Preparation method of 15-ketone

Abstract

The invention relates to a preparation method of a drug intermediate 15-ketone in the field of chemistry. The preparation method comprises the following steps: (1) in the first organic solvent, adding (-)-benzoyl coli lactone, an oxidizing agent and a catalyst for oxidation reaction to obtain a reaction solution A; (2) adding the reaction solution A to the reaction solution A obtained in step (1) Stir and filter after adding dilute acid dropwise, after the filtrate is directly extracted with the first organic solvent, wash the organic phase with water, dehydrate with a desiccant, filter to obtain (‑)‑benzoyl coli lactone aldehyde solution; (3) to step (2) Add the Wittig reagent in the obtained (‑)-benzoyl corylidene aldehyde solution to carry out the Wittig reaction to obtain the reaction solution B, concentrate, add the second organic solvent, cool down, and crystallize to obtain the crystallization liquid; (4) The crystal liquid obtained in step (3) is filtered, the filter cake is washed with the third organic solvent, the filter cake is dissolved with the first organic solvent to remove impurities, filtered, and concentrated to obtain an oily substance. The invention has the advantages of good product quality and the like.

Description

technical field [0001] The invention relates to a preparation method of prostaglandin drug intermediate 15-ketone in the field of chemical pharmacy. Background technique [0002] Prostaglandins (PG for short) are a large class of biologically active substances with a wide range of physiological effects. Therefore, PG compounds, as a class of important drugs, are used for regulating menstruation, anti-early pregnancy, inducing labor, oxytocin, lowering blood pressure, anticoagulant, antitumor, treating asthma and gastric ulcer disease, etc. [0003] Natural prostaglandins mostly exist in the seminal vesicles of animals. Due to the low content, difficulty in extraction, and poor stability, people have successively synthesized a series of prostaglandin substances or analogs to meet clinical needs. Among them, 15-ketone is a key intermediate for the total synthesis of prostaglandins, and it can be used in the synthesis of drugs such as carboprost methyl ester, carboprost tromet...

AI Technical Summary

Problems solved by technology

As in US20090124695, "Prostaglandin E 1 and E 2 Analogs for the treatment of various medical conditions" patent uses benzoyl coli lactone aldehyde as a raw material, and (2-oxoheptyl) phosphonic acid dimethyl in two kinds of mixed solvents of dichloromethane and tetrahydrofuran Ester reaction, post-treatment is cumbersome, and the product needs to be separated and purified by silica gel column chromatography, which is not suitable for industrial production

WO2007091697 "Method for preparing prostaglandin derivative" patent also requires silica gel column chromatography for purification and the final product obtained is oily, although the yield reaches 91.5%, but due to the shortcomings of poor quality and low content, there are also problems in industrial production

In Journal of Organic Chemistry, 68(16), p6437-6439(2003), in tetrahydrofuran (2-oxoheptyl) phosphonic acid dimethyl ester reacts with sodium hydrogen, introduces the lower side chain, after column chromatography, The resulting product is an oily substance, which has the disadvantages of poor quality, low content, and large safety hazards in industrial production.

In Bioorganic&MedicinalChemistry Letters, 15(7), p1873-1876(2005) and Journal of Organic Chemistry, 73(18), p7213-7218(2008), benzoyl corylide aldehyde was used as the reaction raw material, and used in the reaction Strongly basic reagents LiHMDS or NaHMDS, because the lactone ring of the raw material will undergo a ring-opening reaction under strong basic conditions, the paper reports that the yield is 80% to 96% oily substance, and the content is not mentioned, and the reaction temperature is - 78°C is not easy to control

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