A process for the preparation of a bugulifuran intermediate

Abstract

The present application relates to a kind of methods for preparing bugg furan intermediate, belong to the technical field of biopharmaceutical process.Taking dihydrocarveol and 1-octene-3-ketone into reaction solution, then methanol and sodium hydroxide are added into reaction solution in sequence, stirring is heated to 45 DEG C, reaction is carried out for 4-5 h, then sodium hydroxide is added, heated to 85 DEG C, reflux reaction is carried out for 6 h, then solvent is spun dry, ice water is added, then extracted with ethyl acetate twice, organic phase is combined, then washed with saturated sodium chloride water once, dried with anhydrous sodium sulfate, solvent is spun dry, and oil-like crude product is obtained, column chromatography purification is carried out, PE:EA=50:1, colorless oil is obtained by purification, that is, intermediate I-2, intermediate I-2 can be synthesized in 11 h by the method, and the yield is controlled to be more than 97%, the present application is simple, convenient and effective to reduce reagent use, and can be quickly and high yield.

Description

Technical Field

[0001] This invention relates to a method for preparing a bouguran intermediate, belonging to the field of biopharmaceutical process technology. Background Technology

[0002] Burgerfuran is a modified product of α-agarfuran, a natural active ingredient isolated from the traditional Chinese medicine agarwood. This compound was first prepared by researchers at the Institute of Medical Sciences, Chinese Academy of Medical Sciences. It has been shown to have good anti-anxiety, antidepressant, and sleep disorder relief effects, and has low toxicity. It was independently developed in my country and is undergoing clinical trials as a Class I new drug in China (Chinese Patent Nos. ZL98122447.4, ZL001808339.2; US Patent No. US6486201B1; European Patent No. EP1132383B1; Japanese Patent No. JP4321967). Its indication is generalized anxiety disorder.

[0003]

[0004] Burgerfuran is a novel compound with a high cost of extraction from agarwood, making its preparation via total chemical synthesis particularly important. Currently, few preparation methods have been reported. Patent CN106883185A describes a process involving an addition reaction to obtain intermediate I-1, followed by a Robinson cyclization reaction to obtain intermediate I-2; however, this process is cumbersome and consumes significant amounts of solvents and reagents. Summary of the Invention

[0005] To address the technical problems existing in the prior art, this invention provides a simple, convenient, and efficient method for preparing bougerfuran intermediates that effectively reduces reagent usage and achieves rapid and high yields.

[0006] To achieve the above objectives, the technical solution adopted in this invention is a method for preparing a burgerfuran intermediate. The method involves the following steps: adding dihydrocarvone and 1-octen-3-one to a reaction solution, then sequentially adding methanol and sodium hydroxide, stirring and heating to 45°C for 4-5 hours. Sodium hydroxide is then added, and the mixture is refluxed at 85°C for 6 hours. The solvent is then evaporated, ice water is added, and the mixture is extracted twice with ethyl acetate. The organic phases are combined, washed once with saturated sodium chloride water, dried over anhydrous sodium sulfate, and the solvent is evaporated again to obtain an oily crude product. This product is purified by column chromatography (PE:EA = 50:1), yielding a colorless oily product, which is intermediate I-2. This method allows for the synthesis of intermediate I-2 within 11 hours, with a yield controlled above 97%.

[0007] Compared with the prior art, the present invention has the following technical effects: The present invention adopts a one-pot reaction, which greatly improves the synthesis efficiency of intermediate I-2. Moreover, this method is simple and convenient to operate, effectively reduces the use of reagents, and can quickly and with high yield obtain intermediate I-2. Attached Figure Description

[0008] Figure 1 This is the carbon NMR spectrum of intermediate I-2 in this invention. Detailed Implementation

[0009] To make the technical problems to be solved, the technical solutions, and the beneficial effects of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention.

[0010] Currently, the existing synthetic routes for the bougerfuran intermediate I-2 are as follows: .

[0011] The synthetic route in this invention is as follows: .

[0012] The synthesis of the bougerfuran intermediate I-2 was carried out using a one-pot reaction, which greatly improved the synthesis efficiency of intermediate I-2.

[0013] The specific implementation method is as follows:

[0014] Example 1 10 g (1.0 eq) of dihydrocarvone and 7.5 g (0.9 eq) of 1-octen-3-one were added to the reaction solution in a three-necked flask. 50 ml of methanol and 2.4 g (1.0 eq) of sodium hydroxide were added. The mixture was stirred and heated to 45 °C and reacted for 4-5 h. 2.4 g (1.0 eq) of sodium hydroxide was added, and the mixture was heated to 85 °C and refluxed for 6 h. The product I-2 was detected by TLC.

[0015] Post-processing: the solvent was evaporated, 30 ml of ice water was added, and the product was extracted twice with 25 ml of ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride water, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 14.3 g of crude oil (92.3% crude product yield). The product was purified by column chromatography (PE:EA = 50:1) to obtain 13 g of colorless oil (84% yield). The structure of intermediate I-2 was determined. 1H NMR (600 MHz, CDCl3): δ 4.80 (s, 1H), 4.65 (s, 1H), 2.88 (d, J = 15.9 Hz, 1H), 2.57 – 2.48 (m, 3H), 2.42 – 2.35 (m, 2H), 2.15 (m, 1H), 1.91 – 1.80 (m, 2H), 1.72 (s, 3H), 1.69 – 1.63 (m, 2H), 1.53 (m 1H), 1.35 – 1.24 (m, 8H), 0.88 (t,J = 7.1 Hz, 3H).

[0016] Example 2 10 g (1.0 eq) of dihydrocarvone and 7.5 g (0.9 eq) of 1-octen-3-one were added to the reaction solution in a three-necked flask. 50 ml of methanol and 2.4 g (1.0 eq) of sodium hydroxide were added. The mixture was stirred and heated to 45 °C and reacted for 4-5 h. 1.9 g (0.8 eq) of sodium hydroxide was added, and the mixture was heated to 85 °C and refluxed for 6-8 h. The product I-2 was detected by TLC.

[0017] Post-processing: the solvent was evaporated, 30 ml of ice water was added, and the mixture was extracted twice with 25 ml of ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride water, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 15.1 g of crude oil (crude product yield 97.4%).

[0018] Example 3 10 g (1.0 eq) of dihydrocarvone and 7.5 g (0.9 eq) of 1-octen-3-one were added to the reaction solution in a three-necked flask. 50 ml of methanol and 2.4 g (1.0 eq) of sodium hydroxide were added. The mixture was stirred and heated to 45 °C and reacted for 4-5 h. 0.85 g (0.4 eq) of sodium hydroxide was added, and the mixture was heated to 85 °C and refluxed for 6-8 h. The product I-2 was detected by TLC.

[0019] Post-processing: the solvent was evaporated, 30 ml of ice water was added, and the product was extracted twice with 25 ml of ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride water, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain 15 g of crude oil (crude product yield 96.8%).

[0020] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of the present invention.

Claims

1. A method for preparing a bougerfuran intermediate, characterized in that: The following steps were performed: Dihydrocarvone and 1-octen-3-one were added to a three-necked flask, followed by the addition of methanol and sodium hydroxide. The mixture was stirred and heated to 45°C for 4-5 hours. Sodium hydroxide was then added, and the mixture was refluxed at 85°C for 6 hours. The solvent was then evaporated, ice water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride water, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain an oily crude product. The product was purified by column chromatography (PE:EA = 50:1) to obtain a colorless oil, which is intermediate I-2. This method can synthesize intermediate I-2 within 11 hours with a yield of over 97%. The structural formula of intermediate I-2 is: 。

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