Ulipristal acetate related chiral impurities and synthetic preparation method thereof

Abstract

The invention discloses ulipristal acetate related chiral impurities and a synthetic preparation method thereof. Part of chiral impurities can be prepared by the following steps: by taking 3-ketal asan initial raw material, carrying out an addition reaction to obtain an intermediate II; deprotecting the intermediate II in an acidic condition to obtain an intermediate III; carrying out hydrolysisand oxidation to obtain an intermediate IV; and adding protecting groups to obtain the part of chiral impurities; or carrying out a Grignard reaction on a 3,20-diketal oxidative product to obtain thepart of chiral impurities. Structures of all the impurity compounds are confirmed by a magnetic resonance hydrogen spectrum, a high resolution mass spectrum and high performance liquid chromatography.The purities of the ulipristal acetate related chiral impurity compounds prepared by the method are over 95% and can be used as reference substances for quality research.

Description

technical field [0001] The invention belongs to the field of organic chemistry, in particular to the field of pharmaceutical synthesis chemistry. The invention provides chiral impurities related to ulipristal acetate and a synthesis and preparation method thereof. The chiral impurity compounds are applied to the quality analysis of ulipristal acetate raw materials and preparations thereof. Background technique [0002] Ulipristal Acetate (Ulipristal Acetate; compound XI; chemical name: 17α-acetoxy-11β-[4-(N,N-dimethylamino)phenyl]-19-norpregna-4,9 -diene-3,20-dione) is a potent antiprogestogen and antiglucocorticoid drug. Its structural formula is as follows: [0003] [0004] Ulipristal acetate has been approved for marketing in Europe and the United States as an emergency contraceptive. It is used within 5 days after unprotected sex or known or suspected contraceptive failure. It is an effective and safe emergency contraceptive. Emergency contraception, defined as a ...

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Problems solved by technology

The fourth is the use of asymmetric catalysts: Catalytic asymmetric synthesis is the most ideal method for the synthesis of chiral compounds, because a large number of chiral products can be obtained by using a small amount of asymmetric catalysts, but the challenges that coexist with opportunities are transition metals and Chiral ligands are expensive and cannot meet large-scale production, so screening asymmetric synthetic catalysts with high activity, high stereoselectivity and low price is also one of the hot research fields

Many new methods have also been developed, such as mechanical resolution of racemic mixtures, preferential crystallization and preferential enrichment, etc., but not all compounds are suitable for this method, so although the operation is simple, there are also limitations of unsuitable substrates

The second method is thin-layer chromatography, which uses the difference in polarity or adsorption capacity of enantiomers to separate enantiomers by thin-layer chromatography, which is more suitable for laboratory operations, but most enantiomers The properties of the isomers are very similar, and the polarity or adsorption capacity is also very similar. The ordinary thin-layer chromatography cannot be separated, so the separation can only be achieved through a large number of experiments on the types and proportions of the developing agent.

The third method is to separate by chiral chromatographic column. The advantage of this method is that it is highly efficient and can obtain products with high purity, but its disadvantages are also very obvious. It cannot prepare a large amount of target compounds and is only suitable for the preparation of a small amount of target compounds in small laboratories.

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