Process for preparing ambroxol, analogue thereof or salts thereof

A synthesis method and amino technology are applied in the synthesis field for preparing ambroxol hydrochloride, and can solve the problems of reduced yield, complicated operation and high cost

Active Publication Date: 2009-01-07
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The main disadvantages of these methods are that the route is long, the operation is complicated, more highly polluting reagents are involved, or the reaction conditions are not easy to control, resulting in too many unnecessary side reactions and reducing the yield, or the reagents are expensive and costly, etc.

Method used

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  • Process for preparing ambroxol, analogue thereof or salts thereof
  • Process for preparing ambroxol, analogue thereof or salts thereof
  • Process for preparing ambroxol, analogue thereof or salts thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0019] Preparation Example 1 N-(trans-4-hydroxycyclohexyl)-2-amino-3,5-dibromobenzamide (II)

[0020]

[0021] According to the method reported in the literature (ES 8605219), N-(trans-4-hydroxycyclohexyl)-2-amino-3,5 -dibromobenzamide (II), its three-step total yield is 61%.

Embodiment 1

[0022] Example 1 N-(trans-4-hydroxycyclohexyl)-N-(2-amino-3,5-dibromobenzyl)amine (I) (LiCl method)

[0023]

[0024] Dissolve N-(trans-4-hydroxycyclohexyl)-2-amino-3,5-dibromobenzamide (II, 3.90g, 0.010mol) in 120ml of dry tetrahydrofuran, and cool to 0 ℃, add 0.46g (0.011mol) of anhydrous lithium chloride to form a suspension, add 0.25g (0.007mol) of sodium borohydride, keep 0℃ for 4 hours, rise to room temperature, evaporate the solvent under reduced pressure, and use the residue Extract with 80ml of ethanol, acidify the extraction solution with concentrated hydrochloric acid, add a small amount of ether, and crystallize the crude product of ambroxol hydrochloride. The crude product was recrystallized from ethanol-ether to obtain 3.65 g of pure ambroxol hydrochloride (88% yield). Mp: 216-217.5. ESI MS: 379 (M+1).

Embodiment 2

[0025] Example 2 N-(trans-4-hydroxycyclohexyl)-N-(2-amino-3,5-dibromobenzyl)amine (I)(TiCl 4 Law)

[0026] Dissolve N-(trans-4-hydroxycyclohexyl)-2-amino-3,5-dibromobenzamide (II, 3.97g, 0.012mol) in 120ml of dry tetrahydrofuran, and cool to 0 ℃, add 1.40ml (0.013mol) of titanium tetrachloride, add 0.30g (0.008mol) of sodium borohydride, keep the reaction at 0℃ for 4 hours, rise to room temperature, evaporate the solvent under reduced pressure, and extract 80ml of the residue with ethanol to extract The solution was acidified with concentrated hydrochloric acid, and a small amount of ether was added to crystallize crude ambroxol hydrochloride. The crude product was recrystallized from ethanol-ether to obtain 4.75 g of pure ambroxol hydrochloride (95% yield). MP: 216-217. ESI MS: 379 (M+1).

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Abstract

The invention provides a simple method for synthesizing ambroxol hydrochloride, which is characterized in that the ambroxol product is obtained conveniently from amide, the precursor of ambroxol, by a proper reduction method.

Description

technical field [0001] The present invention relates to the synthetic method of ambroxol and its analog or its salt, further relate to the synthetic method of preparing ambroxol hydrochloride. Background technique [0002] Ambroxol I is the active metabolite of bromhexine. It is widely used clinically in the adjuvant treatment of acute and chronic bronchitis, bronchial asthma, neonatal respiratory distress and lung surgery accompanied by abnormal secretion of the respiratory tract. It has low toxicity, The advantages of definite curative effect. [0003] At present, the synthesis of ambroxol mainly includes four approaches (US 3,536,713), such as the bromination reaction on the benzene ring, the substitution reaction of trans 4-aminocyclohexanol to multi-substituted benzyl halides, the reduction of the nitro group on the benzene ring to Reduction reaction of ammonia and polysubstituted benzamide or benzylidene ammonia (Equation 1). The main disadvantages of these methods a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/44C07C213/08C07C233/74
Inventor 孙飘扬沈大鹏陈永江
Owner JIANGSU HENGRUI MEDICINE CO LTD
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