Preparation method of 4-cyclopropyl-1-naphthylamine

A technology of cyclopropyl and naphthylamine, which is applied in the field of preparation of Lesinurad intermediates, can solve problems such as difficult application, and achieve the effect of reducing production cost and high reaction yield

Inactive Publication Date: 2019-07-02
SUZHOU PENGXU PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The shortcomings of these two routes are difficult to make them well applied in scale-up production

Method used

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  • Preparation method of 4-cyclopropyl-1-naphthylamine
  • Preparation method of 4-cyclopropyl-1-naphthylamine
  • Preparation method of 4-cyclopropyl-1-naphthylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The synthesis of embodiment 1,4-cyclopropyl-1-bromonaphthalene

[0035]

[0036] 1-Cyclopropylnaphthalene (5.0 g, 30 mmol) was dissolved in 15 mL of acetic acid, liquid bromine (5.68 g, 36 mmol) was added dropwise, and the mixture was reacted at 10-20 °C for 1-2 hours. After the reaction was completed, the reaction solution was quenched with water, extracted with dichloromethane, washed with alkali, washed with sodium sulfite solution, washed with water, concentrated to remove dichloromethane, and purified by silica gel column to obtain 6.24 g of 4-cyclopropyl-1-bromonaphthalene. The yield is 85%.

[0037] Product NMR data: 1 H NMR (400 MHz, DMSO) δ 8.51 – 8.42 (m, 1H), 8.23 ​​–8.13 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.73 – 7.66 (m, 2H), 7.17 (d, J = 7.7Hz, 1H), 2.38 (m, 1H), 1.11 – 1.01 (m, 2H), 0.78 – 0.68 (m, 2H).

Embodiment 2

[0038] The synthesis of embodiment 2,4-cyclopropyl-1-bromonaphthalene

[0039]

[0040] 1-Cyclopropylnaphthalene (5.0 g, 30 mmol) was dissolved in 50 mL of acetonitrile, NBS (7.1 g, 40 mmol) was added, and the mixture was reacted at 50 °C for 24 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, concentrated to remove acetonitrile, added 50 mL of n-heptane, stirred and filtered. The filtrate was concentrated and then purified by a silica gel column to obtain 6.7 g of 4-cyclopropyl-1-bromonaphthalene with a yield of 90%.

Embodiment 3

[0041] The synthesis of embodiment 3,4-cyclopropyl-1-naphthylamine

[0042]

[0043] 4-Cyclopropyl-1-bromonaphthalene (6.0 g, 24 mmol) was dissolved in 12 mL of N, N-dimethylformamide (DMF), added cuprous oxide (0.52 g, 3.6 mmol), ammonia water 12 mL (Ammonia mass concentration 25%), airtight autoclave and press into ammonia gas 20-30min. The mixed system was reacted at 100 °C for 28 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, 36 ml of water was added, extracted twice with 70 mL of methyl tert-butyl ether, concentrated, and purified by a silica gel column to obtain 3.56 g of 4-cyclopropyl-1-naphthylamine , the yield is 80%.

[0044] Product NMR data: 1 H NMR (400 MHz, DMSO) δ 8.25 (d, J = 7.9 Hz, 1H), 8.07(d, J = 8.0 Hz, 1H), 7.48 (m, 1H), 7.39 (m, 1H), 6.99 (m, 1H), 6.59 (d, J =7.7 Hz, 1H), 5.50 (s, 2H), 2.14 (m, 1H), 1.00 – 0.83 (m, 2H), 0.61 – 0.47 (m, 2H).

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Abstract

The invention relates to a novel preparation method of 4-cyclopropyl-1-naphthylamine. The raw materials needed for the preparation method are cheap in price and easy to obtain, the reaction step operation is simple, and the total yield is better than that of the prior art level. Moreover, the nitrification, hydrogenation reduction, Suzuki coupling and other reactions are avoided to use, and thus the production difficulty and production cost is greatly reduced. A relatively economical, efficient, safe and environment-friendly synthetic route is provided for the preparation of 4-cyclopropyl-1-naphthylamine.

Description

technical field [0001] The invention belongs to the technical field of preparation of Lesinurad intermediates, in particular to a preparation method of 4-cyclopropyl-1-naphthylamine, a key intermediate of Lesinurad. 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. In December 2015, the FDA approved AstraZeneca's gout drug Lesinurad for the treatment of gout-related hyperuricemia in combination with xanthine oxidase inhibitors. It is of great social and economic significance to develop new, more effective, and lower-cost process methods. [0003] To realize the preparation of the drug Lesinurad, the synthesis of its key intermediate 4-cyclopropyl-1-naphthylamine is very important, and it is of great significance to find a method...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/10C07C209/00C07C211/58
CPCC07C17/12C07C209/00C07C209/10C07C25/22C07C211/58
Inventor 李丕旭王鹏刘远华蒋强华
Owner SUZHOU PENGXU PHARM TECH CO LTD
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