Preparation method for 2-dibutylamido-1-1(2,7- dichloro-9H-fluorine-4base)-ethanol

Abstract

The invention discloses a preparation method for 2-dibutylamido-1-1(2,7- dichloro-9H-fluorine-4base)-ethanol. In an existing method, the yield is low, or the yield is high, but new impurities are generated, and yield is still needed to be improved. The preparation method comprises the following steps of: using 2,7-dichlorofluorene as a material; and carrying out an acylation reaction, reduction reaction and amination in sequence to obtain 2-dibutylamido-1-1(2,7- dichloro-9H- fluorine-4base)-ethanol, wherein the molar ratio of reducing agent in the reduction reaction to 2,7-dichlorofluorene is (0.4-1.3):1; and the molar ratio of amination accelerator in amination reaction to the 2,7-dichlorofluorene is (0.4-1.3):1. The preparation method avoids the problems such as product loss, health damage, environment pollution and the like caused by separating, purifying and drying steps of the acylation reaction and reduction reaction, further simplifies process steps, shortens a production period, reduces production cost and remarkably improves the yield and the product quality.

Description

technical field [0001] The invention relates to the field of chemical pharmacy, in particular to a preparation method of 2-dibutylamino-1-(2,7-dichloro-9H-fluoren-4-yl)-ethanol. Background technique [0002] Lumefantrine (Lumefantrine, the structure is shown in formula I), that is, 2-n-butylamino-1-[2,7-dichloro-9-(4-chlorobenzylidene)-fluoren-4-yl]-ethanol , is a yellow crystalline non-hygroscopic powder, easily soluble in N,N-dimethylformamide, chloroform and ethyl acetate, soluble in dichloromethane, slightly soluble in ethanol and methanol, insoluble in water, with a melting point of 128°C- 132°C. Benefantrine is a mefloquine drug created in my country, which can be used to treat various malaria, especially falciparum malaria caused by chloroquine-resistant strains. [0003] [0004] The existing preparation method of benzfluorenol comprises 5 steps of reaction, i.e. fluorene → chloride → acylate → epoxy → aminate → benzfluorenol, wherein, the reaction of preparing ...

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Problems solved by technology

This method has the following defects: ① the sensitization of the acylate is obvious, and the sensitization of the acylate will affect the health of the contact personnel during the separation, purification and drying process of the acylate; ② 2,7-dichlorofluorene-4-cyclo Filtration of oxyethane is difficult, and the wet product has a high moisture content, resulting in a long production cycle for filtration, drying and other processes; ③The volatilized solvent in the material affects the health of the contact personnel; ④There are many reaction steps and the production cycle is long. The product yield is low, and the product yield and quality need to be improved; ⑤The five reaction steps all produce a certain amount of scraps and waste solvents, which need to be recycled and have an impact on environmental protection

[0009] The document "An Improved Manufacturing Process for the Antimalaria Drug Coartem.Part II" (Organic Process Research & Development 2007, 11, 341-345) discloses the preparation method of benzfluorenol, which completes the acylate in the preparation of benzfluorenol by sequential reaction Reduction reaction and amination reaction to obtain amide, which shortens the production cycle, but has the following defects: 1) the yield of the crude product of benzfluorenol prepared from amine is reduced; 2) new impurities are produced during the preparation, and New impurities cannot be completely removed in subsequent crystallization, thus affecting product quality; 3) The reaction is sensitive to impurities brought in by raw materials or equipment, and the stability of this method needs to be improved

The characteristics of this method include: 1) prolong the reduction reaction time to 10-24h; 2) wash the solid separated from the reaction liquid with water until neutral to remove excess sodium borohydride or potassium borohydride; 3) recover and separate The ethanol in the mother liquor obtained after solidification, wherein the recovery of ethanol is 50-60% of the initial volume of anhydrous ethanol, and the recovered ethanol can be recycled for the reduction reaction step of the next batch of production; 4) The mother liquor concentrate is used as The solvent in the subsequent process realizes the recycling of absolute ethanol, which significantly reduces the production cost; however, the intermediate separation, purification, drying and other processes in this method are complicated, and the yield is only 51%-60%

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