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A kind of quaternary ammonium salt catalysis and application

A catalyst and compound technology, applied in the field of medicine, can solve the problems of difficult post-processing, low yield, high cost, etc.

Active Publication Date: 2018-03-06
BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Patent CN103524440B has protected Lesinurad brominated intermediate (chemical name is 2-(5-bromo-4-(4-cyclopropylnaphthalene-1-yl)- 4H -1,2,4-triazole-3-mercapto) acetates) preparation method, the method only uses bromination reagents to carry out bromination, although improved compared with previous methods, there are still many deficiencies: 1 ) The yield is low, only 50-80%; 2) The bromination method needs to use 6 equivalents of brominated reagents, and the large amount of brominated reagents and by-products make post-processing difficult and expensive; 3) High reaction The temperature needs to be above 60°C for reflux reaction; 4) Since the compound of formula Ⅴ is oily and the bromination efficiency is low, it is difficult to refine compound Ⅴ. This patent uses column chromatography for purification and purification, which is very unfavorable for industrial production

Method used

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  • A kind of quaternary ammonium salt catalysis and application
  • A kind of quaternary ammonium salt catalysis and application
  • A kind of quaternary ammonium salt catalysis and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The preparation of embodiment 1 catalyst b1

[0025]

[0026] Dissolve compound a1 (50g, 147.3mmol, 1.0eq.) in 500mL of acetone, stir to dissolve at 20~30°C, add methyl bromoacetate (1473mmol, 10eq.), react for 12 hours, and concentrate the reaction solution to dryness , the concentrate was recrystallized from ethyl acetate to obtain 56.4 g of catalyst b1, yield: 77.8%.

[0027] 1 H NMR (CDCl 3 , 500 MHz) δ 11.65 (s, 1H), 8.59 (d, 1H, J = 8.0 Hz),7.66-7.73 (m, 3H), 7.34-7.44 (m, 2H), 6.15(d, 1H, J = 16.5 Hz), 5.69 (d, 1H, J = 16.5 Hz), 3.98-4.10 (m, 2H), 3.87 (s,3H), 3.77 (s,3H), 2.40-2.49 (m, 1H),1.25-1.31 (t, 3H, J = 7.0 Hz), 1.14-1.24 (m, 2H), 0.78-0.95(m, 2H).

[0028] 13 C NMR (CDCl 3 , 125 MHz) δ 166.1, 165.1, 155.9, 147.0, 145.6, 134.3,128.8, 127.8, 127.5, 125.7, 125.6, 124.0, 123.0, 120.9, 53.7, 52.3, 52.6, 7.1,

[0029] ESI-MS [M] + m / z 426.

Embodiment 2

[0030] The preparation of embodiment 2 catalyst b2

[0031]

[0032] Dissolve compound a2 (50g, 141.5mmol, 1.0eq.) in 500mL acetone, stir to dissolve at 20~30°C, add ethyl bromoacetate (1415mmol, 10eq.), react for 12 hours, and concentrate the reaction solution to dryness , the concentrate was recrystallized from ethyl acetate to obtain 53.1 g of catalyst b2, yield: 72.2%.

[0033] 1 H NMR (CDCl 3 , 500 MHz) δ 11.63 (s, 1H), 8.57 (d, 1H, J = 8.0 Hz),7.65-7.72 (m, 3H), 7.34-7.41 (m, 2H), 6.15 (d, 1H, J = 16.5 Hz), 5.71 (d, 1H, J = 16.5 Hz), 4.30-4.37 (m, 2H), 4.18-4.25 (m, 2H), 3.98-4.10 (m, 2H), 2.40-2.49 (m, 1H), 1.32-1.39 (t, 3H, J = 7.0 Hz), 1.24-1.30 (t, 3H, J = 7.0 Hz),1.13-1.23 (m, 2H),0.77-0.94(m, 2H).

[0034] 13 C NMR (CDCl 3, 125 MHz) Δ 166.1, 165.1, 155.9, 147.0, 145.6, 134.3,128.8, 127.5, 125.7, 124.0, 123.0, 120.9, 62.8, 53.9.9, 13.5, 7.9, 6.9.

[0035] ESI-MS [M] + m / z 440.

Embodiment 3

[0036] The preparation of embodiment 3 catalyst b5

[0037]

[0038] Dissolve compound a5 (50g, 127.5mmol, 1.0eq.) in 500mL ethyl acetate, stir to dissolve at 25~35°C, add ethyl bromoacetate (1275mmol, 10eq.), react for 12 hours, and concentrate the reaction solution To dryness, the concentrate was recrystallized with ethyl acetate to obtain 57.4 g of catalyst b5, yield: 80.5%.

[0039] 1 H NMR (CDCl 3 , 500 MHz) δ 11.64 (s, 1H), 8.58 (d, 1H, J = 8.0 Hz),7.65-7.72 (m, 3H), 7.34-7.41 (m, 2H), 6.14 (d, 1H, J = 16.5 Hz), 5.70 (d, 1H, J = 16.5 Hz), 4.31-4.37 (m, 2H), 4.19-4.25 (m, 2H), 3.98-4.10 (m, 2H), 1.31-1.38 (t, 3H, J = 7.0 Hz), 1.23-1.29 (t, 3H, J = 7.0 Hz).

[0040] 13 C NMR (CDCl 3 , 125 MHz) δ 166.1, 165.1, 155.9, 147.0, 134.3, 128.8,127.8, 127.5, 125.7, 125.6, 124.0, 123.0, 120.9, 120.0, 63.3, 62.9, 53.9,13.5,

[0041] ESI-MS [M] + m / z 478.

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Abstract

The invention provides novel 4H-1,2,4-triazole quaternary ammonium salt derivatives (shown as formula I), a preparing method thereof and applications of the derivatives especially as bromination catalysts, and belongs to the technical field of chemical medicine synthesis. Through adding the catalysts to reactions, the reaction activity is increased, reaction temperatures are reduced, the using amounts of bromination agents are greatly reduced, a column chromatography purification step is avoided, and the production cost is reduced. The derivatives are stable and controllable in quality, are suitable for commercial production of medicine intermediates, and make catalysis bromination more environmentally friendly.

Description

technical field [0001] The invention relates to the field of medicine, and relates to a Lesinurad intermediate 2-(5-bromo-4-(4-cyclopropylnaphthalene-1-yl)- 4H -1,2,4-triazole-3-mercapto) acetate compound quaternary ammonium salt catalyzed preparation method. Background technique [0002] Gout is a crystal-associated arthropathy caused by the deposition of monosodium urate, which is directly related to hyperuricemia caused by disturbance of purine metabolism or decreased uric acid excretion. Lesinurad is an oral uricosuric agent that inhibits the renal proximal tubule uric acid transporter URAT1. Developed by the British pharmaceutical giant AstraZeneca, it was launched in the United States on December 22, 2015. There are more than 20 million gout patients in the world, so it has a good market prospect. [0003] Patent CN103524440B has protected Lesinurad brominated intermediate (chemical name is 2-(5-bromo-4-(4-cyclopropylnaphthalene-1-yl)- 4H -1,2,4-triazole-3-mercapto...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D249/12B01J31/02
CPCB01J31/0284B01J2231/40C07D249/12
Inventor 王辉姚云凡张翔甄志彬
Owner BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
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