANGYU JINGXIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The present invention greatly improves the utilization rate of the calcipotriol mother nucleus, saves time-consuming, large waste of solvents, and low-efficiency preparation liquid phase separation means, making the preparation of vitamin D series derivatives more economical, reasonable and low-cost , less pollution, high efficiency, overcomes the defects of the existing synthetic process route, and breaks through the limitations of the existing synthetic methods. At the same time, the reagents involved in this synthetic method are cheap and easy to obtain in large quantities through commercial channels

Method used

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  • Preparation method of calcipotriol
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  • Preparation method of calcipotriol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Example 1: Preparation of (1S, 2R)-1-cyclopropyl-2-(p-tolylsulfoxide)ethanol

[0100] Reaction formula:

[0101]

[0102] Steps:

[0103] 100 ml three-necked flask, add 25 ml tetrahydrofuran, add 0.655 g zinc chloride and 0.89 g (2R)-(p-tolylsulfoxide)-1-cyclopropyl ketone, stir and mix well at 20°C, cool to - Below 80°C, through the dropping funnel, add 12 ml of DIBAL-H toluene solution (1M) dropwise within 30 minutes, keep the temperature not higher than -80°C, stir for 1 hour, then quench the reaction system with 5 ml of methanol Remove the solvent by rotary evaporation, add 8 milliliters of 10 milliliters of water and 2.5 mol / liter of sodium hydroxide, and extract the system three times with dichloromethane, each 30 milliliters, the oil layers are combined, dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation, 0.7 g of the product was obtained, which could be directly used in the next hydroxyl protection step; yield: 77%, de=98....

Embodiment 2

[0106] Example 2: Preparation of (1S, 2R)-1-cyclopropyl-2-(p-tolylsulfoxide)ethanol

[0107] 100 ml three-necked flask, add 20 ml 1,4-dioxane, add 0.81 g zinc bromide and 0.67 g (2R)-(p-tolylsulfoxide)-1-cyclopropyl ketone, stir and mix at 20°C Evenly, drop the temperature to below -90°C, drop 10 ml of DIBAL-H toluene solution (1M) within 30 minutes through the dropping funnel, keep the temperature not higher than -90°C, stir the reaction for 1 hour, and then the reaction system Quenched with 5 ml of methanol; the solvent was removed by rotary evaporation, 10 ml of water and 6 ml of 2.5 mol / L sodium hydroxide were added, the system was extracted three times with dichloromethane, 30 ml each time, the oil layers were combined, and dried over anhydrous sodium sulfate , and the solvent was removed by rotary evaporation to obtain 0.47 g of the product, which can be directly used in the next hydroxyl protection step; yield: 74%, de=98.6.

Embodiment 3

[0108] Example 3: Preparation of (1S, 2R)-1-cyclopropyl-2-(p-tolylsulfoxide)ethanol

[0109] 100 ml three-necked flask, add 20 ml of anisole, add 1.01 g of zinc bromide and 0.67 g of (2R)-(p-tolylsulfoxide)-1-cyclopropyl ketone, stir and mix at 20°C, and cool down with To below -50°C, through the dropping funnel, add 5 ml of DIBAL-H toluene solution (1M) dropwise within 30 minutes, keep the temperature not higher than -50°C, stir for 3 hours, then the reaction system is washed with 5 ml of methanol Quenching; the solvent was removed by rotary evaporation, 6 ml of 10 milliliters of water and 2.5 mol / liter of sodium hydroxide were added, the system was extracted three times with toluene, 30 milliliters each time, the oil layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation, Obtain 0.47 g of the product, which can be directly used in the next hydroxyl protection step; yield: 74%, de=98.3 (1S, 2R)-1-cyclopropyl-2-(p-tolylsulf...

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Abstract

The invention discloses a preparation method of calcipotriol. The method comprises the following steps: step (1), a compound represented by the formula III reacts with a compound represented by the formula I in an inert organic solvent in the presence of alkali to generate a compound represented by the formula XV; step (2) the compound represented by the formula XV is subjected to a photoreaction in toluene in the presence of a photosensitizer to generate a compound represented by the formula XVI; and step (3) the compound represented by the formula XVI is used to prepare calcipotriol compound represented by the formula II in an organic reagent in the presence of a hydroxyl protective group removal reagent. The formula I, formula II, formula III, formula XV, and formula XVI are shown in the description.

Description

technical field [0001] The invention relates to a preparation method of calcipotriol, belonging to the technical fields of pharmacy and biochemical industry. Background technique [0002] Calcipotriol, also known as calcipotriol, was first reported by Calverley (1988) as a new anti-psoriasis drug, developed and produced by Danish LeoDenmark Company, and listed in Britain, Denmark and Ireland in March 1991 . Studies have shown that calcipotriol is a strong regulator of keratinocyte differentiation and proliferation, reduces the epidermal IL-6 content of psoriasis patients and the number of activated epidermal T lymphocytes, and it can inhibit the excessive proliferation of skin cells (keratinocytes). Hyperplasia and induce its differentiation, so that the abnormal proliferation and differentiation of psoriatic lesions can be corrected. Calcipotriol acts through vitamin D receptors in the nucleus. Vitamin D is found in cells involved in the pathogenesis of psoriasis, such a...

Claims

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Application Information

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IPC IPC(8): C07C401/00
CPCY02P20/55
Inventor 黄悦文勇
Owner SHANGYU JINGXIN PHARMA
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