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Method for synthesizing raw medicine dihydroindene-1-carboxyl acid for clidabac

A technology of carboxylic acid and indane, which is applied in the field of indane-1-carboxylic acid synthesis, can solve the problems of high production cost and long process route, and achieve the effect of reducing production cost and shortening the synthesis route

Inactive Publication Date: 2009-04-01
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] (4) Take cyclohexylbenzene as raw material, synthesize cycloindenacic acid through seven-step reaction (German patent DE 2330856 in 1977). However, the operational routes of these methods are longer, and expensive reagents such as Pd / C are also needed, and the toxicity is larger Therefore, there is an urgent need to replace the above commonly used routes with simple and economical synthetic routes.
And so far, the synthetic method of existing indane-1-carboxylic acid (I) all needs 5-7 steps, makes the production cost of indane-1-carboxylic acid (I) too high

Method used

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  • Method for synthesizing raw medicine dihydroindene-1-carboxyl acid for clidabac
  • Method for synthesizing raw medicine dihydroindene-1-carboxyl acid for clidabac
  • Method for synthesizing raw medicine dihydroindene-1-carboxyl acid for clidabac

Examples

Experimental program
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Effect test

example 1

[0038] Synthesis of indane-1-carboxylic acid (I) from indane-1-carboxylic acid methyl ester (VIa)

[0039] (1) Synthesis of indane-1-carboxylic acid methyl ester (VIa) (chemical name 1-formyl methyl-2,3-dihydro-1-hydrogen-indene) under nitrogen atmosphere, continuously stirred at 8°C Under certain conditions, 50 mL of tetrahydrofuran solution dissolved in 17.5 g o-bromobenzyl bromide (70 mmol) was added dropwise to tetrahydrofuran (20 mL) solution containing 6.7 g of zinc powder (105 mmol), and reacted for 30 h. After the reaction is completed, the o-bromobenzyl zinc reagent can be obtained, which is sealed and stored for later use.

[0040] In another container, under the same nitrogen atmosphere and constant stirring, add the catalyst Ni(dppf) 2 Cl 2 (0.1mmol) and 10mL tetrahydrofuran as a solvent, then add methyl acrylate (Va) 87mg (1mmol), heat the oil bath to reflux, then dropwise add 3.5mL zinc reagent (3.5mmol), after reacting for 10 hours, the reaction system was coo...

example 2

[0044] Synthesis of indane-1-carboxylic acid (I) from ethyl indane-1-carboxylate (VIb)

[0045] (1) Indane-1-carboxylate ethyl ester (VIb) (chemical name: 1-formyl ethyl-2,3-dihydro-1-hydro-indene) was synthesized under nitrogen atmosphere, continuously stirred at 0°C Under the conditions, 50 mL tetrahydrofuran solution dissolved in 17.5 g o-bromobenzyl bromide (70 mmol) was added dropwise to tetrahydrofuran (50 mL) solution containing 8.9 g zinc powder (140 mmol), and reacted for 10 h. After the reaction is completed, the o-bromobenzyl zinc reagent can be obtained, which is sealed and stored for later use.

[0046] Under nitrogen atmosphere and constant stirring, the catalyst Ni{P(p-MeOC 6 h 4 ) 3} 2 I (0.2mmol) and 15mL ether were used as solvents, then 101mg (1mmol) of ethyl acrylate (Vb) was added, the oil bath was heated to reflux, then 2.8mL zinc reagent (2mmol) was added dropwise, and after 10 hours of reaction, the reaction system was cooled To room temperature, a...

example 3

[0050] Synthesis of indane-1-carboxylic acid (I) from butyl indane-1-carboxylate (VIc)

[0051] (1) Synthesis of butyl indane-1-carboxylate (chemical name 1-butyl carboxylate-2,3-dihydro-1-hydrogen-indene)

[0052] Under nitrogen atmosphere, under the condition of continuous stirring at 20°C, 50 mL of ethylene glycol dimethyl ether solution dissolved in 17.5 g of o-bromobenzyl bromide (70 mmol) was added dropwise to ethylene glycol dimethyl ether solution containing 5.1 g of zinc powder (80 mmol). Diethyl ether (90mL) solution, reacted for 20h. After the reaction is completed, the o-bromobenzyl zinc reagent can be obtained, which is sealed and stored for later use.

[0053] Under nitrogen atmosphere and constant stirring, the catalyst Ni{P(p-F 3 CC 6 h 4 ) 3} 2 Cl 2 (0.3mmol) and 20mL trifluorotoluene as solvent, then add butyl acrylate (Vc) 129mg (1mmol), heat the oil bath to reflux, then add 10mL zinc reagent (5mmol) dropwise, after reacting for 30 hours, the reaction...

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Abstract

The invention relates to a synthetic method of indan-1-carboxylic acid which is a pharmaceutical raw material for clidanac. The synthetic method comprises the following steps: (1) o-bromobenzyl bromide is taken as a starting raw material and reacted with zinc powder, thereby obtaining o-bromobenzyl zinc bromide; (2) the carbon cyclization reaction is carried out on the o-bromobenzyl zinc bromide and an acrylic acid ester compound under the action of a catalyst, thereby obtaining an indan-1-carboxylic acid compound; and (3) the indan-1-carboxylic acid compound is hydrolyzed under the alkaline condition, thereby obtaining the indan-1-carboxylic acid which is the important pharmaceutical raw material for synthesizing the clidanac. The synthetic method can rapidly and simply synthesize the indan-1-carboxylic acid, thereby shortening the synthesis route of the clidanac and further reducing the production cost of the clidanac.

Description

technical field [0001] The invention relates to a method for synthesizing indane-1-carboxylic acid used as a crude drug of cyclocloindenic acid. Background technique [0002] Indane-1-carboxylic acid, chemical name, (±)-2,3-dihydro-1H-indene-1-carboxylic acid, there are two main types of synthesis of this compound in the current literature: [0003] (1) Using benzaldehyde as a raw material, first synthesize indan-1-one (Org. Lett., 5(24), 2003, 4653-4656) through two-step reaction, and then use indan-1-one through four-step reaction To synthesize indane-1-carboxylic acid (J.Org.Chem., 68(19), 2003, 7234-7242), the whole process needs seven steps of reaction. [0004] (2) Use acetophenone as a raw material to synthesize indene through a three-step reaction (J.Chem.Soc., Perkin Trans.1, 3, 2002, 402-415), and then synthesize indene from indene through a two-step reaction- 1-Carboxylic acid (J.Org.Chem., 45(17), 1980, 3456-3461; J.Org.Chem., 30, 1965, 2948-2956), the whole pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C61/40C07C27/02B01J31/22B01J31/28
Inventor 孙良东周维义魏玉萍
Owner TIANJIN UNIV
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