Preparation method of sofosbuvir key intermediate

An intermediate and key technology, which is applied in the field of preparation of key intermediates of sofosbuvir, can solve problems such as danger, high toxicity of reaction reagents, and harsh reaction conditions, and achieve the effects of simple equipment, novel routes, and short synthetic routes

Active Publication Date: 2020-07-03
IANGSU COLLEGE OF ENG & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this synthesis scheme, the witting reaction needs to be reacted at minus 70 °, and the reaction conditions are harsh. Similarly, the fluorination reaction, the reaction reagent is highly toxic and dangerous

Method used

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  • Preparation method of sofosbuvir key intermediate
  • Preparation method of sofosbuvir key intermediate
  • Preparation method of sofosbuvir key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Preparation of 3-((R)-2,2-dimethyl-1,3-dioxolanyl)-3-carbonyl-2-methyl-2-fluoropropionic acid ethyl ester (1 )

[0038] In a 500 milliliter round bottom flask, add 150 grams of β-acetone glyceride and 100 milliliters of dichloromethane, cool to 0° under an ice bath, add 70 grams of oxalyl chloride dropwise, during the dropping process, the temperature is controlled below 5 degrees, After 30 minutes of dripping, after the addition, keep warm for 3 hours. After the reaction, recover dichloromethane under reduced pressure, cool in an ice bath, precipitate oxalic acid, filter, and save the filtrate for future use. Take another No. 500 three-necked reaction flask, add 150 ml of tetrahydrofuran, cool to 0° in an ice bath, add 24 g of NaH, add 120 g of ethyl α-fluoropropionate in batches to the system, stir for 30 minutes, and cool the system to -10 °, dropwise add the β-glycerol acyl chloride acetone prepared above, during the dropping process, the system temperat...

Embodiment 2

[0039] Example 2: Preparation of 3-((R)-2,2-dimethyl-1,3-dioxolanyl)-3-hydroxyl-2-methyl-2-fluoropropionic acid ethyl ester (2 )

[0040] Take a 500 ml round bottom flask, add 124 g of intermediate 1, 200 ml of ethanol, cool in an ice bath to 0 °, add 10 g of sodium borohydride in batches, during the addition process, control the temperature not to exceed 5 °, and complete the addition in 30 minutes. After the addition, the system continued to react for 2 hours. After the reaction was completed, 20 ml of dilute hydrochloric acid (1mol / L) was added to the reaction system, and the stirring was continued for 10 minutes. Extracted twice with ethyl ester, washed with water, combined organic phases, dried over anhydrous sodium sulfate, filtered, the filtrate recovered the solvent under reduced pressure, and the residue was distilled under reduced pressure to obtain 113 grams of light yellow liquid (5 mm Hg, collection temperature 90-94 °) , yield 91%.

Embodiment 3

[0041] Example 3: Preparation of 3-((R)-2,2-dimethyl-1,3-dioxolanyl)-3-benzoyl-2-methyl-2-fluoropropionic acid ethyl ester (3)

[0042] Take a 500 milliliter three-necked reaction flask, install a constant pressure dropping funnel, nitrogen protection device, under nitrogen protection, add 62 grams of intermediate 3, 100 milliliters of dichloromethane, 30 grams of triethylamine to the system, and cool in an ice bath to 5 ° below, add 40 grams of Benjia acid chloride dropwise. During the dropping process, the temperature does not exceed 10 °. After the dropwise addition, the system is warmed up to 40 ° C for 1 hour. After the reaction, add 100 ml of water to the system, separate liquid, organic The phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was recovered from the filtrate under reduced pressure to obtain a yellow solid. Ethyl acetate:petroleum ether=1:1 was recrystallized to obtain 83.1 g of a light yellow solid, with a yield of ...

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Abstract

The invention discloses a preparation method of a sofosbuvir key intermediate ((2R,3R,4R,5R)-3-(benzoyloxy)-5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl)benzoic acid methyl ester. The preparation method comprises the following steps: by using (R)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid as a starting material, performing acylating chlorination, performing a reaction with alpha-fluoropropionic acid, performing carbonyl reduction, performing hydroxyl protection, performing hydrolytic cyclization, performing hydroxymethyl protection, performing reduction, and performing chlorination to prepare the sofosbuvir key intermediate ((2R,3R,4R,5R)-3-(benzoyloxy)-5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl)benzoic acid methyl ester. The preparation scheme has a short synthetic route and a high yield, and avoids a fluorination reaction step in the synthetic process.

Description

technical field [0001] The present invention specifically relates to a preparation method of a sofosbuvir key intermediate. Background technique [0002] Sofosbuvir is a novel hepatitis C virus (HCV) inhibitor that targets HCV NS5B polymerase, and terminates the replication of HCV by interfering with the synthesis of viral genetic material RNA. The drug was developed by Gilead in the United States and was launched on December 6, 2013 under the trade name Sovaldi. Sofosbuvir is used to treat chronic hepatitis C (CHC). It is currently the only marketed drug that targets NS5B polymerase. Other drugs with the same mechanism of action have been terminated or delayed during clinical trials due to toxicity issues. . [0003] Methyl ((2R,3R,4R,5R)-3-(benzoyloxy)-5-chloro-4-fluoro-4-methyltetrahydrofuran-2-yl)benzoate as the key to sofosbuvir The intermediate, whose preparation method mainly uses glyceraldehyde acetone as the starting material. [0004] Scheme 1: Prepared from gl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H13/08C07H1/00
CPCC07H13/08C07H1/00C07B2200/07
Inventor 严宾冯成亮
Owner IANGSU COLLEGE OF ENG & TECH
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