Ulipristal acetate related chiral impurities and synthetic preparation method thereof

An impurity and chirality technology, applied in the fields of organic chemistry and pharmaceutical synthesis chemistry, which can solve the problems of inability to separate thin-layer chromatography, inability to meet large-scale production, and unsuitable substrates.

Inactive Publication Date: 2019-02-22
PHARMA CHANGZHOU PHARMA FACTORY NO 4 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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.

Method used

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  • Ulipristal acetate related chiral impurities and synthetic preparation method thereof
  • Ulipristal acetate related chiral impurities and synthetic preparation method thereof
  • Ulipristal acetate related chiral impurities and synthetic preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Embodiment 1: the preparation of intermediate II

[0074]

[0075] Weigh 75g (668.39mmol) of potassium tert-butoxide, put it into a 1000mL three-neck flask, add 500mL of anhydrous THF, continuously feed acetylene gas, stir at room temperature for 1 hour, then cool to 0°C, add 100g of raw material I ( 318.28mmol), control the temperature below 0°C, keep the introduction of acetylene gas, monitor by TLC, add saturated ammonium chloride solution after the reaction, separate the organic layer, extract the water layer with THF, combine the organic layers, wash with water, concentrate, and The concentrated solution was slowly dropped into ice water, and the solid was precipitated, filtered with suction, and slurried with water to obtain 98 g of the product intermediate II, with a yield of 91%. HRMS (ESI + ): calcd for C 22 h 30 o 3 [M+H] + 341.2111,found 341.2109.

Embodiment 2

[0076] Embodiment 2: the preparation of intermediate III

[0077]

[0078] Weigh 30g (88.18mmol) of Intermediate II, put it into a 500mL single-necked bottle, add 300mL of glacial acetic acid, stir at room temperature, slowly drop in 2.5mL (44.09mmol) of perchloric acid, and control the reaction temperature below 25°C . TLC monitoring, after the reaction was completed, the reaction solution was slowly dropped into ice water, a solid was precipitated, and filtered by suction to obtain 20 g of the product intermediate III, with a yield of 77%. HRMS (ESI + ): calcd for C 20 h 25 o 2 [M+H] + 297.1849, found 297.1847.

Embodiment 3

[0079] Embodiment 3: the preparation of intermediate IV

[0080]

[0081]Weigh 10g (33.76mmol) of intermediate III, dissolve it in 100mL of THF, add 2.5g (8.44mmol) of mercuric sulfate, then add 30mL of 30% sulfuric acid solution, stir at 60°C, monitor by TLC, after the reaction , saturated sodium bicarbonate solution to adjust the pH, dichloromethane extracted the aqueous layer, combined organic layers, washed with water, dried, and column chromatography. 4.8 g of product intermediate IV was obtained, yield: 45%. HRMS (ESI + ): calcd for C 20 h 27 o 3 [M+H] + 315.1955, found 315.1957. 1 H NMR (300MHz, CDCl 3 ):δ1.12(s,3H,–CH 3 ),2.30(s,3H,–CH 3 ),1.26-2.89(m,18H),5.70(s,1H,=CH).

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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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J21/00C07J71/00C07J1/00G01N30/02
CPCC07B2200/13C07J1/0081C07J21/006C07J71/001G01N30/02Y02P20/55
Inventor 李志裕卞金磊徐鹏飞栾红玉王举波屠永锐孙永强陈巍
Owner PHARMA CHANGZHOU PHARMA FACTORY NO 4
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