611-75-6

Basic information

• Product Name: Bromhexine hydrochloride
• Synonyms: LABOTEST-BB LT00244811;BROMHEXINE HCL;BROMHEXINE HYDROCHLORIDE;BROMOHEXINE HYDROCHLORIDE;2-AMINO-3,5-DIBROMO-N-CYCLOHEXYL-N-METHYLBENZY-LAMINE HYDROCHLORIDE;n-(2-amino-3,5-dibromobenzyl)-n-methylcyclohexylamine hydrochloride;2-amino-3,5-dibromo-n-cyclohexyl-n-methyl-benzenemethanaminmonohydrochlo;2-amino-n-cyclohexyl-3,5-dibromo-n-methylbenzylaminehydrochloride
• CAS NO: 611-75-6
• Molecular Formula: C₁₄H₂₀Br₂N₂*ClH
• Molecular Weight: 412.59
• EINECS: 210-280-8
• Product Categories: Amines;Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals;ROCEPHIN
• Mol File: 611-75-6.mol
• Article Data: 7

Chemical Properties

• Melting Point: 240-244 °C
• Boiling Point: 441.5 °C at 760 mmHg
• Flash Point: 220.8 °C
• Appearance: White Solid
• Vapor Pressure: 3.37E-08mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: Very slightly soluble in water, slightly soluble in alcohol and in methylene chloride.
• Merck: 14,1391
• BRN: 4848376
• CAS DataBase Reference: Bromhexine hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Bromhexine hydrochloride(611-75-6)
• EPA Substance Registry System: Bromhexine hydrochloride(611-75-6)

Safety Data

• Hazard Codes: Xn
• Statements: 20/21/22-36/37/38
• Safety Statements: 22-24/25-36-26
• WGK Germany: 2
• RTECS: XS9950000
• Hazardous Substances Data: 611-75-6(Hazardous Substances Data)

Usage

Description

Bromhexine Hydrochloride is the hydrochloride salt form of bromhexine, a secretolytic, with mucolytic activity. Upon administration, bromhexine increases lysosomal activity and enhances hydrolysis of acid mucopolysaccharide polymers in the respiratory tract. This increases the production of serous mucus in the respiratory tract, which makes the phlegm thinner and decreases mucus viscosity. This contributes to its secretomotoric effect, and allows the cilia to more easily transport the phlegm out of the lungs. This clears mucus from the respiratory tract and may aid in the treatment of respiratory disorders associated with abnormal viscid mucus, excessive mucus secretion and impaired mucus transport.

Chemical Properties

White Solid

Uses

Different sources of media describe the Uses of 611-75-6 differently. You can refer to the following data:
1. Bromhexine hydrochloride was used in the secretion of pancreatic juice of low viscosity.
2. Bromhexine hydrochloride is a mucolytic agent used in the treatment of respiratory disorders associated with viscid or excessive mucus.Bromhexine hydrochloride belongs to the group of expectorants (mucoactive agents). The active substance has a secretolytic effect. It is used for the treatment of strong cough, e.g. triggered by a bronchitis.

Definition

ChEBI: A hydrochloride resulting from the reaction of equimolar amounts of bromhexine and hydrogen chloride. It is used as a mucolytic for the treatment of respiratory disorders associated with productive cough (i.e. a cough characterised by the production of spu um).

General Description

Bromhexine hydrochloride is a bronchial mucolytic.

InChI:InChI=1/C14H20Br2N2.ClH/c1-18(12-5-3-2-4-6-12)9-10-7-11(15)8-13(16)14(10)17;/h7-8,12H,2-6,9,17H2,1H3;1H

Synthetic route

N-methylcyclohexylamine (100-60-7) + (2-amino-3,5-dibromophenyl)methanol (50739-76-9) → bromhexine monohydrochloride (611-75-6)

Conditions	Yield
Stage #1: N-methylcyclohexylamine; (2-amino-3,5-dibromophenyl)methanol With bis(trichloromethyl) carbonate; sodium hydrogencarbonate In tetrahydrofuran at 0 - 20℃; for 2h; Stage #2: With hydrogenchloride In ethanol	95%
Stage #1: N-methylcyclohexylamine; (2-amino-3,5-dibromophenyl)methanol With acetic acid In toluene at 85℃; for 12h; Industrial scale; Stage #2: With hydrogenchloride In acetone at 20℃; for 1.33333h; pH=2 - 3; Industrial scale;	80%
Stage #1: N-methylcyclohexylamine; (2-amino-3,5-dibromophenyl)methanol With acetic acid In toluene at 143 - 178℃; for 30h; Stage #2: With hydrogenchloride In water; ethyl acetate; toluene at 0 - 10℃; Reagent/catalyst; Temperature;

N-methylcyclohexylamine (100-60-7) + 2,4-dibromo-6-chloromethylaniline → bromhexine monohydrochloride (611-75-6)

Conditions	Yield
at 45 - 55℃; for 3h;	89.8%
Stage #1: N-methylcyclohexylamine; 2-chloromethyl-4,6-dibromoaniline With pyrographite In ethanol at 20 - 30℃; for 1h; Heating; Stage #2: With hydrogenchloride In ethanol at 0 - 10℃; for 0.5h; pH=4 - Ca. 5; Temperature; pH-value; Solvent; Heating;	63.25%
Stage #1: N-methylcyclohexylamine; 2-chloromethyl-4,6-dibromoaniline In dichloromethane at 0 - 5℃; for 3h; Stage #2: With hydrogenchloride In ethanol; dichloromethane at 25 - 30℃;	59.6%

N-methylcyclohexylamine (100-60-7) + 3,5-dibromo-2-amino benzaldehyde (50910-55-9) → bromhexine monohydrochloride (611-75-6)

Conditions	Yield
Stage #1: N-methylcyclohexylamine; 3,5-dibromo-2-amino benzaldehyde With titanium(IV)isopropoxide In isopropyl alcohol at 20 - 30℃; for 5h; Stage #2: With sodium tetrahydroborate In isopropyl alcohol at 30℃; for 2h; Stage #3: With hydrogenchloride In water; isopropyl alcohol at 30℃; for 3h; Solvent; Temperature; Reagent/catalyst;	81%

N-methylcyclohexylamine (100-60-7) + 2-Amino-3,5-dibromo-benzoyl chloride (63498-16-8) → bromhexine monohydrochloride (611-75-6)

Conditions	Yield
Stage #1: N-methylcyclohexylamine; 2-Amino-3,5-dibromo-benzoyl chloride In ethanol at 20℃; Stage #2: With hydrogenchloride In water; ethyl acetate at 0 - 5℃; pH=5 - 6;	41%

3,5-dibromo-2-amino benzaldehyde (50910-55-9) → bromhexine monohydrochloride (611-75-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate / ethanol / 10 - 40 °C 2.1: thionyl chloride / 0 - 40 °C 3.1: ethanol / 20 °C 3.2: 0 - 5 °C / pH 5 - 6 View Scheme

2-carbomethoxyaniline (134-20-3) → bromhexine monohydrochloride (611-75-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: bromine / dichloromethane; water / 0.17 h / 20 °C / Industrial scale 1.2: 6 h / Industrial scale 2.1: ethanol; potassium borohydride / 0.5 h / 20 - 40 °C / Industrial scale 3.1: acetic acid / toluene / 12 h / 85 °C / Industrial scale 3.2: 1.33 h / 20 °C / pH 2 - 3 / Industrial scale View Scheme

bromhexine monohydrochloride (611-75-6) + sodium 2-(4-isobutylphenyl)propionate (31121-93-4) → bromohexinium ibuprofenate (1347703-29-0)

Conditions	Yield
In methanol at 20℃;	84%

2-(2-methylphenyl)pyridine (10273-89-9) + bromhexine monohydrochloride (611-75-6) → C38H40N4

Conditions	Yield
With C17H24N5Ru(1+)*F6P(1-); potassium acetate; potassium carbonate In 1-methyl-pyrrolidin-2-one at 50℃; for 72h; Inert atmosphere; Glovebox;	69%

carbon monoxide (201230-82-2) + bromhexine monohydrochloride (611-75-6) + phenylboronic acid (98-80-6) → 4-benzoyl-2-bromo-6-{[cyclohexyl(methyl)amino]methyl}aniline (1571070-22-8) + 2,4-dibenzoyl-6-{[cyclohexyl(methyl)amino]methyl}aniline (1571070-15-9)

Conditions	Yield
With N,N,N,N,-tetramethylethylenediamine; palladium diacetate; catacxium A In toluene at 100℃; under 7500.75 Torr; for 20h; Reagent/catalyst; Solvent; Suzuki-Miyaura Coupling; Inert atmosphere; Autoclave;	A 24% B 60%

bromhexine monohydrochloride (611-75-6) → N-nitroso-N-methylcyclohexylamine (5432-28-0)

Conditions	Yield
With sodium nitrite In water for 6h; Product distribution; time, pH, and concentration dependence of the reaction;

bromhexine monohydrochloride (611-75-6) → 3,5-dibromo-2-amino benzaldehyde (50910-55-9) + 3-Cyclohexyl-6,8-dibromchinazolin + 3-Cyclohexyl-6,8-dibromchinazolin-4-on (114390-40-8)

Conditions	Yield
With oxygen
With oxygen In hydrogenchloride for 100h; Mechanism; Heating; other solvents and temperature;
With acid Title compound not separated from byproducts;
With oxygen Title compound not separated from byproducts;

bromhexine monohydrochloride (611-75-6) → 3,5-dibromo-2-amino benzaldehyde (50910-55-9) + 3-Cyclohexyl-6,8-dibromchinazolin-4-on (114390-40-8)

Conditions	Yield
With water Mechanism; Heating;

bromhexine monohydrochloride (611-75-6) + acetyl chloride (75-36-5) → SF-150B(1) (114390-43-1)

Conditions	Yield
Ambient temperature;

bromhexine monohydrochloride (611-75-6) + Methacryloyl chloride (920-46-7) → C18H24Br2N2O

Conditions	Yield
With dmap; triethylamine In dichloromethane at 0 - 20℃;

bromhexine monohydrochloride (611-75-6) → N-benzyl-N-(2,4-dibromo-6-((cyclohexyl(methyl)amino)methyl)phenyl)methacrylamide

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine; dmap / dichloromethane / 0 - 20 °C 2.1: sodium hydride / tetrahydrofuran; paraffin oil / 0.5 h / 0 - 20 °C 2.2: 4 h / 0 - 20 °C View Scheme

bromhexine monohydrochloride (611-75-6) → 1-benzyl-6-bromo-8-((cyclohexyl(methyl)amino)methyl)-3-methylquinolin-2(1H)-one

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine; dmap / dichloromethane / 0 - 20 °C 2.1: sodium hydride / tetrahydrofuran; paraffin oil / 0.5 h / 0 - 20 °C 2.2: 4 h / 0 - 20 °C 3.1: cesium fluoride; 1,3-bis(4-methoxy-2-methylphenyl)-4,5-dimethyl-1H-imidazol-3-ium chloride / toluene / 40 h / 140 °C / Glovebox; Sealed tube; Inert atmosphere View Scheme

Upstream product

• 134-20-3 2-carbomethoxyaniline 
• 100-60-7 N-methylcyclohexylamine 
• 50910-55-9 3,5-dibromo-2-amino benzaldehyde 
• 63498-16-8 2-Amino-3,5-dibromo-benzoyl chloride 
• 50739-76-9 (2-amino-3,5-dibromophenyl)methanol 

Downstream Products

• 1347703-29-0 bromohexinium ibuprofenate 
• 114390-43-1 SF-150B⁽¹⁾ 
• 50910-55-9 3,5-dibromo-2-amino benzaldehyde 
• 114390-40-8 3-Cyclohexyl-6,8-dibromchinazolin-4-on 
• 5432-28-0 N-nitroso-N-methylcyclohexylamine 

Relevant articles and documents

Efficient production method of bromhexine hydrochloride

The invention belongs to the technical field of biological medicines, and particularly relates to an efficient production method of bromhexine hydrochloride. The production method of bromhexine hydrochloride comprises the following steps: (1) reducing 3,5-dibromo-2-aminobenzaldehyde by a reducing agent to obtain an intermediate 3,5-dibromo-2-aminobenzyl alcohol; (2) reacting the intermediate 3,5-dibromo-2-aminobenzyl alcohol with N-methylcyclohexylamine, and then carrying out salt forming reaction to obtain a bromhexine hydrochloride crude product; and (3) purifying the bromhexine hydrochloride crude product to obtain the bromhexine hydrochloride.

Preparation method of bromhexine hydrochloride

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a bromhexine hydrochloride synthesis method. The synthesis method comprises following steps: step A, carrying out a reduction reaction between 2-amino-3,5-dibromobenzaldehyde and a reducing agent to generate 2-amino-3,5-dibromobenzyl alcohol; step B, reacting 2-amino-3,5-dibromobenzyl alcohol obtained in the step A with thionyl chloride to generate 2,4-bromo-6-chloromethyl aniline; and step C, carrying out an amination reaction between 2, 4-bromo-6-chloromethyl aniline obtained in the step B and N-methyl cyclohexyl amine, and then carrying out a salt forming reaction with an HCl salifying reagent to obtain bromhexine hydrochloride. According to the preparation method, thionyl chloride is only used as a reactant; in addition, the steps are simple, the intermediates obtained in the steps A and B do not need to be purified and directly used for the next step of reactions, therefore, the working hours required by the whole production route are remarkably shortened, the final yield is increased by 5% or above, and the method is particularly suitable for large-scale production.