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Synthesis method of velpatasvir

A synthesis method and velpatasvir technology, applied in the field of velpatasvir synthesis, can solve problems such as difficult removal of impurities, and achieve the effect of simplifying the post-treatment process

Inactive Publication Date: 2017-12-22
ANHUI TWISUN HI TECH PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] CN105732765 also uses dibromide III as a raw material to synthesize velpatasvir, and its synthesis process is shown in reaction flow 4. Through this process, in the synthesis of velpatasvir, impurity 2 and impurity 4 will also be produced, and impurities are difficult to remove problem still unresolved

Method used

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  • Synthesis method of velpatasvir
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  • Synthesis method of velpatasvir

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preparation example Construction

[0045] The invention provides a synthetic method of velpatasvir, comprising:

[0046] 1) reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV);

[0047]

[0048] Wherein, R is tert-butoxycarbonyl or formula (R-a),

[0049]

[0050] 2) converting the compound of formula (IV) into a compound of formula (I);

[0051]

[0052] According to the present invention, the present invention reacts the compound of formula (II) structure with the compound of formula (III) structure, obtains the compound of formula (IV) structure; Wherein, the solvent of described reaction is preferably polar solvent, more preferably di One or more of oxygen hexane, N, N-dimethylacetamide, N-methylpyrrolidone and ethylene glycol dimethyl ether; also add alkaline substance, palladium catalyst and organophosphorus complex in the reaction body; wherein, the alkaline substance is preferably one or more of potassium carbonate, potassium tert-butoxide...

Embodiment 1

[0071] The reaction process is as follows:

[0072]

[0073] Concrete reaction steps are:

[0074] 1.1 Synthesis of Compound 15

[0075] Add 50.0 g of compound 14 and 250 mL of methanol into a 1.0 L reaction flask, and then add 55.0 g of concentrated hydrochloric acid dropwise under stirring. After the dropwise addition, the temperature was raised to 55-60° C., and the reaction was stirred for 12 hours. TLC (PE:EA=1:1, Rf=0.1) showed that the reaction was complete. At 50°C, it was concentrated to dryness under reduced pressure. Add an appropriate amount of methanol and steam twice to obtain 57.0 g of the product. The yield is 100%, and it is directly used in the next step reaction.

[0076] 1.2 Synthesis of Compound 16 (Formula V)

[0077] 61 g of CDMT (2-chloro-4,6-dimethoxy-1,3,5-triazine) and 400 mL of methanol were added to a 1.0 L reaction flask. Under the protection of nitrogen, use an ice bath to cool down to 0-5°C, add 81g of N-methylmorpholine quickly, and s...

Embodiment 2

[0099] The reaction process is:

[0100]

[0101] Specifically synthesized as:

[0102] 2.1 Synthesis of Compound 23 (Formula III-a)

[0103] Add 7.0 g of compound 22 (formula VI-a) and 70 mL of tetrahydrofuran into a 250 mL three-necked flask. Under the protection of nitrogen, cool down to 0-5°C with an ice bath. Then, 1.0 g of sodium hydrogen was added in batches, and the feeding was controlled at a temperature of 0-10°C. After the addition, the reaction was stirred for half an hour at 0-10°C. 2.6 g of 2-(trimethylsilyl)ethoxymethyl chloride was added dropwise, and after the dropwise addition was completed, the reaction was stirred for three hours. Sampling was sent to LC-MS detection to show that the reaction was complete. Add 70 mL of saturated ammonium chloride solution dropwise to quench the reaction (a large number of bubbles are generated), and extract three times with ethyl acetate (150 mL×3). The organic phases were combined, washed twice with 100 mL of satu...

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Abstract

The invention provides a synthesis method of velpatasvir. The method comprises the following steps that reaction is performed on a compound of a structure shown as a formula (II) and a compound of a structure shown as a formula (III) to obtain a compound of a structure shown as a formula (IV); then, the compound of the structure shown as the formula (IV) is converted into the compound shown as the formula (I); the compound of the structure shown as the formula (II) and the compound of the structure shown as the formula (III) are directly subjected to carbon-hydrogen activation coupling; the generation of feature impurities in the synthesis step can be effectively avoided; meanwhile, a final product can be purified through continuous salifying crystallization; the post treatment process is simplified to a great degree; in addition, the purity of the obtained velpatasvir is greater than 99.0 percent; the maximum individual impurities are less than 0.1 percent.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a synthesis method of velpatasvir. Background technique [0002] Epclusa is a pan-genotype hepatitis C cocktail therapy drug composed of sofosbuvir and velpatasvir compound, developed for all 6 genotypes (GT-1, -2, -3, -4, -5, -6) Treatment of hepatitis C patients. Among them, Sofosbuvir is a nucleoside analog polymerase inhibitor, and Velpatasvir is a pan-genotype NS5A inhibitor. Since Epclusa has made significant progress compared with existing treatment options, the US FDA has identified it as a breakthrough drug and approved its marketing application in June 2016. Epclusa demonstrated a consistently high cure rate for a pan-genotypic drug, including patients infected with HCV genotypes 2 and 3, which have long required combination therapy with ribavirin or other multidrug combinations. It provides a safe, easy and effective treatment for patients infected with all 6 genotypes of h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/052
CPCC07D491/052C07B2200/07
Inventor 叶方国龙双喜刘庆庆
Owner ANHUI TWISUN HI TECH PHARM CO LTD
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