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A kind of stereoselective reduction method of morphinone compound

A stereoselective, compound technology, applied in the direction of organic chemistry, bulk chemical production, etc., can solve the problems of harsh storage conditions, high price, equipment corrosion, etc., and achieve the effects of convenient preparation, easy storage and low price

Active Publication Date: 2019-04-26
CHINA NAT MEDICINES GUORUI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is to overcome the cumbersome preparation and harsh storage conditions of the reducing agent potassium tri-sec-butyl borohydride or sodium tri-sec-butyl borohydride used in the stereoselective reduction reaction of morphinone compounds in the prior art , high price, serious equipment corrosion during use, and low conversion rate of reducing agent sodium triacetoxyborohydride, etc., and a stereoselective reduction method for morphinone compounds is provided

Method used

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  • A kind of stereoselective reduction method of morphinone compound
  • A kind of stereoselective reduction method of morphinone compound
  • A kind of stereoselective reduction method of morphinone compound

Examples

Experimental program
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Effect test

Embodiment 1

[0031] The preparation of embodiment 1 compound 1

[0032] Add naloxone hydrochloride (1.5g, 3.76mmol), N, N-diisopropylethylamine (2.91g, 22.56mmol) and 30ml dichloromethane to the 50ml eggplant-shaped bottle, add 2 - Methoxyethoxymethyl chloride (1.87g, 15.04mmol), reacted overnight. The reaction solution was directly spin-dried to obtain compound 1 (yellow oil).

Embodiment 2

[0033] Example 2 Preparation of (6α)-3-(methoxyethoxy)methoxy-17-allyl-4,5α-epoxymorphinan-6,14-diol (compound 2)

[0034]

[0035] Add compound 1 (2.33g, 3.76mmol), 8ml acetonitrile and 8ml (140mmol) glacial acetic acid in the 100ml round bottom flask, add tetramethyl ammonium triacetoxyborohydride (1.32g, 4.89mmol) under-15 ℃, react 4h is over. Add a 10% ammonium chloride aqueous solution (40ml) in mass percent concentration, stir for 10min, add sodium hydroxide to make it alkaline, extract the aqueous phase with dichloromethane (30ml×3), dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate A yellow oil was obtained (2.32 g); yield 99.1%, de>99.8%.

[0036] The determination conditions of high performance liquid phase (HPLC) are:

[0037] Chromatographic column: Fortis SILICA 5μm (250×4.6mm)

[0038] Mobile phase: A phase=n-hexane, B phase=ethanol; A:B=80:20

[0039] Detection wavelength: 210nm

[0040] Column temperature: 30°C

[0041] Flow ra...

Embodiment 3

[0045]

[0046] Add hydromorphone (0.5g, 1.75mmol), 2.5ml acetonitrile and 2.5ml (44mmol) glacial acetic acid into a 100ml round bottom flask, add tetramethylammonium triacetoxyborohydride (0.68g, 2.62mmol) at 25°C , The reaction ends in 4h. Add a 10% ammonium chloride aqueous solution (40ml) in mass percent concentration, stir for 10min, add sodium hydroxide to make it alkaline, extract the aqueous phase with dichloromethane (30ml×3), dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate A yellow oil was obtained (0.49 g); yield 98.9%, de>98%.

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Abstract

The invention discloses a stereoselective reduction method of morphinone compounds. The stereoselective reduction method comprises the step as follows: the morphinone compounds and tetramethylammonium triacetoxyborohydride are subjected to a reaction in an organic solvent in the presence of acid. A reducing agent, namely, tetramethylammonium triacetoxyborohydride, used in the method is convenient to prepare, low in cost, easy to store and non-corrosive to equipment, besides, reaction yield can basically reach about 99%, and de value can reach 98% or higher.

Description

technical field [0001] The invention relates to a stereoselective reduction method of morphinone compounds. Background technique [0002] Chinese patent CN101466381A has reported that the steric hindrance of tri-sec-butyl potassium borohydride and tri-sec-butyl sodium borohydride is used to carry out stereoselective reduction of morphinone compounds. The product was dissolved in a dry tetrahydrofuran solution, cooled to near zero, and then the tetrahydrofuran solution of the above-mentioned reducing agent was added. After a period of reaction, post-treatment was carried out to obtain the desired configuration product with a conversion rate of 100% and de>99%. However, the preparation of tri-sec-butyl borohydride is very cumbersome, and requires low-temperature storage, isolation of oxygen and water. Most of the commercially available products are imported and expensive. The most important thing is that the borohydride is extremely corrosive to production equipment. Sex, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D489/08C07D489/02
CPCY02P20/55
Inventor 张福利张林杨哲洲张杰陈灵灵贾淼焦慧荣何晓清顾振龙蒋敏
Owner CHINA NAT MEDICINES GUORUI PHARMA
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