Synthesis method of nature-identical raspberry keytone

Patent metadata

Field	Value
Publication number	US-2025034072-A1
Application number	US-202418779503-A
Country	US
Kind code	A1
Filing date	Jul 22, 2024
Priority date	Jul 24, 2023
Publication date	Jan 30, 2025
Grant date	—

Abstract

A method for synthesizing nature-identical raspberry ketone is provided, belonging to the technical field of pharmaceutical synthesis. The nature-identical raspberry ketone is obtained by using natural p-anisaldehyde and natural acetone as initial raw materials to allow three-step continuous reactions of basic resin-catalyzed Claisen-Schmidt condensation, enzyme-catalyzed reduction, and demethylation of sodium ethanethiolate. The synthesis method is safe and clean, and has a stable yield reaching approximately 85%, providing a basis for industrial continuous production. The synthesis method not only meets the requirements for clean production, but also saves labor costs by virtue of the continuous process, and is suitable for large-scale industrial production.

First claim

What is claimed is:

1 . A method synthesizing nature-identical raspberry ketone, comprising the following steps:
(1) conducting Claisen-Schmidt condensation, comprising: mixing p-anisaldehyde and acetone to obtain a reaction solution, introducing the reaction solution into a reactor filled with a basic anion resin through a microchannel with a diameter of approximately 2.5 mm to allow a reaction, collecting an obtained effluent and rinsing the microchannel with a small amount of the acetone, and adding water to allow dilution until solids are completely precipitated to obtain 4-(4-methoxyphenyl)but-3-en-2-one; wherein the reactor filled with the basic anion resin has an inner diameter of 13 mm and a filling volume of 60 mm; (2) conducting enzyme-catalyzed reduction, comprising: adding dimethyl sulfoxide (DMSO), glucose, 4-(4-methoxyphenyl)but-3-en-2-one, an ene-reductase, glucose dehydrogenase (GDH), and nicotinamide adenine dinucleotide (NAD+) into phosphate-buffered saline (PBS) to obtain a mixed solution, stirring the mixed solution to allow a reaction at 35° C. for 24 h, maintaining a pH value of an obtained reaction solution at 7.0 by adding a saturated sodium bicarbonate solution dropwise using a pH titrator, and determining that the reaction is completed by thin layer chromatography (TLC) detection; extracting the reaction solution three times with isopropyl acetate, combining obtained isopropyl acetate phases, washing with a saturated salt solution, drying over anhydrous magnesium sulfate, and filtering to obtain a filtrate, and subjecting the filtrate to evaporation to remove solvents to obtain a product anisyl acetone; and (3) conducting demethylation of sodium ethanethiolate, comprising: adding an anhydrous N,N-dimethylformamide (DMF) solution of ethanethiol into an anhydrous DMF suspension of sodium hydride under a nitrogen atmosphere, stirring for 5 min to 8 min to allow full mixing to obtain a sodium ethanethiolate solution, and then adding anisyl acetone prepared in step (2) to allow heating reflux for 3 h; adjusting an obtained reaction product to a pH value of 6, extracting twice with chloroform, combining obtained organic phases, washing twice with water, conducting liquid separation, recycling chloroform by atmospheric distillation, recycling anisyl acetone by vacuum distillation to allow reuse, and conducting recrystallization to obtain nature-identical raspberry ketone.

2 . The method according to claim 1 , wherein p-anisaldehyde in the reaction solution in step (1) has a volume fraction of 1% to 30%.

3 . The method according to claim 1 , wherein the reaction solution in step (1) has a flow rate of 1.0 mL/min to 1.5 mL/min in the microchannel.

4 . The method according to claim 1 , wherein the basic anion resin in step (1) is a hydroxide-type strongly basic anion exchange resin.

5 . The method according to claim 1 , wherein DMSO, glucose, 4-(4-methoxyphenyl)but-3-en-2-one, the ene-reductase, the GDH, the NAD+, and a total volume of the mixed solution are at a ratio of (0.05-0.25) mL: (20-60) mg: (170-180) mg: (0.03-0.67) mg: (0.01-0.2) mg: (0.002-0.01) mg: 2 mL in the mixed solution in step (2).

6 . The method according to claim 5 , wherein PBS has a pH value of 7.0 and a concentration of 0.2 mol/L.

7 . The method according to claim 1 , wherein the stirring in step (2) is conducted at 400 rpm.

8 . The method according to claim 1 , wherein ethanethiol in the anhydrous DMF solution of ethanethiol in step (3) has a concentration of 0.03 g/mL to 0.035 g/mL; and sodium hydride in the anhydrous DMF suspension of sodium hydride has a concentration of 0.01 g/mL to 0.015 g/mL.

9 . The method according to claim 8 , wherein the anhydrous DMF solution of ethanethiol and the anhydrous DMF suspension of sodium hydride are at a volume ratio of 1:1.

10 . The method according to claim 1 , wherein ethanethiol, sodium hydride and anisyl acetone in step (3) are at a mass ratio of (0.3-0.35):(0.1-0.15):1.

Assignees

• Dai Huifang
• Liu Baolu
• Li Bin
• Dai Huali
• Mei Aoxue

Inventors

• Dai Huifang
• Liu Baolu
• Li Bin
• Dai Huali
• Mei Aoxue

Classifications

• C07C45/74

  combined with dehydration · CPC title

• C12P7/26 Primary

  Ketones · CPC title

• C12P7/28 Primary

  Acetone-containing products · CPC title

• C07C319/02

  of thiols · CPC title

• C07C45/64

  by introduction of functional groups containing oxygen only in singly bound form · CPC title