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5-(5-bromo-2methylphenyl)-1-(4-fluorophenyl)pentane-1,4-dione, preparation method and applications thereof

A technology of methylphenyl and fluorophenyl, which is applied in the preparation of carbon-based compounds, chemical instruments and methods, and the preparation of organic compounds, and can solve problems such as unsuitable for industrialization, cumbersome steps, and complicated preparation

Active Publication Date: 2014-10-01
SHANGHAI FANGNAN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, because the preparation of raw materials in this method is complicated and the steps are cumbersome, it is not suitable for industrialization.

Method used

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  • 5-(5-bromo-2methylphenyl)-1-(4-fluorophenyl)pentane-1,4-dione, preparation method and applications thereof
  • 5-(5-bromo-2methylphenyl)-1-(4-fluorophenyl)pentane-1,4-dione, preparation method and applications thereof
  • 5-(5-bromo-2methylphenyl)-1-(4-fluorophenyl)pentane-1,4-dione, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0029] Synthesis of Example 13-(5-bromo-2-methylphenyl)-2-oxopropionic acid (formula III)

[0030] The synthesis of 3-(5-bromo-2-methylphenyl)-2-oxopropionic acid refers to the literature of Raap et al. (Eur.J.Org.Chem.1999, 2609-2621).

[0031] Add 2-methyl-5-bromobenzaldehyde (20g, 100mmol), hydantoin (15g, 150mmol), sodium acetate (20g, 244mmol) and 150mL glacial acetic acid into a 250mL reaction flask, heat the reaction system to reflux overnight, and cool the system to room temperature, slowly pour into 500mL ice-water system, lower to room temperature, filter, and wash the filter cake with 500mL water until neutral. Collect the solid, add the solid into a 250mL reaction flask, add 100mL of 20% NaOH solution, reflux the system for 3h under the protection of nitrogen, cool down to 20-30°C, and neutralize the system with 6N hydrochloric acid aqueous solution to pH=7-8, 10 g of solid sodium bicarbonate was added, and the system was extracted three times with ethyl acetate. ...

example 25

[0033] Synthesis of Example 25-(5-bromo-2-methylphenyl)-1-(4-fluorophenyl)pentane-1,4-diketone (Formula I)

[0034] Method 1): In a 500mL three-necked flask, add 3-(5-bromo-2-methylphenyl)-2-carbonylpropionic acid (formula III, 25.7g, 100mmol), 1-(4-fluorophenyl)- 2-ene-1-propanone (formula II, 15g, 100mmol), triethylamine (10.1g, 100mmol), 5-(2-hydroxyethyl)-4-methyl-3-benzyl-thiazole chloride (2.7g, 10mmol), ethanol 150mL, heat the system to reflux, cool down after 15h, add 100mL of 10% saline to the system, extract with 200mL ethyl acetate, concentrate the organic phase, and perform column chromatography (PE / EA=7 / 1) 27.6 g of the compound of formula I was obtained, with a yield of 76%.

[0035] MS(ESI)363.0(M+H + , 100%)

[0036] Method 2): In a 500mL three-necked flask, add 3-(5-bromo-2-methylphenyl)-2-carbonylpropionic acid (formula III, 25.7g, 100mmol), 1-(4-fluorophenyl)- 2-ene-1-propanone (formula II, 15g, 100mmol), triethylamine (10.1g, 100mmol), 5-(2-hydroxyethy...

example 3

[0042] Synthesis of Example 32-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene (formula X)

[0043] Method 1): Add 5-(5-bromo-2-methylphenyl)-1-(4-fluorophenyl)pentane-1,4-dione (Formula I, 18g, 50mmol) into a 250mL three-necked flask , toluene 100mL, Lowe's reagent (20g, 50mmol), the system was refluxed for 6h, TLC detected that all the raw materials I disappeared, the system was cooled down, concentrated and then column chromatographed (PE / EA=3 / 1) to obtain 14g of the compound of formula X. The rate is 78%.

[0044] MS(ESI)361.0(M+H + , 100%)

[0045] Method 2): Add 5-(5-bromo-2-methylphenyl)-1-(4-fluorophenyl)pentane-1,4-dione (Formula I, 18g, 50mmol) into a 250mL three-necked flask , xylene 100mL, Lowe’s reagent (20g, 50mmol), the system was refluxed for 8h, TLC detected that all the raw materials I disappeared, the system was cooled down, concentrated and then column chromatographed (PE / EA=3 / 1) to obtain 15g of the compound of formula X, The yield is 83%.

[004...

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Abstract

The invention discloses a compound 5-(5-bromo-2methylphenyl)-1-(4-fluorophenyl)pentane-1,4-dione represented by the formula I, a preparation method and applications thereof. The compound represented by the formula I can be taken as the raw material to carry out reactions in the presence of a vulcanizer so as to obtain an intermediate compound represented by the formula X of a drug Canagliflozin for treating diabetes II. The raw materials and reagents required in the preparation method are relatively cheap, and the preparation method has the advantages of low cost, convenient and safe operation, high yield, little environmental pollution, good economic profits, and suitability for industrial production.

Description

technical field [0001] The present invention relates to formula I compound 5-(5-bromo-2-methylphenyl)-1-(4-fluorophenyl)pentane-1,4-dione and its preparation method and application, especially to the The compound of formula I is used as an intermediate to prepare the compound of formula X which is the intermediate compound of Canagliflozin, an anti-II diabetes drug. Background technique [0002] Canagliflozin developed by Johnson & Johnson is a selective type II sodium-glucose transporter (SGLT-2) inhibitor. An advisory panel of the US Food and Drug Administration (FDA) recommended that the FDA approve the new diabetes drug Canagliflozin, which is expected to become the first drug approved in the United States. A SGLT2 inhibitor diabetes drug, the structural formula is as follows: [0003] [0004] It can be seen from the above structure that Canagliflozin is mainly obtained by coupling the aromatic ring side chain X with D-glucose, wherein the structure of the aromatic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/72C07C49/813C07D333/12
CPCC07C45/72C07D333/12C07C49/813
Inventor 张念
Owner SHANGHAI FANGNAN PHARMA
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