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Preparation method and application of 2-amino-3,5-bibromobenzyl intermediate compound

A technology of dibromobenzyl and compound, which is applied in the field of medicine and chemical industry, can solve the problems of corrosion and cumbersome handling, and achieve the effects of less environmental pollution, mild reaction conditions, and avoiding genotoxic impurities

Inactive Publication Date: 2018-12-28
苏州华健瑞达医药技术有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In view of the problems of corrosiveness, cumbersome handling, and potential reactants containing toxic impurities in the above-mentioned prior art, the present invention provides a method for preparing 2-amino-3,5-dibromobenzyl intermediate compounds and its Application in the preparation of bromhexine and ambroxol

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  • Preparation method and application of 2-amino-3,5-bibromobenzyl intermediate compound
  • Preparation method and application of 2-amino-3,5-bibromobenzyl intermediate compound

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preparation example Construction

[0049] On the other hand, the present invention further discloses a method for preparing the above-mentioned 2-amino-3,5-dibromobenzyl intermediate compound I, the method comprising the following steps:

[0050]

[0051] S1, in the toluene solution of the compound of formula II, reduce the aldehyde group or thioaldehyde group of the compound of formula II with a reducing agent to obtain the compound of formula III;

[0052] S2, in the tetrahydrofuran solution of the compound of formula III, react the compound of formula III with the activator of formula IV to obtain compound I;

[0053] The activator of formula IV is N'N-carbonyldiimidazole.

[0054] As a further improvement of the embodiment of the present invention, in the step S1, the reducing agent is selected from at least one of Vitride red aluminum solution, sodium borohydride or potassium borohydride;

[0055] As a further improvement of the embodiment of the present invention, the molar ratio of the compound of fo...

Embodiment 1

[0076] This example discloses a method for preparing 2-amino-3,5-dibromobenzyl alcohol, which specifically includes the following steps:

[0077] In a 500ml three-neck flask, under nitrogen protection, add 20.0g (71.1mmol, 1.0eg) 2-amino-3,5-dibromobenzaldehyde, 200ml toluene, stir to dissolve, cool down to -5°C, and add Vitride red dropwise while keeping warm Aluminum solution 42.6ml (107.5mmol, 1.5eg, specification: 70% toluene solution, 3.6mol / L), the solution changed from light yellow to yellow. After the dropwise addition, return to room temperature for reaction for 5-6h. After the reaction was complete, the temperature was lowered to 10° C., and 20 ml of 10% sodium hydroxide was added dropwise to quench the reaction. Add 100ml of water for extraction and separation, wash the organic phase with pure water and saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and evaporate the filtrate to give 19.8 g of a yellow solid, which is the product, wit...

Embodiment 2

[0079] This example discloses a method for preparing 2-amino-3,5-dibromobenzyl-1H-imidazole-1-carbonate, which specifically includes the following steps:

[0080] In a 250ml single-necked bottle, add 10.0g (35.6mmol, 1.0eg) 2-amino-3,5-dibromobenzyl alcohol, 60ml tetrahydrofuran and stir to dissolve. Under nitrogen protection, cool down to 5°C, and add 6.34g ( 39.1mmol, 1.1eg) N'N-carbonyldiimidazole, control the temperature to be less than 15°C, after completion, rise to 20°C and react for 1h, TLC plate, the reaction is complete, evaporate most of the tetrahydrofuran solvent under reduced pressure below 30°C to obtain a concentrated solution , adding 100ml of 10% citric acid ice water and 100ml of ethyl acetate for extraction, layered, the organic phase was washed with saturated brine, dried, filtered, and spin-dried at room temperature to obtain 13.0g of white solid, which was the product, with a yield of 97.7%.

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Abstract

The invention provides a preparation method of a 2-amino-3,5-bibromobenzyl intermediate compound and further discloses an application of the 2-amino-3,5-bibromobenzyl intermediate compound in preparation of bromhexine and ambroxol. A cheap and available raw material 2-amino-3,5-dibromobenzaldehyde is adopted, 2-amino-3,5-dibromobenzyl alcohol is obtained through reduction, and the reaction condition is milder; N'N-carbonyldiimidazole is used for activating hydroxyl of 2-amino-3,5-dibromobenzyl alcohol to produce active ester, and the active ester is subjected to a condensation reaction with N-methylcyclohexylamine and trans-p-aminocyclohexanol to produce corresponding products respectively. The preparation method has the advantages that the reproducibility is good, the process is simple, the product purity is high and potential gene poison impurities can be avoided, and the medication safety of the 2-amino-3,5-bibromobenzyl intermediate compound can be further improved.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, and relates to a preparation method of 2-amino-3,5-dibromobenzyl intermediate compound and its application in preparing bromhexine and ambroxol. Background technique [0002] Ambroxol (Ambroxol), chemical name: trans-4-[(2-amino-3,5-dibromobenzyl) amino]-cyclohexanol, American Chemical Abstracts registration number CAS: 18683-91-5. Ambroxol is a drug first developed and listed by Boehringer Ingelheim of Germany in 1984, and it is now a commonly used expectorant approved by many countries in the world. Ambroxol is the active metabolite of bromhexine. It is widely used clinically in the treatment of acute and chronic bronchitis, bronchial asthma, neonatal respiratory distress and pulmonary surgery with low toxicity. The advantages of definite curative effect. The hydrochloride of ambroxol is included in the 2010 edition of the Chinese Pharmacopoeia and the 2009 edition of the British...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/56C07C213/08C07C215/44C07C209/68C07C211/52C07C231/10C07C237/32
CPCC07C209/68C07C213/08C07C231/10C07D233/56C07C2601/14C07C215/44C07C211/52C07C237/32Y02P20/55
Inventor 许磊肖鹏
Owner 苏州华健瑞达医药技术有限公司
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