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Thebaine derivative as well as preparation method and application thereof

A derivative, thebaine technology, applied in the field of drug synthesis, can solve the problems of no practical significance and production value, and achieve the effect of simple operation, strong operability and high reaction yield

Active Publication Date: 2021-12-28
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, although scientists have developed many new strategies and methods for constructing morphine skeletons, so far, the existing total synthesis methods of morphine and its derivatives do not have practical significance and production value. Starting from natural sources of thebaine , semi-synthesis is still the only way to obtain morphine drugs in industry

Method used

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  • Thebaine derivative as well as preparation method and application thereof
  • Thebaine derivative as well as preparation method and application thereof
  • Thebaine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] The preparation of embodiment 1 compound 10, reaction scheme is as follows:

[0089]

[0090] Include the following steps:

[0091] Compound 9 (20.0g, 40.4mmol) was dissolved in 200mL of glacial acetic acid and reacted at 90°C for 40h. LC / MS detection showed that the raw materials disappeared completely, and the reaction solution was cooled to room temperature and stirred for 30 min. The reaction solution was filtered to obtain a gray solid. The obtained filtrate was concentrated and recrystallized from ethyl acetate to obtain off-white solid. The solids obtained above were combined, dispersed in 10 mL of ethyl acetate, stirred at room temperature for 5 min, filtered and dried in vacuo to obtain white solid compound 10 (13.6 g, yield 85%), which was directly used in the next reaction without purification.

[0092] Compound 10: 1 H NMR (400MHz, CDCl 3 )δ7.70(d, J=8.0Hz, 2H), 7.43(s, 1H), 7.25(d, J=8.0Hz, 2H), 6.74(d, J=8.4Hz, 1H), 6.59(d, J=8.4Hz, 1H), 6.20(s, 1...

Embodiment 2

[0093] Example 2 Synthesis of thebaine derivative 1, the reaction scheme is as follows:

[0094]

[0095] Include the following steps:

[0096] Compound 10 (2.50g, 5.03mmol, 1.0equiv) was dissolved in 40mL of methanol / dichloromethane (1:1), and sodium borohydride (382mg, 10.06mmol, 2.0equiv) was slowly added at 0°C, and the addition was completed. The reaction solution was gradually raised to room temperature for 30 min. After TLC showed that the reaction was complete, a saturated ammonium chloride solution (30 mL) was added to the reaction solution under an ice bath to quench the reaction, extracted with dichloromethane (30 mL×3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated The crude compound 11 (2.65 g) was obtained as a white foam.

[0097] Under the protection of argon, the above crude compound 11 was dissolved in 15 mL of dry 1,4-dioxane, and N,N-dimethylformamide dimethyl acetal (15 mL, 0.11 mol) was added to rea...

Embodiment 3

[0100] The synthesis of embodiment 3 compound 5, reaction scheme is as follows:

[0101]

[0102]Thebaine derivative 1 (1.7g, 3.64mmol, 1.0equiv) was dispersed in dry ethylene glycol dimethyl ether (40mL) under the protection of argon, and lithium aluminum hydride (1.0M / LinTHF, 18.2 mL, 5.0 equiv.), after the addition, the reaction solution was gradually raised to room temperature for 40 hours. TLC detection showed that the raw material disappeared completely, and 5 mL of isopropanol was added to the reaction solution under an ice bath, and 0.7 mL of water was slowly added after stirring for 5 min, and 0.7 mL of 15% aqueous sodium hydroxide solution was added after stirring for 5 min, and 2 mL of water was added after stirring for 5 min. The reaction solution was raised to room temperature and stirred for 30 min. The reaction solution was filtered, the filter cake was washed 6 times with dichloromethane, and the filtrate was concentrated to obtain an off-white powder (crud...

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Abstract

The invention relates to the technical field of medicine synthesis, and discloses a thebaine derivative and a preparation method thereof. The invention also discloses an application of the thebaine derivative in preparation of codeine, the codeine can be prepared from the thebaine derivative only through several simple steps of conversion, and the prepared codeine can be further converted into morphine in one step, wherein in the reaction process, the used reagents are common chemical reagents and do not need to be specially prepared; meanwhile, the requirements on conditions of each reaction are not harsh, the sensitivity to substances such as water and oxygen is not high, the post-treatment of each reaction step is simple, the operability is great, and the effects of high reaction yield and simple operation are achieved.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a thebaine derivative and its preparation method and application. Background technique [0002] Morphine is an alkaloid isolated from opium, and its weight accounts for about 14% to 17% of the weight of opium (Herbert, R.B.; Venter, H.; Pos, S.Nat.Prod.Rep.2000,17,317) , is a common anesthetic and analgesic drug. In addition to morphine, natural morphine alkaloids also include codeine, thebaine, and codeinone. [0003] [0004] The morphine molecule is a highly compact five-ring fused complex molecule, which contains a five-membered dihydrofuran ring, a nitrogen-containing bridge ring, and five continuous chiral centers including a benzylic quaternary carbon center. The star natural product molecules in the field of synthetic chemistry. In order to realize the efficient and practical total synthesis of morphine and solve the problem of the source of morphine drugs, since the G...

Claims

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Application Information

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IPC IPC(8): C07D489/02
CPCC07D489/02Y02P20/55
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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