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Preparation method of lesinurad related impurities

A technology for impurities and acidic substances, which is applied in the field of preparation of impurities related to Recinade, can solve the problems of difficult separation by column chromatography and difficult removal of impurities.

Pending Publication Date: 2022-01-28
HAINAN XINOPEN SOURCE MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of impurity is difficult to remove. Using the literature method, due to the extremely close polarity, it is difficult to separate by conventional column chromatography

Method used

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  • Preparation method of lesinurad related impurities
  • Preparation method of lesinurad related impurities
  • Preparation method of lesinurad related impurities

Examples

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preparation example Construction

[0040] The invention provides a method for preparing Lesinald-related impurities, comprising the following steps: S1) nitrating 1-cyclopropylnaphthalene to obtain a nitrated mixture; S2) reducing the nitrated mixture to obtain reducing the mixture; S3) mixing the reducing mixture with the acidic substance in the first organic solvent, and performing the first cooling and crystallization to obtain the compound represented by the formula (II); S4) combining the compound represented by the formula (II) The compound shown in formula (III) is reacted with thiophosgene to obtain the compound shown in formula (III); S5) the compound shown in the formula (III) is reacted with formic hydrazide to obtain the compound shown in formula (IV); S6) the compound shown in formula (IV) is obtained; The compound shown in the formula (IV) is reacted with the haloacetate shown in the formula (V) to obtain the compound shown in the formula (VI); S7) the compound shown in the formula (VI) is brominat...

Embodiment 1

[0062] Step 1: Add 50.0g cyclopropylnaphthalene and 300ml 1,2-dichloroethane into a 1L three-neck flask, stir to dissolve, add HNO dropwise 3 40.3g, after dropping, heated to reflux for 6h, added dropwise 50ml of ice water, stirred and separated, washed with 5% sodium bicarbonate solution 50ml×3, dried the organic phase with anhydrous sodium sulfate, filtered, concentrated to dryness The yellow oil mixture of formula (1) and formula (2) was directly put into the next step without treatment.

[0063] Step 2: Add the obtained light yellow oil, 150ml of purified water, 150ml of acetic acid, and 50.0g of iron powder into a 1L three-necked flask, heat to reflux for reaction until TLC shows that the reaction is complete (usually about 5 to 6 hours), and cool down to room temperature Filtrate, slowly pour the filtrate into 1L of ice water, stir, then extract with 500ml of dichloromethane × 3, combine the organic phases, wash with 300ml of saturated sodium bicarbonate × 2, wash once ...

Embodiment 2

[0071] Step 1: Same as Example 1.

[0072] Step 2: Add the obtained light yellow oil, 200ml of saturated ammonium chloride purified aqueous solution, and 48.0g of iron powder into a 1L three-necked flask, heat to reflux until TLC shows that the reaction is complete (usually about 5 to 6 hours), and cool down to Filtrate at room temperature, slowly pour the filtrate into 1L of ice water, stir, then extract with 500ml of dichloromethane × 3, combine the organic phases, wash with 300ml of saturated sodium bicarbonate × 2, wash once with 300ml of saturated saline, and dry over anhydrous sodium sulfate. Filter and concentrate to dryness to obtain a brownish-red oil, add 200ml of methanol and 46g of tartaric acid, slowly cool down to -10°C, crystallize for 4h, filter, wash with ice methanol, and dry under vacuum at 50°C to obtain 31.3g of a reddish-brown solid, which is the formula ( II) Crude product of the indicated compound.

[0073] Take 31.0g of the obtained reddish-brown soli...

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Abstract

The invention provides a preparation method of lesinurad related impurities. Compared with the prior art, the preparation method has the advantages that intermediate related impurities and position isomer impurities of the lesinurad can be obtained, the synthesis method is simple, the obtained target product is high in purity, technological research and quality standard formulation of the lesinurad are facilitated, the research and development cost is effectively reduced, and the preparation method is of great significance to drug development.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of a lecienard-related impurity. Background technique [0002] Lesinurad was approved by the US Food and Drug Administration (FDA) on December 22, 2015. In addition, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the drug to be approved for marketing in the EU on December 18. The drug was previously developed by Ardea, which AstraZeneca acquired in 2012, giving it access to the product. The trade name of the drug in the United States is Zurampic. [0003] Recinade is the world's first approved urate reabsorption transporter (URAT1) inhibitor, combined with a xanthine oxidase inhibitor to treat gout associated with hyperuricemia. Zurampic is a tablet for oral use, the strength is 200 mg. The recommended dose is 200 mg once daily in combination with allopurinol or febuxosta...

Claims

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Application Information

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IPC IPC(8): C07D249/12
CPCC07D249/12
Inventor 吴进张丽杰王海霞
Owner HAINAN XINOPEN SOURCE MEDICAL TECH CO LTD
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