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Preparation method of fluorene ethyl ketone derivative

A compound and acetylation technology, applied in the field of preparation of ledipasvir synthetic intermediates, can solve the problems of Weinreb amide being expensive and unsuitable for industrial production

Active Publication Date: 2015-04-15
SHANGHAI FOREFRONT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The above-mentioned method carries out fluorination reaction safer, and the selectivity of acetylation is better, but Weinreb amide (being 2-chloro-N-methoxy-N-methyl-acetamide) is more expensive, is not suitable for industrialized production

Method used

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  • Preparation method of fluorene ethyl ketone derivative
  • Preparation method of fluorene ethyl ketone derivative
  • Preparation method of fluorene ethyl ketone derivative

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preparation example Construction

[0095] Specifically, the preparation method of the compound of formula 1 provided by the invention comprises the following steps (a) and step (b):

[0096] (a) By (a1), (a2), (a3) ​​or (a4), the compound of formula 2 is used as a raw material to prepare the compound of formula 3, formula 4, formula 5 or formula 6. In this step, by selecting different bases , can be made into different metal reagents. for the next coupling reaction. The specific conditions of each step are as follows:

[0097] (a1) reacting the compound of formula 2 with a base to obtain the compound of formula 3;

[0098]

[0099] where X 1 、X 2 Ditto, X 3 Be Br, I or H, M is Li, in step (a1), the base that can be selected includes (but not limited to): C1-C4 alkyllithium;

[0100] The reaction conditions of the step (a1), such as temperature, reaction time, solvent, etc., are not particularly limited, and those skilled in the art can select an appropriate temperature according to actual needs, and de...

Embodiment 1

[0161]

[0162] (1) Add 2.5g of compound 2A and 25mL of anhydrous THF into the reaction flask, and stir to dissolve. The obtained solution was cooled to -5°C with an ice-salt bath, and 3.93mL of i-PrMgCl tetrahydrofuran solution (concentration: 2mol / L) was slowly added dropwise for 10 minutes. After completion, the system was reacted at -5-0° C. for 1 hour to obtain a reaction mixture.

[0163] (2) Add 2.59g of acetic anhydride in another three-necked flask, replace with nitrogen 3 times, cool to -5°C in an ice-salt bath, and add the above-prepared Grignard reagent (i.e. the reaction mixture prepared in step (1)) dropwise to In acetic anhydride, the dropwise addition time is 20 minutes, and the dropwise addition process keeps the temperature not exceeding 0°C. After the dropwise addition, the system reacts at -5~0°C for 1 hour.

[0164] (3) 20mL of saturated ammonium chloride solution was added dropwise to the system to quench the reaction, and the liquids were separated; ...

Embodiment 2

[0168]

[0169] (1) The three-necked flask equipped with a thermometer, a dropping funnel, and a nitrogen protection device was replaced with nitrogen three times, and 4.07 g of compound 2A and 50 mL of anhydrous THF were added to the reaction flask, and stirred to dissolve. The obtained solution was cooled to -70°C with a dry ice acetone bath, and 4 mL of n-butyllithium / tetrahydrofuran solution (concentration: 2.5 mol / L) was slowly added dropwise for 10 minutes, and the dropping process kept the temperature below -65°C , after the dropwise addition, the system was reacted at -65° C. for 1 hour to obtain a reaction mixture.

[0170] (2) 3.06 g of acetic anhydride was slowly added dropwise to the above reaction mixture for 10 minutes. During the dropwise addition, the temperature was kept below -65°C. After the dropwise addition, the system was reacted at -55°C for 1 hour.

[0171] (3) Add 20 mL of saturated ammonium chloride solution dropwise to the system to quench the react...

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Abstract

The present invention provides a preparation method of a fluorene ethyl ketone derivative, and particularly provides a preparation method of compounds of formula 1, definition of each group is as described in the specification. The compounds can be used as intermediates for preparation of ledipasvir, and used for the preparation of ledipasvir synthesis key intermediates and further preparation of ledipasvir. The method is low in cost, mild in reaction conditions, and suitable for industrialized production.

Description

technical field [0001] The invention relates to the field of preparation of pharmaceutical intermediates, specifically, the invention provides a method for preparing a synthetic intermediate of ledipasvir. Background technique [0002] Ledipasvir (LDV) is a hepatitis C drug developed by Gilead. The FDA has granted Breakthrough Therapy Designation to LDV / SOF (Sofosbuvir) fixed-dose combination drug, which is expected to cure the genotype in as little as 8 weeks 1 For HCV patients, there is no need to inject interferon or combine ribavirin (Ribavirin). [0003] At present, in the preparation methods of ledipasvir known in the art, most of the key intermediates shown in the following formula 7 are required (where X, X 1 are all halogen). Therefore, in order to produce ledipasvir industrially, a method capable of efficiently synthesizing the compound of formula 7 is needed in the art. [0004] US20100310512 reports a preparation method of a compound of formula 7 as shown be...

Claims

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Application Information

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IPC IPC(8): C07C49/813C07C45/63C07D403/14
CPCC07C45/455C07C45/63C07C49/813C07D403/14
Inventor 黄成军魏哲文傅绍军李巍张锡璇
Owner SHANGHAI FOREFRONT PHARMA CO LTD
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