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Calcipotriol intermediate compound and preparation method thereof

A technology of calcipotriol and compounds, which is applied in the field of intermediate compounds of calcipotriol and its preparation, and can solve problems such as waste

Active Publication Date: 2016-07-20
SHANGYU JINGXIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Adopting the present invention to prepare calcipotriol can greatly improve the utilization rate of calcipotriol mother nucleus, save time-consuming, a large amount of waste of solvent, preparation liquid phase separation means with low preparation efficiency, and make the vitamin D series derivatives The preparation is more economical, reasonable, low-cost, less polluting, and 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 present invention and the preparation of calcipotriol involved in the present invention Reagents are cheap and easy to obtain in large quantities through commercial channels

Method used

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  • Calcipotriol intermediate compound and preparation method thereof
  • Calcipotriol intermediate compound and preparation method thereof
  • Calcipotriol intermediate compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0107] Reaction formula:

[0108]

[0109] Steps:

[0110] 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

[0113] Example 2: Preparation of (1S, 2R)-1-cyclopropyl-2-(p-tolylsulfoxide)ethanol

[0114] 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

[0115] Example 3: Preparation of (1S, 2R)-1-cyclopropyl-2-(p-tolylsulfoxide)ethanol

[0116] 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 calcipotriol intermediate compound and a preparation method thereof. The structure of the compound is represented by general formula I shown in the description. In the general formula I, R1 is selected from a carbobenzoxy group (Cbz), a trimethylsilyl group (TMS), a triethylsilyl group (TES), a t-butyldimethylsilyl group (TBDMS), a triisopropylsilyl group (TIPS), a t-butyl-diphenylsilyl group (TBDPS) or a methoxymethyl group (MOM); and R2 is one of groups shown in the description.

Description

technical field [0001] The invention relates to an intermediate compound of calcipotriol and a preparation method thereof, 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 ...

Claims

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Application Information

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IPC IPC(8): C07D277/76C07D257/04C07F7/18C07C401/00
Inventor 黄悦文勇
Owner SHANGYU JINGXIN PHARMA
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