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Preparation method of fluorene ethyl ketone derivative

A compound and inert solvent technology, applied in the field of preparation of ledipasvir synthesis intermediates, can solve the problems of expensive Weinreb amides, unsuitable for industrial production, etc.

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

AI Technical Summary

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

Examples

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preparation example Construction

[0117] The present invention also provides a preparation method of a compound of formula I, said method comprising the steps of:

[0118]

[0119] (iv) deprotecting with the compound of formula VII in an inert solvent to obtain the compound of formula I; wherein, the definition of each group is as described above.

[0120] The deprotection is preferably carried out by a hydrolysis reaction; preferably, the deprotection in the step (iv) is carried out under acid catalysis;

[0121] The acid is not particularly limited, and is preferably an acid selected from the following group: H 2 SO 4 , HX, H 3 PO 4 , polyphosphoric acid, HNO 3 、CH 3 SO 4 、CF 3 SO 4 , HOAc, CF 3 COOH, Sulfonic acid ion exchange resin, HXO 4 , or a combination thereof; where, R 6 is H or C1-C4 alkyl; X is selected from the following group: Cl, Br, I.

[0122] In the above reaction, the raw material compound of formula VII can be prepared by the method described in the present invention, and can...

Embodiment 1

[0157] Synthesis of Example 1 Compound 4-1

[0158]

[0159] In a 250ml four-necked flask, add 16.2g (123mmol, 1.5eq) aluminum trichloride, 150ml dichloromethane, start stirring, slowly add 20g compound 2 (82mmol, 1.0eq), and stir for 30 minutes until most of the Aluminum trichloride dissolves.

[0160] The reaction mixture was cooled to 0°C, and 11g (98.4mmol, 1.2eq) of chloroacetyl chloride was slowly added dropwise. After the addition was complete, it was kept at 0°C for 1 hour, then naturally warmed to room temperature, and stirred for 2 hours. TLC traced until the disappearance of the starting material.

[0161] The reaction solution was poured into 100ml of 10% ice water-hydrochloric acid mixture, stirred for 30 minutes, and the organic layer was separated. The organic phase was washed with water, 10% sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was recrystallized to obtain 19.3 ...

Embodiment 2

[0162] Synthesis of Example 2 Compound 4-2

[0163]

[0164] In a 250ml four-necked flask, add 16.2g (123mmol, 1.5eq) aluminum trichloride, 150ml dichloromethane, start stirring, slowly add 20g compound 2 (82mmol, 1.0eq), and stir for 30 minutes until most of the Aluminum trichloride dissolves.

[0165] The reaction mixture was cooled to 0°C, and 7.7g (98.4mmol, 1.2eq) of acetyl chloride was slowly added dropwise. After the dropwise addition, it was kept at 0°C for 1 hour, then naturally warmed to room temperature, and continued to stir for 2 hours. TLC traced until the disappearance of the starting material.

[0166] The reaction solution was poured into 100ml of 10% ice water-hydrochloric acid mixture, stirred for 30 minutes, and the organic layer was separated. The organic phase was washed with water, 10% sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 22.0 g of compound 4-2 (yield: 93.8%).

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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 I, definition of each group is as described in the specification. The compound can be used as an intermediate for preparation of ledipasvir, and the intermediate is used for the preparation of a ledipasvir synthesis key intermediate 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 treatment drug developed by Gilead. The FDA has granted Breakthrough Therapy Designation to the LDV / SOF (Sofosbuvir) fixed-dose combination drug, which is expected to cure the genotype in as little as 8 weeks 1HCV patients do not need to inject interferon or combine with 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 I are required (where Z 1 ,Z 2 are all halogen). Therefore, in order to produce ledipasvir industrially, there is a need in the art for a method capable of efficiently synthesizing the compound of formula 5. [0004] US20100310512 reports the synthesis of formula I as follows:...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D319/06C07D317/16C07C49/813C07C45/63C07C45/60C07C45/46C07D403/14
CPCC07C45/46C07C45/59C07C45/60C07C45/63C07C2603/18C07D317/16C07D319/06C07C49/813C07D403/14
Inventor 张锡璇傅绍军魏哲文李巍黄成军
Owner SHANGHAI FOREFRONT PHARMA CO LTD
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