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Process for producing phenyl-substituted heterocyclic derivative through coupling using transition metal catalyst

一种制造方法、苯基取代的技术，应用在杂环化合物有效成分、散装化学品生产、含有效成分的医用配制品等方向，能够解决苯基取代杂环衍生物没有报道等问题

Active Publication Date: 2012-01-25
TEIJIN LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there has been no report of synthesizing the phenyl-substituted heterocyclic derivatives of the present invention with metal catalysts other than nickel catalysts

Method used

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  • Process for producing phenyl-substituted heterocyclic derivative through coupling using transition metal catalyst
  • Process for producing phenyl-substituted heterocyclic derivative through coupling using transition metal catalyst
  • Process for producing phenyl-substituted heterocyclic derivative through coupling using transition metal catalyst

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0255] Hereinafter, the present invention will be specifically described by way of examples and the like. However, it does not mean that the scope of the present invention is limited by these examples.

[0256] In this example, the following equipment and the like were used for analysis and purification.

[0257] TLC: E. Merck Silicone 60F 254 (0.25mm)

[0258] Flash column chromatography: Biotage Flash, Si40

[0259] Preparative thin-layer chromatography (PTLC): Merck silica gel 60F 254 (1mm)

[0260] Liquid Chromatography / Mass Spectrometry (LC / MS)

[0261] Analysis system: SHIMAZU LCMS-2010A

[0262] Software: LCMS Solution

[0263] Experimental conditions:

[0264] Column: Phenomenex Gemini 3μm 4.6mm×30mm

[0265] Flow rate: 1.2mL / min

[0266] Measuring temperature: 40°C

[0267] A Solvent: 5%MeCN / 95%H 2 O+0.05% TFA

[0268] B Solvent: 95% MeCN / 5% H 2 O+0.05% TFA

[0269] MS mode: ESI+

[0270] ESI voltage: 4.5KV

[0271] Source temperature: 130°C

[0272] D...

reference example 1

[0280] Synthesis of tert-butyl 4-methylthiazole-5-carboxylate

[0281]

[0282] A mixture of 4-methyl-5-thiazolecarboxylic acid (1.36 g, 9.48 mmol) and thionyl chloride (28.7 mL) was stirred at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure to remove thionyl chloride, and the resulting crude product was dried under reduced pressure. To a dichloromethane (5.68 mL) solution of the crude product were added tert-butanol (2.84 mL) and pyridine (16.9 mL), followed by stirring at 60° C. overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and saturated aqueous sodium carbonate solution and ethyl acetate were added to the obtained crude product. After separating ethyl acetate, ethyl acetate was added to saturated aqueous sodium bicarbonate solution for extraction. The combined organic phases were washed with saturated brine and dried over anhydrous magnesium sulfate. After magnesium sulfate ...

reference example 2

[0285] Synthesis of 5-iodo-2-isobutoxybenzonitrile

[0286]

[0287] A solution of 2-methyl-1-propanol (0.56 mL, 6.06 mmol) in N,N-dimethylformamide (10 mL) was cooled to 0° C. and sodium hydride (242 mg, 60% in mineral oil) was added in small portions suspension, 6.06 mmol). After stirring the suspended reaction liquid at 0°C for 5 minutes, the temperature was raised to 23°C, stirred at room temperature for 10 minutes, and cooled to 0°C again. 2-Fluoro-5-iodobenzonitrile (1.0 g, 4.04 mmol) was added to the reaction liquid, and the reaction liquid was warmed up to room temperature, followed by stirring for 1.5 hours. After the reaction, water (20 mL) was added to the reaction liquid, and extracted with ethyl acetate (3×30 mL). The organic phases were combined, washed with saturated brine (3×30 mL), and dried over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the solvent was concentrated under reduced pressure, and the obtained crude product was...

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Abstract

A process for efficiently producing, through few steps, either a xanthine oxidase inhibitor, which is a therapeutic agent for hyperuricemia, or an intermediate therefor. The process is a novel coupling process which comprises subjecting a compound represented by formula (1) to coupling reaction with a compound represented by formula (2) in the presence of a transition metal compound to thereby obtain a compound represented by formula (3).

Description

technical field [0001] The present invention relates to a method for producing phenyl substituted heterocyclic derivatives. The method adopts a novel coupling method of phenyl derivatives and heterocyclic derivatives using a transition metal catalyst. More specifically, the present invention relates to a favorable method for producing a phenyl-substituted heterocyclic derivative or an intermediate thereof that is useful as a xanthine oxidase inhibitor such as a treatment for gout and hyperuricemia. Background technique [0002] Gout is based on hyperuricemia, and hyperuricemia improvement therapy is implemented after the attack is relieved. Drugs for treating hyperuricemia are broadly classified into uric acid excretion accelerators and uric acid synthesis inhibitors (xanthine oxidase inhibitors), and are appropriately selected according to the form and degree of the disease. [0003] Examples of xanthine oxidase (XOD) inhibitors include 2-phenylthiazole derivatives (Patent...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/20A61K31/426A61P19/06A61P43/00C07D277/56
CPCC07D277/20C07D277/56Y02P20/55A61P19/06A61P43/00A61K31/42A61K31/426C07D277/30
Inventor 小宫山真人矢岛直树黑川真行
Owner TEIJIN LTD
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