Preparation method of gout treatment drug Lesinurad and Lesinurad intermediate

An intermediate and representative technology, applied in the field of preparation of gout treatment drug Lesinurad, can solve the problems of complicated operation, expensive raw materials and high cost, and achieve the effects of simple operation, easy separation and purification, and low price.

Active Publication Date: 2015-09-09
SUZHOU PENGXU PHARM TECH CO LTD
View PDF10 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This step is complicated to operate and the raw materials are expensive, which is not conducive to cost reduction
In addition, most of the existing Lesinurad preparation methods use thiophosgene, which is inconvenient to operate and not safe. Although the Chinese patent CN102040546A adopts the method of avoiding the use of thiophosgene, this method greatly prolongs the synthesis route of Lesinurad, making the process more complex and costly

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of gout treatment drug Lesinurad and Lesinurad intermediate
  • Preparation method of gout treatment drug Lesinurad and Lesinurad intermediate
  • Preparation method of gout treatment drug Lesinurad and Lesinurad intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Embodiment 1 prepares compound 12 by compound 1

[0063]

[0064] In a single-necked bottle, add 4-cyclopropyl-1-naphthylamine (compound 1, 1.0eq), add DMF (8.2Vol) to dissolve it, add NaOH (1.2eq) and CS 2 (1.2eq), stirred and reacted at room temperature for 1h, added hydrazine hydrate (3.0eq) and transferred to 70°C oil bath, stirred and refluxed for 4h, LC confirmed that the reaction was complete, stopped heating and stirring, added 10mL water per 1g of raw material after cooling, and suction filtered , the filter cake was recrystallized with 95% ethanol, suction filtered, and the solid was dried to obtain compound 12 with a yield of 50%-70%.

[0065] The NMR data of the product are as follows: 1 H NMR (400MHz,DMSO)δ9.16(s,1H),8.43(d,J=7.8Hz,1H),7.98–7.89(m,1H),7.66-7.48(m,3H),7.26(d, J=7.6Hz,1H),5.54–4.50(m,1H),2.46–2.34(m,1H),1.12–1.02(m,2H),0.80–0.69(m,2H).

Embodiment 2

[0066] Embodiment 2 prepares compound 13 by compound 12

[0067]

[0068] Add compound 12 (1.0eq) in the single-necked bottle, add 1,4-dioxane (7.5Vol) to make it dissolve, add N,N-dimethylformamide dimethyl acetal (1.0eq), at 100 Stir and reflux at ℃ for 1.5-2h, LC confirmed the completion of the reaction, after cooling the reaction solution to room temperature, add 10mL of water to 1g of the raw material, the precipitated solid was suction filtered, the filter cake was washed twice with 95% ethanol, and the solid was dried to obtain compound 13【Lesinurad Intermediate, chemical name: 4-(4-cyclopropylnaphthalene)-3-mercapto-1,2,4-triazole)]. The yield is 70%-80%.

[0069] The NMR data of the product are as follows: 1 H NMR(400MHz,DMSO)δ8.69(s,1H),8.57(d,J=8.4Hz,1H),7.72(t,J=7.3Hz,1H),7.64(t,J=7.4Hz,1H ),7.54(d,J=7.6Hz,1H),7.44–7.37(m,2H),2.56–2.50(m,1H),1.19-1.09(m,2H),0.90–0.75(m,2H).

Embodiment 3

[0070] Embodiment 3 prepares compound 15 by compound 13

[0071]

[0072] The NMR data of the product are as follows: Compound 13 (4g, 1eq) was added to a single-necked bottle, and the solvent DMF (67mL, 16.8vol) was added to dissolve, stirred at room temperature, and K 2 CO 3 (2.272g, 1.1eq), then add compound 14 (1.74mL, 1.05eq) dropwise, control the drop rate at 0.5mL / min, stir at room temperature for 2h, the reaction is complete, add EA (ethyl acetate) and water to dilute the reaction solution, extracted three times with EA, washed three times with saturated brine, anhydrous MgSO 4 dry. The organic phase was spin-dried to obtain a white solid [that is, compound 15, a Lesinurad intermediate, chemical name: 4-(4-cyclopropylnaphthalene)-3-ethyl thioacetate-1,2,4-triazole], After drying, 5.13 g was obtained, and the yield was 97%.

[0073] The NMR data of the product are as follows: 1 H NMR (400MHz, CDCl 3 )δ8.54(d,J=8.4Hz,1H),8.30(s,1H),7.70-7.62(m,1H),7.61-7.53(m,...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

Provided are a novel Lesinurad intermediate, providing a synthetic process more economical, more efficient, safer, more environmentally friendly, and suitable for large-scale industrial production for the preparation of Lesinurad. Also provided is a method for preparing the known Lesinurad intermediate and Lesinurad via the provided novel Lesinurad intermediate. Using the novel Lesinurad intermediate of the present invention to synthesize Lesinurad has the following advantages of using cheap and easily available required raw materials, avoiding the use of heavy metals and solvents harmful to the environment, easily separating and purifying the intermediate and the product with a simple operation, avoiding the use of the thiophosgene having high toxicity and difficulty of operation, and enabling the total yield of the reaction to reach a level equal to or higher than the prior art.

Description

technical field [0001] The invention relates to a preparation method of Lesinurad, a drug for treating gout, and a key intermediate thereof. Background technique [0002] Gout is a crystal-associated arthropathy caused by deposition of monosodium urate (MSU), which is directly related to hyperuricemia caused by disturbance of purine metabolism and / or decreased uric acid excretion. There are more than 20 million gout patients worldwide. Lesinurad (RDEA594) is an oral uricosuric agent that inhibits the renal proximal tubule uric acid transporter URAT1. Previous exploratory studies in gout patients have shown that allopurinol (ALLO), combined with lesinurad, can reduce serum uric acid (SUA) more effectively than ALLO alone. Through the study of more than 500 healthy people and gout patients, it was found that Lesinurad reduced blood uric acid in a dose-dependent manner, and Febuxostat was well tolerated. It is also a xanthine oxidase inhibitor approved for the treatment of h...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Patents(China)
IPC IPC(8): C07D249/12C07C335/40
CPCC07C335/40C07D249/12
Inventor 王鹏李丕旭谷向永
Owner SUZHOU PENGXU PHARM TECH CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap