CN-122010884-A - Preparation method of tetrahydronaphtho [1,2-b ] furan-2 (3H) -ketone compound

Abstract

A preparation method of tetrahydronaphtho [1,2-b ] furan-2 (3H) -ketone compound, belonging to the technical field of organic synthesis. The preparation method comprises the steps of reacting a compound 1 with tetra-n-butyl ammonium fluoride to obtain a compound 2, reacting the compound 2 with alkali and L-DTTA to obtain a compound 3, reacting the compound 3 with methanesulfonic acid to obtain a crude product of tetralin [1,2-b ] furan-2 (3H) -one compound, and purifying the crude product of tetralin [1,2-b ] furan-2 (3H) -one compound to obtain the tetralin [1,2-b ] furan-2 (3H) -one compound. The product obtained by the preparation method has high yield and purity, and low isomer content and production cost.

Inventors

• Xiao Chuangmeng
• YANG SHUYIN
• XIA SHUYING
• HU SIYUAN

Assignees

• 江西普正制药股份有限公司

Dates

Publication Date

20260512

Application Date

20260130

Claims (10)

1. 1. A process for the preparation of a tetralin [1,2-b ] furan-2 (3H) -one compound, comprising the steps of: (1) Reacting the compound 1 with tetra-n-butyl ammonium fluoride to obtain a compound 2; (2) Reacting the compound 2, alkali and L-DTTA to obtain a compound 3; (3) Reacting the compound 3 with methanesulfonic acid to obtain a crude tetrahydronaphtho [1,2-b ] furan-2 (3H) -one compound; (4) Purifying the crude tetrahydronaphtho [1,2-b ] furan-2 (3H) -one compound to obtain tetrahydronaphtho [1,2-b ] furan-2 (3H) -one compound; the compound 1 is: the compound 2 is: the compound 3 is: The tetrahydronaphtho [1,2-b ] furan-2 (3H) -one compound is: 。
2. 2. the process according to claim 1, wherein the molar ratio of compound 1 to tetra-n-butylammonium fluoride in step (1) is 1 (3-4.5), and/or The reaction in the step (1) is that the compound 1 and tetra-n-butyl ammonium fluoride react for 2-4 hours at 20-30 ℃.
3. 3. The process of claim 1, wherein the base in step (2) is dimethylamine.
4. 4. The process according to claim 3, wherein the solvent of dimethylamine is tetrahydrofuran.
5. 5. The process according to claim 1, wherein the molar ratio of compound 2 to L-DTTA in step (2) is 1 (1-1.5).
6. 6. The process of claim 1, wherein the solvent of the reaction of step (2) is methylene chloride.
7. 7. The preparation method according to claim 1, wherein the reaction in the step (2) is that the compound 2 is reacted with alkali at 20-30 ℃ for 10-20 hours, and then L-DTTA is added for 20-30 ℃ for 1-2 hours.
8. 8. The preparation method according to claim 1, wherein the reaction in the step (3) is that the compound 3 is extracted by adding inorganic base and an organic phase is collected, and the organic phase is reacted with methanesulfonic acid at 20-30 ℃ for 0.5-2h; The inorganic base is at least one of sodium hydroxide, potassium carbonate, potassium hydroxide and sodium carbonate.
9. 9. The method of claim 1, wherein the purification of step (4) is recrystallisation.
10. 10. The method of claim 9, wherein the solvent for recrystallization is acetone containing 1-5wt% of water.

Description

Preparation method of tetrahydronaphtho [1,2-b ] furan-2 (3H) -ketone compound Technical Field The invention provides a preparation method of tetralin [1,2-b ] furan-2 (3H) -ketone compounds, belonging to the technical field of organic synthesis. Background Tetrahydronaphtho [1,2-b ] furan-2 (3H) -one compounds of the formula: The Chinese cultural name is (3S, 3aS,9 bR) -8- (2-bromobenzyl methoxy) -3- ((dimethyl) aminomethyl-6, 9-dimethyl-3 a,4,5,9 b-tetrahydronaphthalene [1,2-b ] furan-2 (3H) -ketone mesylate, and the English cultural name ：(3S,3aS,9bR)-8-((2-bromobenzyl)oxy)-3-((dimethylamino)methyl)-6,9-dimethyl-3a,4,5,9b-tetrahydronaphtho[1,2-b]furan-2(3H)-one mesylate, is an effective rheumatoid arthritis therapeutic drug. In chinese patent CN111247132B, the preparation method comprises preparing compound 51 (i.e. compound 2 of the present invention) by the method of example 1, preparing compound 59 (i.e. compound 4 of the present invention) by using compound 51 by the method of example 4, weighing compound (3 aS, 9 bR) -8- (2-bromobenzyloxy) -6, 9-dimethyl-3-methylene-3 a, 4, 5, 9B-tetrahydronaphtho [1, 2-B ] furan-2 (3H) -one, preparing compound 51 (1.0 g, 2.43 mmol, 1.0 eq) and dimethylamine hydrochloride (0.3 g, 3.64 mmol, 1.5 eq) in 20ml ethanol, dropping triethylamine (0.37 g, 3.64 mmol, 0.51 ml, 1.5 eq) at 0 ℃, naturally rising to room temperature, monitoring by TLC, after complete consumption of compound 51, removing ethanol under reduced pressure, adding dichloromethane and water, and saturated brine (5B) to obtain white solid (i.e. ethyl acetate, washing 5B ] furan-2 (3H) -2) (1.0 mg, 3 mg, 3.43 mmol, 1.5 eq) and 5 mg of dimethylamine hydrochloride (0.3 g,3 mg, 3.64 mmol, 1.5 eq) in 20ml ethanol, and drying the aqueous solution of ethyl acetate, and washing the saturated aqueous solution (2-methyl film) to obtain pure PE, anhydrous acetone. The preparation method has higher purity, but needs two column chromatography, which is unfavorable for the scale-up production. Meanwhile, the product prepared by the preparation method has higher isomer content. In the case of chiral isomers, resolution is usually carried out by chiral column methods, such as those described in chromatographic chiral separation techniques and applications (Yuan Liming et al, 2020, chemical industry Press), chiral mobile phase additive methods, chiral derivatization reagent methods, chiral gas chromatography, etc., but this method is expensive and not suitable for mass production. For chiral isomers, the molecular structures of the chiral isomers are mirror images but cannot be overlapped, and the conventional achiral separation technology is difficult to realize effective resolution, so that the related technology and the matching method of the chiral column are used for precise separation and purification in the industry. Among them, chiral separation techniques and applications (Yuan Liming et al, 2020, chemical industry Press) describe chiral mobile phase additive methods, chiral derivatization reagent methods, chiral gas chromatography methods, and the like. However, the separation method based on the chiral column has the remarkable limitations that the preparation process of the chiral stationary phase material is complex, the cost is high, the service life is limited, the cost of production consumables is greatly increased due to frequent replacement, meanwhile, special solvents or auxiliary agents are often needed in the chiral separation process, the subsequent solvent recovery treatment is difficult, the environmental protection cost is high, in addition, the separation efficiency of the chromatographic method is influenced by various parameters such as flow rate, temperature and the like, and the problems of unstable separation effect, limited productivity and the like easily occur in the large-scale amplification process, so that the method is not suitable for industrial-scale large-scale production scenes as a whole. Patent WO2021143853A1 discloses a tetrahydronaphtho [1,2-b ] furan-2 (3H) -one compound and a crystal form research thereof, wherein the reaction route is as follows: 。 This patent states that the yield of compound VII obtained by three recrystallisation after the reaction is only 72% and it contains 90% of the S configuration and 10% of the R configuration, requiring three recrystallisation steps to obtain a single S configuration compound. The preparation method of the patent has the advantages that more isomer compounds are generated in the preparation process, so that the purification difficulty is increased and the yield is reduced. Disclosure of Invention The invention provides a preparation method of tetralin [1,2-b ] furan-2 (3H) -ketone compound, which has high yield and purity of the product obtained by the preparation method and low isomer content and production cost. Description of the terminology: Unless defined otherwise, all technical and scientific terms used herein have the same