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Synthetic method of ambroxol hydrochloride

A technology of ambroxol hydrochloride and a synthetic method, which is applied in the field of drug synthesis, can solve the problems of high industrial price of trifluoromethanesulfonic anhydride, high risk and difficult industrial amplification, and unfavorable cost control, etc., and achieve long-term stability in dark storage, Strong reducibility and easy post-processing

Active Publication Date: 2021-02-09
CHINA PHARM UNIV
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Problems solved by technology

[0007] The total yield of this route is low, only 4.2%, and the utilization rate of atoms is low, uneconomical, and pollutes the environment greatly
Lithium tetrahydrogen is used in a large amount, which is highly dangerous and difficult to scale up industrially. Secondly, the price is relatively high, which is not conducive to cost control.
[0019] The bromine reagent in this route uses molecular bromine and hydrogen peroxide, and the molar ratio of molecular bromine can be reduced to 1 times the equivalent of the raw material. The second condensation reaction needs to add a catalytic amount of N,N'-diisopropylcarbodiethylene Amine (DIC) and 4-dimethylaminopyridine (DMAP), currently the price of DIC and DMAP on the market is relatively expensive, which increases the production cost
The third reduction operation uses Hans ester 1,4-dihydropyridine as a reducing agent, and trifluoromethanesulfonic anhydride needs to be added as a catalyst, and the industrial price of trifluoromethanesulfonic anhydride is expensive
The carbonyl reducing agent needs to be self-made, and the reaction of formaldehyde, ammonium carbonate, ethyl acetoacetate, PEG-400 and water makes the whole operation cumbersome

Method used

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  • Synthetic method of ambroxol hydrochloride
  • Synthetic method of ambroxol hydrochloride
  • Synthetic method of ambroxol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Embodiment 1: the synthesis of trans-4-[(2-aminobenzoyl) amino] cyclohexanol (compound 4)

[0075] Add 7.2g (62.5mmol) trans-4-aminocyclohexanol into a 500ml three-neck flask, add 100ml water to dissolve, add 10g (61.3mmol) isatoic anhydride in batches at 20°C, then keep warm at 30°C and stir The speed was 200 rpm, and bubbles appeared during the stirring process. After 5 hours, TLC monitoring (dichloromethane / methanol=10 / 1) showed that the reaction was complete. Suction filtration then obtains trans-4-[(2-aminobenzoyl)amino]cyclohexanol (compound 4), 10ml ice ethanol washes the filter cake twice to take away moisture, and obtains 13.5g off-white solid after drying under reduced pressure , yield 94%, mp 216°C-218°C. 1 H NMR (300MHz, DMSO-d6) δ7.92(d, J=7.7Hz, 1H), 7.50– 7.40(m, 1H), 7.18–7.07(m, 1H), 6.68(d, J=8.2Hz, 1H), 6.51(t, J=7.4Hz, 1H), 6.33(s, 2H), 4.64–4.51(m, 1H), 3.77–3.60(m, 1H), 3.41(d, J=7.0Hz, 1H ), 1.91–1.74(m,4H), 1.46–1.14(m,4H); ESI-MS, Calcd for C...

Embodiment 2

[0076] Example 2: Synthesis of trans-4-[(2-aminobenzoyl) amino]cyclohexanol (compound 4)

[0077] Add 7.45g (64.8mmol) trans-4-aminocyclohexanol into a 500ml three-neck flask, add 150ml of water to dissolve into a yellow-brown transparent liquid, add 10g (61.3mmol) isatoic anhydride in batches at 10-15°C, and react The solution turned grayish white and turbid, reacted in a water bath at 40°C, bubbles appeared when stirring continuously, and then kept warm for 2.5 hours, and the reaction was complete as monitored by TLC. Suction filtration then obtains trans-4-[(2-aminobenzoyl) amino] cyclohexanol (compound 4), washes three times with 10ml glacial ethanol and takes away moisture, obtains off-white solid 14.14g after drying under reduced pressure, yield 98.5%.

Embodiment 3

[0078] Example 3: Synthesis of trans-4-[(2-amino-3,5-dibromobenzoyl)amino]cyclohexanol (compound 3)

[0079] Add 13g (55.6mmol) trans-4-[(2-aminobenzoyl)amino]cyclohexanol (compound 4) into a 500ml three-necked flask, add 200ml of glacial acetic acid:water volume ratio=7:3 The mixture was dissolved and clarified. Add 5.7ml (111.3mmol) of bromine in 10ml of glacial acetic acid diluent dropwise under an ice bath, stir fully at a stirring speed of 200 rpm, the reaction solution turns white and turbid, and keep the temperature at 5-15°C for reaction. After the bromine drops, TLC (dichloromethane / methanol=10 / 1) monitors that the reaction is complete, add 200ml of sodium metabisulfite aqueous solution with a mass fraction of 1%, stir well, the color becomes pure white, filter with suction, filter cake with 200mL of 1% sodium metabisulfite The aqueous solution of sodium metabisulfite was stirred and neutralized, then suction filtered, washed with water, and dried to obtain 21.8 g of...

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Abstract

The invention relates to a synthetic method of ambroxol hydrochloride. The method comprises the following steps: reacting isatoic anhydride serving as an initial raw material with trans-4-aminocyclohexanol to obtain trans-4-[(2-aminobenzoyl) amino] cyclohexanol; carrying out bromine substitution on the trans-4-[(2-aminobenzoyl) amino] cyclohexanol to obtain trans-4-[(2-amino-3, 5-dibromo benzoyl)amino] cyclohexanol; trans-4-[(2-amino-3, 5-dibromobenzoyl) amino] cyclohexanol is subjected to amido bond reduction, so that ambroxol is obtained; and finally salifying the ambroxol to obtain the ambroxol hydrochloride. The method is easy to operate, mild in condition, high in yield, environmentally friendly, stable in raw material property, easy to store and suitable for industrial mass production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a synthesis method of ambroxol hydrochloride. Background technique [0002] Ambroxol Hydrochloride (Ambroxol Hydrochloride), the chemical name is trans-4-[(2-amino-3,5-dibromobenzyl)amino]cyclohexanol hydrochloride, and its chemical structural formula is: [0003] [0004] Ambroxol hydrochloride is widely used clinically in acute and chronic respiratory diseases with abnormal secretion, especially the expectorant treatment of chronic bronchitis, neonatal respiratory distress and adjuvant treatment of lung surgery. It has low toxicity, definite curative effect, It can be used in combination with antibiotics to produce good synergistic effects, and is one of the most commonly used expectorants. [0005] There are many synthetic methods of ambroxol hydrochloride at present. The document J. Keck Justus Liebig s Annalen der Chemie (1967) reported that the original research company B...

Claims

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Application Information

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IPC IPC(8): C07C213/02C07C213/08C07C215/44C07C231/02C07C231/12C07C237/38
CPCC07C213/02C07C213/08C07C231/02C07C231/12C07C2601/14C07C237/38C07C215/44
Inventor 李玉艳任陇飞李小芳王锦涛李琦一王丹丹
Owner CHINA PHARM UNIV
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