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Method for preparing 17 beta-HSD1 inhibitor

An inhibitor and solvent technology, applied in the field of drug synthesis, can solve the problems of low total yield, low yield and the like

Inactive Publication Date: 2013-10-23
LINHAI LIANSHENG CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the yield of each step of this method is low, the yield of the first step can only reach about 24%, and the yield of the second step can only reach about 49% simultaneously, and the total yield is then lower

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] The raw material 5-chloro-2-thiophene boronic acid pinacol ester 244mg (1mmol), 2,4-dibromopyridine 472mg (2mmol), KOH112mg (2mmol), palladium acetate 11mg (0.05mmol), PPh 3 52mg (0.2mmol) and 6mL CH 3 Add the CN solvent into a 25 mL round-bottomed flask, then, under the protection of nitrogen, raise the temperature to 70°C, and stir for 24 hours. After the reaction, filter with a sand core funnel, collect the filtrate, and remove the solvent under reduced pressure to obtain a solid The residue was then dissolved in 10 mL of dichloromethane, washed with 10 mL of saturated sodium chloride solution for 2-3 times, allowed to stand and separated, and the organic phase was collected, then concentrated to remove the solvent, and then Column chromatography (using petroleum ether / ethyl acetate as the mobile phase, the volume ratio of petroleum ether and ethyl acetate is 200:1), after the column chromatography is completed, the solvent is removed and dried to obtain a yellow so...

Embodiment 2

[0043] The raw material 5-chloro-2-thiophene boronic acid pinacol ester 244mg (1mmol), 2,4-dibromopyridine 521mg (2.2mmol), NaOH 120mg (3mmol), palladium acetate 11mg (0.05mmol), PPh 3 52 mg (0.2 mmol) and 10 mL of CH 3 Add the CN solvent into a 25mL round-bottomed flask, then, under the protection of nitrogen, raise the temperature to 65°C, control the temperature at 65°C, and stir for 25h. After the reaction, filter with a sand core funnel to collect the filtrate , remove the solvent under reduced pressure to obtain a solid residue, then add 10mL of dichloromethane to dissolve, then wash with 10mL of saturated sodium chloride solution, wash 2-3 times, let stand, separate layers, collect the organic phase, and then separate the organic phase After concentration to remove the solvent, column chromatography (petroleum ether / ethyl acetate as the mobile phase, the volume ratio of petroleum ether to ethyl acetate is 200:1), remove the solvent, and dry to obtain the yellow solid i...

Embodiment 3

[0046] The raw material 2,4-dibromopyridine 498mg (2mmol), 5-chloro-2-thiophene boronic acid pinacol ester 244mg (1mmol), NaOH 100mg (2.5mmol), palladium acetate 11mg (0.05mmol), PPh 3 52mg (0.2mmol) and 10mLCH 3 Add the CN solvent into a 25mL round-bottomed flask, then, under the protection of nitrogen, raise the temperature to 75°C, control the temperature at 75°C, and stir for 25h. After the reaction, filter with a sand core funnel and collect the filtrate , remove the solvent under reduced pressure to obtain a solid residue, then add 10mL dichloromethane to dissolve, then wash with 10mL saturated sodium chloride solution, wash 2-3 times, let stand, separate layers, collect the organic phase, and then separate the organic phase After concentrating the solvent, go through column chromatography (petroleum ether / ethyl acetate as the mobile phase, the volume ratio of petroleum ether to ethyl acetate is 200:1), remove the solvent, and dry to obtain a yellow solid interme...

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Abstract

The invention relates to a method for preparing a 17 beta-HSD1 inhibitor, belonging to the technical field of pharmaceutical synthesis. In order to solve the technical problem of low yield in the prior art, the invention provides a method for preparing a 17 beta-HSD1 inhibitor. The method comprises the following steps: A. under the action of an inorganic alkali, reacting bromopyridine disclosed as Formula II with 5-chloro-2-thienylboronic acid pinacol cyclic ester in the presence of a palladium-containing catalyst and a phosphorous compound to obtain an intermediate compound; and under the action of an inorganic weak alkali, in the presence of the palladium-containing catalyst and phosphorous compound, carrying out Suzuki reaction on the intermediate compound and meta-hydroxyphenylboric acid in a nitrile-alcohol mixed solvent to obtain the 17 beta-HSD1 inhibitor. The method provided by the invention has the advantages of high yield, high purity of the final product, and short process route, and can easily implement industrial production.

Description

technical field [0001] The invention relates to a method for preparing 17β-HSD1 inhibitor, which belongs to the technical field of medicine synthesis. Background technique [0002] β-Hydroxysterol dehydrogenase (17β-HSD) is an NAD(H) or ANDP(H)-dependent enzyme that converts inactive 17-keto-steroids to their active 17β-hydroxy-form or catalyzes The 17β-hydroxy-form is oxidized to the 17-keto-steroid. Since both estrogens and androgens have the highest affinity for their receptors in the 17β-hydroxyl form, it appears that the 17β-HSD enzyme plays a major role in the selective regulation of the active tissue of sex steroid hormones. At present, there are 10 types of 17β-HSD enzyme family (1-5, 7, 8, 10-12), and among them, 17β-HSD1 enzyme has the best characteristics. Under physiological conditions in vivo, this enzyme only catalyzes from According to the reduction reaction of estrone to estradiol, the 17β-HSD1 was found to be expressed in various hormone-dependent tissues,...

Claims

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Application Information

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IPC IPC(8): C07D409/04
Inventor 周其忠张斌陈仁尔蒋华江俞小鸥
Owner LINHAI LIANSHENG CHEM
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