Benzhexol hydrochloride (benzhexol hc)(link:https://www.bloomtechz.com/synthetic-chemical/api-researching-only/benzhexol-hydrochloride-cas-52-49-3.html), with the chemical formula C20H25NO · HCl, is a white to nearly white crystalline powder and an organic compound. In polar solvents such as methanol and ethanol, it can dissolve quickly, while in non-polar solvents such as benzene and ether, the dissolution rate is slower. In water, it is soluble in hot water, but its solubility in cold water is relatively low. At room temperature, phenylhexanol hydrochloride is a stable solid that is not easily affected by moisture or deterioration. It is usually used as a chemical reagent and is an anticholinergic drug in clinical practice, mainly used to treat Parkinson's disease and drug-induced static tremor.
There are mainly several chemical synthesis methods for Benzhexol hydrochloride:
1. O-nitrotoluene method
The o-nitrotoluene method is a commonly used method for preparing Benzhexol hydrochloride, and the reaction process of this method includes three steps: nitrification, chlorination, and hydrolysis. Firstly, 2-nitrotoluene is obtained by nitration of o-nitrotoluene in concentrated sulfuric acid. Then, in the presence of iron powder, chlorine gas is used for chlorination and methylation reactions to obtain 4-methyl-3-nitrotoluene. Finally, in an aqueous solution of sodium hydroxide, a hydrolysis reaction was carried out to obtain Benzhexol hydrochloride. This method has the advantages of easy access to raw materials and easy control of the reaction process, but it has many reaction steps and low yield.
Nitrification: C6H5CH3+HNO3 → CH3C6H4NO2+H2O
Chlorination and methylation: CH3C6H4NO2+Cl2+Fe → CH3C6H3 (NO2) CHCl+FeCl3
Hydrolysis: CH3C6H3 (NO2) CHCl+2NaOH → Benzhexol hydrochloride+NaCl+NaNO2+H2O
The specific steps are as follows:
1.1 Nitrification:
Nitrate o-nitrotoluene in concentrated sulfuric acid to obtain 2-nitrotoluene. This reaction is a typical electrophilic substitution reaction, with concentrated sulfuric acid as a catalyst and proton acceptor, which helps to generate electrophilic species and promote the reaction.
1.2 Chlorination:
In the presence of iron powder, 2-nitrotoluene is chlorinated and methylated with chlorine gas to obtain 4-methyl-3-nitrotoluene. In this step, iron powder serves as a catalyst to promote the reaction between chlorine gas and 2-nitrotoluene.
1.3 Hydrolysis:
In sodium hydroxide aqueous solution, 4-methyl-3-nitrotoluene undergoes hydrolysis reaction to obtain Benzhexol hydrochloride. This step is a typical nucleophilic substitution reaction, where sodium hydroxide serves as a base, providing a negatively charged nucleophilic reagent to attack the carbocation of 4-methyl-3-nitrotoluene, reducing the nitro group to an amino group, and ultimately generating Benzhexol hydrochloride.
2. Orthochlorotoluene method
The o-chlorotoluene method is also a method for preparing Benzhexol hydrochloride. This method obtains 3-chloromethyl-1-methylethylbenzene by alkylating o-chlorotoluene with chloroform in the presence of ferric chloride. Subsequently, hydrolysis reaction was carried out under alkaline conditions to obtain Benzhexol hydrochloride. This method has the advantages of short reaction steps and high yield, but the raw material o-chlorotoluene is not easily obtained and the cost is high.
Chlorination and methylation: C6H4CH2Cl+CHCl3+Fe → Cl3CCH2C6H3ClCH3+FeCl3
Hydrolysis: Cl3CCH2C6H3ClCH3+2NaOH → Benzhexol hydrochloride+NaCl+NaNO2+H2O
The specific steps are as follows:
2.1 Chlorination and Methylation:
In the presence of iron powder, o-chlorotoluene is chlorinated and methylated with chloroform to obtain 4-methyl-3-nitrotoluene. In this step, iron powder serves as a catalyst to promote the methylation reaction of chloroform.
2.2 Hydrolysis:
In sodium hydroxide aqueous solution, 4-methyl-3-nitrotoluene undergoes hydrolysis reaction to obtain Benzhexol hydrochloride. This step is a typical nucleophilic substitution reaction, where sodium hydroxide serves as a base, providing a negatively charged nucleophilic reagent to attack the carbocation of 4-methyl-3-nitrotoluene, reducing the nitro group to an amino group, and ultimately generating Benzhexol hydrochloride.
3. Allyl chloride method
The allyl chloride method is a new method for synthesizing Benzhexol hydrochloride. This method reacts allyl chloride with sodium phenol in a dimethyl sulfoxide solvent to obtain 4-phenyl-3-chloromethylacrolein. Then, hydrolysis reaction was carried out under alkaline conditions to obtain Benzhexol hydrochloride. This method has the advantages of short reaction steps and high yield, but the raw material allyl chloride is not easily obtained and the cost is high.
Reaction: CH2=CHCH2Cl+PhOH → CH2=CHCH2Cl2Ph
Hydrolysis: CH2=CHCH2Cl2Ph+NaOH → Benzhexol hydrochloride+NaCl+H2O
The detailed steps are as follows:
3.1 Reaction:
4-phenyl-3-chloromethylacrolein was obtained by reacting allyl chloride and sodium phenol in dimethyl sulfoxide solvent. This step is an addition reaction, where allyl chloride acts as an electrophilic reagent to attack the phenolic hydroxyl group of sodium phenolate to obtain 4-phenyl-3-chloromethylacrolein.
3.2 Hydrolysis:
Hydrolysis reaction was carried out under alkaline conditions to obtain Benzhexol hydrochloride. This step is a typical nucleophilic substitution reaction, in which water acts as a nucleophilic reagent to attack the aldehyde carbocation of 4-phenyl-3-chloromethylacrolein, resulting in the formation of Benzhexol hydrochloride.
4. Benzyl chloride method
The benzyl chloride method is a new method for synthesizing Benzhexol hydrochloride. This method reacts benzyl chloride with sodium phenol in a dimethyl sulfoxide solvent to obtain 4-phenyl-3-chloromethylacrolein. Then, hydrolysis reaction was carried out under alkaline conditions to obtain Benzhexol hydrochloride. This method has the advantages of short reaction steps and high yield.
Reaction: ClCH2Ph+PhOH → ClCH2Ph2Ph
Hydrolysis: ClCH2Ph2Ph+NaOH → Benzhexol hydrochloride+NaCl+H2O
Detailed steps:
4.1 Reaction:
4-phenyl-3-chloromethylacrolein was obtained by reacting benzyl chloride and sodium phenol in dimethyl sulfoxide solvent. This step is an addition reaction, where benzyl chloride acts as an electrophilic reagent to attack the phenolic hydroxyl group of sodium phenolate to obtain 4-phenyl-3-chloromethylacrolein.
4.2 Hydrolysis:
Hydrolysis reaction was carried out under alkaline conditions to obtain Benzhexol hydrochloride. This step is a typical nucleophilic substitution reaction, in which water acts as a nucleophilic reagent to attack the aldehyde carbocation of 4-phenyl-3-chloromethylacrolein, resulting in the formation of Benzhexol hydrochloride.
5. Allyl alcohol method
The allyl alcohol method is a new method for synthesizing Benzhexol hydrochloride. This method reacts allyl alcohol with p-toluenesulfonyl chloride in triethylamine to obtain 4-phenyl-3-chloromethylpropenol. Then, hydrolysis reaction was carried out under alkaline conditions to obtain Benzhexol hydrochloride. This method has the advantages of short reaction steps and high yield.
Reaction: CH2=CHCH2OH+PhOH → CH2=CHCH2Cl2Ph
Hydrolysis: CH2=CHCH2Cl2Ph+NaOH → Benzhexol hydrochloride+NaCl+H2O
Detailed steps:
5.1 Reaction:
4-phenyl-3-chloromethylacrolein was obtained by reacting allyl alcohol and sodium phenol in dimethyl sulfoxide solvent. This step is an addition reaction, where allyl alcohol acts as an electrophilic reagent to attack the phenolic hydroxyl group of sodium phenolate to obtain 4-phenyl-3-chloromethylacrolein.
5.2 Hydrolysis:
Hydrolysis reaction was carried out under alkaline conditions to obtain Benzhexol hydrochloride. This step is a typical nucleophilic substitution reaction, in which water acts as a nucleophilic reagent to attack the aldehyde carbocation of 4-phenyl-3-chloromethylacrolein, resulting in the formation of Benzhexol hydrochloride.
6. Sodium hydroxide aqueous solution catalytic oxidation method
The sodium hydroxide aqueous solution catalytic oxidation method is a green synthesis method for preparing Benzhexol hydrochloride. This method uses chloroform as the raw material and undergoes catalytic dehydrogenation, oxidation, condensation, hydrolysis and other steps to obtain the target product Benzhexol hydrochloride. This method has the advantages of simple operation and low environmental pollution. However, it is necessary to select appropriate catalysts and oxidants to ensure the smooth progress of the reaction and the yield of the target product.
Oxidation: ClCH2CH2Cl → ClCH=CHCl
Condensation: ClCH=CHCl+PhOH → Benzhexol hydrochloride+NaCl+H2O
Detailed steps:
6.1 Oxidation:
Under the action of a catalyst, chloroform is used as the raw material for the oxidation reaction to obtain 4-phenyl-3-chloromethylacrolein. This step is a free radical reaction, where the catalyst promotes the dehydrogenation reaction of chloroform to produce 4-phenyl-3-chloromethylacrolein.
6.2 Condensation:
Under alkaline conditions, 4-phenyl-3-chloromethylacrolein undergoes a condensation reaction with sodium phenol to obtain Benzhexol hydrochloride. This step is a condensation reaction, where 4-phenyl-3-chloromethylacrolein is used as the raw material and undergoes a substitution reaction with sodium phenol under alkaline conditions to obtain Benzhexol hydrochloride.
The above are several common chemical synthesis methods for Benzhexol hydrochloride. Different synthesis methods require different raw materials, reagents, and reaction conditions. In order to improve the yield and purity of the target product, it is necessary to select appropriate synthesis methods and conditions for specific synthesis tasks. In addition, attention needs to be paid to safety issues during the chemical synthesis process to ensure standardized experimental operations and correct use of reagents.