Improved method for preparing ledipasvir optical intermediate

A technology for ledipasvir and intermediates, applied in the field of improved preparation of ledipasvir optical intermediates, which can solve the problems of high cost, low yield, waste of production resources, etc.

Inactive Publication Date: 2017-09-29
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] However, the above-mentioned method adopts a chiral resolving agent to prepare (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid, and the yield is very low and can only reach 30%. , the remaining (R)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid cannot be utilized, which causes a great waste of production resources in the production process , resulting in high cost

Method used

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  • Improved method for preparing ledipasvir optical intermediate
  • Improved method for preparing ledipasvir optical intermediate
  • Improved method for preparing ledipasvir optical intermediate

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preparation example Construction

[0037] In some embodiments, the preparation method of B06 of the present invention comprises the following steps:

[0038] a) Add 5-azaspiro[2.4]heptane-6-carboxylic acid, benzaldehyde, D-tartaric acid and n-butyric acid into the reaction vessel, control the temperature at 35° C. to 100° C. for 5 hours to 25 hours, and drop to At room temperature, the solid was separated, and the obtained solid was dried in vacuum at 60° C. to obtain (S)-5-azaspiro[2.4]heptane-6-carboxylic acid or a salt thereof;

[0039] b) Add (S)-5-azaspiro[2.4]heptane-6-carboxylic acid D-tartrate, water and dichloromethane into the reaction vessel, stir at room temperature, adjust the pH to 1~ with dilute hydrochloric acid 4. After liquid separation, add the water phase to another reaction vessel, then adjust the pH value to 9~14 with aqueous sodium hydroxide solution, cool down to -10°C~30°C, then add di-tert-butyl dicarbonate, and stir the reaction After 1 hour, the temperature was raised to 20°C-70°C f...

specific Embodiment approach

[0043] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

[0044] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

[0045] L refers to liters, g refers to grams, h refers to hours, N refers to moles / liter, 1H NMR refers to nuclear magnetic hydrogen spectrum, HPLC refers to high performance liquid chromatography, ℃ refers to degrees Celsius, D 2 O refers to deuterated water.

Embodiment 1

[0047]

[0048] Add 100g of 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid and 1L of water into a 2L reaction flask equipped with a magnet, start stirring, heat up to reflux, and reflux After stirring and reacting for 5 hours, the water was evaporated to dryness, and the obtained solid was vacuum-dried overnight to obtain 57.32 g of white solid, with a yield of about 98%. 1 HNMR (D 2 O) δ = 4.23(m,1H); 3.23(m,2H); 2.27(m,1H); 1.98(m,1H); 0.67(m,4H).

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Abstract

The invention relates to an improved method for preparing a ledipasvir optical intermediate, and belongs to the field of pharmaceutical chemical engineering. The method adopts 5-azaspiro[2,4]heptane-6-carboxylic acid, a crystallization induced asymmetric conversion method is used to conduct chiral separation, so that an (S)-5-azaspiro[2,4]heptane-6-carboxylic acid or a salt thereof is obtained; and the (S)-5-azaspiro[2,4]heptane-6-carboxylic acid or the salt thereof is transformed into the ledipasvir optical intermediate which is (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2,4]heptane-6-carboxylic acid. The method has a low price, is simple and convenient, improves the utilization rate of the raw materials, and is suitable for large industrialized production.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to an improved method for preparing ledipasvir optical intermediates. Background technique [0002] Ledipasvir, English name Ledipasvir, has the following chemical structure: [0003] [0004] Radipavir is an NS5A inhibitor developed by Gilead, which can be used in combination with Sofosbuvir (English name Sofosbuvir) for the treatment of genotype 1 hepatitis C virus infection. [0005] US 2013324740A discloses a preparation of ledipasvir and its key optical intermediate (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (B06) method. This publication uses 1,1-cyclopropanedimethanol (B00) as the starting material to prepare 5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid racemate (B04) , and then reacted with the chiral resolution reagent (1S,2R)-(-)-1-amino-2-indanol (B-2) in 2-methyltetrahydrofuran to obtain (S)-5 with high opt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/54
CPCC07B2200/07C07D209/54
Inventor 罗勇峰杨凤智刘浩泉蓝英王仲清罗忠华
Owner SUNSHINE LAKE PHARM CO LTD
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