Procaine hydrochloride(hcl) is white crystalline powder, odorless, slightly bitter taste, very soluble in water, slightly soluble in ethanol and chloroform. The molecular weight of the compound is 272.77g/mol, the melting point is 153-156°C, and the boiling point is 373.6°C. Also known as Novocain. It is an organic compound used in medicine to reduce pain by blocking nerve signals. Due to the chemical properties of procaine hydrochloride, it has a wide range of applications in medicine and pharmacy, but it also has many reactive properties.
Its pH is usually between 4.5-6. This pH is very important both for its stability and how it behaves in the body. It is a relatively soft substance, usually between 1-2 Molar hardness. This means its surface is more susceptible to scratches and damage. Moisture content is very critical to its quality. Too high and too low moisture content will affect its stability and activity. Usually, its moisture content should be between 1-2%.
Procaine hydrochloride is a local anesthetic that is also used as an over-the-counter medicine to relieve mild pain, such as a toothache. It is widely used in the medical industry because it is a safe and effective local anesthetic. Several methods for the synthesis of procaine hydrochloride will be discussed here.
1. Para-aminobenzoic acid (PABA) and diethylaminoethanol reaction:
The earliest preparation method of Procaine hydrochloride is to react PABA and diethylaminoethanol under alkaline conditions to form procaine. This method was discovered in 1905 by Ernest Fourneau and Pierre Refrain.
First, PABA is acidified with concentrated sulfuric acid to form the corresponding amide, and then it is reacted with ethylenediamine under the action of sodium hydroxide to form procaine base. Finally, the procaine base is neutralized with hydrochloric acid solution to obtain procaine hydrochloride.
2. Reaction of Procainamide and PABA:
Procainamide is an advanced psychotropic drug obtained by sulfonation of procaine. Therefore, procaine reacts with p-Toluenesulfonic acid and H2SO4 to generate 14-methylated procainamide, and reacts with PABA to generate HCL salt.
3. Procaine and benzoic acid reaction:
Procaine hydrochloride can be prepared by heating reaction of procaine and benzoic acid at 300°C.
4. The reaction between Procaine and p-amino Benzoic Acid ethyl ester:
React procaine and p-amino benzoic acid ethyl ester in methanol, and then use hydrochloric acid aqueous solution to precipitate ions to directly prepare procaine hydrochloride.
5. Reaction of BOC-protected ethylene diamine:
BOC-protected ethylene diamine can react with PABA, carry out diazotization reaction in the presence of sodium bicarbonate, then react with procainamide to obtain procaine, and finally convert into procaine hydrochloride.
5.1. OC-protected ethylene diamine is a diamine-based compound with a chemical formula of C6H14N2O2. It is prepared by reacting ethylene diamine with BOC-OSu (N-alkoxycalenyl chloride). The reaction equation is as follows:
H2NCH2CH2NH2 + BOC-OSu → H2N(CH2)2NHBoc + HCl + CO2
Among them, HCl and CO2 are reaction by-products, and BOC-protected ethylene diamine is the target product.
5.2. Reactions with procaine hydrochloride:
BOC-protected ethylene diamine can react with procaine hydrochloride to form new compounds with higher biological activity. The reaction equation is as follows:
H2N(CH2)2NHBoc + C13H20N2O2Cl → C19H30N4O3 + HCl + Boc-NH2
Among them, C19H30N4O3 is the target product, and Boc-NH2 is the reaction by-product.
5.3. Reaction steps
(1) Dissolve BOC-protected ethylene diamine in 5 mL dry chloroform, add 2.2 mmol AlMe3, and stir gently at room temperature for 2 h.
(2) Dissolve procaine hydrochloride in 5 mL dry chloroform, add N,N-dimethylformamide (DMF) and 30% sodium hydroxide (NaOH) solution to adjust the pH to 9-10.
(3) The above two reaction systems were mixed and heated at 60 ºC for 4 h.
(4) After cooling, the mixture was washed with water and transferred to a separatory funnel.
(5) Extract the organic phase with chloroform three times.
(6) The organic phases were combined and dried over Anhydrous Na2SO4.
(7) Chloroform was removed using a rotary evaporator, and the residue was dissolved in a small amount of chloroform and filtered.
(8) The product was collected and crudely extracted with diethyl ether, then washed with a 70% water-methanol mixture (v/v).
(9) The solvent was removed using a rotary evaporator, and the residue was dried under vacuum.
(10) Determine the physical and chemical properties of the product, and detect its absorption peaks with a UV-Vis spectrometer.
5.4. Conclusion:
By protecting procaine hydrochloride with N-alkoxycarbenyl group and using BOC-protected ethylene diamine to react, new compounds with higher biological activity can be prepared. During the reaction process, it is necessary to pay attention to the control of reaction conditions, including temperature, pH value, reaction time, etc., to ensure the purity and yield of the product. The product can be identified and analyzed by measuring the physical and chemical properties of the product and detecting its absorption peak with an ultraviolet-visible spectrometer.
6. Esterification method:
Procaine hydrochloride can be prepared by using the Esterification method. First, react PABA with propanoic anhydride or benzoyl chloride to obtain procaine methyl ester or procaine benzyl ester. Subsequently, ethylenediamine or propylene glycol is used to react with procaine methyl ester or procaine benzyl ester to obtain procaine base. Finally, it is neutralized with hydrochloric acid solution to prepare procaine hydrochloride. This synthetic method can be realized through the following steps.
6.1. Determining the selection of alcohol and acid for esterification
First of all, an appropriate esterified alcohol should be selected for reaction with an acid. Usually, the hydroxyl group of the selected alcohol is more active and easy to react with the acid. In procaine hydrochloride synthesis, the esterified alcohol can be chosen as procainamide, and the acid can be chosen as dimethylcarbamic acid (DMAMC). The mechanism of esterification reaction is to generate fatty acid ester through the acid-catalyzed reaction of hydroxyl and carboxyl groups.
6.2. Determine the reaction conditions
Usually, the esterification reaction needs to be carried out under certain temperature, pressure and reaction time, and these conditions should be determined during the experiment to obtain high yield and high purity products. In procaine hydrochloride synthesis, the reaction temperature is 60-80 ℃, the reaction pressure is 1.5-2.0 atm, and the reaction time is 16-24 hours.
6.3. Preparation of experimental setup and reactants
Prepare necessary experimental equipment and materials, including reaction kettle, magnetic stirrer, reactor cover, vacuum tube, sealer, weighing instrument, etc. The esterified alcohol and acid required for the reaction are mixed according to a certain molar ratio, and dissolved in an appropriate solvent.
6. 4. Esterification reaction
Pour the mixed reactants into a reaction kettle, add an esterification catalyst at room temperature, then heat to the reaction temperature and stir. Typically, a large amount of gas is produced at the beginning of the reaction, and an acidic sorbent is used to absorb the acid and water. After the reaction was completed, the reaction solution was cooled to room temperature, and the esterification product was separated by vacuum distillation.
6.5. Follow-up processing steps
After the esterification product is separated, subsequent treatments including decolorization, crystallization and purification are required. Usually, the esterification product is dissolved in an organic solvent, decolorized by activated carbon adsorbent, then crystallized and purified, and finally the product is refined by high performance liquid chromatography (HPLC) and other techniques.
After the above steps are completed, procaine hydrochloride ester compounds with higher purity can be obtained. This synthesis method can bring convenience to the research of procaine hydrochloride, and can also provide a reference for the synthesis of other ester compounds.