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Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol

A technology of aminobenzyl and ambroxol is applied in the new preparation field of trans-4-[amino]-cyclohexanol, a key intermediate of expectorant drug ambroxol, and can solve the problem of unfavorable large-scale application and many reaction steps. and other problems, to achieve the effect of reasonable design, easy operation and high yield

Inactive Publication Date: 2011-05-11
EAST CHINA UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0030] This route has many reaction steps and uses expensive reducing reagent LiAlH 4 , still not conducive to large-scale application

Method used

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  • Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol
  • Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol
  • Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052]Add 150ml of methanol, o-nitrobenzaldehyde (10.0g, 66.2mmol), trans-4-aminocyclohexanol (11.4g, 99.0mmol), sodium methoxide (0.2g, 3.7mmol) into the autoclave, room temperature Stir for 2.5 h, then add 10% Pd / C catalyst (0.5 g), replace the air with nitrogen and fill with hydrogen, and stir at room temperature for 8 h under hydrogen pressure of 0.2-0.3 MPa. Open the autoclave after replacing the hydrogen with nitrogen, filter and reclaim the Pd / C catalyst, reclaim the solvent methanol, and column chromatography separates the product I to be 13.9g (eluent: ethyl acetate / petroleum ether / triethylamine (v / v / v)=1 / 1 / 0.01), yield 95.3%, mp 93~94°C. 0.36 g of by-product 2-aminobenzyl alcohol was obtained, with a yield of 4.4%. 3.3 g of the trans-4-aminocyclohexanol raw material was recovered.

[0053] Spectral data for product I:

[0054] EI-MS (m / z): 220[M + ];

[0055] 1 H NMR (500MHz, CDCl 3 , ppm), δ: 1.12~1.17 (m, 2H, CH 2 CHN), 1.25~1.36(m, 4H, CH 2 CHOH), 1.96~2...

Embodiment 2

[0060] Add 150ml of methanol, o-nitrobenzaldehyde (10.0g, 66.2mmol), trans-4-aminocyclohexanol (10.0g, 86.8mmol), sodium methoxide (0.2g, 3.7mmol) into the autoclave, room temperature Stir for 2.5 h, then add 10% Pd / C catalyst (0.5 g), replace the air with nitrogen and fill with hydrogen, and stir at room temperature for 8 h at a hydrogen pressure of 0.5-0.6 MPa. After replacing the hydrogen with nitrogen, the autoclave was opened, the Pd / C catalyst was filtered off, the solvent methanol was reclaimed, and the product I was separated by column chromatography to be 13.8g (eluent: ethyl acetate / petroleum ether / triethylamine (v / v / v)=1 / 1 / 0.01), the yield is 94.6%. 0.30 g of by-product 2-aminobenzyl alcohol was obtained with a yield of 3.7%; 0.09 g of by-product 2-methylaniline was obtained with a yield of 1.3%. 1.8 g of trans-4-aminocyclohexanol raw material was recovered.

[0061] The spectral data of product I is with embodiment 1.

[0062] Spectral data of by-product 2-amin...

Embodiment 3

[0067] Add 150ml of methanol, o-nitrobenzaldehyde (10.0g, 66.2mmol), trans-4-aminocyclohexanol (10.0g, 86.8mmol), sodium methoxide (0.2g, 3.7mmol) into the autoclave, room temperature Stir for 2.5 h, then add Raney-Ni catalyst (3.0 g), replace the air with nitrogen and fill with hydrogen, and stir at room temperature for 8 h under hydrogen pressure of 0.5-0.6 MPa. After replacing the hydrogen with nitrogen, the autoclave was opened, the catalyst was recovered by filtration, the solvent methanol was recovered, and the product I was separated by column chromatography to be 13.1g (eluent: ethyl acetate / petroleum ether / triethylamine (v / v / v) =1 / 1 / 0.01), the yield was 89.9%. 0.33 g of by-product 2-aminobenzyl alcohol was obtained with a yield of 4.0%; 0.11 g of by-product 2-methylaniline was obtained with a yield of 1.6%. 1.8 g of trans-4-aminocyclohexanol raw material was recovered.

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Abstract

The invention relates to a method for preparing an expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol. Nitrobenzaldehyde and trans-4-amino cyclohexanol are subjected to the combination reaction of condensation, carbon and nitrogen double-bond hydrogenation and nitro reduction to prepare the trans-4-[(2-amino benzyl) amino]-cyclohexanol in a high-yield mode. The method has the advantages of reasonable process route design, simple and convenient process, high reaction yield, low raw material cost and no harsh reaction conditions and is easy for scale production.

Description

【Technical field】 [0001] The invention relates to the technical field of medicine manufacturing, in particular to a new preparation method of trans-4-[(2-aminobenzyl)amino]-cyclohexanol, a key intermediate of the expectorant drug ambroxol. The intermediate directly undergoes bromination reaction to obtain 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, Has the following structure: [0003] [0004] 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 ef...

Claims

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Application Information

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IPC IPC(8): C07C215/44C07C213/02
Inventor 冀亚飞王超禹艳坤刘爱霞江健安刘倩王毅
Owner EAST CHINA UNIV OF SCI & TECH
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