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2-(5-bromo-4-(4-cyclopropyl naphthalen-1-yl)-4H-1,2,4-triazol-3-yl thio)acetic acid intermediates

A cyclopropyl naphthalene, thio-based technology, applied in the direction of organic chemistry and the like, can solve the problems of unstable starting materials of the synthetic route, low synthetic yield of the synthetic route, unfavorable industrial production and the like, and improve product yield and quality. , the effect of reducing the cost of industrialization and reducing pollution

Active Publication Date: 2017-03-08
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] 1. The starting material of this synthetic route is unstable, which is not conducive to preservation;
[0016] 2. The synthetic route has a low synthetic yield, which is unfavorable for industrialized production
[0019] The main shortcoming of route 4 is: this synthetic route easily produces last two by-products of methyl thioglycolate; Selectivity is poor

Method used

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  • 2-(5-bromo-4-(4-cyclopropyl naphthalen-1-yl)-4H-1,2,4-triazol-3-yl thio)acetic acid intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] The synthesis of embodiment 1 compound (L-3)

[0058] Reaction formula:

[0059]

[0060] Feeding:

[0061]

[0062] experiment procedure:

[0063] (1) Add L-2 (39g, 0.22mol) and potassium carbonate (91g, 0.66mol) in tetrahydrofuran (400mL), N 2 Under protection, cool down to -10°C;

[0064] (2) Dissolve phenyl chloroformate (36.5 mL, 0.29 mol) in 100 ml of tetrahydrofuran, and slowly drop into the above system. After dropping, keep warm for 1 hour.

[0065] (3) Water (200 mL) was added to the system. After separation, the aqueous layer was extracted with ethyl acetate (200 mL), and the organic phases were combined and concentrated to give a brick red solid (65 g, yield: 98.5%).

[0066] 1 H-NMR (400MHz, DMSO-D 6 )δ10.03(s,1H),8.45(d,J=2.4MHz,1H),8.42(d,J=1.2MHz,1H),8.23~8.14(m,2H),7.68~7.58(m,2H ),7.54(d,J=7.6MHz,1H),7.47~7.38(m,2H),7.32~7.20(m,4H).

[0067] MS:305.20[M+H + ].

Embodiment 2

[0068] The synthesis of embodiment 2 compound (L-3)

[0069] Feeding amount:

[0070]

[0071] experiment procedure:

[0072] (1) Add L-2 (39g, 0.22mol) and potassium carbonate (182.4g, 1.32mol) in tetrahydrofuran (700mL), N 2 Under protection, cool down to -20°C;

[0073] (2) Dissolve phenyl chloroformate (68.9, 0.44mol) in 200ml tetrahydrofuran, and slowly drop it into the above system. After dropping, keep warm for 5 hours.

[0074] (3) Water (400 mL) was added to the system, and after liquid separation, the aqueous layer was extracted with ethyl acetate (400 mL), and the organic phases were combined and concentrated to obtain 63 g of a brick-red solid.

[0075] MS:305.20[M+H + ].

Embodiment 3

[0076] The synthesis of embodiment 3 compound (L-3)

[0077] With reference to the reaction steps of Example 1, the molar ratio of compound (L-2) to phenyl chloroformate and potassium carbonate is 1:1:2, compound L-2 and potassium carbonate are added in tetrahydrofuran (500mL), N 2 Under protection, the temperature was lowered to 5°C; phenyl chloroformate was dissolved in 200ml of tetrahydrofuran, and slowly dropped into the above system. After dropping, keep the reaction for 1 hour, add water (300 mL) to the system, and extract the water layer with ethyl acetate (300 mL) after liquid separation, combine the organic phases, and concentrate to obtain 64 g of a brick-red solid.

[0078] MS:305.20[M+H + ].

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Abstract

Lesinurad key intermediate compounds (L-4) and (L-5) are prepared; a preparation method is simple in postprocessing of reaction, the product is relatively high in purity and relatively good in stability, the preparation method is suitable for industrialized production, and a new simple and feasible method is provided for preparation of 2-(5-bromo-4-(4-cyclopropyl naphthalen-1-yl)-4H-1,2,4-triazol-3-yl thio)acetic acid key intermediate compound (L-6) and a final finished product raw material medicine thereof; the pollution to the environment is reduced, the product yield and quality of the prepared raw material medicine are improved to a great extent, and medicine industrialization costs are reduced.

Description

technical field [0001] The present invention belongs to the technical field of medicine, and more specifically relates to a chemical medicine field. , 2,4-triazol-3-ylthio)acetic acid key intermediate and preparation method thereof. Background technique [0002] Lesinurad, Chinese name: 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid, English name: Acetic acid, 2-[[5-bromo-4-(4-cyclopropyl-1-naphthalenyl)-4H-1,2,4-triazol-3-yl]thio]-; molecular weight: 404.28. [0003] Lesinurad is an oral uricosuric drug that inhibits the renal proximal tubule uric acid transporter URAT1 for the treatment of gout patients with hyperuricemia. The structure of the drug is shown below: [0004] [0005] The synthetic routes of Lesinurad medicine announced in the existing literature mainly contain the following types: [0006] Route 1 [0007] [0008] The main disadvantages of route 1 are: 1. The synthetic route is relatively long, and palladium-car...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/12C07C281/06
CPCC07C281/06C07D249/12
Inventor 包金远宋志春蒋玉伟张孝清
Owner NANJING HUAWE MEDICINE TECH DEV