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Synthesizing method of ambroxol hydrochloride related substance

A technology of ambroxol hydrochloride and related substances, applied in the field of organic synthesis, can solve the problems of the highest purity less than 95%, low purity of tetrahydroquinazoline, low synthesis yield, etc.

Pending Publication Date: 2019-05-28
HEFEI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the research found that the synthesis yield is low, the highest is 35%, and the product separation and purification adopts methanol / ether recrystallization, the purity is low, the highest purity is less than 95%, and it is difficult to be used as a drug impurity standard
[0008] Because the ambroxol trans impurity 6,8-dibromo-3-(trans-4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazoline purity that above-mentioned route prepares is lower, therefore Difficult to meet the requirements as a pharmaceutical impurity standard

Method used

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  • Synthesizing method of ambroxol hydrochloride related substance
  • Synthesizing method of ambroxol hydrochloride related substance
  • Synthesizing method of ambroxol hydrochloride related substance

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Embodiment 1

[0031] 1. Synthesis of 4-(6,8-dibromo-1,4-dihydroquinazolin-3(2H)-yl)-cyclohexanol hydrochloride

[0032] Ambroxol hydrochloride (8.3g, 20mmol), methanol (60mL), and water (20mL) were successively added to a 250mL round-bottomed flask, and 37% formaldehyde aqueous solution (15mL) was slowly added, stirred at 25°C for 10h, and the reaction was detected by TLC . After the reaction, methanol was recovered under reduced pressure at 40°C, crystallized by cooling, suction filtered, washed with cold absolute ethanol, and dried at 50°C to obtain a white solid with a yield of 93% and a purity of 98.6%.

[0033] 2. Synthesis of 4-(6,8-dibromo-3,4-dihydroquinazolin-3-yl)-cyclohexanol hydrochloride

[0034] The product from the previous step (6g, 14mmol), dichloromethane (200mL), and cerium ammonium nitrate (19.2g, 35mmol) were successively added into a 250mL round bottom flask, stirred at room temperature for 10 h, and the reaction was detected by TLC. After the reaction, add water (10...

Embodiment 2

[0036] 1. Synthesis of 4-(6,8-dibromo-1,4-dihydroquinazolin-3(2H)-yl)-cyclohexanol hydrochloride

[0037] With embodiment 1.

[0038] 2. Synthesis of 4-(6,8-dibromo-3,4-dihydroquinazolin-3-yl)-cyclohexanol hydrochloride

[0039] The product from the previous step (6g, 14mmol), dichloromethane (200mL), and manganese dioxide (3g, 35mmol) were sequentially added into a 250mL round-bottomed flask, stirred at room temperature for 10h, and the reaction was detected by TLC. After the reaction, add water (100mL), separate the aqueous layer, adjust the pH to 7-8 with 5% sodium carbonate solution, extract with ethyl acetate (80mL*3), combine the organic layers, and wash the organic layer with water (50mL*3), without Dry over sodium sulfate, recover ethyl acetate under reduced pressure to 10 mL, add concentrated hydrochloric acid (1 mL) with stirring, cool and crystallize, filter with suction, wash with ethyl acetate, and dry at 50°C to obtain a white solid.

Embodiment 3

[0041]1. Synthesis of 4-(6,8-dibromo-1,4-dihydroquinazolin-3(2H)-yl)-cyclohexanol hydrochloride

[0042] With embodiment 1.

[0043] 2. Synthesis of 4-(6,8-dibromo-3,4-dihydroquinazolin-3-yl)-cyclohexanol hydrochloride

[0044] The product from the previous step (6 g, 14 mmol), dichloromethane (200 mL), and 10% palladium carbon (5 g) were successively added into a 250 mL round bottom flask, stirred at room temperature for 10 h, and the reaction was detected by TLC. Add water (100mL) after the reaction, separate the aqueous layer, adjust the pH to 7-8 with 5% sodium carbonate solution, extract with ethyl acetate (80mL*3), combine the organic layers, wash the organic layer with water (50mL*3), and remove Dry over sodium sulfate, recover ethyl acetate under reduced pressure to 10 mL, add concentrated hydrochloric acid (1 mL) under stirring, cool and crystallize, filter with suction, wash with ethyl acetate, and dry at 50°C to obtain a white solid.

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Abstract

The invention discloses a synthesizing method of an ambroxol hydrochloride related substance, and relates to the technical field of organic synthesis. Ambroxol hydrochloride serves as a raw material,is subjected to a cyclization reaction with formaldehyde firstly to synthesize 4-(6,8-dibromo-1,4-dihydroquinazolin-3(2H)-yl)-cyclohexanol hydrochloride, and then is subjected to an oxidation reactionto synthesize 4-(6,8-dibromo-3,4-dihydroquinazolin-3-yl)-cyclohexanol hydrochloride. According to the synthesizing method, the product yield can reach 90% or above, meanwhile the purity reaches 99% or above, the requirement for serving as a drug impurity standard product is met, and thus the content of the impurity 4-(6,8-dibromo-3,4-dihydroquinazolin-3-yl)-cyclohexanol hydrochloride in the ambroxol hydrochloride is controlled advantageously.

Description

Technical field: [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing ambroxol hydrochloride related substances. Background technique: [0002] Ambroxol hydrochloride is a strong expectorant, commonly used clinically for acute and chronic lung diseases accompanied by abnormal sputum secretion and poor expectoration function, such as acute exacerbation of chronic bronchitis, asthmatic bronchitis and expectorant treatment of bronchial asthma; preventive treatment of pulmonary complications after surgery; treatment of infant respiratory distress syndrome in premature infants and newborns. Ambroxol hydrochloride injection has been clinically used for many years at home and abroad. Its curative effect is definite and its quality is stable. It has been widely recognized by the market and consumers. The clinical dosage is large, especially suitable for critical illness, postoperative, fasting and other inappropriate It...

Claims

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Application Information

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IPC IPC(8): C07D239/74
Inventor 陈仕云
Owner HEFEI UNIV
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