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Synthesis method of morphine derivative buprenorphine

A synthetic method and compound technology, applied in organic chemical methods, bulk chemical production, organic chemistry, etc., can solve problems such as cumbersome operations, and achieve high reactivity, cost reduction, and high chemical and optical yields

Pending Publication Date: 2022-01-21
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the removal of nitrogen methyl group is a difficult point in the synthesis, which involves multi-step transformation. For example, it is necessary to use cyanogen bromide to introduce a cyano group on the nitrogen atom, and then remove the cyano group, etc., and the operation is more cumbersome.
Although there are many reports on the synthesis of buprenorphine by the above-mentioned route, most of them are the improvement of the reaction conditions and the improvement of the process of the above-mentioned conversion steps, and the starting point of the synthesis of the natural product thebaine is still used, and the need to use thebapine as a raw material has not been fundamentally resolved. The problem with semi-synthesis

Method used

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  • Synthesis method of morphine derivative buprenorphine
  • Synthesis method of morphine derivative buprenorphine
  • Synthesis method of morphine derivative buprenorphine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0215] The preparation method of embodiment 1 compound 5, with R 3 For H, X is bromine as an example, synthetic compound 5a;

[0216] Include the following steps:

[0217]

[0218] 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 3Aqueous solution (500mL) was used to quench the reaction, stirred at 0°C for 1h, and the precipitate was completely precipitated, filtered, washed with water (500mL × 3), and the obtained off-white solid 2a was collected, dried 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%).

[0219] ...

Embodiment 2

[0222] The preparation method of embodiment 2 compound 5, with R 3 For Me, X is bromine as an example, synthetic compound 5b;

[0223] Include the following steps:

[0224]

[0225] Ph 3 P + CH 2 OMeCl-(911g, 2.66mol, 3.1equiv.) was dispersed in dry tetrahydrofuran (2500mL), cooled to 0°C in an ice bath, and t-BuOK (279g, 2.48mol, 2.9equiv.) was slowly added to it, and the reaction solution became orange Red, stirred 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, and concen...

Embodiment 3

[0228] 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:

[0229]

[0230] Include the following steps:

[0231] 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. Filtration, the filter cake was washed successively with methanol / water (v / v=1:1) (200mL × 3), absolute ethanol (200mL × 2), and the solid was collected and dried under reduced pressure with a water pump to obtain compound 7 (bright yellow fine needles). crystals, 185 g, yield 72%).

[0232] 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 ...

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Abstract

The invention belongs to the field of synthesis of chemical drugs, and particularly relates to a novel synthesis method of a morphine derivative buprenorphine. Based on a possible biogenic pathway of morphine derivatives, a thibaine analogue intermediate is synthesized by taking an intramolecular oxidation dearomatization Heck reaction as a key reaction through a biomimetic synthesis strategy, and by starting from the intermediate through a Diels-Alder reaction, catalytic hydrogenation, addition with a tert-butyl Grignard reagent, removal of a secondary amine protecting group, introduction of cyclopropyl methyl, and removal of methyl and the like, efficient synthesis of the morphine derivative buprenorphine is realized. Compared with the existing route, the synthesis route has the advantages of few steps, high total yield and obvious reduction of the production cost.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing morphine derivative buprenorphine. Background technique [0002] Morphine drugs represented by hydrocodone, oxycodone, buprenorphine, nalaxone, naltrexone, dihydroetorphine, etc. Opioid receptor agonists are mainly used clinically for moderate and severe pain and palliative treatment caused by severe trauma, burns, fractures, cancer, etc., as well as opioid receptor antagonists for the treatment of respiratory depression and withdrawal of opioid drugs and alcohol Drugs for the treatment of addiction are recognized as essential drugs 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 statistics of the IQVIA database, in 2018, the total produc...

Claims

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Application Information

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IPC IPC(8): C07D489/12
CPCC07D489/12C07B2200/07Y02P20/55
Inventor 秦勇薛芳琳石珍薛斐宋颢
Owner SICHUAN UNIV
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