Intermediate as well as preparation method and application thereof

An intermediate and reaction technology, applied in the field of intermediates and their preparation, can solve the problems that the total synthesis method does not have practical significance and production value, the production process is complicated, the management and control process is long, etc., and the post-reaction treatment is simple and easy to operate and operate. Simple and effective in reducing the discharge of three wastes

Pending Publication Date: 2022-04-29
SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] One of the purposes 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, but also has complex production procedures and high cost, and the control The process is long and complicated, and it is easy to cause serious social problems due to inadequate control. At the same time, the total synthesis method still does not have practical significance and production value. An intermediate and its preparation method are provided to achieve a biomimetic synthesis strategy. , for the total synthesis of morphine derivatives, the key intermediates and the effects of the reaction steps are provided with a significant increase in the reaction yield

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  • Intermediate as well as preparation method and application thereof
  • Intermediate as well as preparation method and application thereof
  • Intermediate as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0246] The preparation method of embodiment 1 compound 3, synthetic route is:

[0247]

[0248] Include the following steps:

[0249] Compound 1 (71.3g, 0.317mol) was dissolved in 380mL of dichloromethane, imidazole (53.9g, 0.793mol) was added successively, DMAP (15.5g, 0.126mol) was stirred at room temperature, TBSCl (81.3g , 0.538mol), and stirred at room temperature for 1 h after addition. TLC detects that the reaction raw materials all disappear. use NH 4 The reaction was quenched with saturated aqueous Cl, and dichloromethane and water were added to the mixture until the solid precipitate was completely dissolved. The aqueous phase was extracted with ethyl acetate (200mL×5), the combined organic phases were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate, add PE:DCM=10:1 (v / v) 200mL, stir evenly, filter, filter cake wash twice with PE:DCM=10:1(v / v), wash three times with PE and dry , to obtain bright yellow solid compound 2 (100 g, yield 93%).

[025...

Embodiment 2

[0253] The preparation of embodiment 2 compound 5, synthetic route is:

[0254]

[0255] Include the following steps:

[0256]Compound 4 (55.0g, 0.211mol), compound 3 (85.0g, 0.274mol) and TBTU (71.0g, 0.222mol) were placed in a 2L dry and clean round bottom flask, and after adding 750mL of dry dichloromethane to dissolve, the The reaction was placed in an ice bath with stirring and triethylamine (73 mL) was added. After the reaction was warmed to room temperature and stirred overnight, 1 L of saturated aqueous ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted with dichloromethane (700 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. After the crude product was dissolved in 1L ethyl acetate, the organic phase was washed with 0.1M aqueous hydrochloric acid (350 mL×3). The organic phase was washed with saturated aqueous sodium bicarbonate (800 mL×2), dried over anhydrous so...

Embodiment 3

[0258] The preparation of embodiment 3 compound 6, synthetic route is:

[0259]

[0260] Include the following steps:

[0261] Compound 5 (60.6 g, 0.109 mol) was dissolved in 550 mL of acetonitrile, anhydrous potassium carbonate (45.2 g, 0.327 mol) and PMBCl (15.6 mL, 0.115 mol) were added in sequence, and the temperature was raised to 40° C. for 32 hours. TLC showed that the reaction of the raw materials was complete, and 21 mL of methylamine (2M / L methanol solution) was added to the reaction liquid, and stirred at room temperature for 2 hours. The mixture was filtered through celite, and the resulting filtrate was concentrated to obtain a crude product. The crude product was dissolved in 500 mL of ethyl acetate, the organic layer was washed with 0.1M hydrochloric acid aqueous solution (150 mL×3), saturated sodium bicarbonate aqueous solution (400 mL×2), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a light brown foam crude...

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Abstract

The invention relates to the field of drug synthesis, and discloses application of an intermediate or a preparation method thereof in total synthesis of morphine derivatives. A transition metal catalyzed asymmetric hydrogenation reaction and an intramolecular oxidation dearomatization Heck reaction in the process of preparing the intermediate are taken as key reactions of total synthesis, and efficient preparation of morphine derivatives, especially representative oxycodone and codeine is realized; the total synthesis method has the advantages of excellent chemical and enantioselectivity, high synthesis efficiency, simple operation and large-scale amplification; meanwhile, the prepared intermediate product can be used for preparing other various morphine derivatives only through simple modification and conversion, and the method has important practical significance for changing the current single industrial production mode of depending on artificial planting, extraction and semi-synthesis of morphine derivative drugs of poppy and guaranteeing supply of morphine drugs.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to an 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 the ...

Claims

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Application Information

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IPC IPC(8): C07D489/02
CPCC07D489/02C07B2200/07Y02P20/55
Inventor 秦勇钟武李松宋颢刘小宇李文斐周骁汉周瑞捷薛斐张丹郑志兵
Owner SICHUAN UNIV
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