N-(trans-4-Hidroxiciclohexil)-(2-amino-3,5-dibromobencil)amina
ambroxol
CAS: 18683-91-5
Molecular Formula: C13H18Br2N2O
N-(trans-4-Hidroxiciclohexil)-(2-amino-3,5-dibromobencil)amina - Names and Identifiers
N-(trans-4-Hidroxiciclohexil)-(2-amino-3,5-dibromobencil)amina - Physico-chemical Properties
| Molecular Formula | C13H18Br2N2O |
| Molar Mass | 378.1 |
| Density | 1.5863 (rough estimate) |
| Melting Point | 233-234 C |
| Boling Point | 468.6±45.0 °C(Predicted) |
| Flash Point | 237.23°C |
| Solubility | Soluble in Water. |
| Vapor Presure | 0mmHg at 25°C |
| Appearance | solid |
| Color | White |
| pKa | 15.12±0.40(Predicted) |
| Storage Condition | Keep in dark place,Sealed in dry,2-8°C |
| Stability | Stable for 1 year from date of purchase as supplied. Solutions in distilled water may be stored at -20° for up to 3 months. |
| Refractive Index | 1.6220 (estimate) |
| Physical and Chemical Properties | Ambroxol hydrochloride: C13H18Br2N2O? HCl. [23828-92-4]. Crystallization from ethanol, melting point 233~234.5 °c (decomposition). Acute toxicity LD50 mice, rats (mg/kg):268,380 intraperitoneal injection; 2720,13400 oral. |
N-(trans-4-Hidroxiciclohexil)-(2-amino-3,5-dibromobencil)amina - Risk and Safety
| Risk Codes | R22 - Harmful if swallowed R36/37/38 - Irritating to eyes, respiratory system and skin. |
| Safety Description | S36 - Wear suitable protective clothing. S26 - In case of contact with eyes, rinse immediately with plenty of water and seek medical advice. |
| WGK Germany | 3 |
| RTECS | GV8423000 |
N-(trans-4-Hidroxiciclohexil)-(2-amino-3,5-dibromobencil)amina - Nature
Open Data Verified Data
from ethanol crystallization, melting point 233~234,5 degrees C (decomposition).
Last Update：2024-01-02 23:10:35
N-(trans-4-Hidroxiciclohexil)-(2-amino-3,5-dibromobencil)amina - Preparation Method
Open Data Verified Data
methyl anthranilate, dichloroethane, water and concentrated sulfuric acid were mixed, bromine was added dropwise at room temperature, and reaction was carried out, and 30% hydrogen peroxide was added to react. 10% sodium sulfite was added dropwise until the brown color was removed and treated to give the dibromide. The dibromide was refluxed with ethylene glycol monoether, hydrazine hydrate. After cooling to room temperature, the crystals were collected by filtration and recrystallized from methanol to obtain the hydrazide. The hydrazide compound was dissolved in dioxane and pyridine, and methanesulfonyl chloride was added dropwise. The reaction was completed, and the treatment was carried out to obtain a methanesulfonyl hydrazide derivative. Mix 1-4-aminocyclohexanol hydrochloride, sodium hydroxide, potassium carbonate and ethylene glycol monomethyl ether, add methanesulfonyl hydrazide derivative in portions, reflux, complete reaction, the compound obtained by the treatment was subjected to hydrogenation reaction with glacial acetic acid and palladium-carbon, and finally Ambroxol hydrochloride crystals were obtained.
Last Update：2022-01-01 09:22:57
N-(trans-4-Hidroxiciclohexil)-(2-amino-3,5-dibromobencil)amina - Preparation solution concentration reference
| 1mg | 5mg | 10mg | |
|---|---|---|---|
| 1 mM | 2.645 ml | 13.224 ml | 26.448 ml |
| 5 mM | 0.529 ml | 2.645 ml | 5.29 ml |
| 10 mM | 0.264 ml | 1.322 ml | 2.645 ml |
| 5 mM | 0.053 ml | 0.264 ml | 0.529 ml |
Last Update：2024-01-02 23:10:35
N-(trans-4-Hidroxiciclohexil)-(2-amino-3,5-dibromobencil)amina - Use
Open Data Verified Data
developed in Germany by Boehnnger Ingelheim. Expectorant for thinning phlegm. It has the function of promoting mucus elimination and dissolving secretions. It can promote the elimination of viscous secretions in the respiratory tract and reduce the retention of mucus, thus significantly promoting sputum excretion and improving respiratory condition. When the patient is treated with the product, the secretion of mucus can be restored to normal condition. Cough and sputum volume is usually significantly reduced, the respiratory mucosa of the surface active substance can thus play its normal protective function. It is suitable for acute and chronic respiratory diseases with abnormal secretion of sputum and poor expectoration function. For the treatment of acute and chronic respiratory diseases, abnormal bronchial secretion.
Last Update：2022-01-01 09:22:58
N-(trans-4-Hidroxiciclohexil)-(2-amino-3,5-dibromobencil)amina - Safety
Open Data Verified Data
mouse, rat LD50( mg/kg):268,380 intraperitoneal injection; 2720, 13400 orally.
Last Update：2022-01-01 09:22:58
N-(trans-4-Hidroxiciclohexil)-(2-amino-3,5-dibromobencil)amina - Reference Information
| NIST chemical information | Information provided by: webbook.nist.gov (external link) |
| Expectorant | Ambroxol is the active metabolite of bromhexine in the body. It is a mucolytic drug and has a stronger effect than bromhexine. Its hydrochloride is usually used. Ambroxol can directly act on the bronchial glands, promote the release of lysosomes from mucus-secreting cells, and differentiate and lyse the mucopolysaccharide fibers in the sputum; it can also inhibit the synthesis of acidic glycoproteins in mucous glands and goblet cells. It secretes small molecule glycoproteins with low viscosity, which reduces the viscosity of sputum and is easy to cough up. In addition, this product can also stimulate the gastric mucosa to cause respiratory tract gland secretion increased, so that sputum dilution. It is clinically used for expectoration of acute and chronic bronchitis and bronchiectasis, bronchial asthma, emphysema and other diseases; preoperative medication for patients with a history of respiratory tract can prevent intraperitoneal pulmonary complications; it is caused by chemotherapy and radiotherapy for lung tumors Pulmonary fibrosis, silicosis and lung damage caused by other causes have a protective effect. |
| use | 1. used for acute and chronic bronchitis, bronchial asthma, bronchiectasis, emphysema, tuberculosis, pneumoconiosis, difficulty in expectoration after surgery, etc. 2. This product injection can be used for the pre-treatment of postoperative pulmonary complications and the treatment of infant respiratory distress syndrome. (2015-12-2) expectorants have good phlegm dissolving effect and lubricating respiratory tract, and can promote the secretion of pulmonary surfactant, the secretion of respiratory fluid and cilia movement. It is used for the treatment of acute and chronic respiratory diseases, abnormal bronchial secretion, etc. an effective neurogenic sodium channel inhibitor inhibits sodium ion current against TTX, phase block, IC50 is 22.5 μM, and sodium ion current sensitive to TTX is inhibited, IC50 is 100 μM. |
| Synthesis method | Using methyl 2-aminobenzoate (2) as the starting material, 3, 5-dibromo-2-aminobenzoate methyl ester (3) was prepared by bromine. 3, 5-dibromo-2-aminobenzyl alcohol (4) was obtained by catalytic reduction with NaBH4, ZnCl2, and triethylamine. 4 Oxidation with MnO2 to give 3, 5-dibromo-2-aminobenzaldehyde (5). 5 Condensation with trans-4-aminocyclohexanol to prepare ambroxol (1). Fig. 1 shows the synthetic route of ambroxol |
| pharmacological effects | 1. sputum dilution and discharge sputum viscosity is mainly determined by acidic glycoproteins. ambroxol hydrochloride is a polysaccharide fiber decomposer, which can lyse polysaccharide fibers in glycoproteins and act on respiratory tract secretory cells, inhibit acidic protein synthesis, increase serous secretion, and make sputum thinner and easy to discharge. At the same time, ambroxol can promote the recovery of normal function of respiratory cilia, increase the self-purification effect of respiratory tract, reduce the adhesion of sticky sputum to respiratory tract wall, and make sputum easy to cough up. 2. Promote the synthesis and release of pulmonary surfactant (PS) PS is a phospholipid protein complex produced by alveolar type II cells. Its physiological functions are mainly:(1) Reduce alveolar air-liquid surface tension to maintain lung function and maintain lung compliance. (2) Participate in the defense function of the lung, increase the chemotaxis of macrophages to the inflammatory site, so that bacteria and other cells are easy to be swallowed. (3) Maintain the stability of the small airway and prevent the small airway from collapsing and gas retention. PS is also beneficial to repair bronchial epithelium, improve the transport function of bronchial mucociliary system, and help discharge secretions. Ambroxol can promote the biosynthesis and release of endogenous PS, thereby improving lung function, shortening the course of the disease, and making the damaged lung tissue recover quickly. 3. Anti-inflammatory and antioxidant effects Ambroxol's anti-inflammatory effect is mainly to reduce the release of inflammatory mediators. Ambroxol can inhibit the aggregation of inflammatory cells such as macrophages in the lung tissue and neutrophil reactions, such as respiratory bursts, The release of lysosomes can also reduce the production of cytokines and arachidonic acid metabolites in the body, and weaken the inflammatory response. Many mechanisms of ambroxol inhibiting the body's inflammatory response have not been fully clarified, but antioxidant effect is one of its important mechanisms. In the pathogenesis of many lung diseases, reactive free oxygen groups produced by external or internal stimuli play an important role. Under normal circumstances, there is a dynamic balance between the antioxidant capacity of the lung and the production of free oxygen groups in the body. When there are more reactive free oxygen groups in tissue cells and too many oxidation products, the activities of various enzymes in tissue cells will be damaged, which will lead to the production of diseases. |
| pharmacokinetics | oral absorption is rapid, the peak time is 0.5~3h, and the bioavailability is 70% ~ 80%. This product is rapidly distributed from blood to tissues, with more distribution in lungs, liver and kidneys. It is mainly metabolized by liver and excreted in urine. The half-life (t1/2) is 4~7h. |
| adverse reactions | 1. central nervous system: rare headache and vertigo. 2. Gastrointestinal tract: occasionally nausea, vomiting, lack of appetite, indigestion, abdominal pain, diarrhea, constipation, stomach discomfort, stomach pain, heartburn. 3. Allergic reactions: ① There are very few allergic reactions, mainly rash, skin swelling, itching, erythema, anaphylactic shock, and angioneurotic edema. (2) There are reports of contact dermatitis. 4. Respiratory system: a small number of patients may have difficulty breathing. 5. Others: ① A small number of patients may have facial swelling, fever with chills, dry mouth and airway, increased saliva secretion, increased nasal secretions, and dysuria. ② It has been reported that rapid intravenous injection can cause waist pain and fatigue. |
| taboo | those who are allergic to this product. |
| precautions | 1. this product injection should not be mixed with alkaline solution. in solution with pH greater than 6.3, ambroxol free alkali precipitation may be caused. This product should be avoided in combination with atropine drugs. 2. The expectorant effect of this product can be enhanced by rehydration. 3. If you miss one dose or less, just take the next dose at the appropriate time. 4. Patients with diabetes and hereditary fructose intolerance should pay attention to the choice of sugar-free type when taking oral solution. 5. If allergic reaction occurs after medication, the drug must be stopped immediately, and symptomatic treatment should be given according to the severity of the reaction. First aid should be given if anaphylactic shock occurs. 6. No poisoning has been found in overdose, and occasionally there are reports of restlessness and diarrhea for a short time. The daily dose of parenteral administration is 15mg/kg, and the daily dose of oral administration is 25mg/kg. This product still has good tolerance. According to preclinical studies, salivation, nausea, vomiting and hypotension may occur in extreme overdose. If overdose occurs, symptomatic treatment is recommended. In addition to extreme overdose, general do not consider vomiting, gastric lavage and other first aid measures. 7. When using this product powder for injection, 5ml of sterile water for injection should be dissolved every 15mg and then injected slowly. It can also be mixed with glucose injection, 0.9% sodium chloride injection or Ringer injection and then injected intravenously. When intravenous drip is used for administration, the product can be diluted with 5% glucose injection (or normal saline) 100~150ml, and then slowly instilled within 30 minutes. 8. The following conditions should be used with caution: ① Liver and kidney insufficiency. ② Patients with gastric ulcer. ③Patients with bronchial cilia motor function blocked and a large number of secretions in the respiratory tract (patients with malignant cilia syndrome, etc., may have the risk of secretions blocking the airway). ④ Glaucoma patients. ⑤ It is recommended that women in early pregnancy should not use it, and women in the middle and late pregnancy and lactating women should use it with caution. |
| drug interaction | 1. it has a synergistic effect with bronchodilators such as β2 adrenergic receptor agonists and theophylline. 2. Combined with antibiotics (such as amoxicillin, amoxicillin and clavulanate potassium, ampicillin, cefuroxime, erythromycin, doxycycline, etc.) can increase the distribution concentration of antibiotics in lung tissue and have a synergistic effect. 3. Combined with antitussive drugs (such as dextromethorphan, a central antitussive drug), because the cough reflex is inhibited, there is a risk of secretions blocking the airway, so this drug should be avoided in combination with antitussive drugs. |
| specification | tablet: 15mg;30mg. Dispersible tablets and orally disintegrating tablets: 30mg. Capsule: 30mg;75mg. Sustained-release capsule: 25mg;75mg. Controlled release capsule: 75mg. Oral solution: 1ml:3mg;5ml:15mg;5ml:30mg;10ml:30mg;60ml:180mg. Syrup: 100ml:0.6g. Injection: 2ml:15mg;4ml:30mg. Aerosol: 2ml:15mg. |
| production method | method 1: methyl anthranilate, dichloroethane, water and concentrated sulfuric acid are mixed, bromine is added dropwise at room temperature, and the reaction is completed. Add 30% hydrogen peroxide and react. Drop 10% sodium sulfite until brown recedes. Cool to room temperature, separate the organic phase, and concentrate to dry under reduced pressure. The residue was recrystallized with methanol to obtain dibromide with 95% yield. The dibromide is refluxed with ethylene glycol monoether and 85% hydrazine hydrate. Cold to room temperature, filtration crystallization, recrystallization with methanol to obtain hydrazide, the yield is 83.7%. The hydrazide is dissolved in dioxane and pyridine, and methylsulfonyl chloride is added dropwise. Jiabi, continue to react. Decompression evaporation and drying, methanol recrystallization to obtain methylsulfonyl hydrazide derivatives, the yield is 98%. Trans -4-aminocyclohexanol hydrochloride, sodium hydroxide, potassium carbonate and ethylene glycol monomethyl ether were mixed, methylsulfonyl hydrazide derivatives were added in batches at 115 ℃, and refluxed. Water was added, filtered, and tetrachloroethylene recrystallized to obtain trans-4-[(2-amino -3, 5-dibromophenylene) amino] cyclohexanol with 74.5% yield. The compound, glacial acetic acid and 5% palladium-carbon were hydrogenated at 0.196MPa and 60 ℃. Vacuum evaporation and drying, ethanol recrystallization, ambroxol. It is added into acetone, concentrated hydrochloric acid is added dropwise, and the precipitated solid is recrystallized in water to obtain white ambroxol hydrochloride crystallization with 79.1% yield and melting point of 235~238 ℃ (decomposition). The total yield was 46% based on methyl anthranilate. Method 2: Compound (I) and 4-aminocyclohexanol are heated in xylene to generate 4-[(2-aminobenzoyl) amino] cyclohexanol; after reduction of lithium aluminum hydride, it is brominated in glacial acetic acid to obtain ambroxol. |
| category | toxic substances |
| toxicity classification | poisoning |
| acute toxicity | oral-rat LD50: 13400 mg kg; Oral-mouse LD50: 2720 mg/kg |
| flammability hazard characteristics | combustible; combustion produces toxic nitrogen oxides and bromide smoke |
| storage and transportation characteristics | warehouse ventilation and low temperature drying |
| fire extinguishing agent | dry powder, foam, sand, carbon dioxide, mist water |
Last Update：2024-04-09 02:00:07
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