Naphthyl thiocarbonyl compound as well as preparation method and application thereof

A technology of naphthylthiocarbonyl and compound, which is applied in the application field of synthesizing racinades, can solve the problems of high risk, high production cost, reduced product purity and yield, etc., and achieves high product purity and low pollution , the effect of low toxicity

Inactive Publication Date: 2019-03-26
JIANGXI SYNERGY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] There are many deficiencies in the above-mentioned synthetic method, which is unfavorable for industrialized large-scale production
Specifically, 1) the nitration reaction uses a large amount of nitric acid, which is not conducive to safe production and environmental protection; 2) the nitro reduction reaction easily makes the cyclopropyl ring open, thereby producing a large amount of impurities, reducing product purity and yield, and using expensive Palladium carbon is used as a catalyst, and the production cost is relatively high; 3) the last step reaction uses the highly toxic reagent thiophosgene, which is highly dangerous and has a very adverse impact on the environment and the personal safety of operators

Method used

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  • Naphthyl thiocarbonyl compound as well as preparation method and application thereof
  • Naphthyl thiocarbonyl compound as well as preparation method and application thereof
  • Naphthyl thiocarbonyl compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Example 1 Preparation of 1-cyclopropylnaphthalene (III)

[0101] Under nitrogen protection, into a dry 2L round bottom flask, add 1-bromonaphthalene (50 g, 241 mmol), ferric chloride (2.0 g, 12.3 mmol) and 100 mL of dry tetrahydrofuran (THF), and stir under ice-water bath cooling, Using a constant pressure dropping funnel, 300 mL of a 1.0 mol / L cyclopropylmagnesium bromide solution in THF was slowly added dropwise to the system. After the dropwise addition, the reaction compound was stirred at room temperature for 5 h under nitrogen protection, then heated to reflux, and reacted for 24 h. After the reaction was completed, most of the solvent was distilled off under reduced pressure, the residue was cooled to room temperature, slowly poured into 2L of stirred ice water, stirred, adjusted to pH 2-3 with concentrated hydrochloric acid, and extracted with dichloromethane (250mL×3) . The organic phases were combined and washed with 500 mL of water. Evaporate to dryness ...

Embodiment 2

[0102] Example 2 Preparation of 1-cyclopropylnaphthalene (III)

[0103] Under nitrogen protection, into a dry 2L round-bottom flask, add 1-bromonaphthalene (50 g, 241 mmol), bistriphenylphosphine nickel dichloride (2.5 g, 4.6 mmol) and 100 mL of dry THF, and cool in an ice-water bath While stirring, 300 mL of a 1.0 mol / L cyclopropylmagnesium bromide solution in THF was slowly added dropwise to the system using a constant pressure dropping funnel. After the dropwise addition, the reaction compound was stirred at room temperature for 5 h under nitrogen protection, then heated to reflux, and reacted for 24 h. After the completion of the reaction, most of the solvent was distilled off under reduced pressure, the residue was cooled to room temperature, slowly poured into 2L of stirred ice water, stirred, adjusted to pH 2-3 with concentrated hydrochloric acid, extracted with dichloromethane (250mL×3) . The organic phases were combined and washed with 500 mL of water. Evaporate...

Embodiment 3

[0104] Example 3 Preparation of 4-cyclopropyl-1-bromonaphthalene (IV)

[0105] Put 300 mL of dichloromethane, 1-cyclopropylnaphthalene (30 g, 178 mmol), and dibromohydantoin (50.9 g, 178 mmol) into a dry reaction flask, control the internal temperature to 30-50 ° C, and stir the reaction until TLC detects that the reaction is complete , stop keeping warm. Add 100 mL of sodium hydrogen sulfite aqueous solution (5%) to wash, 100 mL of sodium hydroxide solution (5%) to wash, and wash with water until neutral. Evaporate to dryness under reduced pressure to obtain 4-cyclopropyl-1-bromonaphthalene (39.8 g, yield 90.48%, purity 97.6%).

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Abstract

The invention provides a naphthyl thiocarbonyl compound of a structural formula I. The invention further provides a preparation method of the compound and application of the compound in preparation ofa lesinurad key intermediate 1-cyclopropylnaphthalene-4-benzyl isothiocyanate of a structural formula VII. The structural formula is as shown in the specification. In the formula, R represents hydroxyl or thio.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a novel naphthylthiocarbonyl compound, a preparation method thereof, and an application in the synthesis of Lesinurad. Background technique [0002] Lesinurad, the molecular structure is shown in X, CAS: 878672-00-5, is a selective uric acid reuptake inhibitor, which can block URAT1 transport, normalize uric acid excretion and reduce serum uric acid levels, thereby relieving pain symptoms caused by gout. A phase III clinical study in patients who did not respond to allopurinol and febuxostat showed that resinad alone significantly reduced serum levels of uric acid. In December 2015, Recinade was approved by the US FDA for the treatment of hyperuricemia associated with gout. [0003] With the improvement of living standards, the incidence of hyperuricemia and gout in my country is increasing year by year, and there is a trend of younger onset. Therefore, it can be e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C327/18C07C327/16C07C331/28C07D249/12
CPCC07C327/18C07C1/26C07C17/12C07C45/46C07C51/15C07C51/16C07C327/16C07C331/28C07D249/12C07C25/22C07C13/47C07C63/49C07C49/792
Inventor 冯玉杰黄伟平李波朱高翔万德力姜怡文
Owner JIANGXI SYNERGY PHARMA
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