Synthesis method of key sofosbuvir intermediate

An intermediate, red aluminum technology, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of many reaction by-products, poor trifluoroethanol selectivity, inconvenient reaction and the like, and achieves the effects of low price, good selectivity and production cost saving

Pending Publication Date: 2019-03-08
JIANGSU COBEN PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The selectivity of trifluoroethanol is poor, and there are many reaction by-products, which bring inconvenience to the follow-up reaction

Method used

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  • Synthesis method of key sofosbuvir intermediate
  • Synthesis method of key sofosbuvir intermediate
  • Synthesis method of key sofosbuvir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] A kind of preparation method of sofosbuvir intermediate (I), concrete steps are as follows:

[0025] Step 1, preparation of compound (Ⅲ): In a dry three-necked flask, weigh 61g (0.21mol) of 70% red aluminum and 15g of toluene, then cool the mixture to -15°C, and then drop it into the three-necked flask The mixed solution of 16.5g (0.19mol) of morphine and 10g of toluene, during this process, the temperature is controlled at -10°C, after dropping, keep warm for 30min, slowly rise to 25±5°C, add dropwise to the end of the temperature rise, and obtain the modified red aluminum solution spare.

[0026] Put 49.4g (0.133mol) of compound (II) and 150g of toluene into a dry three-necked flask, cool down to -15°C, add the modified red aluminum solution prepared above dropwise, raise the temperature to 15°C after dropping, and keep it warm for 24h After that, the starting material disappears, and the compound (Ⅲ) is obtained.

[0027] Step 2, preparation of compound (Ⅳ): on the...

Embodiment 2

[0031] A kind of preparation method of sofosbuvir intermediate (I), concrete steps are as follows:

[0032] Step 1, preparation of compound (III): In a dry three-necked flask, weigh 70.7g (0.21mol) of 60% red aluminum and 15g of toluene, then cool the mixture to -20°C, and then drop into the three-necked flask The mixed solution of 21.4g (0.25mol) of morpholine and 10g of toluene, during this process, the temperature is controlled at -15°C, after dropping, keep warm for 20min, slowly rise to 25±5°C, add dropwise to the end of the temperature rise, to obtain modified red aluminum The solution is ready for use.

[0033] Throw 52.4g (0.141mol) of compound (II) and 150g of toluene into a dry three-necked flask, cool down to -15°C, add the modified red aluminum solution prepared above dropwise, raise the temperature to 15°C after dropping, and keep it warm for 20 hours After that, the starting material disappears, and the compound (Ⅲ) is obtained.

[0034]Step 2, preparation of c...

Embodiment 3

[0038] A kind of preparation method of sofosbuvir intermediate (I), concrete steps are as follows:

[0039] Step 1, preparation of compound (Ⅲ): In a dry three-necked flask, weigh 68.9g (0.22mol) of 65% red aluminum and 15g of toluene, then cool the mixture to -15°C, and then drop into the three-necked flask The mixed solution of 14g (0.16mol) of morpholine and 10g of toluene, during this process, the temperature is controlled at -20°C, after dropping, keep warm for 40°C, slowly rise to 25±5°C, add dropwise to the end of the temperature rise, and obtain the modified red aluminum solution spare.

[0040] Feed 53.8g (0.145mol) of compound (II) and 150g of toluene on the spot plate, cool down to -15°C, add the modified red aluminum solution prepared above dropwise, raise the temperature to 25°C and keep it warm after dropping, and react for 26 hours Until the spot plate raw material disappears, compound (Ⅲ) is obtained.

[0041] Step 2, the preparation of compound (Ⅳ): on the b...

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Abstract

The invention relates to a synthesis method of a key sofosbuvir intermediate shown as a formula (I). The synthesis method comprises the following steps: with a compound 3,5-dibenzoyl-2-deoxy-2-fluoro-2methyl-D-ribose-gamma-lactone as a raw material, selectively reducing by using modified passivated red aluminum to produce a compound [(2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl] methyl benzoate, chlorinating the compound [(2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl] methyl benzoate, performing condensation on the compound [(2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl] methyl benzoate and N-benzoyl-O-(trimethylsilyl)cytosine to produce the sofosbuvir intermediate (2'R)-N-benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine-3',5'-dibenzoate. By the synthesis method, the compound [(2R,3R,4R)-3-(benzoyloxy)-4-fluoro-5-hydroxy-4-methyltetrahydrofuran-2-yl] methyl benzoate is highly selectively prepared by replacing commonly used trifluoroethanol with a passivating agent morpholine; in the reaction process, byproducts are reduced, so that progression of a subsequent reaction is facilitated; and the synthesismethod has a huge industrial production prospect.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of a sofosbuvir key intermediate. technical background [0002] Sofosbuvir (also translated as Sofosbuvir, English name Sofosbuvir, trade name Sovaldi) is a new drug developed by Gilead for the treatment of chronic hepatitis C. It was approved by the US Food and Drug Administration (FDA) on December 6, 2013. ) was approved for marketing in the United States, and was approved for marketing in EU countries by the European Medicines Agency (EMEA) on January 16, 2014. Not yet available in China. The drug is the first to safely and effectively treat certain types of hepatitis C without the need for interferon. Clinical trials have confirmed that for hepatitis C types 1 and 4, the overall sustained virological response rate (SVR) of the drug combined with peginterferon and ribavirin is as high as 90%; for hepatitis C type 2, the drug combin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/067C07H1/00
CPCC07H1/00C07H19/067
Inventor 游金宗蒋善会史磊郭红强何牮石
Owner JIANGSU COBEN PHARMA CO LTD
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