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Preparation method of 4-cyclopropyl-1-isothiocyanatonaphthalene

A technology of naphthyl isothiocyanate and cyclopropyl, which is applied in the field of preparation of 4-cyclopropyl-1-naphthyl isothiocyanate, can solve the problem of high boiling point of viscous oily matter, which is unfavorable for large-scale production , The product purity is not high, etc., to achieve the effect of low cost, easy industrialization, and simple and easy-to-obtain raw materials

Active Publication Date: 2016-11-09
山东川成医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During use, a large amount of toxic gas can be released, causing great environmental pollution.
[0010] 2) Patent US2015252010A1, 4-cyclopropyl-1-naphthylamine, water and xylene, react at 140°C, post-treatment with silica gel, troublesome operation is not conducive to large-scale production, high reaction temperature also has high requirements for equipment
In addition, if the temperature is too high, the purity of the product is not high, which is not conducive to the preparation of the next step product, and the target product obtained is a viscous oil with a high boiling point, so it is not feasible to purify by distillation or recrystallization.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Put 18.4g of 4-cyclopropyl-1-naphthol and 8.36g of ammonium thiocyanate into 92g of dichloromethane, stir to dissolve, control the temperature in an ice bath at 0-5°C, slowly add 18g of oxalic acid dropwise, dropwise After the completion, add 0.37g of iodine, raise the temperature to 20-30°C, and react for 2.5h. After the reaction, add 100ml of water and stir for 0.5h, let stand to separate layers, and wash the organic layer with 50ml of saturated saline. Dry over sodium sulfate, dichloromethane is distilled off from the filtrate under reduced pressure, and the residue is 4-cyclopropyl-1-naphthyl isothiocyanate, which is 21.5 g of brown sticky matter, yield 95.7%, HPLC: 99.3 %. GC-MS m / z: 225. 1H-NMR (400 MHz, DMSO-d6) δ: 8.47 (1H, d), 8.09 (1H, d), 7.67~7.72 (2H, m), 7.48 (1H, dd ), 7.23 (1H, dd), 2.39~2.43 (1H, m), 1.03~1.08 (2H, m), 0.73~0.76 (2H, m).

Embodiment 2

[0033] Put 18.4g of 4-cyclopropyl-1-naphthol and 9.12g of ammonium thiocyanate into 92g of dichloromethane, stir to dissolve, control the temperature in an ice bath at 0-5°C, slowly add 18g of oxalic acid dropwise, dropwise After the completion, add 0.37g of iodine, raise the temperature to 20-30°C, and react for 2.5h. After the reaction, add 100ml of water and stir for 0.5h, let stand to separate layers, and wash the organic layer with 50ml of saturated saline. The filtrate was dried over sodium sulfate, and the toluene was distilled off from the filtrate under reduced pressure. The residue was 4-cyclopropyl-1-naphthyl isothiocyanate, which was 21.7 g of brown sticky matter, with a yield of 96.3%, HPLC: 98.7%. GC-MS m / z: 225. 1H-NMR (400 MHz, DMSO-d6) δ: 8.46 (1H, d), 8.11 (1H, d), 7.69~7.74 (2H, m), 7.49 (1H, dd ), 7.24 (1H, dd), 2.38~2.42 (1H, m), 1.03~1.08 (2H, m), 0.74~0.77 (2H, m).

Embodiment 3

[0035] Put 18.4g of 4-cyclopropyl-1-naphthol and 9.12g of ammonium thiocyanate into 92g of dichloromethane, stir to dissolve, control the temperature in an ice bath at 0-5°C, slowly add 27g of oxalic acid dropwise, dropwise After the completion, add 0.92g of iodine, raise the temperature to 20-30°C, and react for 2.5h. After the reaction is completed, add 100ml of water and stir for 0.5h, let stand to separate layers, wash the organic layer with 50ml of saturated saline, and add 18g of anhydrous Sodium sulfate was dried, and the dichloromethane was evaporated from the filtrate under reduced pressure, and the residue was 4-cyclopropyl-1-naphthyl isothiocyanate, which was 21.9 g of brown sticky matter, yield 96.4%, HPLC: 98.9% . GC-MS m / z: 225. 1H-NMR (400 MHz, DMSO-d6) δ: 8.48 (1H, d), 8.11 (1H, d), 7.70~7.74 (2H, m), 7.51 (1H, dd ), 7.25 (1H, dd), 2.37~2.43 (1H, m), 1.03~1.08 (2H, m), 0.75~0.77 (2H, m).

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Abstract

The invention relates to a preparation method of 4-cyclopropyl-1-isothiocyanatonaphthalene. 4-cyclopropyl-1-isothiocyanatonaphthalene is prepared by taking 4-cyclopropyl-1-naphthol and cyanamide sulfate as main raw materials under the action of oxalic acid and iodine, the total yield is 95% or above, and the purity of a liquid phase is higher than 98.5%. The method is safe in production, friendly to the environment and easy to operate, and industrial production is easy.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of 4-cyclopropyl-1-naphthyl isothiocyanate. Background technique [0002] The chemical name of Lesinurad is 2-[[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]thio]acetic acid, which is Ardea, USA The novel urate reabsorption transactivator 1 (URAT1) inhibitor developed by Biosciences can effectively reduce the concentration of uric acid in the blood, thereby alleviating the symptoms of gout caused by high uric acid. Phase I, II and III clinical results have confirmed that the combination of 1 and xanthine oxidase inhibition can accelerate the elimination of uric acid in patients with gout, with high safety. The drug is a selective uric acid reuptake inhibitor that blocks URAT1 transport and relieves pain symptoms by normalizing uric acid excretion and lowering serum levels of uric acid. Lesinurad alone significantly r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C331/28
CPCC07C331/28
Inventor 刘怀振周艳明马居良郭明
Owner 山东川成医药有限公司
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