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Preparation method of ledipasvir

A compound and chemical formula technology, applied in the field of drug synthesis, can solve the problems of short synthetic route, long synthetic route of ledipasvir, low reaction yield, etc.

Inactive Publication Date: 2017-06-27
常州市勇毅生物药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to solve the problems of long synthetic route of existing ledipasvir and low reaction yield, and provide a preparation method of ledipasvir with short synthetic route and high reaction yield

Method used

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  • Preparation method of ledipasvir
  • Preparation method of ledipasvir
  • Preparation method of ledipasvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Compound (II) (30.43g, 102mmol), compound (III) (35.76g, 100mmol), and acetonitrile (360mL) were stirred uniformly in a three-necked flask, and then potassium carbonate (27.64g, 200mmol) was added and heated to 50°C for reaction After 4-6 hours, water (720 mL) was added after the reaction was completed, cooled to room temperature for beating, filtered, washed with water, and dried to obtain compound (IV) (59.47 g, yield 96%).

[0073]

[0074] After compound (IV) (59.47g, 96mmol), compound (V) (43.94g, 100mmol), tetrakistriphenylphosphine palladium (3.32g, 2.88mmol) and isopropyl acetate (600mL) were stirred and dissolved in a three-necked flask , switch the nitrogen gas under vacuum, add an aqueous deoxygenated potassium phosphate solution (2.0mol / L, 300mL), heat to 80°C and react for 6-8 hours. The organic phase was washed twice with water (300 mL), dried over sodium sulfate, and concentrated to obtain compound (VI) (85 g, crude product 100%), which was directly us...

Embodiment 2

[0084] Compound (II) (24.71g, 102mmol), compound (III) (35.76g, 100mmol), and acetonitrile (360mL) were stirred uniformly in a three-necked flask, then potassium carbonate (27.64g, 200mmol) was added, and heated to 50°C for reaction 4 After -6 hours, add water (720 mL) after the reaction is completed, cool to room temperature, beat, filter, wash with water, and dry to obtain compound (IV) (54.55 g, yield 97%).

[0085]

[0086] Compound (IV) (54.55g, 97mmol), compound (V) (44.39g, 101mmol), tetrakistriphenylphosphine palladium (3.36g, 2.91mmol) and isopropyl acetate (55mL) were stirred and dissolved in a three-necked flask Afterwards, switch the nitrogen gas under vacuum, add an aqueous solution of potassium deoxyphosphate (2.0mol / L, 300mL), heat to 80°C and react for 6-8 hours. The combined organic phases were washed twice with water (300 mL), dried over sodium sulfate, and concentrated to obtain compound (VI) (79.50 g, crude yield 100%), which was directly used for the ne...

Embodiment 3

[0096] Stir compound (II) (30.43g, 102mmol), compound (III) (35.76g, 100mmol), acetonitrile (360mL) in a three-necked flask, add potassium carbonate (27.64g, 200mmol), and heat to 50°C for reaction After 4-6 hours, water (720 mL) was added after the reaction was completed, cooled to room temperature for beating, filtered, washed with water, and dried to obtain compound (IV) (59.47 g, yield 96%).

[0097]

[0098] Compound (IV) (59.47g, 96mmol), compound (V) (49.64g, 100mmol), tetrakistriphenylphosphine palladium (3.32g, 2.88mmol) and isopropyl acetate (600mL) were stirred and dissolved in a three-necked flask Afterwards, switch the nitrogen gas under vacuum, add an aqueous solution of potassium deoxyphosphate (2.0mol / L, 300mL), heat to 80°C and react for 6-8 hours. The combined organic phases were washed twice with water (300 mL), dried over sodium sulfate, and concentrated to obtain compound (VI) (91 g, crude product 100%), which was directly used in the next reaction.

...

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Abstract

The invention belongs to the drug synthesis field and particularly relates to a preparation method of ledipasvir. The preparation method comprises the following steps: reacting by virtue of a compound (II) and a compound (III) under the action of alkali, so as to obtain a compound (IV); reacting by virtue of the compound (IV) and a compound (V) under the action of a metal catalyst, so as to obtain a compound (VI); reacting by virtue of the compound (VI) and an amine reagent, so as to obtain a compound (VII); reacting by virtue of the compound (VII) under the action of acid, so as to obtain a compound (VIII); and reacting by virtue of the compound (VIII) and Moc-L-valine under the action of a condensing agent, so as to obtain the ledipasvir represented by a chemical formula (I). The preparation method has the beneficial effects that the process route is short, the operation is simple and convenient, and the reaction yield is high.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of ledipasvir. Background technique [0002] Leidi Pawei, English name: Ledipasvir, chemical name: Methyl N-[(2S)-1-[(6S)-6-[5-[9,9-Difluoro-7-[2-[(1S,2S ,4R)-3-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]-3-azabicyclo[2.2.1]heptan-2-yl]-3H-benzimidazol-5-yl]fluoren-2-yl ]-1H-imidazol-2-yl]-5-azaspiro[2.4]heptan-5-yl]-3-methyl-1-oxobutan-2-yl]carbamate, the chemical structure is as follows: [0003] [0004] Reddy Pavi is one of the components of Gilead's anti-hepatitis C blockbuster product Harvoni's compound combination, an NS5A inhibitor inhibitor. Harvoni is an anti-HCV drug developed by Gilead in the United States. It is the first all-oral anti-HCV regimen approved for the treatment of genotype 1 hepatitis C infection that does not require combination of interferon or ribavirin. Harvoni can be used alone or in combination with other oral agents su...

Claims

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Application Information

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IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 潘勇夏晓丽
Owner 常州市勇毅生物药业有限公司
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