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Preparation method of indacaterol maleate

A technology of acid indene and ethyl acetate, applied in the field of chemical substances, can solve problems such as high cost and difficult operation, and achieve the effects of convenient post-processing, improved product quality and high purity

Inactive Publication Date: 2018-08-17
南京法恩化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] At present, only Hengrui Medicine is applying for this drug in China. The original research reaction steps are as long as 19 steps. This method is costly and difficult to operate.

Method used

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  • Preparation method of indacaterol maleate

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Effect test

Embodiment 1

[0028] The present embodiment provides a kind of preparation method of indacaterol maleate, specifically comprises the following steps:

[0029] Step 1: Add 90g of 8-benzyloxy-5-(2-bromoacetyl)-2-hydroxyquinoline and 15ml (1.8M) of toluene solution of R-Me-CBS into THF900ml, nitrogen protection, ice salt Cool the bath down to -10°C, add 294ml (1M) of borane tetrahydrofuran solution dropwise, after 3h, continue the low temperature reaction for 1h; add 250ml methanol to quench, spin the reaction solution, add 300ml ethyl acetate and 300ml The phase was dried and spin-dried to obtain 72.5 g of intermediate 1, yield: 81%.

[0030] Step 2: Add 70.2g of intermediate 1 to 260ml of DMF, protect with nitrogen, cool down in an ice bath, slowly add 99.8g of TBSOTF and 40.3g of 2,6-lutidine, after the addition is complete, return to room temperature and react for 1h; add Quenched with 45ml of methanol, then added 500ml of ethyl acetate:cyclohexane=1:1 mixed solution and 500ml of saline; ...

Embodiment 2

[0034] The present embodiment provides a kind of preparation method of indacaterol maleate, specifically comprises the following steps:

[0035] Step 1: Add 90g of 8-benzyloxy-5-(2-bromoacetyl)-2-hydroxyquinoline and 15ml (1.8M) of toluene solution of R-Me-CBS into THF900ml, nitrogen protection, ice salt Cool the bath down to -10°C, add 294ml (1M) of borane tetrahydrofuran solution dropwise, after 3h, continue the low temperature reaction for 1h; add 250ml methanol to quench, spin the reaction solution, add 300ml ethyl acetate and 300ml The phase was dried and spin-dried to obtain 71 g of intermediate 1 with a yield of 79%.

[0036] Step 2: Add 70.2g of intermediate 1 to 260ml of DMF, protect with nitrogen, cool down in an ice bath, slowly add 99.8g of TBSOTF and 40.3g of 2,6-lutidine, after the addition is complete, return to room temperature and react for 1h; add Quenched with 45ml of methanol, then added 500ml of ethyl acetate:cyclohexane=1:1 mixed solution and 500ml of sa...

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Abstract

The invention relates to a preparation method of indacaterol maleate, in particular, the indacaterol maleate is prepared from 8-benzyloxy-5-(2-bromoacetyl)-2-hydroxyquinoline, (R)-2-methyl-CBS-oxazolidine borane, tert-butyldimethylsilyl trifluoromethanesulfonate, 5,6-diethyl-2,3-dihydro-1H-2-amine hydrochloride, palladium / carbon and maleic acid as raw materials through four-step reaction of chiralreduction reaction, TBS hydroxyl protection reaction, condensation reaction and hydrogenation reduction reaction, and the preparation method of the indacaterol maleate provided by the invention is high in yield, low in cost, environmentally friendly, easy to operate, and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of chemical substances, in particular to a preparation method of indacaterol maleate. 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). [0003] Indacaterol has the characteristics of 5-minute onset and 24-hour duration. This product is produced by Swiss Novartis Pharmaceuticals. Since 2009, it has been listed in more than 70 countries and regions around the world; Launched on the market, it is the first LABA single preparation approved for the treatment of COPD in China. [0004] Clinical research data show that compared with salmeterol (an early LABA drug), indacaterol can significantly improve the main clinical evaluation indicators in patients with moderate and severe COPD, and its safety and tolerance are good; Compared with amines...

Claims

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Application Information

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IPC IPC(8): C07D215/26C07C57/145C07C51/41
CPCY02P20/55C07D215/26
Inventor 王坤鹏杨阳
Owner 南京法恩化学有限公司
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