Synthesizing method of indacaterol amino fragment 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride

A technology of amine hydrochloride and diethyl, applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of poor economy and environmental friendliness, unsuitable for scale-up production, difficult to industrialized production and the like, and achieves low production cost and large scale. Implementation of value and socioeconomic benefits, mild conditions

Active Publication Date: 2013-10-23
武汉恒和达生物医药有限公司
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Problems solved by technology

[0008] Route 1 uses a very expensive raw material: o-diethylbenzene (10,000 yuan per kilogram), a large number of isomers are generated in the second step cyclization reaction, column purification is required, and the Expensive palladium carbon is used as a catalyst and a large amount of sulfuric acid and acetic acid are used as solvents. The

Method used

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  • Synthesizing method of indacaterol amino fragment 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride
  • Synthesizing method of indacaterol amino fragment 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride
  • Synthesizing method of indacaterol amino fragment 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037](1) Put 4.1Kg of zinc chloride and 10L of dichloromethane into the reaction kettle, cool down to about -5°C in an ice bath, add 1.55Kg of 3-chloropropionyl chloride and 1.3Kg of ethylbenzene dropwise in sequence, and then rise to room temperature React for 2 hours. The reaction was processed in a conventional manner to obtain 3.2Kg of 3-chloro-1-(4-ethylphenyl)propan-1-one, with a yield of 92%.

[0038] (2) Add 2kg of 3-chloro-1-(4-ethylphenyl)propan-1-one in batches to a reaction kettle filled with 10L of concentrated sulfuric acid, raise the temperature to 100°C after the addition, and react for 1.5 hours. Pour into ice water for extraction, and treat according to conventional methods to obtain 1.5Kg of 5-ethyl-2,3-dihydro-1H-inden-1-one. The yield is 92%.

[0039] (3) Dissolve 900g of 5-ethyl-2,3-dihydro-1H-inden-1-one methanol in 4.5L of methanol, add 700g of n-butyl nitrite dropwise, react at 40°C for 30 minutes, then add dropwise Concentrated hydrochloric acid 5...

Embodiment 2

[0046] (1) Put 4.0Kg of aluminum trichloride and 10L of dichloromethane into the reaction kettle, cool down to about -5°C in an ice bath, add 1.55Kg of 3-chloropropionyl chloride and 1.3Kg of ethylbenzene dropwise in sequence, and then rise to React at room temperature for 2 hours. The reaction was processed in a conventional manner to obtain 3.4Kg of 3-chloro-1-(4-ethylphenyl)propan-1-one, with a yield of 98%.

[0047] (2) Add 2kg of 3-chloro-1-(4-ethylphenyl)propan-1-one in batches to a reaction kettle filled with 5L of concentrated sulfuric acid and 5L of 1,2-dichloroethane. Afterwards, the temperature was raised to reflux for 1.5 hours, poured into ice water for extraction, and treated according to conventional methods to obtain 1.43 Kg of 5-ethyl-2,3-dihydro-1H-inden-1-one. Yield 88%.

[0048] (3) Dissolve 900g of 5-ethyl-2,3-dihydro-1H-inden-1-one methanol in 4.5L of methanol, add 700g of n-butyl nitrite dropwise, react at 40°C for 30 minutes, then add dropwise Concen...

Embodiment 3

[0055] (1) Put 7.8Kg of tin tetrachloride and 10L of carbon disulfide into the reaction kettle, cool down to about -5°C in an ice bath, add 1.55Kg of 3-chloropropionyl chloride and 1.3Kg of ethylbenzene dropwise in sequence, and then rise to room temperature for reaction 2 hours. The reaction was processed in a conventional manner to obtain 2.78Kg of 3-chloro-1-(4-ethylphenyl)propan-1-one, with a yield of 80%.

[0056] (2) Add 2kg of 3-chloro-1-(4-ethylphenyl)propan-1-one in batches to a reaction kettle filled with 5kg of polyphosphoric acid and 20L of 1,2-dichloroethane, add After completion, the temperature was raised to reflux for 6 hours, poured into ice water for extraction, and treated according to conventional methods to obtain 1.2Kg of 5-ethyl-2,3-dihydro-1H-inden-1-one. Yield 74%.

[0057] (3) Dissolve 900g of 5-ethyl-2,3-dihydro-1H-inden-1-one methanol in 4.5L of methanol, add 700g of n-butyl nitrite dropwise, react at 40°C for 30 minutes, then add dropwise Concen...

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Abstract

The invention discloses a synthesizing method of an indacaterol amino fragment 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride. According to the invention, ethylbenzene I is adopted as a raw material, and a Friedel-Crafts reaction is carried out, such that a compound II is obtained; the compound II is subjected to cyclization, such that ethylindene III is obtained; ethylindene III is subjected to alpha-site oximation reaction, such that a compound IV is obtained; the compound IV is subjected to RaneyNi reduction, such that a compound V is obtained; the compound V is processed with a Tf-protection and sodium borohydride reduction one-pot method, such that a compound VI is obtained; the compound VI is subjected to a Friedel-Crafts reaction, such that a compound VII is obtained; the compound VII is reduced, such that a compound VIII is obtained; and the compound VIII is subjected to protection removing and hydrochloride salt formation, such that a final product compound IX is obtained, and the 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride is obtained. The method provided by the invention is simple and convenient, and has low cost. The content of the product is higher than 99%. The method also has the advantages of low environmental pollution and suitability for industrialized production.

Description

technical field [0001] The present invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a key intermediate 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride of indacaterol Salt preparation method. Background technique [0002] Indacaterol is a bronchodilator that belongs to the long-acting inhaled β2-agonist (LABA) class and is suitable for the maintenance treatment of adults with chronic obstructive pulmonary disease (COPD). It takes effect in 5 minutes and lasts for 24 hours. Indacaterol is produced by Swiss Novartis Pharmaceuticals, and has been listed in more than 70 countries and regions around the world since 2009; it was approved by the State Food and Drug Administration in June 2012 to be listed in China, with the trade name Angrun ( ), is the first LABA single preparation approved for the treatment of COPD in China. [0003] 5,6-diethyl-2,3-dihydro-1H-inden-2-amine is a key intermediate in the synthesis ...

Claims

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Application Information

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IPC IPC(8): C07C211/42C07C209/62
Inventor 周叶兵鲁东安刘伟张圣波
Owner 武汉恒和达生物医药有限公司
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