Novel intermediate as well as preparation method and application thereof

An intermediate and reaction technology, applied in the field of novel intermediates and their preparation, can solve the problems of complicated procedures, reduced reaction steps, complicated production processes, etc., and achieves high chemical and optical yields, high reactivity, and high reaction yields. Effect

Active Publication Date: 2022-05-13
SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The purpose of the present invention is to overcome the industrial production method of morphine and its derivatives in the prior art, which not only occupies a large amount of farmland, the production process is complicated, and the cost is high, but also the control process is long and the procedure is complicated, and it is easy to cause serious social problems due to inadequate control At the same time, it overcomes the shortcomings of the total synthesis method that still does not have practical significance and production value, and provides a new type of intermediate and its preparation method, which significantly improves the yield of the final product, reduces the reaction steps, and reduces the production cost.

Method used

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  • Novel intermediate as well as preparation method and application thereof
  • Novel intermediate as well as preparation method and application thereof
  • Novel intermediate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0301] The preparation method of embodiment 1 compound 5, with R 3 For H, X is bromine as an example, synthetic compound 5a;

[0302] Include the following steps:

[0303]

[0304] Isvanillin 1a (150 g, 0.986 mol, 1.0 equiv.) was dissolved in dichloromethane (2500 mL), and cooled to 0° C. in an ice bath. Slowly add dibromohydantoin (155g, 0.542mol, 0.55equiv.) in batches under stirring, then the reaction solution is raised to room temperature for reaction, after TLC detects that the raw material disappears completely (about 4 hours), the reaction solution is cooled to 0°C, add saturated Na 2 S 2 o 3 Quench the reaction with aqueous solution (500mL), stir at 0°C for 1h, wait until the precipitate is completely precipitated, filter, wash the filter cake (500mL×3) with water, collect the resulting off-white solid 2a, dry it in an oven at 90°C for 5 hours, and then vacuum It was dried (50°C) for 6 hours and used directly in the next reaction (193 g, yield 85%).

[0305] P...

Embodiment 2

[0308] The preparation method of embodiment 2 compound 5, with R 3 For Me, X is bromine as an example, synthetic compound 5b;

[0309] Include the following steps:

[0310]

[0311] Ph 3 P + CH 2 OMeCl － (911g, 2.66mol, 3.1equiv.) was dispersed in dry tetrahydrofuran (2500mL), and after cooling to 0°C in an ice bath, t-BuOK (279g, 2.48mol, 2.9equiv.) was slowly added thereto, and the reaction solution became orange-red, Stir vigorously for 45 minutes. Compound 2b (210 g, 0.857 mol, 1.0 equiv.) was slowly added to the suspension in batches, and the reaction was naturally raised from 0°C to 20°C. After the disappearance of the raw material was monitored by TLC (about 1 hour). The reaction solution was cooled down to 0 °C again, and water (1000 mL) was added thereto to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (1000 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, a...

Embodiment 3

[0314] The preparation of embodiment 3 compound 9I: with R 22 Taking the hydrogen atom as an example, compound 9a is synthesized, and the synthetic route is:

[0315]

[0316] Include the following steps:

[0317] Vanillin 6 (200g, 1.31mol, 1.0equiv.) was dissolved in CH 3 NO 2 (1000mL), ethylenediamine (1.0mL) was added thereto under stirring, and heated to reflux. After the reaction was complete (about 2 hours) as monitored by TLC, the reaction solution was cooled to room temperature, and a large amount of yellow solids were precipitated. Filter, wash the filter cake with methanol / water (v / v=1:1) (200mL×3), absolute ethanol (200mL×2) successively, collect the solid, and dry it under reduced pressure with a water pump to obtain compound 7 (bright yellow fine needles). crystals, 185 g, yield 72%).

[0318] Compound 7 (40.0g, 0.205mol, 1.0equiv.) was dissolved in a THF / EtOH mixed solution (v / v=1:1, 480mL), cooled to 0°C in an ice bath, and NaBH was slowly added in batches ...

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Abstract

The invention relates to the field of drug synthesis, in particular to a novel intermediate as well as a preparation method and application thereof, the structural formula of the novel intermediate is as shown in formula I, and in the formula, R is a secondary amine protecting group. Based on a possible biogenic pathway of the morphine derivative, through a biomimetic synthesis strategy, an asymmetric transfer hydrogenation reaction and an intramolecular oxidation dearomatization Heck reaction in a process of preparing the intermediate are taken as key reactions of total synthesis, and efficient synthesis of the morphine derivative is realized. The novel intermediate provided by the invention is used for synthesizing the morphine derivative, and has the characteristics of obviously reducing the synthesis steps, improving the yield, reducing the emission of three wastes and saving the production cost.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a novel intermediate and its preparation method and application. Background technique [0002] Morphine drugs represented by hydrocodone, oxycodone, buprenorphine, nalaxone, and naltrexone are used as opioid receptor agonists in the Clinically, it is mainly used for moderate and severe pain and palliative treatment caused by severe trauma, burns, fractures, cancer, etc., and as an opioid receptor antagonist for the treatment of respiratory depression and withdrawal of opioid and alcohol addiction Medicines are essential medicines recognized by the World Health Organization. According to statistics, among the top 200 drugs by global prescription usage in 2016, morphine drugs accounted for 7 varieties, playing an irreplaceable role and extremely important clinical value in the drug market. According to the IQVIA database statistics, in 2018, the total production of morphine drugs in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D489/02C07D489/08C07D221/28C07D217/20
CPCC07D489/02C07D489/08C07D221/28C07D217/20C07B2200/07Y02P20/55
Inventor 秦勇钟武李松薛斐宋颢刘小宇张丹何欢薛芳琳张茂杰胡照李纯鑫朱建全张一凡唐渝王蕊李雪蔡宇坤
Owner SICHUAN UNIV
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